Molecules

2023

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11 pages, 1110 KiB

Open AccessArticle

Synthesis of New Polyheterocyclic Pyrrolo[3,4-b]pyridin-5-ones via an Ugi-Zhu/Cascade/Click Strategy

by Roberto E. Blanco-Carapia, Enrique A. Aguilar-Rangel, Mónica A. Rincón-Guevara, Alejandro Islas-Jácome and Eduardo González-Zamora

Molecules 2023, 28(10), 4087; https://doi.org/10.3390/molecules28104087 - 14 May 2023

Cited by 2 | Viewed by 1838

Abstract

A diversity-oriented synthesis (DOS) of two new polyheterocyclic compounds was performed via an Ugi-Zhu/cascade (N-acylation/aza Diels-Alder cycloaddition/decarboxylation/dehydration)/click strategy, both step-by-step to optimize all involved experimental stages, and in one pot manner to evaluate the scope and sustainability of this polyheterocyclic-focused [...] Read more.

A diversity-oriented synthesis (DOS) of two new polyheterocyclic compounds was performed via an Ugi-Zhu/cascade (N-acylation/aza Diels-Alder cycloaddition/decarboxylation/dehydration)/click strategy, both step-by-step to optimize all involved experimental stages, and in one pot manner to evaluate the scope and sustainability of this polyheterocyclic-focused synthetic strategy. In both ways, the yields were excellent, considering the high number of bonds formed with release of only one carbon dioxide and two molecules of water. The Ugi-Zhu reaction was carried out using the 4-formylbenzonitrile as orthogonal reagent, where the formyl group was first transformed into the pyrrolo[3,4-b]pyridin-5-one core, and then the remaining nitrile group was further converted into two different nitrogen-containing polyheterocycles, both via click-type cycloadditions. The first one used sodium azide to obtain the corresponding 5-substituted-1H-tetrazolyl-pyrrolo[3,4-b]pyridin-5-one, and the second one with dicyandiamide to synthesize the 2,4-diamino-1,3,5-triazine-pyrrolo[3,4-b]pyridin-5-one. Both synthesized compounds may be used for further in vitro and in silico studies because they contain more than two heterocyclic moieties of high interest in medicinal chemistry, as well as in optics due to their high π-conjugation. Full article

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12 pages, 1746 KiB

Open AccessArticle

Macrocycle with Equatorial Coordination Sites Provides New Opportunity for Structure-Diverse Metallacages

by Yibo Zhao, Yunfeng Lu, Ao Liu, Zhi-Yuan Zhang, Chunju Li and Andrew C.-H. Sue

Molecules 2023, 28(6), 2537; https://doi.org/10.3390/molecules28062537 - 10 Mar 2023

Cited by 2 | Viewed by 2237

Abstract

Reported here is the synthesis of a macrocycle with equatorial coordination sites for the construction of self-assembled metallacages. The macrocycle is prepared via a post-modification on the equator of biphen[n]arene. Utilizing this macrocycle as a ligand, three prismatic cages and one [...] Read more.

Reported here is the synthesis of a macrocycle with equatorial coordination sites for the construction of self-assembled metallacages. The macrocycle is prepared via a post-modification on the equator of biphen[n]arene. Utilizing this macrocycle as a ligand, three prismatic cages and one octahedral cage were synthesized by regulating the geometric structures and coordination number of metal acceptors. The multi-cavity configuration of prismatic cage was revealed by single-crystal structure. We prove that a macrocycle with equatorial coordination sites can be an excellent building block for synthesizing structure-diverse metallacages. Our results provide a typical example and a general method for the design and synthesis of metallacages. Full article

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2022

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23 pages, 6098 KiB

Open AccessArticle

Synthesis, Structure and Photochemistry of Dibenzylidenecyclobutanones

by Marina V. Fomina, Alexandra Y. Freidzon, Lyudmila G. Kuz’mina, Anna A. Moiseeva, Roman O. Starostin, Nikolai A. Kurchavov, Vyacheslav N. Nuriev and Sergey P. Gromov

Molecules 2022, 27(21), 7602; https://doi.org/10.3390/molecules27217602 - 5 Nov 2022

Cited by 2 | Viewed by 2098

Abstract

A series of symmetrical dibenzylidene derivatives of cyclobutanone were synthesized with the goal of studying the physicochemical properties of cross-conjugated dienones (ketocyanine dyes). The structures of the products were established and studied by X-ray diffraction and by NMR and electronic spectroscopy. All the [...] Read more.

A series of symmetrical dibenzylidene derivatives of cyclobutanone were synthesized with the goal of studying the physicochemical properties of cross-conjugated dienones (ketocyanine dyes). The structures of the products were established and studied by X-ray diffraction and by NMR and electronic spectroscopy. All the products had E,E-geometry. The oxidation and reduction potentials of the dienones were determined by cyclic voltammetry. The potentials were shown to depend on the nature, position, and number of substituents in the benzene rings. A linear correlation was found between the difference of the electrochemical oxidation and reduction potentials and the energy of the long-wavelength absorption maximum. This correlation can be employed to analyze the properties of other compounds of this type. Quantum chemistry was used to explain the observed regularities in the electrochemistry, absorption, and fluorescence of the dyes. The results are in good agreement with the experimental redox potentials and spectroscopy data. Full article

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16 pages, 5349 KiB

Open AccessArticle

Experimental and Computational Analysis of Newly Synthesized Benzotriazinone Sulfonamides as Alpha-Glucosidase Inhibitors

by Zunera Khalid, Maha Abdallah Alnuwaiser, Hafiz Adnan Ahmad, Syed Salman Shafqat, Munawar Ali Munawar, Kashif Kamran, Muhammad Mujtaba Abbas, M. A. Kalam and Menna A. Ewida

Molecules 2022, 27(20), 6783; https://doi.org/10.3390/molecules27206783 - 11 Oct 2022

Cited by 5 | Viewed by 2156

Abstract

Diabetes mellitus is a chronic metabolic disorder in which the pancreas secretes insulin but the body cells do not recognize it. As a result, carbohydrate metabolism causes hyperglycemia, which may be fatal for various organs. This disease is increasing day by day and [...] Read more.

Diabetes mellitus is a chronic metabolic disorder in which the pancreas secretes insulin but the body cells do not recognize it. As a result, carbohydrate metabolism causes hyperglycemia, which may be fatal for various organs. This disease is increasing day by day and it is prevalent among people of all ages, including young adults and children. Acarbose and miglitol are famous alpha-glucosidase inhibitors but they complicate patients with the problems of flatulence, pain, bloating, diarrhea, and loss of appetite. To overcome these challenges, it is crucial to discover new anti-diabetic drugs with minimal side effects. For this purpose, benzotriazinone sulfonamides were synthesized and their structures were characterized by FT-IR, ¹H-NMR and ¹³C-NMR spectroscopy. In vitro alpha-glucosidase inhibition studies of all synthesized hybrids were conducted using the spectrophotometric method. The synthesized compounds revealed moderate-to-good inhibition activity; in particular, nitro derivatives 12e and 12f were found to be the most effective inhibitors against this enzyme, with IC₅₀ values of 32.37 ± 0.15 µM and 37.75 ± 0.11 µM. In silico studies, including molecular docking as well as DFT analysis, also strengthened the experimental findings. Both leading compounds 12e and 12f showed strong hydrogen bonding interactions within the enzyme cavity. DFT studies also reinforced the strong binding interactions of these derivatives with biological molecules due to their lowest chemical hardness values and lowest orbital energy gap values. Full article

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15 pages, 31883 KiB

Open AccessArticle

Synthesis, Experimental and Theoretical Study of Azidochromones

by Ena G. Narváez-Ordoñez, Kevin A. Pabón-Carcelén, Daniel A. Zurita-Saltos, Pablo M. Bonilla-Valladares, Trosky G. Yánez-Darquea, Luis A. Ramos-Guerrero, Sonia E. Ulic, Jorge L. Jios, Gustavo A. Echeverría, Oscar E. Piro, Peter Langer, Christian D. Alcívar-León and Jorge Heredia-Moya

Molecules 2022, 27(9), 2636; https://doi.org/10.3390/molecules27092636 - 20 Apr 2022

Cited by 1 | Viewed by 2687

Abstract

A series of 2-(haloalkyl)-3-azidomethyl and 6-azido chromones has been synthetized, characterized and studied by theoretical (DFT calculations) and spectroscopic methods (UV-Vis, NMR). The crystal structure of 3-azidomethyl-2-difluoromethyl chromone, determined by X-ray diffraction methods, shows a planar framework due to extended π-bond delocalization. Its [...] Read more.

A series of 2-(haloalkyl)-3-azidomethyl and 6-azido chromones has been synthetized, characterized and studied by theoretical (DFT calculations) and spectroscopic methods (UV-Vis, NMR). The crystal structure of 3-azidomethyl-2-difluoromethyl chromone, determined by X-ray diffraction methods, shows a planar framework due to extended π-bond delocalization. Its molecular packing is stabilized by F···H, N···H and O···H hydrogen bonds, π···π stacking and C–O···π intermolecular interactions. Moreover, AIM, NCI and Hirshfeld analysis evidenced that azido moiety has a significant role in the stabilization of crystal packing through weak intermolecular interactions, where analysis of electronic density suggested closed-shell (CS) interatomic interactions. Full article

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12 pages, 2772 KiB

Open AccessArticle

Total Synthesis of Eliglustat via Diastereoselective Amination of Chiral para-Methoxycinnamyl Benzyl Ether

by Younggyu Kong, Pulla Reddy Boggu, Gi Min Park, Yeon Su Kim, Seong Hwan An, In Su Kim and Young Hoon Jung

Molecules 2022, 27(8), 2603; https://doi.org/10.3390/molecules27082603 - 18 Apr 2022

Cited by 2 | Viewed by 3109

Abstract

Eliglustat (Cerdelga^®, Genzyme Corp. Cambridge, MA, USA) is an approved drug for a non-neurological type of Gaucher disease. Herein, we describe the total synthesis of eliglustat 1 starting from readily available 1,4-benzodioxan-6-carbaldehyde via Sharpless asymmetric dihydroxylation and diastereoselective amination of chiral [...] Read more.

Eliglustat (Cerdelga^®, Genzyme Corp. Cambridge, MA, USA) is an approved drug for a non-neurological type of Gaucher disease. Herein, we describe the total synthesis of eliglustat 1 starting from readily available 1,4-benzodioxan-6-carbaldehyde via Sharpless asymmetric dihydroxylation and diastereoselective amination of chiral para-methoxycinnamyl benzyl ethers using chlorosulfonyl isocyanate as the key steps. Notably, the reaction between syn-1,2-dibenzyl ether 6 and chlorosulfonyl isocyanate in the mixture of toluene and hexane (10:1) afforded syn-1,2-amino alcohol 5 at a 62% yield with a diastereoselectivity > 20:1. This observation can be explained by competition between the S_Ni and the S_N1 mechanisms, leading to the retention of stereochemistry. Full article

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13 pages, 2006 KiB

Open AccessArticle

3,4-Unsubstituted 2-tert-Butyl-pyrrolidine-1-oxyls with Hydrophilic Functional Groups in the Side Chains

by Andrey I. Taratayko, Yurii I. Glazachev, Ilia V. Eltsov, Elena I. Chernyak and Igor A. Kirilyuk

Molecules 2022, 27(6), 1922; https://doi.org/10.3390/molecules27061922 - 16 Mar 2022

Cited by 5 | Viewed by 2228

Abstract

Pyrrolidine nitroxides with four bulky alkyl substituents adjacent to N–O group are known for their high resistance to bioreduction. The 3,4-unsubstituted 2-tert-butyl-2-ethylpyrrolidine-1-oxyls were prepared from the corresponding 2-tert-butyl-1-pyrroline-1-oxides via either the addition of ethinylmagnesium bromide with subsequent hydrogenation or [...] Read more.

Pyrrolidine nitroxides with four bulky alkyl substituents adjacent to N–O group are known for their high resistance to bioreduction. The 3,4-unsubstituted 2-tert-butyl-2-ethylpyrrolidine-1-oxyls were prepared from the corresponding 2-tert-butyl-1-pyrroline-1-oxides via either the addition of ethinylmagnesium bromide with subsequent hydrogenation or via treatment with ethyllithium. The new nitroxides showed excellent stability to reduction with ascorbate with no evidence for additional large hyperfine couplings in the EPR spectra. Full article

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13 pages, 6496 KiB

Open AccessArticle

Synthesis and Fluorescent Properties of Aminopyridines and the Application in “Click and Probing”

by Zongyang Li, Yaxuan Li, Wenxu Chang, Sen Pang, Xuefeng Li, Liusheng Duan and Zhenhua Zhang

Molecules 2022, 27(5), 1596; https://doi.org/10.3390/molecules27051596 - 28 Feb 2022

Cited by 2 | Viewed by 2291

Abstract

Unsubstituted pyridin-2-amine has a high quantum yield and is a potential scaffold for a fluorescent probe. However, the facile access to conjugated highly substituted aminopyridines and the study of their fluorescent properties is scarce. In this paper, synthesis and fluorescent properties of multisubstituted [...] Read more.

Unsubstituted pyridin-2-amine has a high quantum yield and is a potential scaffold for a fluorescent probe. However, the facile access to conjugated highly substituted aminopyridines and the study of their fluorescent properties is scarce. In this paper, synthesis and fluorescent properties of multisubstituted aminopyridines were studied based on a recently developed Rh-catalyzed coupling of vinyl azide with isonitrile to form a vinyl carbodiimide intermediate, following tandem cyclization with an alkyne. An aminopyridine substituted with an azide group as a potential probe was further designed, synthesized, and evaluated. The “clicking-and-probing” experiment of it on BSA protein showed the potential of aminopyridine as a scaffold of a biological probe. Full article

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Scheme 1

2021

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9 pages, 1821 KiB

Open AccessCommunication

BN-Embedded Perylenes

by Xiangdong Fang

Molecules 2021, 26(23), 7148; https://doi.org/10.3390/molecules26237148 - 25 Nov 2021

Cited by 7 | Viewed by 3598

Abstract

Transition metal catalyzed coupling reaction strategy has been utilized in the synthesis of two novel BN-perylenes starting from halogenated BN-naphthalene derivatives. The molecular structures and packing modes of BN-perylenes were confirmed by NMR spectroscopy and X-ray single-crystal diffraction experiments. Their photophysical properties were [...] Read more.

Transition metal catalyzed coupling reaction strategy has been utilized in the synthesis of two novel BN-perylenes starting from halogenated BN-naphthalene derivatives. The molecular structures and packing modes of BN-perylenes were confirmed by NMR spectroscopy and X-ray single-crystal diffraction experiments. Their photophysical properties were further investigated using UV-vis and fluorescence spectroscopy and DFT calculations. Interestingly, the isosteric BN-insertion in perylene system resulted in stronger π-π stacking interaction both in solid and solution phases. The synthesized BN-perylenes are proved to be highly stable and thus provide a new valuable platform for novel organic materials applications which is otherwise inaccessible to date. Full article

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28 pages, 22086 KiB

Open AccessArticle

Studies towards the Design and Synthesis of Novel 1,5-Diaryl-1H-imidazole-4-carboxylic Acids and 1,5-Diaryl-1H-imidazole-4-carbohydrazides as Host LEDGF/p75 and HIV-1 Integrase Interaction Inhibitors

by Thompho J. Rashamuse, Muhammad Q. Fish, E. Mabel Coyanis and Moira L. Bode

Molecules 2021, 26(20), 6203; https://doi.org/10.3390/molecules26206203 - 14 Oct 2021

Cited by 9 | Viewed by 2699

Abstract

Two targeted sets of novel 1,5-diaryl-1H-imidazole-4-carboxylic acids 10 and carbohydrazides 11 were designed and synthesized from their corresponding ester intermediates 17, which were prepared via cycloaddition of ethyl isocyanoacetate 16 and diarylimidoyl chlorides 15. Evaluation of these new target [...] Read more.

Two targeted sets of novel 1,5-diaryl-1H-imidazole-4-carboxylic acids 10 and carbohydrazides 11 were designed and synthesized from their corresponding ester intermediates 17, which were prepared via cycloaddition of ethyl isocyanoacetate 16 and diarylimidoyl chlorides 15. Evaluation of these new target scaffolds in the AlphaScreen^TM HIV-1 IN-LEDGF/p75 inhibition assay identified seventeen compounds exceeding the pre-defined 50% inhibitory threshold at 100 µM concentration. Further evaluation of these compounds in the HIV-1 IN strand transfer assay at 100 μM showed that none of the compounds (with the exception of 10a, 10l, and 11k, with marginal inhibitory percentages) were actively bound to the active site, indicating that they are selectively binding to the LEDGF/p75-binding pocket. In a cell-based HIV-1 antiviral assay, compounds 11a, 11b, 11g, and 11h exhibited moderate antiviral percentage inhibition of 33–45% with cytotoxicity (CC₅₀) values of >200 µM, 158.4 µM, >200 µM, and 50.4 µM, respectively. The antiviral inhibitory activity displayed by 11h was attributed to its toxicity. Upon further validation of their ability to induce multimerization in a Western blot gel assay, compounds 11a, 11b, and 11h appeared to increase higher-order forms of IN. Full article

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19 pages, 2106 KiB

Open AccessArticle

Synthesis of 6-Membered-Ring Fused Thiazine-Dicarboxylates and Thiazole-Pyrimidines via One-Pot Three-Component Reactions

by Reagan L. Mohlala, Elena Mabel Coyanis, Muhammad Q. Fish, Manuel A. Fernandes and Moira L. Bode

Molecules 2021, 26(18), 5493; https://doi.org/10.3390/molecules26185493 - 10 Sep 2021

Cited by 7 | Viewed by 2865

Abstract

A facile and efficient one-pot three-component reaction method for the synthesis of thiazine-dicarboxylates is reported. Reaction of an isocyanide and dialkyl acetylenedicarboxylate with 2-amino-4H-1,3-thiazin-4-one derivatives containing both an acidic proton and an internal nucleophile gave the products in good yields of [...] Read more.

A facile and efficient one-pot three-component reaction method for the synthesis of thiazine-dicarboxylates is reported. Reaction of an isocyanide and dialkyl acetylenedicarboxylate with 2-amino-4H-1,3-thiazin-4-one derivatives containing both an acidic proton and an internal nucleophile gave the products in good yields of 76–85%. The reactivity of dialkyl acetylenedicarboxylates was further tested in the synthesis of thiazole-pyrimidines where a two-component reaction of 2-aminothiazole with dialkyl acetylenedicarboxylates was successfully converted to a more efficient three-component reaction of a thiourea, α-haloketone and dialkyl acetylenedicarboxylate (DMAD/DEtAD) to give thiazole-pyrimidines in good yields of 70–91%. Full article

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28 pages, 40332 KiB

Open AccessReview

4,5,6,7-Tetrahydroindol-4-Ones as a Valuable Starting Point for the Synthesis of Polyheterocyclic Structures

by Tomas Horsten and Wim Dehaen

Molecules 2021, 26(15), 4596; https://doi.org/10.3390/molecules26154596 - 29 Jul 2021

Cited by 4 | Viewed by 3178

Abstract

This review focuses on the synthesis of polyheterocyclic structures with a variety of medicinal and optoelectronic applications, starting from readily available 4,5,6,7-tetrahydroindol-4-one analogs. First, routes toward the 4,5,6,7-tetrahydroindol-4-one starting materials are summarized, followed by synthetic pathways towards polyheterocyclic structures which are categorized based [...] Read more.

This review focuses on the synthesis of polyheterocyclic structures with a variety of medicinal and optoelectronic applications, starting from readily available 4,5,6,7-tetrahydroindol-4-one analogs. First, routes toward the 4,5,6,7-tetrahydroindol-4-one starting materials are summarized, followed by synthetic pathways towards polyheterocyclic structures which are categorized based on the size and attachment point of the newly formed (hetero)cyclic ring. Full article

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10 pages, 1496 KiB

Open AccessArticle

3-Benzoylisoxazolines by 1,3-Dipolar Cycloaddition: Chloramine-T-Catalyzed Condensation of α-Nitroketones with Dipolarophiles

by Xinhui Pan, Xiaobing Xin, Ying Mao, Xin Li, Yanan Zhao, Yidi Liu, Ke Zhang, Xiaoda Yang and Jinhui Wang

Molecules 2021, 26(12), 3491; https://doi.org/10.3390/molecules26123491 - 8 Jun 2021

Cited by 6 | Viewed by 2714

Abstract

In this study, 3-benzoylisoxazolines were synthesized by reacting alkenes with various α-nitroketones using chloramine-T as the base. The scope of α-nitroketones and alkenes is extensive, including different alkenes and alkynes to form various isoxazolines and isoxazoles. The use of chloramine-T, as the low-cost, [...] Read more.

In this study, 3-benzoylisoxazolines were synthesized by reacting alkenes with various α-nitroketones using chloramine-T as the base. The scope of α-nitroketones and alkenes is extensive, including different alkenes and alkynes to form various isoxazolines and isoxazoles. The use of chloramine-T, as the low-cost, easily handled, moderate base for 1,3-dipolar cycloaddition is attractive. Full article

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20 pages, 4683 KiB

Open AccessArticle

Synthesis and Rational Design of New Appended 1,2,3-Triazole-uracil Ensembles as Promising Anti-Tumor Agents via In Silico VEGFR-2 Transferase Inhibition

by Nadipolla Naresh Reddy, Sung-Jen Hung, Merugu Kumara Swamy, Ananthula Sanjeev, Vankadari Srinivasa Rao, Rondla Rohini, Atcha Krishnam Raju, Kuthati Bhaskar, Anren Hu and Puchakayala Muralidhar Reddy

Molecules 2021, 26(7), 1952; https://doi.org/10.3390/molecules26071952 - 30 Mar 2021

Cited by 9 | Viewed by 2850

Abstract

Angiogenesis inhibition is a key step towards the designing of new chemotherapeutic agents. In a view to preparing new molecular entities for cancer treatment, eighteen 1,2,3-triazole-uracil ensembles 5a–r were designed and synthesized via the click reaction. The ligands were well characterized [...] Read more.

Angiogenesis inhibition is a key step towards the designing of new chemotherapeutic agents. In a view to preparing new molecular entities for cancer treatment, eighteen 1,2,3-triazole-uracil ensembles 5a–r were designed and synthesized via the click reaction. The ligands were well characterized using ¹H-, ¹³C-NMR, elemental analysis and ESI-mass spectrometry. The in silico binding propinquities of the ligands were studied sequentially in the active region of VEGFR-2 using the Molegro virtual docker. All the compounds produced remarkable interactions and potentially inhibitory ligands against VEGFR-2 were obtained with high negative binding energies. Drug-likeness was assessed from the ADME properties. Cytotoxicity of the test compounds was measured against HeLa and HUH-7 tumor cells and NIH/3T3 normal cells by MTT assay. Compound 5h showed higher growth inhibition activity than the positive control, 5-fluorouracil (5-FU), against both HeLa and HUH-7 cells with IC₅₀ values of 4.5 and 7.7 μM respectively. Interestingly, the compounds 5a–r did not show any cytotoxicity towards the normal cell lines. The results advance the position of substituted triazoles in the area of drug design with no ambiguity. Full article

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22 pages, 10490 KiB

Open AccessArticle

Dihydroquinolines, Dihydronaphthyridines and Quinolones by Domino Reactions of Morita-Baylis-Hillman Acetates

by Joel K. Annor-Gyamfi, Ebenezer Ametsetor, Kevin Meraz and Richard A. Bunce

Molecules 2021, 26(4), 890; https://doi.org/10.3390/molecules26040890 - 8 Feb 2021

Cited by 3 | Viewed by 2704

Abstract

An efficient synthetic route to highly substituted dihydroquinolines and dihydronaphthyridines has been developed using a domino reaction of Morita-Baylis-Hillman (MBH) acetates with primary aliphatic and aromatic amines in DMF at 50–90 °C. The MBH substrates incorporate a side chain acetate positioned adjacent to [...] Read more.

An efficient synthetic route to highly substituted dihydroquinolines and dihydronaphthyridines has been developed using a domino reaction of Morita-Baylis-Hillman (MBH) acetates with primary aliphatic and aromatic amines in DMF at 50–90 °C. The MBH substrates incorporate a side chain acetate positioned adjacent to an acrylate or acrylonitrile aza-Michael acceptor as well as an aromatic ring activated toward S_NAr ring closure. A control experiment established that the initial reaction was an S_N2′-type displacement of the side chain acetate by the amine to generate the alkene product with the added nitrogen nucleophile positioned trans to the S_NAr aromatic ring acceptor. Thus, equilibration of the initial alkene geometry is required prior to cyclization. A further double bond migration was observed for several reactions targeting dihydronaphthyridines from substrates with a side chain acrylonitrile moiety. MBH acetates incorporating a 2,5-difluorophenyl moiety were found to have dual reactivity in these annulations. In the absence of O₂, the expected dihydroquinolines were formed, while in the presence of O₂, quinolones were produced. All of the products were isolated in good to excellent yields (72–93%). Numerous cases (42) are reported, and mechanisms are discussed. Full article

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2020

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16 pages, 1483 KiB

Open AccessArticle

A General and Scalable Synthesis of Polysubstituted Indoles

by David Tejedor, Raquel Diana-Rivero and Fernando García-Tellado

Molecules 2020, 25(23), 5595; https://doi.org/10.3390/molecules25235595 - 28 Nov 2020

Cited by 4 | Viewed by 3558

Abstract

A consecutive 2-step synthesis of N-unprotected polysubstituted indoles bearing an electron-withdrawing group at the C-3 position from readily available nitroarenes is reported. The protocol is based on the [3,3]-sigmatropic rearrangement of N-oxyenamines generated by the DABCO-catalyzed reaction of N-arylhydroxylamines and [...] Read more.

A consecutive 2-step synthesis of N-unprotected polysubstituted indoles bearing an electron-withdrawing group at the C-3 position from readily available nitroarenes is reported. The protocol is based on the [3,3]-sigmatropic rearrangement of N-oxyenamines generated by the DABCO-catalyzed reaction of N-arylhydroxylamines and conjugated terminal alkynes, and delivers indoles endowed with a wide array of substitution patterns and topologies. Full article

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75 pages, 27336 KiB

Open AccessReview

Synthetic Strategies, Reactivity and Applications of 1,5-Naphthyridines

by Maria Fuertes, Carme Masdeu, Endika Martin-Encinas, Asier Selas, Gloria Rubiales, Francisco Palacios and Concepcion Alonso

Molecules 2020, 25(14), 3252; https://doi.org/10.3390/molecules25143252 - 16 Jul 2020

Cited by 7 | Viewed by 5782

Abstract

This review covers the synthesis and reactivity of 1,5-naphthyridine derivatives published in the last 18 years. These heterocycles present a significant importance in the field of medicinal chemistry because many of them exhibit a great variety of biological activities. First, the published strategies [...] Read more.

This review covers the synthesis and reactivity of 1,5-naphthyridine derivatives published in the last 18 years. These heterocycles present a significant importance in the field of medicinal chemistry because many of them exhibit a great variety of biological activities. First, the published strategies related to the synthesis of 1,5-naphthyridines are presented followed by the reactivity of these compounds with electrophilic or nucleophilic reagents, in oxidations, reductions, cross-coupling reactions, modification of side chains or formation of metal complexes. Finally, some properties and applications of these heterocycles studied during this period are examined. Full article

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10 pages, 1423 KiB

Open AccessCommunication

Two Annulated Azaheterocyclic Cores Readily Available from a Single Tetrahydroisoquinolonic Castagnoli–Cushman Precursor

by Elizaveta Karchuganova, Olga Bakulina, Dmitry Dar’in and Mikhail Krasavin

Molecules 2020, 25(9), 2049; https://doi.org/10.3390/molecules25092049 - 28 Apr 2020

Cited by 3 | Viewed by 2936

Abstract

A novel approach to indolo[3,2-c]isoquinoline and dibenzo[c,h][1,6]naphthyridine tetracyclic systems was discovered based on switchable reduction of 2-methoxy-3-(2-nitrophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid prepared via Castagnoli–Cushman reaction. Reduction with ammonium formate resulted in the expected selective transformation of the nitro group (thus [...] Read more.

A novel approach to indolo[3,2-c]isoquinoline and dibenzo[c,h][1,6]naphthyridine tetracyclic systems was discovered based on switchable reduction of 2-methoxy-3-(2-nitrophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid prepared via Castagnoli–Cushman reaction. Reduction with ammonium formate resulted in the expected selective transformation of the nitro group (thus providing access to substituted dibenzo[c,h][1,6]naphthyridine via cyclization and dehydrogenation). However, attempted reduction with sodium sulfide initiated a previously unknown reaction cascade including double reduction, cyclization, and decarboxylation, leading to formation of indolo[3,2-c]isoquinoline polyheterocycle in one synthetic step. Full article

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14 pages, 2630 KiB

Open AccessArticle

Synthesis and Antibacterial Evaluation of Novel 1,3,4-Oxadiazole Derivatives Containing Sulfonate/Carboxylate Moiety

by Lei Wang, Xia Zhou, Hui Lu, Xianfu Mu and Linhong Jin

Molecules 2020, 25(7), 1488; https://doi.org/10.3390/molecules25071488 - 25 Mar 2020

Cited by 6 | Viewed by 3319

Abstract

In order to discover new lead compounds with high antibacterial activity, a series of new derivatives were designed and synthesized by introducing a sulfonate or carboxylate moiety into the 1,3,4-oxadiazole structure. Antibacterial activity against two phytopathogens, Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas [...] Read more.

In order to discover new lead compounds with high antibacterial activity, a series of new derivatives were designed and synthesized by introducing a sulfonate or carboxylate moiety into the 1,3,4-oxadiazole structure. Antibacterial activity against two phytopathogens, Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas axonopodis pv. citri (Xac), was assayed in vitro. The preliminary results indicated that ten compounds including 4a-1-4a-4 and 4a-11-4a-16 had good antibacterial activity against Xoo, with EC₅₀ values ranging from 50.1-112.5 µM, which was better than those of Bismerthiazol (253.5 µM) and Thiodiazole copper (467.4 µM). Meanwhile, 4a-1, 4a-2, 4a-3 and 4a-4 demonstrated good inhibitory effect against Xanthomonas axonopodis pv. citri with EC₅₀ values around 95.8-155.2 µM which were better than those of bismerthiazol (274.3 µM) and thiodiazole copper (406.3 µM). In addition, in vivo protection activity of compound 4a-2 and 4a-3 against rice bacterial leaf blight was 68.6% and 62.3%, respectively, which were better than bismerthiazol (49.6%) and thiodiazole copper (42.2%). Curative activity of compound 4a-2 and 4a-3 against rice bacterial leaf blight was 62.3% and 56.0%, which were better than bismerthiazol (42.9%) and thiodiazole copper (36.1%). Through scanning electron microscopy (SEM) analysis, it was observed that compound 4a-2 caused the cell membrane of Xanthomonas oryzae pv. oryzae ruptured or deformed. The present results indicated novel derivatives of 5-phenyl sulfonate methyl 1,3,4-oxadiazole might be potential antibacterial agents. Full article

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8 pages, 1303 KiB

Open AccessArticle

Formal [3+2] Cycloaddition Reactions of Electron-Rich Aryl Epoxides with Alkenes under Lewis Acid Catalysis Affording Tetrasubstituted Tetrahydrofurans

by Víctor E. Macías-Villamizar, Luís Cuca-Suárez, Santiago Rodríguez and Florenci V. González

Molecules 2020, 25(3), 692; https://doi.org/10.3390/molecules25030692 - 6 Feb 2020

Viewed by 4374

Abstract

We report on the regio- and stereoselective synthesis of tetrahydrofurans by reaction between epoxides and alkenes in the presence of a Lewis acid. This is an unprecedented formal [3+2] cycloaddition reaction between an epoxide and an alkene. The chemical reaction represents a very [...] Read more.

We report on the regio- and stereoselective synthesis of tetrahydrofurans by reaction between epoxides and alkenes in the presence of a Lewis acid. This is an unprecedented formal [3+2] cycloaddition reaction between an epoxide and an alkene. The chemical reaction represents a very concise synthesis of tetrahydrofurans from accessible starting compounds. Full article

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2019

Jump to: 2023, 2022, 2021, 2020, 2018, 2017, 2016, 2015

18 pages, 1428 KiB

Open AccessArticle

A Suitable Functionalization of Nitroindazoles with Triazolyl and Pyrazolyl Moieties via Cycloaddition Reactions

by Mohammed Eddahmi, Nuno M. M. Moura, Latifa Bouissane, Ouafa Amiri, M. Amparo F. Faustino, José A. S. Cavaleiro, Ricardo F. Mendes, Filipe A. A. Paz, Maria G. P. M. S. Neves and El Mostapha Rakib

Molecules 2020, 25(1), 126; https://doi.org/10.3390/molecules25010126 - 28 Dec 2019

Cited by 4 | Viewed by 3600

Abstract

The alkylation of a series of nitroindazole derivatives with 1,2-dibromoethane afforded the corresponding N-(2-bromoethyl)- and N-vinyl-nitro-1H-indazoles. The Cu(I)-catalysed azide- alkyne 1,3-dipolar cycloaddition was selected to substitute the nitroindazole core with 1,4-disubstituted triazole units after converting one of the N [...] Read more.

The alkylation of a series of nitroindazole derivatives with 1,2-dibromoethane afforded the corresponding N-(2-bromoethyl)- and N-vinyl-nitro-1H-indazoles. The Cu(I)-catalysed azide- alkyne 1,3-dipolar cycloaddition was selected to substitute the nitroindazole core with 1,4-disubstituted triazole units after converting one of the N-(2-bromoethyl)nitroindazoles into the corresponding azide. The reactivity in 1,3-dipolar cycloaddition reactions with nitrile imines generated in situ from ethyl hydrazono-α-bromoglyoxylates was studied with nitroindazoles bearing a vinyl unit. The corresponding nitroindazole-pyrazoline derivatives were obtained in good to excellent yields. Full article

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17 pages, 813 KiB

Open AccessArticle

Synthesis and Antimicrobial Activity of a New Series of Thiazolidine-2,4-diones Carboxamide and Amino Acid Derivatives

by Rakia Abd Alhameed, Zainab Almarhoon, Sarah I. Bukhari, Ayman El-Faham, Beatriz G. de la Torre and Fernando Albericio

Molecules 2020, 25(1), 105; https://doi.org/10.3390/molecules25010105 - 27 Dec 2019

Cited by 18 | Viewed by 3943

Abstract

Novel thiazolidine-2,4-dione carboxamide and amino acid derivatives were synthesized in excellent yield using OxymaPure/N,N′-diisopropylcarbodimide coupling methodology and were characterized by chromatographic and spectrometric methods, and elemental analysis. The antimicrobial and antifungal activity of these derivatives was evaluated against two Gram-positive bacteria [...] Read more.

Novel thiazolidine-2,4-dione carboxamide and amino acid derivatives were synthesized in excellent yield using OxymaPure/N,N′-diisopropylcarbodimide coupling methodology and were characterized by chromatographic and spectrometric methods, and elemental analysis. The antimicrobial and antifungal activity of these derivatives was evaluated against two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), two-Gram negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and one fungal isolate (Candida albicans). Interestingly, several samples demonstrated weak to moderate antibacterial activity against Gram-negative bacteria, as well as antifungal activity. However, only one compound namely, 2-(5-(3-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl)acetic acid, showed antibacterial activity against Gram-positive bacteria, particularly S. aureus. Full article

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16 pages, 1650 KiB

Open AccessArticle

Synthesis and Antimicrobial Activity of Some New Substituted Quinoxalines

by Mohamed A. El-Atawy, Ezzat A. Hamed, Mahjoba Alhadi and Alaa Z. Omar

Molecules 2019, 24(22), 4198; https://doi.org/10.3390/molecules24224198 - 19 Nov 2019

Cited by 28 | Viewed by 5524

Abstract

A number of new symmetrically and asymmetrically 2,3-disubstituted quinoxalines were synthesized through functionalization of 2,3-dichloroquinoxaline (2,3-DCQ) with a variety of sulfur and/or nitrogen nucleophiles. The structures of the obtained compounds were established based on their spectral data and elemental analysis. The antimicrobial activity [...] Read more.

A number of new symmetrically and asymmetrically 2,3-disubstituted quinoxalines were synthesized through functionalization of 2,3-dichloroquinoxaline (2,3-DCQ) with a variety of sulfur and/or nitrogen nucleophiles. The structures of the obtained compounds were established based on their spectral data and elemental analysis. The antimicrobial activity for the prepared compounds was investigated against four bacterial species and two fungal strains. The symmetrically disubstituted quinoxalines 2, 3, 4, and 5 displayed the most significant antibacterial activity, while compounds 6a, 6b, and the pentacyclic compound 10 showed considerable antifungal activity. Furthermore, compounds 3f, 6b showed broad antimicrobial spectrum against most of the tested strains. Full article

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21 pages, 4977 KiB

Open AccessReview

Pyrido[2,3-d]pyrimidin-7(8H)-ones: Synthesis and Biomedical Applications

by Guillem Jubete, Raimon Puig de la Bellacasa, Roger Estrada-Tejedor, Jordi Teixidó and José I. Borrell

Molecules 2019, 24(22), 4161; https://doi.org/10.3390/molecules24224161 - 16 Nov 2019

Cited by 28 | Viewed by 6382

Abstract

Pyrido[2,3-d]pyrimidines (1) are a type of privileged heterocyclic scaffolds capable of providing ligands for several receptors in the body. Among such structures, our group and others have been particularly interested in pyrido[2,3-d]pyrimidine-7(8H)-ones (2) [...] Read more.

Pyrido[2,3-d]pyrimidines (1) are a type of privileged heterocyclic scaffolds capable of providing ligands for several receptors in the body. Among such structures, our group and others have been particularly interested in pyrido[2,3-d]pyrimidine-7(8H)-ones (2) due to the similitude with nitrogen bases present in DNA and RNA. Currently there are more than 20,000 structures 2 described which correspond to around 2900 references (half of them being patents). Furthermore, the number of references containing compounds of general structure 2 have increased almost exponentially in the last 10 years. The present review covers the synthetic methods used for the synthesis of pyrido[2,3-d]pyrimidine-7(8H)-ones (2), both starting from a preformed pyrimidine ring or a pyridine ring, and the biomedical applications of such compounds. Full article

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12 pages, 1783 KiB

Open AccessArticle

A Simple, Efficient, and Eco-Friendly Method for the Preparation of 3-Substituted-2,3-dihydroquinazolin-4(1H)-one Derivatives

by Zainab Almarhoon, Kholood A. Dahlous, Rakia Abd Alhameed, Hazem A. Ghabbour and Ayman El-Faham

Molecules 2019, 24(22), 4052; https://doi.org/10.3390/molecules24224052 - 9 Nov 2019

Cited by 3 | Viewed by 4094

Abstract

A simple, cost-effective method under environmentally benign conditions is a very important concept for the preparation of 2,3-dihydroquinazolin-4(1H)-one derivatives. The present work describes an efficient and eco-friendly protocol for the synthesis of 2-amino-N-(2-substituted-ethyl)benzamide and 3-substituted-2,3-dihydroquinazolin-4(1H)-one derivatives. The [...] Read more.

A simple, cost-effective method under environmentally benign conditions is a very important concept for the preparation of 2,3-dihydroquinazolin-4(1H)-one derivatives. The present work describes an efficient and eco-friendly protocol for the synthesis of 2-amino-N-(2-substituted-ethyl)benzamide and 3-substituted-2,3-dihydroquinazolin-4(1H)-one derivatives. The novel feature of this protocol is the use of 2-methyl tetrahydrofuran (2-MeTHF) as an eco-friendly alternative solvent to tetrahydrofuran (THF) in the first step. In the second step, methanol in the presence of potassium carbonate as a catalyst was used under conventional heating or microwave irradiation, which provided an eco-friendly method to afford the target products in excellent yields and purities. NMR (¹H and ¹³C), elemental analysis, and LC-MS confirmed the structures of all compounds. X-ray crystallography further confirmed the structure of the intermediate 2-amino-N-(2-substituted-ethyl)benzamide 3a. The molecular structure of 3a was monoclinic crystal, with P21/c, a = 13.6879 (11) Å, b = 10.2118 (9) Å, c = 9.7884 (9) Å, β = 105.068 (7)°, V = 1321.2 (2) Å3, and Z = 4. Full article

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12 pages, 1483 KiB

Open AccessArticle

One Pot and Metal-Free Approach to 3-(2-Hydroxybenzoyl)-1-aza-anthraquinones

by Jiaqi Yuan, Qian He, Shanshan Song, Xiaofei Zhang, Zehong Miao and Chunhao Yang

Molecules 2019, 24(16), 3017; https://doi.org/10.3390/molecules24163017 - 20 Aug 2019

Cited by 4 | Viewed by 3761

Abstract

Herein, a direct strategy to synthesize 3-(2-hydroxybenzoyl)-1-aza-anthraquinones with excellent efficiency, mild conditions, and benign functional group compatibility was reported. A variety of 3-formylchromone compounds were employed as compatible substrates and this protocol gave the 3-(2-hydroxybenzoyl)-1-aza-anthraquinone derivatives in good to excellent yields without inert [...] Read more.

Herein, a direct strategy to synthesize 3-(2-hydroxybenzoyl)-1-aza-anthraquinones with excellent efficiency, mild conditions, and benign functional group compatibility was reported. A variety of 3-formylchromone compounds were employed as compatible substrates and this protocol gave the 3-(2-hydroxybenzoyl)-1-aza-anthraquinone derivatives in good to excellent yields without inert gas and expensive transition metal catalysts. Some compounds displayed good anti-proliferative activities. Full article

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14 pages, 2044 KiB

Open AccessArticle

Intramolecular Carbene C-H Insertion Reactions of 2-Diazo-2-sulfamoylacetamides

by Chuqiang Que, Peipei Huang, Zhanhui Yang, Ning Chen and Jiaxi Xu

Molecules 2019, 24(14), 2628; https://doi.org/10.3390/molecules24142628 - 19 Jul 2019

Cited by 3 | Viewed by 5037

Abstract

The intramolecular C-H insertions of carbenes derived from 2-diazo-2-sulfamoylacetamides were studied. 2-Diazo-2-sulfamoylacetamides were first prepared from chloroacetyl chloride and secondary amines through acylation followed by sequential treatments with sodium sulfite, phosphorus oxychloride, secondary amines, and 4-nitrobenzenesulfonyl azide. The results indicate that: (1) 2-diazo- [...] Read more.

The intramolecular C-H insertions of carbenes derived from 2-diazo-2-sulfamoylacetamides were studied. 2-Diazo-2-sulfamoylacetamides were first prepared from chloroacetyl chloride and secondary amines through acylation followed by sequential treatments with sodium sulfite, phosphorus oxychloride, secondary amines, and 4-nitrobenzenesulfonyl azide. The results indicate that: (1) 2-diazo-N,N-dimethyl-2-(N,N-diphenylsulfamoyl)acetamide can take the formal aromatic 1,5-C-H insertion in its N-phenylsulfonamide moiety to afford the corresponding 1,3-dihydrobenzo[c]isothiazole-3-carboxamide 2,2-dioxide derivative; (2) no aliphatic C-H insertions occur for 2-diazo-2-(N,N-dialkylsulfamoyl)acetamides; and (3) for 2-diazo-N-phenyl-2-(N-phenylsulfamoyl)acetamides, the formal aromatic 1,5-C-H insertion in the N-phenylacetamide moiety is favorable to afford the corresponding 3-sulfamoylindolin-2-one derivatives as sole or major products. The intramolecular competitive aromatic 1,5-C-H insertion reactions of 2-diazo-2-sulfamoylacetamides with aryl groups on both amide and sulfonamide groups reveal that the N-aryl substituents on acetamide are more active than those on sulfonamide. The chemoselectivity is controlled by electronic effect of the aryl group. Full article

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33 pages, 3134 KiB

Open AccessArticle

Novel Synthesis of Substituted 2-Trifluoromethyl and 2-Perfluoroalkyl N-Arylpyridinium Compounds—Mechanistic Insights

by Salem El Kharrat, Philippe Laurent, Laurent Boiteau and Hubert Blancou

Molecules 2019, 24(12), 2328; https://doi.org/10.3390/molecules24122328 - 25 Jun 2019

Cited by 3 | Viewed by 4395

Abstract

We report a new one-pot synthesis of 2-trifluoromethylated/2-perfluoroalkylated N-aryl-substituted pyridiniums, 5,6,7,8-tetrahydroquinoliniums and 6,7,8,9-tetrahydro-5H-cyclohepta[b]-pyridinium compounds starting from an activated β-dicarbonyl analogue (here a perfluoro-alkylated gem-iodoacetoxy derivative), an aromatic amine and a (cyclic or acyclic) ketone. The key step of [...] Read more.

We report a new one-pot synthesis of 2-trifluoromethylated/2-perfluoroalkylated N-aryl-substituted pyridiniums, 5,6,7,8-tetrahydroquinoliniums and 6,7,8,9-tetrahydro-5H-cyclohepta[b]-pyridinium compounds starting from an activated β-dicarbonyl analogue (here a perfluoro-alkylated gem-iodoacetoxy derivative), an aromatic amine and a (cyclic or acyclic) ketone. The key step of this multicomponent reaction, involves the formation of a 3-perfluoroalkyl-N,N’-diaryl-1,5-diazapentadiene intermediate, various examples of which were isolated and characterized for the first time, together with investigation of their reactivity. We propose a mechanism involving a concurrent inverse electron demand Diels-Alder or Aza-Robinson cascade cyclisation, followed by a bis-de-anilino-elimination. Noteworthy, a meta-methoxy substituent on the aniline directs the reaction towards a 2-perfluoroalkyl-7-methoxyquinoline, resulting from the direct cyclization of the diazapentadiene intermediate, instead of pyridinium formation. This is the first evidence of synthesis of pyridinium derivatives from activated β-dicarbonyls, ketones, and an aromatic amine, the structures of which (both reactants and products) being analogous to species involved in biological systems, especially upon neurodegenerative diseases such as Parkinson’s. Beyond suggesting chemical/biochemical analogies, we thus hope to outline new research directions for understanding the mechanism of in vivo formation of pyridiniums, hence possible pharmaceutical strategies to better monitor, control or prevent it. Full article

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13 pages, 1349 KiB

Open AccessArticle

Facile Assembling of Novel 2,3,6,7,9-pentaazabicyclo- [3.3.1]nona-3,7-diene Derivatives under Microwave and Ultrasound Platforms

by Hamad M. Al-Matar, Kamal M. Dawood, Wael M. Tohamy and Mona A. Shalaby

Molecules 2019, 24(6), 1110; https://doi.org/10.3390/molecules24061110 - 20 Mar 2019

Cited by 6 | Viewed by 3038

Abstract

Reactions of a series of 3-oxo-2-arylhydrazonopropanal derivatives with two molar ratio of ammonium acetate afforded a library of tetrasubstituted 2,3,6,7,9-pentaazabicyclo[3.3.1]nona- 3,7-diene derivatives in good to excellent isolated yields. The reaction was activated with triethylamine catalyst under three different heating modes: thermal, ultrasonic and [...] Read more.

Reactions of a series of 3-oxo-2-arylhydrazonopropanal derivatives with two molar ratio of ammonium acetate afforded a library of tetrasubstituted 2,3,6,7,9-pentaazabicyclo[3.3.1]nona- 3,7-diene derivatives in good to excellent isolated yields. The reaction was activated with triethylamine catalyst under three different heating modes: thermal, ultrasonic and microwave irradiating conditions in ethanol solvent. The structures of the isolated products were fully characterized by spectral and analytical data as well as X-ray single crystal of selected examples. Full article

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20 pages, 1545 KiB

Open AccessArticle

Synthesis, In Vitro Antimicrobial and Cytotoxic Activities of Some New Pyrazolo[1,5-a]pyrimidine Derivatives

by Ahmed M. Fouda, Hebat-Allah S. Abbas, Eman H. Ahmed, Ali A. Shati, Mohammad Y. Alfaifi and Serag Eldin I. Elbehairi

Molecules 2019, 24(6), 1080; https://doi.org/10.3390/molecules24061080 - 19 Mar 2019

Cited by 46 | Viewed by 4723

Abstract

A new series of pyrazole 4–7 and pyrazolo[1,5-a]pyrimidine 8–13 were synthesized by using a simple, efficient procedure, and screened for their in-vitro antimicrobial and antitumor activities. Symmetrical and asymmetrical 3,6-diarylazo-2,5,7-triaminopyrazolo[1,5-a]pyrimidine were synthesized by the conventional [...] Read more.

A new series of pyrazole 4–7 and pyrazolo[1,5-a]pyrimidine 8–13 were synthesized by using a simple, efficient procedure, and screened for their in-vitro antimicrobial and antitumor activities. Symmetrical and asymmetrical 3,6-diarylazo-2,5,7-triaminopyrazolo[1,5-a]pyrimidine were synthesized by the conventional method and also subjected to microwave irradiation and under ultrasound conditions. The biological results revealed that most of the tested compounds proved to be active as antibacterial and antifungal agents. The antitumor activity of the synthesized compounds was evaluated against human cancer cell lines, MCF-7, HCT-116, and HepG-2, as compared with Doxorubicin as a control. Full article

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13 pages, 3049 KiB

Open AccessArticle

Convenient Synthesis of 6,7,12,13-Tetrahydro-5H-Cyclohepta[2,1-b:3,4-b’]diindole Derivatives Mediated by Hypervalent Iodine (III) Reagent

by Lei Peng, Xiaofei Zhang and Chunhao Yang

Molecules 2019, 24(5), 960; https://doi.org/10.3390/molecules24050960 - 8 Mar 2019

Cited by 9 | Viewed by 3796

Abstract

Bisindolyl alkaloids represent a large family of natural and synthetic products that display various biological activities. Among the bisindole compounds, 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindoles have received little attention. Only two methods have been developed for the construction of the 6,7,12,13-tetrahydro-5 [...] Read more.

Bisindolyl alkaloids represent a large family of natural and synthetic products that display various biological activities. Among the bisindole compounds, 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindoles have received little attention. Only two methods have been developed for the construction of the 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindole scaffold thus far, including the classical Fischer indole synthesis conducted by reacting indole-fused cycloheptanone and hydrazines, and the condensation reaction to build the seven-membered ring. Here, we report for the first time a new route to synthesize 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindoles through intramolecular oxidative coupling of 1,3-di(1H-indol-3-yl)propanes in the presence of PIFA, DDQ and TMSCl with moderate to excellent yields. Full article

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15 pages, 2717 KiB

Open AccessArticle

Facile Access to Fe(III)-Complexing Cyclic Hydroxamic Acids in a Three-Component Format

by Evgeny Chupakhin, Olga Bakulina, Dmitry Dar’in and Mikhail Krasavin

Molecules 2019, 24(5), 864; https://doi.org/10.3390/molecules24050864 - 28 Feb 2019

Cited by 7 | Viewed by 3756

Abstract

Cyclic hydroxamic acids can be viewed as effective binders of soluble iron and can therefore be useful moieties for employing in compounds to treat iron overload disease. Alternatively, they are analogs of bacterial siderophores (iron-scavenging metabolites) and can find utility in designing antibiotic [...] Read more.

Cyclic hydroxamic acids can be viewed as effective binders of soluble iron and can therefore be useful moieties for employing in compounds to treat iron overload disease. Alternatively, they are analogs of bacterial siderophores (iron-scavenging metabolites) and can find utility in designing antibiotic constructs for targeted delivery. An earlier described three-component variant of the Castagnoli—Cushman reaction of homophthalic acid (via in situ cyclodehydration to the respective anhydride) was extended to involve hydroxylamine in lieu of the amine component of the reaction. Using hydroxylamine acetate and O-benzylhydroxylamine was key to the success of this transformation due to greater solubility of the reagents in refluxing toluene (compared to hydrochloride salt). The developed protocol was found suitable for multigram-scale syntheses of N-hydroxy- and N-(benzyloxy)tetrahydroisoquinolonic acids. The cyclic hydroxamic acids synthesized in the newly developed format have been tested and shown to be efficient ligands for Fe³⁺, which makes them suitable candidates for the above-mentioned applications. Full article

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20 pages, 5334 KiB

Open AccessArticle

Synthesis of 4-Alkyl-4H-1,2,4-triazole Derivatives by Suzuki Cross-Coupling Reactions and Their Luminescence Properties

by Monika Olesiejuk, Agnieszka Kudelko, Marcin Swiatkowski and Rafal Kruszynski

Molecules 2019, 24(3), 652; https://doi.org/10.3390/molecules24030652 - 12 Feb 2019

Cited by 8 | Viewed by 4418

Abstract

New derivatives of 4-alkyl-3,5-diaryl-4H-1,2,4-triazole were synthesized utilizing the Suzuki cross-coupling reaction. The presented methodology comprises of the preparation of bromine-containing 4-alkyl-4H-1,2,4-triazoles and their coupling with different commercially available boronic acids in the presence of ionic liquids or in conventional [...] Read more.

New derivatives of 4-alkyl-3,5-diaryl-4H-1,2,4-triazole were synthesized utilizing the Suzuki cross-coupling reaction. The presented methodology comprises of the preparation of bromine-containing 4-alkyl-4H-1,2,4-triazoles and their coupling with different commercially available boronic acids in the presence of ionic liquids or in conventional solvents. The obtained compounds were tested for their luminescence properties. Full article

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2018

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10 pages, 1033 KiB

Open AccessArticle

HFIP-Promoted Bischler Indole Synthesis under Microwave Irradiation

by Guangkai Yao, Zhi-Xiang Zhang, Cheng-Bei Zhang, Han-Hong Xu and Ri-Yuan Tang

Molecules 2018, 23(12), 3317; https://doi.org/10.3390/molecules23123317 - 14 Dec 2018

Cited by 6 | Viewed by 5145

Abstract

1,1,1,3,3,3-Hexafluoropropan-2-ol (HFIP) was found to be effective for the Bischler indole synthesis under microwave irradiation in the absence of a metal catalyst. Under the catalysis of HFIP, a wide range of α-amino arylacetones were successfully transformed into indole derivatives with moderate to good [...] Read more.

1,1,1,3,3,3-Hexafluoropropan-2-ol (HFIP) was found to be effective for the Bischler indole synthesis under microwave irradiation in the absence of a metal catalyst. Under the catalysis of HFIP, a wide range of α-amino arylacetones were successfully transformed into indole derivatives with moderate to good yields. Full article

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16 pages, 1657 KiB

Open AccessArticle

Synthesis, Antibacterial, and Anti HepG2 Cell Line Human Hepatocyte Carcinoma Activity of Some New Potentially Benzimidazole-5-(Aryldiazenyl)Thiazole Derivatives

by Mohamed E. Khalifa, Adil A. Gobouri, Fahad M. Kabli, Tarik A. Altalhi, Abdulraheem S. A. Almalki and Mahmoud A. Mohamed

Molecules 2018, 23(12), 3285; https://doi.org/10.3390/molecules23123285 - 11 Dec 2018

Cited by 18 | Viewed by 4400

Abstract

The paper describes the synthesis and biological evaluation of some new benzimidazole derivatives as potent clinical drugs that are useful in the treatment of some microbial infections and tumor inhibition. The starting compound 2-(bromomethyl)-1H-benzimidazole (1) was prepared, and hence [...] Read more.

The paper describes the synthesis and biological evaluation of some new benzimidazole derivatives as potent clinical drugs that are useful in the treatment of some microbial infections and tumor inhibition. The starting compound 2-(bromomethyl)-1H-benzimidazole (1) was prepared, and hence underwent interesting functionalization reactions to afford several series of benzimidazole-5-(aryldiazenyl)thiazole derivatives: 3a–c, 7a–c, and 8a–c. The antibacterial activities of the synthesized compounds were evaluated by calculation of the inhibition zone diameter (mm) and the determination of minimum inhibitory concentration (µg/mL) against selected pathogenic bacteria Staphylococcus aureus (Gram-positive bacteria) and Escherichia coli (Gram-negative bacteria).Noticeable efficiency was found based on in vitro screening for their antioxidant activity and cytotoxicity effect against the human liver cancer cell line (HepG2) and human hepatocyte carcinoma cells at relatively high concentrations. Full article

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9 pages, 770 KiB

Open AccessArticle

Conversion of Medium-Sized Lactams to α-Vinyl or α-Acetylenyl Azacycles via N,O-Acetal TMS Ethers

by Minjun Kim, Jaebong Jang, Goyoung Choi, Sungkyun Chung, Changjin Lim, Joonseong Hur, Hyun Su Kim, Younghwa Na, Woo Sung Son, Young-Ger Suh, Jong-Wha Jung and Seok-Ho Kim

Molecules 2018, 23(11), 3023; https://doi.org/10.3390/molecules23113023 - 19 Nov 2018

Cited by 5 | Viewed by 3954

Abstract

α-Vinyl or α-acetylenyl azacycles were easily synthesized from 7- to 9-membered lactams and 6- to 9-membered lactams via N,O-acetal trimethylsilyl (TMS) ethers. Organocopper and organostannane reagents afforded reasonable yields for the respective N-acyliminium ion vinylation and acetylenylation intermediates generated [...] Read more.

α-Vinyl or α-acetylenyl azacycles were easily synthesized from 7- to 9-membered lactams and 6- to 9-membered lactams via N,O-acetal trimethylsilyl (TMS) ethers. Organocopper and organostannane reagents afforded reasonable yields for the respective N-acyliminium ion vinylation and acetylenylation intermediates generated from N,O-acetal TMS ethers in the presence of a Lewis acid. Full article

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13 pages, 1551 KiB

Open AccessFeature PaperArticle

Eco-Friendly Synthesis, Characterization and Biological Evaluation of Some Novel Pyrazolines Containing Thiazole Moiety as Potential Anticancer and Antimicrobial Agents

by Mastoura M. Edrees, Sraa Abu- Melha, Amirah M. Saad, Nabila A. Kheder, Sobhi M. Gomha and Zeinab A. Muhammad

Molecules 2018, 23(11), 2970; https://doi.org/10.3390/molecules23112970 - 14 Nov 2018

Cited by 45 | Viewed by 4100

Abstract

The one-pot synthesis of a series of pyrazoline derivatives containing the bioactive thiazole ring has been performed through a 1,3-dipolar cycloaddition reaction of N-thiocarbamoylpyrazoline and different hydrazonoyl halides or α-haloketones in the presence of DABCO (1,4-diazabicyclo[2.2.2] octane) as an eco-friendly catalyst using [...] Read more.

The one-pot synthesis of a series of pyrazoline derivatives containing the bioactive thiazole ring has been performed through a 1,3-dipolar cycloaddition reaction of N-thiocarbamoylpyrazoline and different hydrazonoyl halides or α-haloketones in the presence of DABCO (1,4-diazabicyclo[2.2.2] octane) as an eco-friendly catalyst using the solvent-drop grinding method. The structure of the synthesized compounds was elucidated using elemental and spectroscopic analyses (IR, NMR, and Mass). The activity of these compounds against human hepatocellular carcinoma cell line (HepG2) was tested and the results showed that the pyrazoline 11f, which has a fluorine substituent, is the most active. The antimicrobial activities of the newly synthesized compounds were determined against two fungi and four bacterial strains, and the results indicated that some of the newly synthesized pyrazolines are more potent than the standard drugs against test organisms. Full article

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22 pages, 6119 KiB

Open AccessFeature PaperArticle

From Quinoxaline, Pyrido[2,3-b]pyrazine and Pyrido[3,4-b]pyrazine to Pyrazino-Fused Carbazoles and Carbolines

by Frédéric Lassagne, Timothy Langlais, Elsa Caytan, Emmanuelle Limanton, Ludovic Paquin, Manon Boullard, Coline Courtel, Idriss Curbet, Clément Gédéon, Julien Lebreton, Laurent Picot, Valérie Thiéry, Mohamed Souab, Blandine Baratte, Sandrine Ruchaud, Stéphane Bach, Thierry Roisnel and Florence Mongin

Molecules 2018, 23(11), 2961; https://doi.org/10.3390/molecules23112961 - 13 Nov 2018

Cited by 5 | Viewed by 5530

Abstract

2,3-Diphenylated quinoxaline, pyrido[2,3-b]pyrazine and 8-bromopyrido[3,4-b]pyrazine were halogenated in deprotometalation-trapping reactions using mixed 2,2,6,6-tetramethyl piperidino-based lithium-zinc combinations in tetrahydrofuran. The 2,3-diphenylated 5-iodo- quinoxaline, 8-iodopyrido[2,3-b]pyrazine and 8-bromo-7-iodopyrido[3,4-b]pyrazine thus obtained were subjected to palladium-catalyzed couplings with arylboronic acids [...] Read more.

2,3-Diphenylated quinoxaline, pyrido[2,3-b]pyrazine and 8-bromopyrido[3,4-b]pyrazine were halogenated in deprotometalation-trapping reactions using mixed 2,2,6,6-tetramethyl piperidino-based lithium-zinc combinations in tetrahydrofuran. The 2,3-diphenylated 5-iodo- quinoxaline, 8-iodopyrido[2,3-b]pyrazine and 8-bromo-7-iodopyrido[3,4-b]pyrazine thus obtained were subjected to palladium-catalyzed couplings with arylboronic acids or anilines, and possible subsequent cyclizations to afford the corresponding pyrazino[2,3-a]carbazole, pyrazino[2′,3′:5,6] pyrido[4,3-b]indole and pyrazino[2′,3′:4,5]pyrido[2,3-d]indole, respectively. 8-Iodopyrido[2,3-b] pyrazine was subjected either to a copper-catalyzed C-N bond formation with azoles, or to direct substitution to introduce alkylamino, benzylamino, hydrazine and aryloxy groups at the 8 position. The 8-hydrazino product was converted into aryl hydrazones. Most of the compounds were evaluated for their biological properties (antiproliferative activity in A2058 melanoma cells and disease-relevant kinase inhibition). Full article

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16 pages, 3608 KiB

Open AccessArticle

Quinazolin-4(3H)-ones and 5,6-Dihydropyrimidin-4(3H)-ones from β-Aminoamides and Orthoesters

by Joshua T. Gavin, Joel K. Annor-Gyamfi and Richard A. Bunce

Molecules 2018, 23(11), 2925; https://doi.org/10.3390/molecules23112925 - 9 Nov 2018

Cited by 15 | Viewed by 4740

Abstract

Quinazolin-4(3H)-ones have been prepared in one step from 2-aminobenzamides and orthoesters in the presence of acetic acid. Simple 2-aminobenzamides were easily converted to the heterocycles by refluxing in absolute ethanol with 1.5 equivalents of the orthoester and 2 equivalents of acetic [...] Read more.

Quinazolin-4(3H)-ones have been prepared in one step from 2-aminobenzamides and orthoesters in the presence of acetic acid. Simple 2-aminobenzamides were easily converted to the heterocycles by refluxing in absolute ethanol with 1.5 equivalents of the orthoester and 2 equivalents of acetic acid for 12–24 h. Ring-substituted and hindered 2-aminobenzamides as well as cases incorporating an additional basic nitrogen required pressure tube conditions with 3 equivalents each of the orthoester and acetic acid in ethanol at 110 °C for 12–72 h. The reaction was tolerant towards functionality on the benzamide and a range of structures was accessible. Workup involved removal of the solvent under vacuum and either recrystallization from ethanol or trituration with ether-pentane. Several 5,6-dihydropyrimidin-4(3H)-ones were also prepared from 3-amino-2,2-dimethylpropionamide. All products were characterized by melting point, FT-IR, ¹H-NMR, ¹³C-NMR, and HRMS. Full article

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15 pages, 4884 KiB

Open AccessFeature PaperArticle

Regioselective Synthesis of New 2,4-(Het)aryl-3H-pyrido[1′,2′:1,5]pyrazolo[4,3-d]pyrimidines Involving Palladium-Catalyzed Cross-Coupling Reactions

by Abdelaziz Ejjoummany, Rabia Belaroussi, Ahmed El Hakmaoui, Mohamed Akssira, Gérald Guillaumet, Frédéric Buron and Sylvain Routier

Molecules 2018, 23(11), 2740; https://doi.org/10.3390/molecules23112740 - 23 Oct 2018

Cited by 6 | Viewed by 3352

Abstract

The design of some novel di-(het)arylated-3H-pyrido[1′,2′:1,5]pyrazolo[4,3-d]pyrimidine derivatives is reported. The series was developed from 1-aminopyridinium iodide, which afforded the key intermediate bearing two thiomethyl and amide functions, each of them useful for palladium catalyzed cross coupling reactions by alkyl [...] Read more.

The design of some novel di-(het)arylated-3H-pyrido[1′,2′:1,5]pyrazolo[4,3-d]pyrimidine derivatives is reported. The series was developed from 1-aminopyridinium iodide, which afforded the key intermediate bearing two thiomethyl and amide functions, each of them useful for palladium catalyzed cross coupling reactions by alkyl sulfur release and C-O activation, respectively. The two regioselective and successive cross-coupling reactions were first carried out in C-4 by in situ C-O activation and next in C-2 by a methylsulfur release. Process optimization furnished conditions leading to products in high yields. The scope and limitations of the methodologies were evaluated and the final compounds characterized. Full article

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19 pages, 26755 KiB

Open AccessReview

Synthesis of Multi-Substituted Pyrrole Derivatives Through [3+2] Cycloaddition with Tosylmethyl Isocyanides (TosMICs) and Electron-Deficient Compounds

by Zhengning Ma, Zicheng Ma and Dawei Zhang

Molecules 2018, 23(10), 2666; https://doi.org/10.3390/molecules23102666 - 17 Oct 2018

Cited by 52 | Viewed by 15382

Abstract

Pyrrole and its polysubstituted derivatives are important five-membered heterocyclic compounds, which exist alone or as a core framework in many pharmaceutical and natural product structures, some of which have good biological activities. The Van Leusen [3+2] cycloaddition reaction based on tosylmethyl isocyanides (TosMICs) [...] Read more.

Pyrrole and its polysubstituted derivatives are important five-membered heterocyclic compounds, which exist alone or as a core framework in many pharmaceutical and natural product structures, some of which have good biological activities. The Van Leusen [3+2] cycloaddition reaction based on tosylmethyl isocyanides (TosMICs) and electron-deficient compounds as a substrate, which has been continuously developed due to its advantages such as operationally simple, easily available starting materials, and broadly range of substrates, is one of the most convenient methods to synthetize pyrrole heterocycles. In this review, we discuss the different types of two carbon synthons in the Van Leusen pyrrole reaction and give a summary of the progress of these synthesis methods in the past two decades. Full article

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14 pages, 5283 KiB

Open AccessArticle

Synthesis, Spectroscopic Characterization, and In Vitro Antibacterial Evaluation of Novel Functionalized Sulfamidocarbonyloxyphosphonates

by Abdeslem Bouzina, Khaoula Bechlem, Hajira Berredjem, Billel Belhani, Imène Becheker, Jacques Lebreton, Marc Le Borgne, Zouhair Bouaziz, Christelle Marminon and Malika Berredjem

Molecules 2018, 23(7), 1682; https://doi.org/10.3390/molecules23071682 - 10 Jul 2018

Cited by 13 | Viewed by 4694

Abstract

Several new sulfamidocarbonyloxyphosphonates were prepared in two steps, namely carbamoylation and sulfamoylation, by using chlorosulfonyl isocyanate (CSI), α-hydroxyphosphonates, and various amino derivatives and related (primary or secondary amines, β-amino esters, and oxazolidin-2-ones). All structures were confirmed by ¹H, ¹³C, and ³¹ [...] Read more.

Several new sulfamidocarbonyloxyphosphonates were prepared in two steps, namely carbamoylation and sulfamoylation, by using chlorosulfonyl isocyanate (CSI), α-hydroxyphosphonates, and various amino derivatives and related (primary or secondary amines, β-amino esters, and oxazolidin-2-ones). All structures were confirmed by ¹H, ¹³C, and ³¹P NMR spectroscopy, IR spectroscopy, and mass spectroscopy, as well as elemental analysis. Eight compounds were evaluated for their in vitro antibacterial activity against four reference bacteria including Gram-positive Staphylococcus aureus (ATCC 25923), and Gram-negative Escherichia coli (ATCC 25922), Klebsiella pneumonia (ATCC 700603), Pseudomonas aeruginosa (ATCC 27853), in addition to three clinical strains of each studied bacterial species. Compounds 1a–7a and 1b showed significant antibacterial activity compared to sulfamethoxazole/trimethoprim, the reference drug used in this study. Full article

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3 pages, 175 KiB

Open AccessCorrection

Correction: El-kalyoubi, S.; et al. Novel 2-Thioxanthine and Dipyrimidopyridine Derivatives: Synthesis and Antimicrobial Activity. Molecules, 2015, 20, 19263–19276

by Samar El-kalyoubi, Fatmah Agili and Shaker Youssif

Molecules 2018, 23(7), 1592; https://doi.org/10.3390/molecules23071592 - 29 Jun 2018

Viewed by 2898

Abstract

The authors wish to make the following changes to their paper [1].[...] Full article

11 pages, 3978 KiB

Open AccessArticle

Synthesis of 8-Fluoro-3,4-dihydroisoquinoline and Its Transformation to 1,8-Disubstituted Tetrahydroisoquinolines

by Csilla Hargitai, Tamás Nagy, Judit Halász, Gyula Simig and Balázs Volk

Molecules 2018, 23(6), 1280; https://doi.org/10.3390/molecules23061280 - 26 May 2018

Cited by 3 | Viewed by 4587

Abstract

A simple procedure for the synthesis of 8-fluoro-3,4-dihydroisoquinoline is described below, based on a directed ortho-lithiation reaction. This key intermediate was then applied in various transformations. Fluorine–amine exchange afforded the corresponding 8-amino-3,4-dihydroisoquinolines, suitable starting compounds for the synthesis of 1-substituted 8-amino-tetrahydroisoquinolines. On [...] Read more.

A simple procedure for the synthesis of 8-fluoro-3,4-dihydroisoquinoline is described below, based on a directed ortho-lithiation reaction. This key intermediate was then applied in various transformations. Fluorine–amine exchange afforded the corresponding 8-amino-3,4-dihydroisoquinolines, suitable starting compounds for the synthesis of 1-substituted 8-amino-tetrahydroisoquinolines. On the other hand, reduction and alkylation reactions of 8-fluoro-3,4-dihydroisoquinoline led to novel 1,2,3,4-tetrahydroisoquinoline derivatives that can be used as building blocks in the synthesis of potential central nervous system drug candidates. Full article

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17 pages, 3418 KiB

Open AccessArticle

Synthesis and Pharmacological Studies of Unprecedented Fused Pyridazino[3′,4′:5,6][1,2,4]triazino[3,4-b][1,3,4]thiadiazine Derivatives

by Rania S. Ali and Hosam A. Saad

Molecules 2018, 23(5), 1024; https://doi.org/10.3390/molecules23051024 - 27 Apr 2018

Cited by 5 | Viewed by 4330

Abstract

A novel fused system with three or four fused rings—pyridazino[3′,4′:5,6][1,2,4]triazino[4,3-b][1,2,4,5]tetrazine and pyridazino[3′,4′:5,6][1,2,4]triazino[3,4-b]pyrimido[4,5-e][1,3,4]thiadiazine was obtained from the starting materials 4(6H)-amino-3-hydrazino-7-(2-thienyl)pyridazino[3,4-e][1,2,4]-triazine 2 and 9-amino-3-(2-thienyl)-2H,8H-pyridazino[3′,4′:5,6][1,2,4]triazino[3,4-b][1,3,4]thiadiazine-8-carbonitrile 12. Each of the [...] Read more.

A novel fused system with three or four fused rings—pyridazino[3′,4′:5,6][1,2,4]triazino[4,3-b][1,2,4,5]tetrazine and pyridazino[3′,4′:5,6][1,2,4]triazino[3,4-b]pyrimido[4,5-e][1,3,4]thiadiazine was obtained from the starting materials 4(6H)-amino-3-hydrazino-7-(2-thienyl)pyridazino[3,4-e][1,2,4]-triazine 2 and 9-amino-3-(2-thienyl)-2H,8H-pyridazino[3′,4′:5,6][1,2,4]triazino[3,4-b][1,3,4]thiadiazine-8-carbonitrile 12. Each of the starting compounds was subjected to a number of cyclization reactions to obtain a series of new heterocyclic fused systems, 3–10 and 13–23, via bifunctional reagents. Some of the synthesized compounds were screened against three cell lines including HepG2, HCT-116 and MCF-7 to discover their anticancer activity. The synthesized compounds were characterized depending on their elemental analyses and spectral data. Full article

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24 pages, 4066 KiB

Open AccessArticle

Synthesis of Some Novel Fused Pyrimido[4″,5″:5′,6′]-[1,2,4]triazino[3′,4′:3,4] [1,2,4]triazino[5,6-b]indoles with Expected Anticancer Activity

by Rania S. Ali and Hosam A. Saad

Molecules 2018, 23(3), 693; https://doi.org/10.3390/molecules23030693 - 19 Mar 2018

Cited by 12 | Viewed by 5047

Abstract

Our current goal is the synthesis of polyheterocyclic compounds starting from 3-amino-[1,2,4]triazino[5,6-b]indole 1 and studying their anticancer activity to determine whether increasing of the size of the molecules increases the anticancer activity or not. 1-Amino[1,2,4]triazino[3′,4′:3,4]-[1,2,4]triazino[5,6-b]indole-2-carbonitrile (4) was [...] Read more.

Our current goal is the synthesis of polyheterocyclic compounds starting from 3-amino-[1,2,4]triazino[5,6-b]indole 1 and studying their anticancer activity to determine whether increasing of the size of the molecules increases the anticancer activity or not. 1-Amino[1,2,4]triazino[3′,4′:3,4]-[1,2,4]triazino[5,6-b]indole-2-carbonitrile (4) was prepared by the diazotization of 3-amino[1,2,4]-triazino[5,6-b]indole 1 followed by coupling with malononitrile in basic medium then cyclization under reflux to get 4. Also, new fused pyrimido[4″,5″:5′,6′][1,2,4]triazino-[3′,4′:3,4][1,2,4]triazino[5,6-b]indole derivative 6 was prepared and used to obtain polycyclic heterocyclic systems. Confirmation of the synthesized compounds’ structures was carried out using elemental analyses and spectral data (IR, ¹H-NMR and ¹³C-NMR and mass spectra). The anticancer activity of some of the synthesized compounds was tested against HepG2, HCT-116 and MCF-7 cell lines. The anticancer screening results showed that some derivatives display good activity which was more potent than that of the reference drug used. Molecular docking was used to predict the binding between some of the synthesized compounds and the prostate cancer 2q7k hormone and breast ‎cancer 3hb5 receptors. Full article

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13 pages, 1481 KiB

Open AccessFeature PaperArticle

Syntheses of 1-Aryl-5-nitro-1H-indazoles and a General One-Pot Route to 1-Aryl-1H-indazoles

by Joel K. Annor-Gyamfi, Krishna Kumar Gnanasekaran and Richard A. Bunce

Molecules 2018, 23(3), 674; https://doi.org/10.3390/molecules23030674 - 16 Mar 2018

Cited by 8 | Viewed by 5780

Abstract

An efficient route to substituted 1-aryl-1H-indazoles has been developed and optimized. The method involved the preparation of arylhydrazones from acetophenone or benzaldehyde substituted by fluorine at C2 and nitro at C5, followed by deprotonation and nucleophilic aromatic substitution (S_NAr) [...] Read more.

An efficient route to substituted 1-aryl-1H-indazoles has been developed and optimized. The method involved the preparation of arylhydrazones from acetophenone or benzaldehyde substituted by fluorine at C2 and nitro at C5, followed by deprotonation and nucleophilic aromatic substitution (S_NAr) ring closure in 45–90%. Modification of this procedure to a one-pot domino process was successful in the acetophenone series (73–96%), while the benzaldehyde series (63–73%) required a step-wise addition of reagents. A general one-pot protocol for 1-aryl-1H-indazole formation without the limiting substitution patterns required for the S_NAr cyclization has also been achieved in 62–78% yields. A selection of 1-aryl-1H-indazoles was prepared in high yield by a procedure that requires only a single laboratory operation. Full article

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16 pages, 1556 KiB

Open AccessArticle

Synthesis of Dihydrooxepino[3,2-c]Pyrazoles via Claisen Rearrangement and Ring-Closing Metathesis from 4-Allyloxy-1H-pyrazoles

by Yoshihide Usami, Aoi Kohno, Hiroki Yoneyama and Shinya Harusawa

Molecules 2018, 23(3), 592; https://doi.org/10.3390/molecules23030592 - 6 Mar 2018

Cited by 10 | Viewed by 3830

Abstract

Synthesis of novel pyrazole-fused heterocycles, i.e., dihydro-1H- or 2H-oxepino[3,2-c]pyrazoles (6 or 7) from 4-allyloxy-1H-pyrazoles (1) via combination of Claisen rearrangement and ring-closing metathesis (RCM) has been achieved. A suitable catalyst for [...] Read more.

Synthesis of novel pyrazole-fused heterocycles, i.e., dihydro-1H- or 2H-oxepino[3,2-c]pyrazoles (6 or 7) from 4-allyloxy-1H-pyrazoles (1) via combination of Claisen rearrangement and ring-closing metathesis (RCM) has been achieved. A suitable catalyst for the RCM of 5-allyl-4-allyloxy-1H-pyrazoles (4) was proved to be the Grubbs second generation catalyst (Grubbs^2nd) to give the predicted RCM product at room temperature in three hours. The same reactions of the regioisomer, 3-allyl-4-allyloxy-1H-pyrazoles (5), also proceeded to give the corresponding RCM products. On the other hand, microwave aided RCM at 140 °C on both of 4 and 5 afforded mixtures of isomeric products with double bond rearrangement from normal RCM products in spite of remarkable reduction of the reaction time to 10 min. Full article

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12 pages, 1200 KiB

Open AccessArticle

Synthesis and Optical Properties of Near-Infrared meso-Phenyl-Substituted Symmetric Heptamethine Cyanine Dyes

by Andrew Levitz, Fahad Marmarchi and Maged Henary

Molecules 2018, 23(2), 226; https://doi.org/10.3390/molecules23020226 - 24 Jan 2018

Cited by 29 | Viewed by 8094

Abstract

Heptamethine cyanine dyes are a class of near infrared fluorescence (NIRF) probes of great interest in bioanalytical and imaging applications due to their modifiability, allowing them to be tailored for particular applications. Generally, modifications at the meso-position of these dyes are achieved [...] Read more.

Heptamethine cyanine dyes are a class of near infrared fluorescence (NIRF) probes of great interest in bioanalytical and imaging applications due to their modifiability, allowing them to be tailored for particular applications. Generally, modifications at the meso-position of these dyes are achieved through Suzuki-Miyaura C-C coupling and S_RN1 nucleophilic substitution of the chlorine atom at the meso-position of the dye. Herein, a series of 15 meso phenyl-substituted heptamethine cyanines was synthesized utilizing a modified dianil linker. Their optical properties, including molar absorptivity, fluorescence, Stokes shift, and quantum yield were measured. The HSA binding affinities of two representative compounds were measured and compared to that of a series of trimethine cyanines previously synthesized by our lab. The results indicate that the binding of these compounds to HSA is not only dependent on hydrophobicity, but may also be dependent on steric interferences in the binding site and structural dynamics of the NIRF compounds. Full article

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14 pages, 8069 KiB

Open AccessArticle

Regioselectivity in Reactions between Bis(2-benzothiazolyl)ketone and Vinyl Grignard Reagents: C- versus O-alkylation—Part III

by Carla Boga, Silvia Bordoni, Lucia Casarin, Gabriele Micheletti and Magda Monari

Molecules 2018, 23(1), 171; https://doi.org/10.3390/molecules23010171 - 15 Jan 2018

Cited by 3 | Viewed by 5160

Abstract

The reaction between bis(2-benzothiazolyl)ketone and vinyl Grignard reagents bearing different substituents on the vinyl moiety gave the product derived from attack on the carbonylic carbon- and/or oxygen-atom. The regioselectivity of the attack depends on the kind of substituents bound to the vinylic carbon [...] Read more.

The reaction between bis(2-benzothiazolyl)ketone and vinyl Grignard reagents bearing different substituents on the vinyl moiety gave the product derived from attack on the carbonylic carbon- and/or oxygen-atom. The regioselectivity of the attack depends on the kind of substituents bound to the vinylic carbon atoms and on their relative position. The reaction between vinylmagnesium bromide and 2-methyl-1-propenylmagnesium bromide was carried out under different experimental conditions and in the presence of radical scavengers. The results indicate a plausible mechanistic pathway involving radical intermediates in the case of O-alkylation, but a polar ones in the case of classic C-alkylation. This agrees with our previous reports indicating a key role played by the delocalization ability of the substituents bound to the carbonyl group in driving the regioselectivity of the vinylmagnesium bromide attack towards O-alkylation. Further support of this was obtained by diffractometric analysis of four distinct bis(heteroaryl)ketones. Full article

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2017

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5363 KiB

Open AccessArticle

Energetic Di- and Trinitromethylpyridines: Synthesis and Characterization

by Yiying Zhang, Xiaoyu Sun, Shannan Yu, Lingxiang Bao, Chenghui Sun and Siping Pang

Molecules 2018, 23(1), 2; https://doi.org/10.3390/molecules23010002 - 21 Dec 2017

Cited by 4 | Viewed by 5402

Abstract

Pyridine derivatives based on the addition of trinitromethyl functional groups were synthesized by the reaction of N₂O₄ with the corresponding pyridinecarboxaldoximes, then they were converted into dinitromethylide hydrazinium salts. These energetic compounds were fully characterized by IR and NMR spectroscopy, [...] Read more.

Pyridine derivatives based on the addition of trinitromethyl functional groups were synthesized by the reaction of N₂O₄ with the corresponding pyridinecarboxaldoximes, then they were converted into dinitromethylide hydrazinium salts. These energetic compounds were fully characterized by IR and NMR spectroscopy, elemental analysis, differential scanning calorimetry (DSC), and X-ray crystallography. These pyridine derivatives have good densities, positive enthalpies of formation, and acceptable sensitivity values. Theoretical calculations carried out using Gaussian 03 and EXPLO5 programs demonstrated good to excellent detonation velocities and pressures. Each of these compounds is superior in performance to TNT, while 2,6-bis(trinitromethyl)pyridine (D = 8700 m·s⁻¹, P = 33.2 GPa) shows comparable detonation performance to that of RDX, but its thermal stability is too low, making it inferior to RDX. Full article

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2955 KiB

Open AccessArticle

Nucleobase–Guanidiniocarbonyl-Pyrrole Conjugates as Novel Fluorimetric Sensors for Single Stranded RNA

by Željka Ban, Biserka Žinić, Robert Vianello, Carsten Schmuck and Ivo Piantanida

Molecules 2017, 22(12), 2213; https://doi.org/10.3390/molecules22122213 - 13 Dec 2017

Cited by 9 | Viewed by 5365

Abstract

We demonstrate here for the first time that a guanidiniocarbonyl-pyrrole (GCP) unit can be applied for the fine recognition of single stranded RNA sequences—an intuitively unexpected result since so far binding of the GCP unit to ds-DNA or ds-RNA relied strongly on minor [...] Read more.

We demonstrate here for the first time that a guanidiniocarbonyl-pyrrole (GCP) unit can be applied for the fine recognition of single stranded RNA sequences—an intuitively unexpected result since so far binding of the GCP unit to ds-DNA or ds-RNA relied strongly on minor or major groove interactions, as shown in previous work. Two novel nucleobase–GCP isosteric conjugates differing in the flexibility of GCP unit revealed a fluorimetric recognition of various single stranded RNA, which could be additionally regulated by pH. The more rigid conjugate showed a specific fluorescence increase for poly A only at pH 7, whereby this response could be reversibly switched-off at pH 5. The more flexible derivative revealed selective fluorescence quenching by poly G at pH 7 but no change for poly A, whereas its recognition of poly AH⁺ can be switched-on at pH 5. The computational analysis confirmed the important role of the GCP fragment and its protonation states in the sensing of polynucleotides and revealed that it is affected by the intrinsic dynamical features of conjugates themselves. Both conjugates showed a negligible response to uracil and cytosine ss-RNA as well as ds-RNA at pH 7, and only weak interactions with ds-DNA. Thus, nucleobase–GCP conjugates can be considered as novel lead compounds for the design of ss-RNA or ss-DNA selective fluorimetric probes. Full article

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5518 KiB

Open AccessCommunication

From α-Bromomethylbutenolide to Fused Tri(Tetra) Cyclic Dihydrofurandiones through Barbier Reaction–Heck Arylation Sequence

by Arbia Talbi, Anne Gaucher, Flavien Bourdreux, Jérôme Marrot, Mohamed L. Efrit, Hédi M’Rabet and Damien Prim

Molecules 2017, 22(12), 2171; https://doi.org/10.3390/molecules22122171 - 8 Dec 2017

Cited by 2 | Viewed by 4286

Abstract

A Barbier reaction–Heck arylation sequence from α-bromomethylbutenolide to fused tri and tetracyclic lactones has been developed. The first step involving a Barbier reaction enabled installing ortho-bromoaromatics in α-ylidene γ-lactones. The latter substrates were subjected to intramolecular Heck reaction conditions which selectively afforded [...] Read more.

A Barbier reaction–Heck arylation sequence from α-bromomethylbutenolide to fused tri and tetracyclic lactones has been developed. The first step involving a Barbier reaction enabled installing ortho-bromoaromatics in α-ylidene γ-lactones. The latter substrates were subjected to intramolecular Heck reaction conditions which selectively afforded 6,5,5 or 6,6,5 fused ring systems depending on the nature of the base employed. Full article

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1725 KiB

Open AccessArticle

Multi Component Reactions under Increased Pressure: On the Mechanism of Formation of Pyridazino[5,4,3-de][1,6]naphthyridine Derivatives by the Reaction of Malononitrile, Aldehydes and 2-Oxoglyoxalarylhydrazones in Q-Tubes

by Majdah A. AL-Johani, Khadijah M. Al-Zaydi, Sameera M. Mousally, Norah F. Alqahtani, Noha Hilmy Elnagdi and Mohamed H. Elnagdi

Molecules 2017, 22(12), 2114; https://doi.org/10.3390/molecules22122114 - 1 Dec 2017

Cited by 6 | Viewed by 4693

Abstract

Efficient synthesis of phenanthridin-6(5H)-one derivatives 12a–n in a four-component reaction of aldehyde hydrazone, aromatic aldehydes and malononitrile in Q-Tubes is reported. The results showed that the methodology has the advantage of being a one-pot synthesis of tricyclic systems in [...] Read more.

Efficient synthesis of phenanthridin-6(5H)-one derivatives 12a–n in a four-component reaction of aldehyde hydrazone, aromatic aldehydes and malononitrile in Q-Tubes is reported. The results showed that the methodology has the advantage of being a one-pot synthesis of tricyclic systems in good yields. Potential routes leading to formation of compounds 12 are discussed. The structures of the synthesized compounds could be unequivocally established via X-ray crystal structure determination and spectroscopic methods. Full article

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1317 KiB

Open AccessArticle

A New Synthetic Route to Polyhydrogenated Pyrrolo[3,4-b]pyrroles by the Domino Reaction of 3-Bromopyrrole-2,5-Diones with Aminocrotonic Acid Esters

by Khidmet Shikhaliev, Artem Sabynin, Valeri Sekirin, Michael Krysin, Fedor Zubkov and Kristina Yankina

Molecules 2017, 22(11), 2035; https://doi.org/10.3390/molecules22112035 - 22 Nov 2017

Viewed by 4794

Abstract

A new synthetic approach to polyfunctional hexahydropyrrolo[3,4-b]pyrroles was developed based on cyclization of N-arylbromomaleimides with aminocrotonic acid esters. A highly chemo- and stereoselective reaction is a Hantzsch-type domino process, involving the steps of initial nucleophilic C-addition or substitution and subsequent intramolecular [...] Read more.

A new synthetic approach to polyfunctional hexahydropyrrolo[3,4-b]pyrroles was developed based on cyclization of N-arylbromomaleimides with aminocrotonic acid esters. A highly chemo- and stereoselective reaction is a Hantzsch-type domino process, involving the steps of initial nucleophilic C-addition or substitution and subsequent intramolecular nucleophilic addition without recyclyzation of imide cycle. Full article

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Synthesis of Novel Glycerol-Derived 1,2,3-Triazoles and Evaluation of Their Fungicide, Phytotoxic and Cytotoxic Activities

by Adilson Vidal Costa, Marcos Vinicius Lacerda de Oliveira, Roberta Tristão Pinto, Luiza Carvalheira Moreira, Ediellen Mayara Corrêa Gomes, Thammyres de Assis Alves, Patrícia Fontes Pinheiro, Vagner Tebaldi de Queiroz, Larissa Fonseca Andrade Vieira, Robson Ricardo Teixeira and Waldir Cintra de Jesus Júnior

Molecules 2017, 22(10), 1666; https://doi.org/10.3390/molecules22101666 - 7 Oct 2017

Cited by 33 | Viewed by 6394

Abstract

The synthesis of a series of 1,2,3-triazoles using glycerol as starting material is described. The key step in the preparation of these triazolic derivatives is the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), also known as click reaction, between 4-(azidomethyl)-2,2-dimethyl-1,3-dioxolane (3) and different terminal [...] Read more.

The synthesis of a series of 1,2,3-triazoles using glycerol as starting material is described. The key step in the preparation of these triazolic derivatives is the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), also known as click reaction, between 4-(azidomethyl)-2,2-dimethyl-1,3-dioxolane (3) and different terminal alkynes. The eight prepared derivatives were evaluated with regard to their fungicide, phytotoxic and cytotoxic activities. The fungicidal activity was assessed in vitro against Colletotrichum gloeosporioides, the causative agent of papaya anthracnose. It was found that the compounds 1-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-1,2,3-triazol-4-yl)-cyclo-hexanol (4g) and 2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-1,2,3-triazol-4-yl)propan-2-ol (4h) demonstrated high efficiency in controlling C. gloeosporioides when compared to the commercial fungicide tebuconazole. The triazoles did not present any phytotoxic effect when evaluated against Lactuca sativa. However, five derivatives were mitodepressive, inducing cell death detected by the presence of condensed nuclei and acted as aneugenic agents in the cell cycle of L. sativa. It is believed that glycerol derivatives bearing 1,2,3-triazole functionalities may represent a promising scaffold to be explored for the development of new agents to control C. gloeosporioides. Full article

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Hydrogen-Bonding Interactions in Luminescent Quinoline-Triazoles with Dominant 1D Crystals

by Shi-Qiang Bai, David James Young and T. S. Andy Hor

Molecules 2017, 22(10), 1600; https://doi.org/10.3390/molecules22101600 - 22 Sep 2017

Cited by 2 | Viewed by 5075

Abstract

Quinoline-triazoles 2-((4-(diethoxymethyl)-1H-1,2,3-triazol-1-yl)methyl)quinoline (1), 2-((4-(m-tolyl)-1H-1,2,3-triazol-1-yl)methyl)quinoline (2) and 2-((4-(p-tolyl)-1H-1,2,3-triazol-1-yl)methyl)quinoline (3) have been prepared with CuAAC click reactions and used as a model series to probe the relationship between lattice H-bonding interaction and crystal [...] Read more.

Quinoline-triazoles 2-((4-(diethoxymethyl)-1H-1,2,3-triazol-1-yl)methyl)quinoline (1), 2-((4-(m-tolyl)-1H-1,2,3-triazol-1-yl)methyl)quinoline (2) and 2-((4-(p-tolyl)-1H-1,2,3-triazol-1-yl)methyl)quinoline (3) have been prepared with CuAAC click reactions and used as a model series to probe the relationship between lattice H-bonding interaction and crystal direction of growth. Crystals of 1–3 are 1D tape and prism shapes that correlate with their intermolecular and solvent 1D lattice H-bonding interactions. All compounds were thermally stable up to about 200 C and blue-green emissive in solution. Full article

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A Facile Oxidative Opening of the C-Ring in Luotonin A and Derivatives

by Amra Ibric, Kathrin Dutter, Brigitte Marian and Norbert Haider

Molecules 2017, 22(9), 1540; https://doi.org/10.3390/molecules22091540 - 12 Sep 2017

Cited by 6 | Viewed by 4556

Abstract

An oxidative ring opening reaction of the central ring C in the alkaloid Luotonin A and two of its derivatives was found to occur upon heating with an excess amine and potassium carbonate in dimethylsulfoxide (DMSO) solution in the presence of air oxygen. [...] Read more.

An oxidative ring opening reaction of the central ring C in the alkaloid Luotonin A and two of its derivatives was found to occur upon heating with an excess amine and potassium carbonate in dimethylsulfoxide (DMSO) solution in the presence of air oxygen. The structure of the novel amide-type products was elucidated and a possible mechanism for this reaction is proposed. Four of the new compounds show moderate in vitro anticancer activity towards human colon adenocarcinoma cells. Full article

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Synthesis and DFT Calculations of Novel Vanillin-Chalcones and Their 3-Aryl-5-(4-(2-(dimethylamino)-ethoxy)-3-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbaldehyde Derivatives as Antifungal Agents

by Luis Alberto Illicachi, Joel José Montalvo-Acosta, Alberto Insuasty, Jairo Quiroga, Rodrigo Abonia, Maximiliano Sortino, Susana Zacchino and Braulio Insuasty

Molecules 2017, 22(9), 1476; https://doi.org/10.3390/molecules22091476 - 5 Sep 2017

Cited by 26 | Viewed by 7760

Abstract

Novel (E)-1-(aryl)-3-(4-(2-(dimethylamino)ethoxy)-3-methoxyphenyl) prop-2-en-1-ones 4 were synthesized by a Claisen-Schmidt reaction of 4-(2-(dimethylamino)ethoxy)-3-methoxy-benzaldehyde (2) with several acetophenone derivatives 3. Subsequently, cyclocondensation reactions of chalcones 4 with hydrazine hydrate afforded the new racemic 3-aryl-5-(4-(2-(dimethylamino)ethoxy)-3-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbaldehydes 5 when the reaction [...] Read more.

Novel (E)-1-(aryl)-3-(4-(2-(dimethylamino)ethoxy)-3-methoxyphenyl) prop-2-en-1-ones 4 were synthesized by a Claisen-Schmidt reaction of 4-(2-(dimethylamino)ethoxy)-3-methoxy-benzaldehyde (2) with several acetophenone derivatives 3. Subsequently, cyclocondensation reactions of chalcones 4 with hydrazine hydrate afforded the new racemic 3-aryl-5-(4-(2-(dimethylamino)ethoxy)-3-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbaldehydes 5 when the reaction was carried out in formic acid. The antifungal activity of both series of compounds against eight fungal species was determined. In general, chalcone derivatives 4 showed better activities than pyrazolines 5 against all tested fungi. None of the compounds 4a–g and 5a–g showed activity against the three Aspergillus spp. In contrast, most of the compounds 4 showed moderate to high activities against three dermatophytes (MICs 31.25–62.5 µg/mL), being 4a followed by 4c the most active structures. Interestingly, 4a and 4c possess fungicidal rather than fungistatic activities, with MFC values between 31.25 and 62.5 μg/mL. The comparison of the percentages of inhibition of C. neoformans by the most active compounds 4, allowed us to know the role played by the different substituents of the chalcones’ A-ring. Also the most anti-cryptococcal compounds 4a–c and 4g, were tested in a second panel of five clinical C. neoformans strains in order to have an overview of their inhibition capacity not only of standardized but also of clinical C. neoformans strains. DFT calculations showed that the electrophilicity is the main electronic property to explain the differences in antifungal activities for the synthesized chalcones and pyrazolines compounds. Furthermore, a quantitative reactivity analysis showed that electron-withdrawing substituted chalcones presented the higher electrophilic character and hence, the greater antifungal activities among compounds of series 4. Full article

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Voltammetric Study of Some 3-Aryl-quinoxaline-2-carbonitrile 1,4-di-N-oxide Derivatives with Anti-Tumor Activities

by Eric M. Miller, Qing Xia, Mariah E. Cella, Austin W. Nenninger, Monica N. Mruzik, Krystina A. Brillos-Monia, Yong Zhou Hu, Rong Sheng, Christina M. Ragain and Philip W. Crawford

Molecules 2017, 22(9), 1442; https://doi.org/10.3390/molecules22091442 - 31 Aug 2017

Cited by 10 | Viewed by 4957

Abstract

The electrochemical properties of twenty 3-aryl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives with varying degrees of cytotoxic activity were investigated in dimethylformamide (DMF) using cyclic voltammetry and first derivative cyclic voltammetry. With one exception, the first reduction of these compounds was found to be reversible [...] Read more.

The electrochemical properties of twenty 3-aryl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives with varying degrees of cytotoxic activity were investigated in dimethylformamide (DMF) using cyclic voltammetry and first derivative cyclic voltammetry. With one exception, the first reduction of these compounds was found to be reversible or quasireversible and is attributed to reduction of the N-oxide moiety to form a radical anion. The second reduction of the diazine ring was found to be irreversible. Compounds containing a nitro group on the 3-phenyl ring also exhibited a reduction process that may be attributed to that group. There was good correlation between molecular structure and reduction potential, with reduction being facilitated by an enhanced net positive charge at the electroactive site created by electron withdrawing substituents. Additionally, the reduction potential was calculated using two common basis sets, 6-31g and lanl2dz, for five of the test molecules. There was a strong correlation between the computational data and the experimental data, with the exception of the derivative containing the nitro functionality. No relationship between the experimentally measured reduction potentials and reported cytotoxic activities was evident upon comparison of the data. Full article

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RETRACTED: Pyrene-Phosphonate Conjugate: Aggregation-Induced Enhanced Emission, and Selective Fe³⁺ Ions Sensing Properties

by Sachin D. Padghan, Rajesh S. Bhosale, Sidhanath V. Bhosale, Frank Antolasic, Mohammad Al Kobaisi and Sheshanath V. Bhosale

Molecules 2017, 22(9), 1417; https://doi.org/10.3390/molecules22091417 - 29 Aug 2017

Cited by 17 | Viewed by 7369 | Retraction

Abstract

A new pyrene-phosphonate colorimetric receptor 1 has been designed and synthesized in a one-step process via amide bond formation between pyrene butyric acid chloride and phosphonate-appended aniline. The pyrene-phosphonate receptor 1 showed aggregation-induced enhanced emission (AIEE) properties in water/acetonitrile (ACN) solutions. Dynamic light [...] Read more.

A new pyrene-phosphonate colorimetric receptor 1 has been designed and synthesized in a one-step process via amide bond formation between pyrene butyric acid chloride and phosphonate-appended aniline. The pyrene-phosphonate receptor 1 showed aggregation-induced enhanced emission (AIEE) properties in water/acetonitrile (ACN) solutions. Dynamic light scattering (DLS) characterization revealed that the aggregates of receptor 1 at 80% water fraction have an average size of ≈142 nm. Field emission scanning electron microscopy (FE-SEM) analysis confirmed the formation of spherical aggregates upon solvent evaporation. The sensing properties of receptor 1 were investigated by UV-vis, fluorescence emission spectroscopy, and other optical methods. Among the tested metal ions, receptor 1 is capable of recognizing the Fe³⁺ ion selectively. The changes in spectral measurements were explained on the basis of complex formation. The composition of receptor 1 and Fe³⁺ ions was determined by using Job’s plot and found to be 1:1. The receptor 1–Fe³⁺ complex showed a reversible UV-vis response in the presence of EDTA. Full article

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Covalent Porphyrin Hybrids Linked with Dipyrrin, Bidipyrrin or Thiacorrole

by Renbao He, Huan Yue and Jiahui Kong

Molecules 2017, 22(9), 1400; https://doi.org/10.3390/molecules22091400 - 23 Aug 2017

Cited by 3 | Viewed by 5309

Abstract

Novel meso-meso directly linked porphyrin hybrids were successfully targeted and synthesized, with porphyrin units linked with dipyrrin, bidipyrrin or thiacorrole, expanding the ranges of dipyrrin derivatives and showing diverse metal coordinations and further influencing the chemical shift of pyrrole units. The porphyrinyl dipyrrin [...] Read more.

Novel meso-meso directly linked porphyrin hybrids were successfully targeted and synthesized, with porphyrin units linked with dipyrrin, bidipyrrin or thiacorrole, expanding the ranges of dipyrrin derivatives and showing diverse metal coordinations and further influencing the chemical shift of pyrrole units. The porphyrinyl dipyrrin nickel complex 3 was successfully obtained in a high yield by the oxidation of porphyrinyl dipyrromethane 2 and subsequent coordination. Further oxidative coupling reactions of 3 afforded por-bidipyrrin-por hybrid 4. Interestingly, an unexpected methoxy por-bidipyrrin-por hybrid 6 was generated by treating 4 with FeCl₃ in CH₂Cl₂/MeOH and subsequent coordination. In addition to open chain hybrids, an aromatic scaffold hybrid por-thiacorrole-por 8 was synthesized by treating porphyrinyl dibromo-dipyrrin nickel complex 7 with Na₂S·9H₂O. A series of porphyrin hybrids offers a new approach for π-conjugated molecules. Full article

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Tetrabutylammonium Iodide–Promoted Thiolation of Oxindoles Using Sulfonyl Chlorides as Sulfenylation Reagents

by Xia Zhao, Aoqi Wei, Xiaoyu Lu and Kui Lu

Molecules 2017, 22(8), 1208; https://doi.org/10.3390/molecules22081208 - 1 Aug 2017

Cited by 14 | Viewed by 6841

Abstract

3-Sulfanyloxindoles were synthesised by triphenylphosphine-mediated transition-metal-free thiolation of oxindoles using sulfonyl chlorides as sulfenylation reagents. The above reaction was promoted by iodide anions, which was ascribed to the in situ conversion of sulfenyl chlorides into the more reactive sulfenyl iodides. Moreover, the thiolation [...] Read more.

3-Sulfanyloxindoles were synthesised by triphenylphosphine-mediated transition-metal-free thiolation of oxindoles using sulfonyl chlorides as sulfenylation reagents. The above reaction was promoted by iodide anions, which was ascribed to the in situ conversion of sulfenyl chlorides into the more reactive sulfenyl iodides. Moreover, the thiolation of 3-aryloxindoles was facilitated by bases. The use of a transition-metal-free protocol, readily available reagents, and mild reaction conditions make this protocol more practical for preparing 3-sulfanyloxindoles than traditional methods. Full article

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Synthesis, Antitumor Evaluation and Molecular Docking of New Morpholine Based Heterocycles

by Zeinab A. Muhammad, Mastoura M. Edrees, Rasha A. M. Faty, Sobhi M. Gomha, Seham S. Alterary and Yahia N. Mabkhot

Molecules 2017, 22(7), 1211; https://doi.org/10.3390/molecules22071211 - 20 Jul 2017

Cited by 15 | Viewed by 5991

Abstract

A series of new morpholinylchalcones was prepared and then used as building blocks for constructing a series of 7-morpholino-2-thioxo-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones via their reaction with 6-aminothiouracil. The latter thiones reacted with the appropriate hydrazonoyl chloride to give the corresponding pyrido[2,3-d [...] Read more.

A series of new morpholinylchalcones was prepared and then used as building blocks for constructing a series of 7-morpholino-2-thioxo-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones via their reaction with 6-aminothiouracil. The latter thiones reacted with the appropriate hydrazonoyl chloride to give the corresponding pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones. The assigned structures for all the newly synthesized compounds were confirmed on the basis of elemental analyses and spectral data and the mechanisms of their formation were also discussed. Most of the synthesized compounds were tested for in vitro activity against human lung cancer (A-549) and human hepatocellular carcinoma (HepG-2) cell lines compared with the employed standard antitumor drug (cisplatin) and the results revealed that compounds 8, 4e and 7b have promising activities against the A-549 cell line (IC₅₀ values of 2.78 ± 0.86 μg/mL, 5.37 ± 0.95 μg/mL and 5.70 ± 0.91 μg/mL, respectively) while compound 7b has promising activity against the HepG-2 cell lines (IC₅₀ = 3.54 ± 1.11 μg/mL). Moreover, computational studies using MOE 2014.09 software supported the biological activity results. Full article

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Open AccessArticle

Study on the Alkylation Reactions of N(7)-Unsubstituted 1,3-Diazaoxindoles

by Eszter Kókai, Judit Halász, András Dancsó, József Nagy, Gyula Simig and Balázs Volk

Molecules 2017, 22(5), 846; https://doi.org/10.3390/molecules22050846 - 19 May 2017

Cited by 2 | Viewed by 6435

Abstract

The chemistry of the 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (1,3-diazaoxindole) compound family, possessing a drug-like scaffold, is unexplored. In this study, the alkylation reactions of N(7)-unsubstituted 5-isopropyl-1,3-diazaoxindoles bearing various substituents at the C(2) position have been investigated. The starting compounds were [...] Read more.

The chemistry of the 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (1,3-diazaoxindole) compound family, possessing a drug-like scaffold, is unexplored. In this study, the alkylation reactions of N(7)-unsubstituted 5-isopropyl-1,3-diazaoxindoles bearing various substituents at the C(2) position have been investigated. The starting compounds were synthesized from the C(5)-unsubstituted parent compounds by condensation with acetone and subsequent catalytic reduction of the 5-isopropylidene moiety. Alkylation of the thus obtained 5-isopropyl derivatives with methyl iodide or benzyl bromide in the presence of a large excess of sodium hydroxide led to 5,7-disubstituted derivatives. Use of butyllithium as the base rendered alkylation in the C(5) position possible with reasonable selectivity, without affecting the N(7) atom. During the study on the alkylation reactions, some interesting by-products were also isolated and characterized. Full article

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One-Flask Synthesis of Pyrazolo[3,4-d]pyrimidines from 5-Aminopyrazoles and Mechanistic Study

by Wan-Ping Yen, Shuo-En Tsai, Naoto Uramaru, Hiroyuki Takayama and Fung Fuh Wong

Molecules 2017, 22(5), 820; https://doi.org/10.3390/molecules22050820 - 16 May 2017

Cited by 7 | Viewed by 4943

Abstract

A novel one-flask synthetic method was developed in which 5-aminopyrazoles were reacted with N,N-substituted amides in the presence of PBr₃. Hexamethyldisilazane was then added to perform heterocyclization to produce the corresponding pyrazolo[3,4-d]pyrimidines in suitable yields. These one-flask reactions [...] Read more.

A novel one-flask synthetic method was developed in which 5-aminopyrazoles were reacted with N,N-substituted amides in the presence of PBr₃. Hexamethyldisilazane was then added to perform heterocyclization to produce the corresponding pyrazolo[3,4-d]pyrimidines in suitable yields. These one-flask reactions thus involved Vilsmeier amidination, imination reactions, and the sequential intermolecular heterocyclization. To study the reaction mechanism, a series of 4-formyl-1,3-diphenyl-1H-pyrazol-5-yl-N,N-disubstituted formamidines, which were conceived as the chemical equivalent of 4-(iminomethyl)-1,3-diphenyl-1H-pyrazol-5-yl-formamidine, were prepared and successfully converted into pyrazolo[3,4-d]pyrimidines. The experiments demonstrated that the reaction intermediates were the chemical equivalents of 4-(iminomethyl)-1,3-diphenyl-1H-pyrazol-5-yl)formamidines. The rate of the reaction could be described as being proportional to the reactivity of amine reactants during intermolecular heterocyclization, especially when hexamethyldisilazane was used. Full article

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Ortho-Nitro Effect on the Diastereoselective Control in Sulfa-Staudinger and Staudinger Cycloadditions

by Zhanhui Yang, Hassane Abdellaoui, Wei He and Jiaxi Xu

Molecules 2017, 22(5), 784; https://doi.org/10.3390/molecules22050784 - 12 May 2017

Cited by 6 | Viewed by 5146

Abstract

The ortho-nitro effect was discovered in sulfa-Staudinger cycloadditions of ethoxycarbonylsulfene with linear imines. When an ortho-nitro group is present at the C-aryl substituents of linear imines, the sulfa-Staudinger cycloadditions deliver cis-β-sultams in considerable amounts, together with the predominant trans [...] Read more.

The ortho-nitro effect was discovered in sulfa-Staudinger cycloadditions of ethoxycarbonylsulfene with linear imines. When an ortho-nitro group is present at the C-aryl substituents of linear imines, the sulfa-Staudinger cycloadditions deliver cis-β-sultams in considerable amounts, together with the predominant trans-β-sultams. In other cases, the above sulfa-Staudinger cycloadditions give rise to trans-β-sultams exclusively. Further mechanistic rationalization discloses that the ortho-nitro effect is attributed to its strong electron-withdrawing inductive effect. Similarly, the ortho-nitro effect also exists in Staudinger cycloadditions of ethoxycarbonyl ketene with the imines. The current research provides further insights into the diastereoselective control in sulfa-Staudinger and Staudinger cycloadditions. Full article

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Rhodium(I)-Complexes Catalyzed 1,4-Conjugate Addition of Arylzinc Chlorides to N-Boc-4-pyridone

by Fenghai Guo, Matthew A. McGilvary, Malcolm C. Jeffries, Briana N. Graves, Shekinah A. Graham and Yuelin Wu

Molecules 2017, 22(5), 723; https://doi.org/10.3390/molecules22050723 - 1 May 2017

Cited by 1 | Viewed by 5990

Abstract

Rhodium(I)-complexes catalyzed the 1,4-conjugate addition of arylzinc chlorides to N-Boc-4-pyridone in the presence of chlorotrimethylsilane (TMSCl). A combination of [RhCl(C₂H₄)₂]₂ and BINAP was determined to be the most effective catalyst to promote the 1,4-conjugate addition [...] Read more.

Rhodium(I)-complexes catalyzed the 1,4-conjugate addition of arylzinc chlorides to N-Boc-4-pyridone in the presence of chlorotrimethylsilane (TMSCl). A combination of [RhCl(C₂H₄)₂]₂ and BINAP was determined to be the most effective catalyst to promote the 1,4-conjugate addition reactions of arylzinc chlorides to N-Boc-4-pyridone. A broad scope of arylzinc reagents with both electron-withdrawing and electron-donating substituents on the aromatic ring successfully underwent 1,4-conjugate addition to N-Boc-4-pyridone to afford versatile 1,4-adducts 2-substituted-2,3-dihydropyridones in good to excellent yields (up to 91%) and excellent ee (up to 96%) when (S)-BINAP was used as chiral ligand. Full article

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Open AccessArticle

Reactions of 5-Indolizyl Lithium Compounds with Some Bielectrophiles

by Sergey A. Rzhevskii, Victor B. Rybakov, Victor N. Khrustalev and Eugene V. Babaev

Molecules 2017, 22(4), 661; https://doi.org/10.3390/molecules22040661 - 20 Apr 2017

Cited by 4 | Viewed by 6017

Abstract

Abstract: Indolizyl-5-lithium anions react with succinic and phtalic anhidrides giving 1,4-keto acids, with oxallyl chloride giving 1,2-diketone, and with ethyl pyruvate giving 1,2-hydroxyacid. However, with α-halocarbonyl compounds, they react in different ways, forming the products of selective bromination at C-5 (with α-bromo [...] Read more.

Abstract: Indolizyl-5-lithium anions react with succinic and phtalic anhidrides giving 1,4-keto acids, with oxallyl chloride giving 1,2-diketone, and with ethyl pyruvate giving 1,2-hydroxyacid. However, with α-halocarbonyl compounds, they react in different ways, forming the products of selective bromination at C-5 (with α-bromo ketones and esters of α-bromo acids) and 5-chloroacetyl indolizines. Full article

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Molecular Hybridization-Guided One-Pot Multicomponent Synthesis of Turmerone Motif-Fused 3,3′-Pyrrolidinyl-dispirooxindoles via a 1,3-Dipolar Cycloaddition Reaction

by Bing Lin, Gen Zhou, Yi Gong, Qi-Di Wei, Min-Yi Tian, Xiong-Li Liu, Ting-Ting Feng, Ying Zhou and Wei-Cheng Yuan

Molecules 2017, 22(4), 645; https://doi.org/10.3390/molecules22040645 - 17 Apr 2017

Cited by 9 | Viewed by 5322

Abstract

Described herein is the development of a facile and efficient methodology for the synthesis of novel turmerone motif-fused 3,3′-pyrrolidinyl-dispirooxindoles 3–5 via a multicomponent 1,3-dipolar cycloaddition of dienones 2 with azomethine ylides (thermally generated in situfrom isatins and proline or thioproline or sarcosine). Products [...] Read more.

Described herein is the development of a facile and efficient methodology for the synthesis of novel turmerone motif-fused 3,3′-pyrrolidinyl-dispirooxindoles 3–5 via a multicomponent 1,3-dipolar cycloaddition of dienones 2 with azomethine ylides (thermally generated in situfrom isatins and proline or thioproline or sarcosine). Products bearing four or three consecutive stereocenters consist of two oxindole moieties and a pyrrolidinyl core, including vicinal spiroquaternary stereocenters fused in one ring structure were smoothly obtained in high yields (up to 93% yield) with good diastereoselectivity (up to >20:1). Another valuable application of this method was for the design of new hybrid architectures for biological screening through the adequate fusion of these sub-units of turmerone and 3,3′-pyrrolidinyl-dispirooxindole, generating drug-like molecules. Full article

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Consecutive One-Pot versus Domino Multicomponent Approaches to 3-(Diarylmethylene)oxindoles

by Sunhwa Park, Jiyun Lee, Kye Jung Shin, Euichaul Oh and Jae Hong Seo

Molecules 2017, 22(3), 503; https://doi.org/10.3390/molecules22030503 - 22 Mar 2017

Cited by 13 | Viewed by 5282

Abstract

Based on consecutive one-pot conditions combining three palladium-catalyzed reactions (Sonogashira, Heck and Suzuki-Miyaura reactions), a more efficient domino multicomponent method has been successfully developed to access a wide variety of 3-(diarylmethylene)oxindoles. Microwave irradiation and use of a silver salt were the most important [...] Read more.

Based on consecutive one-pot conditions combining three palladium-catalyzed reactions (Sonogashira, Heck and Suzuki-Miyaura reactions), a more efficient domino multicomponent method has been successfully developed to access a wide variety of 3-(diarylmethylene)oxindoles. Microwave irradiation and use of a silver salt were the most important factors to achieve high yields and stereoselectivity. Full article

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Open AccessArticle

Design of New Benzo[h]chromene Derivatives: Antitumor Activities and Structure-Activity Relationships of the 2,3-Positions and Fused Rings at the 2,3-Positions

by Rawda M. Okasha, Fawzia F. Alblewi, Tarek H. Afifi, Arshi Naqvi, Ahmed M. Fouda, Al-Anood M. Al-Dies and Ahmed M. El-Agrody

Molecules 2017, 22(3), 479; https://doi.org/10.3390/molecules22030479 - 18 Mar 2017

Cited by 48 | Viewed by 7286

Abstract

A series of novel 4H-benzo[h]chromenes 4, 6–11, 13, 14; 7H-benzo[h]chromeno[2,3-d]pyrimidines 15–18, 20, and 14H-benzo[h]chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives [...] Read more.

A series of novel 4H-benzo[h]chromenes 4, 6–11, 13, 14; 7H-benzo[h]chromeno[2,3-d]pyrimidines 15–18, 20, and 14H-benzo[h]chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 19a–e, 24 was prepared. The structures of the synthesized compounds were characterized on the basis of their spectral data. Some of the target compounds were examined for their antiproliferative activity against three cell lines; breast carcinoma (MCF-7), human colon carcinoma (HCT-116) and hepatocellular carcinoma (HepG-2). The cytotoxic behavior has been tested using MTT assay and the inhibitory activity was referenced to three standard anticancer drugs: vinblastine, colchicine and doxorubicin. The bioassays demonstrated that some of the new compounds exerted remarkable inhibitory effects as compared to the standard drugs on the growth of the three tested human tumor cell lines. The structure–activity relationships (SAR) study highlights that the antitumor activity of the target compounds was significantly affected by the lipophilicity of the substituent at 2- or 3- and fused rings at the 2,3-positions. Full article

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Open AccessArticle

Facial Regioselective Synthesis of Novel Bioactive Spiropyrrolidine/Pyrrolizine-Oxindole Derivatives via a Three Components Reaction as Potential Antimicrobial Agents

by Huwaida M. E. Hassaneen, Elshimaa M. Eid, Hamid A. Eid, Thoraya A. Farghaly and Yahia Nasser Mabkhot

Molecules 2017, 22(3), 357; https://doi.org/10.3390/molecules22030357 - 26 Feb 2017

Cited by 19 | Viewed by 5113

Abstract

This article presents the synthesis of new derivatives of spirooxindole-spiropiperidinone- pyrrolidines 6a–j and spirooxindole-spiropiperidinone-pyrrolizines 8a–j, through a 1,3-dipolar cycloaddition reaction of azomethineylides generated from isatin, sarcosine, and l-proline, through a decarboxylative route with dipolarophile 4a–j. All [...] Read more.

This article presents the synthesis of new derivatives of spirooxindole-spiropiperidinone- pyrrolidines 6a–j and spirooxindole-spiropiperidinone-pyrrolizines 8a–j, through a 1,3-dipolar cycloaddition reaction of azomethineylides generated from isatin, sarcosine, and l-proline, through a decarboxylative route with dipolarophile 4a–j. All of the newly synthesized compounds were evaluated for their antimicrobial activities and their minimum inhibitory concentration (MIC) against most of the test organisms. The tested compounds displayed excellent activity against all of the tested microorganisms. Full article

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Scheme 1

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Open AccessArticle

Diastereoselective Synthesis of Spirocyclopropanes under Mild Conditions via Formal [2 + 1] Cycloadditions Using 2,3-Dioxo-4-benzylidene-pyrrolidines

by Yi Li, Qing-Zhu Li, Li Huang, Hong Liang, Kai-Chuan Yang, Hai-Jun Leng, Yue Liu, Xu-Dong Shen, Xiao-Jun Gou and Jun-Long Li

Molecules 2017, 22(2), 328; https://doi.org/10.3390/molecules22020328 - 22 Feb 2017

Cited by 10 | Viewed by 6526

Abstract

A highly diastereoselective cyclopropanation of cyclic enones with sulfur ylides was developed under catalyst-free conditions, producing multifunctional spirocyclopropanes in generally excellent yields (up to 99% yield and >99:1 d.r.). The asymmetric version of this method was realized by using an easily available chiral [...] Read more.

A highly diastereoselective cyclopropanation of cyclic enones with sulfur ylides was developed under catalyst-free conditions, producing multifunctional spirocyclopropanes in generally excellent yields (up to 99% yield and >99:1 d.r.). The asymmetric version of this method was realized by using an easily available chiral sulfur ylide, affording products with moderate to good stereoselectivity. Full article

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Open AccessArticle

Cytotoxicity and Antioxidant Potential of Novel 2-(2-((1H-indol-5yl)methylene)-hydrazinyl)-thiazole Derivatives

by Adriana Grozav, Ioan-Dan Porumb, Luiza Ioana Găină, Lorena Filip and Daniela Hanganu

Molecules 2017, 22(2), 260; https://doi.org/10.3390/molecules22020260 - 9 Feb 2017

Cited by 52 | Viewed by 6550

Abstract

Newly synthesized 2-(2-((1H-indol-5yl)methylene)-hydrazinyl)-thiazole derivatives were evaluated for their in vitro cytotoxicity on two carcinoma cell lines A2780 and HeLa. Significant cytotoxic activity for 2-(2-((1H-indol-5-yl)methylene)hydrazinyl)-4-methylthiazole (1) and 2-(2-((1H-indol-5-yl)methylene)hydrazinyl)-4-phenylthiazole (3), on both A2780 [IC₅₀ [...] Read more.

Newly synthesized 2-(2-((1H-indol-5yl)methylene)-hydrazinyl)-thiazole derivatives were evaluated for their in vitro cytotoxicity on two carcinoma cell lines A2780 and HeLa. Significant cytotoxic activity for 2-(2-((1H-indol-5-yl)methylene)hydrazinyl)-4-methylthiazole (1) and 2-(2-((1H-indol-5-yl)methylene)hydrazinyl)-4-phenylthiazole (3), on both A2780 [IC₅₀: 11.6 μM (1), and 12.4 μM (3)] and HeLa [IC₅₀: 22.4 μM (1) and 19.4μM (3)] cell lines is reported. Their antioxidant potential was evaluated by spectrophotometric method, using DPPH radical or Fe (TPTZ)³⁺ complex, and EPR spectroscopy, therefore the compounds 1 and 3 showed remarkable antioxidant activity simultaneously with a cytotoxic effect on A2780 and HeLa cell lines. Furthermore, based on theoretical quantum chemical calculation, the present study analyzed the chemoselectivity of the hydrogen extraction from the indolyl-hydrazinil-thiazoles in reaction with free radicals. Full article

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2016

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Open AccessArticle

Novel 2,3-Dihydro-1H-pyrrolo[3,2,1-ij]quinazolin-1-ones: Synthesis and Biological Evaluation

by Malose J. Mphahlele, Tebogo A. Khoza and Peaceful Mabeta

Molecules 2017, 22(1), 55; https://doi.org/10.3390/molecules22010055 - 30 Dec 2016

Cited by 9 | Viewed by 5318

Abstract

Herein we describe the synthesis and evaluation of a series of novel 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinazolin-1-ones for in vitro cytotoxicity against three human cancer cell lines as well as for potential antimalarial activity against the chloroquine-sensitive strain 3D7 of Plasmodium falciparum. [...] Read more.

Herein we describe the synthesis and evaluation of a series of novel 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinazolin-1-ones for in vitro cytotoxicity against three human cancer cell lines as well as for potential antimalarial activity against the chloroquine-sensitive strain 3D7 of Plasmodium falciparum. The title compounds were prepared via PdCl₂-mediated endo-dig cyclization of 2-aryl-8-(arylethynyl)-6-bromo-2,3-dihydroquinazolin-4(1H)-ones. The latter were prepared, in turn, via initial Sonogashira cross-coupling of 2-amino-5-bromo-3-iodobenzamide with aryl acetylenes followed by boric acid-mediated cyclocondensation of the intermediate 2-amino-3-(arylethynyl)-5-bromobenzamides with benzaldehyde derivatives. The 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinazolin-1-ones 4a–k were evaluated for potential in vitro cytotoxicity against the breast (MCF-7), melanoma (B16) and endothelioma (sEnd.2) cell lines. All of the compounds except 4h and 4i were found to be inactive against the three cancer cell lines. Compound 4h substituted with a 4-methoxyphenyl and 4-fluorophenyl groups at the 3- and 5-positions was found to exhibit significant cytotoxicity against the three cancer cell lines. The presence of phenyl and 3-chlorophenyl groups at the 3- and 5-posiitons of the pyrroloquinazolinone 4i, on the other hand, resulted in significant cytotoxicity against vascular tumour endothelial cells (sEnd.2), but reduced activity against the melanoma (B16) and breast cancer (MCF-7) cells except at higher concentrations. The 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinazolin-1-ones 4a–l were found to be inactive against the chloroquine sensitive 3D7 strain of Plasmodium falciparum. Full article

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Open AccessArticle

Facile Synthesis for Benzo-1,4-Oxazepine Derivatives by Tandem Transformation of C-N Coupling/C-H Carbonylation

by Xiaojia Zhao, Jiong Zhang, Zeqin Zheng and Runsheng Xu

Molecules 2017, 22(1), 53; https://doi.org/10.3390/molecules22010053 - 30 Dec 2016

Cited by 6 | Viewed by 5933

Abstract

A tandem transformation of C-N coupling/C-H carbonylation has been developed for the synthesis of benzo-1,4-oxazepine pharmaceutically derivatives. Notably, this reaction was accomplished by various phenylamine with ally halides under carbon dioxide atmosphere employing 2-(2-dimethylamino-vinyl)-1H-inden-1-olcatalyzed. Furthermore, under the optimized conditions, various benzo-1,4-oxazepine [...] Read more.

A tandem transformation of C-N coupling/C-H carbonylation has been developed for the synthesis of benzo-1,4-oxazepine pharmaceutically derivatives. Notably, this reaction was accomplished by various phenylamine with ally halides under carbon dioxide atmosphere employing 2-(2-dimethylamino-vinyl)-1H-inden-1-olcatalyzed. Furthermore, under the optimized conditions, various benzo-1,4-oxazepine derivatives were obtained in good yields. Finally, a plausible Cu^I/Cu^III mechanism of C-N coupling/C-H carbonylation transformation was proposed. Full article

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Scheme 1

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Open AccessArticle

A Metal-Free Regioselective Multicomponent Approach for the Synthesis of Free Radical Scavenging Pyrimido-Fused Indazoles and Their Fluorescence Studies

by Jeyakannu Palaniraja, Selvaraj Mohana Roopan, G Mokesh Rayalu, Naif Abdullah Al-Dhabi and Mariadhas Valan Arasu

Molecules 2016, 21(11), 1571; https://doi.org/10.3390/molecules21111571 - 18 Nov 2016

Cited by 34 | Viewed by 5938

Abstract

This study deals with a new and efficient metal-free regioselective synthesis of pyrimido-fused indazoles with nitrogen ring junction motifs. We have developed a metal-free domino type reaction between 3-aminoindazole, aryl aldehydes and aceotophenones in the presence of KOH/DMF that leads to pyrimido[1,2-b [...] Read more.

This study deals with a new and efficient metal-free regioselective synthesis of pyrimido-fused indazoles with nitrogen ring junction motifs. We have developed a metal-free domino type reaction between 3-aminoindazole, aryl aldehydes and aceotophenones in the presence of KOH/DMF that leads to pyrimido[1,2-b]indazole analogues. Response Surface Methodology (RSM) coupled with a Box-Behnken design (BBD) were utilized for exploring the effect of base used (A), temperature of reaction (B) and (C), reaction time. This approach can allow access to a variety of pyrimidoindazole fluorophores and related compounds. The compound N,N-dimethyl-4-(2-phenylpyrimido[1,2-b]indazol-4-yl)aniline (4e) displays the maximum fluorescence intensity at 518 nm and shows a fluorescence quantum yield of 0.068. The synthesized pyramido-fused indazoles have been evaluated for their free radical scavenging activity and compound 4f showed good antioxidant activity. Full article

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Open AccessArticle

Practical and Metal-Free Synthesis of Novel Enantiopure Amides Containing the Potentially Bioactive 5-Nitroimidazole Moiety

by Cédric Spitz, Fanny Mathias, Alain Gamal Giuglio-Tonolo, Thierry Terme and Patrice Vanelle

Molecules 2016, 21(11), 1472; https://doi.org/10.3390/molecules21111472 - 4 Nov 2016

Cited by 2 | Viewed by 4049

Abstract

We report here a practical and metal-free synthesis of novel enantiopure amides containing the drug-like 5-nitroimidazole scaffold. The first step was a metal-free diastereoselective addition of 4-(4-(chloromethyl)phenyl)-1,2-dimethyl-5-nitro-1H-imidazole to enantiomerically pure N-tert-butanesulfinimine. Then, the N-tert-butanesulfinyl–protected amine [...] Read more.

We report here a practical and metal-free synthesis of novel enantiopure amides containing the drug-like 5-nitroimidazole scaffold. The first step was a metal-free diastereoselective addition of 4-(4-(chloromethyl)phenyl)-1,2-dimethyl-5-nitro-1H-imidazole to enantiomerically pure N-tert-butanesulfinimine. Then, the N-tert-butanesulfinyl–protected amine was easily deprotected under acidic conditions. Finally, the primary amine was coupled with different acid chlorides or acids to give the corresponding amides. The mild reaction conditions and high tolerance for various substitutions make this approach attractive for constructing pharmacologically interesting 5-nitroimidazoles. Full article

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Open AccessArticle

Structural Characterization and Antimicrobial Activities of 7H-Benzo[h]chromeno[2,3-d]pyrimidine and 14H-Benzo[h]chromeno[3,2-e][1,2,4]triazolo[1,5-c] pyrimidine Derivatives

by Rawda M. Okasha, Fawzia F. Albalawi, Tarek H. Afifi, Ahmed M. Fouda, Al-Anood M. Al-Dies and Ahmed M. El-Agrody

Molecules 2016, 21(11), 1450; https://doi.org/10.3390/molecules21111450 - 1 Nov 2016

Cited by 32 | Viewed by 5535

Abstract

Three new series of chromene molecules have been synthesized in order to explore their antimicrobial activity. The series encompass 2-substituted 14-(4-halophenyl)-12-methoxy-14H-benzo[h]chromeno[3,2-e][1,2,4]-triazolo[1,5-c]pyrimidines 7a–o, 9-benzylideneamino-7-(4-halo-phenyl)-5-methoxy-8-imino-7H-benzo-[h]chromeno[2,3-d]pyrimidines 8a–b [...] Read more.

Three new series of chromene molecules have been synthesized in order to explore their antimicrobial activity. The series encompass 2-substituted 14-(4-halophenyl)-12-methoxy-14H-benzo[h]chromeno[3,2-e][1,2,4]-triazolo[1,5-c]pyrimidines 7a–o, 9-benzylideneamino-7-(4-halo-phenyl)-5-methoxy-8-imino-7H-benzo-[h]chromeno[2,3-d]pyrimidines 8a–b and 3-ethoxycarbonyl-14-(4-halophenyl)-12-methoxy-14H-benzo-[h]chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-2-one derivatives 12a–b. The structure of these novel compounds were confirmed using IR, ¹H- and ¹³C-NMR as well as MS spectroscopy. The new compounds were evaluated in vitro for their antimicrobial activity and it was demonstrated that 7H-benzochromenopyrimidine and derivatives of 14H-benzochromenotriazolopyrimidine exhibited the most promising antibacterial activities compared to the reference antimicrobial agents. The structure activity relationship (SAR) studies of the target compounds agreed with the in vitro essays and confirmed higher potent antimicrobial activity against some of the tested microorganisms. Full article

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Open AccessArticle

Synthesis and In Vitro Cytotoxic Properties of Polycarbo-Substituted 4-(Arylamino)quinazolines

by Hugues Kamdem Paumo, Tshepiso Jan Makhafola and Malose Jack Mphahlele

Molecules 2016, 21(10), 1366; https://doi.org/10.3390/molecules21101366 - 14 Oct 2016

Cited by 8 | Viewed by 5310

Abstract

Herein, we describe the synthesis of novel unsymmetrical polycarbo-substituted 4-anilinoquinazolines derived from the 2-aryl-6-bromo-8-iodoquinazolines via one-pot three-step reaction sequences involving initial amination and subsequent double cross-coupling (bis-Suzuki, Sonogashira/Stille or Sonogashira/Suzuki-Miyaura) reactions with different cross coupling partners for the two carbon–carbon bond formation steps. [...] Read more.

Herein, we describe the synthesis of novel unsymmetrical polycarbo-substituted 4-anilinoquinazolines derived from the 2-aryl-6-bromo-8-iodoquinazolines via one-pot three-step reaction sequences involving initial amination and subsequent double cross-coupling (bis-Suzuki, Sonogashira/Stille or Sonogashira/Suzuki-Miyaura) reactions with different cross coupling partners for the two carbon–carbon bond formation steps. The 4-anilinoquinazolines were evaluated for potential cytotoxicity against three cancer cell lines, namely, human breast adenocarcinoma (MCF-7) cells, human cervical cancer (HeLa) and human lung cancer (A549) cells. The most active compounds, 2b, 2c, 3c, 4a, 4c and 5a, were found to be more selective against the MCF-7 and HeLa cell lines than the human lung carcinoma (A549) cells. We selected compounds 2c, 3c and 7a as representatives for further evaluation for potential to induce apoptosis and/or necrotic properties in the three cancer cell lines. Compound 2c induced apoptosis of MCF-7 cells through cell membrane alteration. Treatment of Hela and A549 cell lines with compounds 3c and 7a, respectively, led to caspase-3 activation in both cell lines. Compound 3c, on the other hand, caused more necrosis than apoptosis induction in the membrane alteration assay. Full article

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Open AccessCommunication

Nucleophilic Substitution on 2-Monosubstituted Quinoxalines Giving 2,3-Disubstituted Quinoxalines: Investigating the Effect of the 2-Substituent

by Ndumiso Thamsanqa Ndlovu and Winston Nxumalo

Molecules 2016, 21(10), 1304; https://doi.org/10.3390/molecules21101304 - 30 Sep 2016

Cited by 8 | Viewed by 6304

Abstract

An investigation on the effect of substituent at the 2-position of mono-substituted quinoxalines in the synthesis of di-substituted quinoxaline derivatives via nucleophilic substitution reactions, is reported. Di-substituted quinoxalines bearing aryl-alky, aryl-aryl, aryl-heteroaryl, aryl-alkynyl, and amino-alkyl substituents were prepared in moderate to good yields. [...] Read more.

An investigation on the effect of substituent at the 2-position of mono-substituted quinoxalines in the synthesis of di-substituted quinoxaline derivatives via nucleophilic substitution reactions, is reported. Di-substituted quinoxalines bearing aryl-alky, aryl-aryl, aryl-heteroaryl, aryl-alkynyl, and amino-alkyl substituents were prepared in moderate to good yields. 2-Monosubstituted quinoxalines bearing a phenyl and butyl substituent reacted readily with alkyl-, aryl-, heteroaryl- and alkynyl- nucluephiles, giving di-substituted quinoxalines. 2-Monosubstituted quinoxalines bearing an amine and alkynyl substituent only reacted with alkyl nucleophiles. Oxidative rearomatization to give 2,3-disubstituted quinoxaline products occurred in atmospheric O₂. Full article

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Open AccessArticle

Optimized Conditions for Passerini-Smiles Reactions and Applications to Benzoxazinone Syntheses

by Elodie Martinand-Lurin, Aurélie Dos Santos, Emmanuelle Robineau, Pascal Retailleau, Philippe Dauban, Laurence Grimaud and Laurent El Kaïm

Molecules 2016, 21(9), 1257; https://doi.org/10.3390/molecules21091257 - 21 Sep 2016

Cited by 6 | Viewed by 7059

Abstract

Initial conditions disclosed for the Passerini-Smiles reaction are associated with a lack of efficiency that has prevented chemists from using it since its discovery. We wish to report herein our thorough study in the development of new experimental conditions for this coupling between [...] Read more.

Initial conditions disclosed for the Passerini-Smiles reaction are associated with a lack of efficiency that has prevented chemists from using it since its discovery. We wish to report herein our thorough study in the development of new experimental conditions for this coupling between electron-poor phenols, isocyanides, and carbonyl derivatives. These new conditions have been applied to several synthetic strategies towards benzoxazinones. Full article

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Open AccessArticle

Synthesis and Antimicrobial Activity of Some New Thiadiazoles, Thioamides, 5-Arylazothiazoles and Pyrimido[4,5-d][1,2,4]triazolo[4,3-a]pyrimidines

by Abdou O. Abdelhamid, Ibrahim E. El Sayed, Mohamed Z. Hussein and Mangoud M. Mangoud

Molecules 2016, 21(8), 1072; https://doi.org/10.3390/molecules21081072 - 17 Aug 2016

Cited by 18 | Viewed by 7604

Abstract

A novel series of 1,3,4-thiadiazoles, 5-arylazothiazoles and hexahydropyrimido-[4,5-d][1,2,4]triazolo[4,3-a]pyrimidines were synthesized via reaction of hydrazonoyl halides with each of alkyl carbothioates, carbothioamides and 7-thioxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidine-2,4(1H,3H)-diones in the presence of triethylamine. The structures of the newly [...] Read more.

A novel series of 1,3,4-thiadiazoles, 5-arylazothiazoles and hexahydropyrimido-[4,5-d][1,2,4]triazolo[4,3-a]pyrimidines were synthesized via reaction of hydrazonoyl halides with each of alkyl carbothioates, carbothioamides and 7-thioxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidine-2,4(1H,3H)-diones in the presence of triethylamine. The structures of the newly synthesized compounds were established based on their spectral data, elemental analyses and alternative synthetic routes whenever possible. Also, the newly synthesized compounds were screened for their antimicrobial activity against various microorganisms. Full article

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Scheme 1

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Open AccessReview

Microwave-Assisted Syntheses of Bioactive Seven-Membered, Macro-Sized Heterocycles and Their Fused Derivatives

by Mohsine Driowya, Aziza Saber, Hamid Marzag, Luc Demange, Khalid Bougrin and Rachid Benhida

Molecules 2016, 21(8), 1032; https://doi.org/10.3390/molecules21081032 - 9 Aug 2016

Cited by 35 | Viewed by 10026

Abstract

This review describes the recent advances in the microwave-assisted synthesis of 7-membered and larger heterocyclic compounds. Several types of reaction for the cyclization step are discussed: Ring Closing Metathesis (RCM), Heck and Sonogashira reactions, Suzuki-Miyaura cross-coupling, dipolar cycloadditions, multi-component reactions (Ugi, Passerini), etc. [...] Read more.

This review describes the recent advances in the microwave-assisted synthesis of 7-membered and larger heterocyclic compounds. Several types of reaction for the cyclization step are discussed: Ring Closing Metathesis (RCM), Heck and Sonogashira reactions, Suzuki-Miyaura cross-coupling, dipolar cycloadditions, multi-component reactions (Ugi, Passerini), etc. Green syntheses and solvent-free procedures have been introduced whenever possible. The syntheses discussed herein have been selected to illustrate the huge potential of microwave in the synthesis of highly functionalized molecules with potential therapeutic applications, in high yields, enhanced reaction rates and increased chemoselectivity, compared to conventional methods. More than 100 references from the recent literature are listed in this review. Full article

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Open AccessReview

Recent Advances in Metal-Free Quinoline Synthesis

by Ginelle A. Ramann and Bryan J. Cowen

Molecules 2016, 21(8), 986; https://doi.org/10.3390/molecules21080986 - 29 Jul 2016

Cited by 125 | Viewed by 22515

Abstract

The quinoline ring system is one of the most ubiquitous heterocycles in the fields of medicinal and industrial chemistry, forming the scaffold for compounds of great significance. These include anti-inflammatory and antitumor agents, the antimalarial drugs quinine and chloroquine, and organic light-emitting diodes. [...] Read more.

The quinoline ring system is one of the most ubiquitous heterocycles in the fields of medicinal and industrial chemistry, forming the scaffold for compounds of great significance. These include anti-inflammatory and antitumor agents, the antimalarial drugs quinine and chloroquine, and organic light-emitting diodes. Quinolines were first synthesized in 1879, and since then a multitude of synthetic routes have been developed. Many of these methods, such as the Skraup, Doebner–Von Miller, and Friedlander quinoline syntheses, are well-known but suffer from inefficiency, harsh reaction conditions, and toxic reagents. This review focuses on recent transition metal-free processes toward these important heterocycles, including both novel routes and modifications to established methods. For example, variations on the Skraup method include microwave irradiation, ionic liquid media, and novel annulation partners, all of which have shown increased reaction efficiency and improved yield of the heteroring-unsubstituted quinoline products. Similarly, modifications to other synthetic routes have been implemented, with the quinoline products displaying a wide variety of substitution patterns. Full article

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Open AccessArticle

Synthesis and Spectral Characterization of Benzo-[6,7][1,5]diazocino[2,1-a]isoindol-12-(14H)-one Derivatives

by Jatinder P. Bassin, Bhavani Anagani, Christopher Benham, Madhu Goyal, Maryam Hashemian and Ute Gerhard

Molecules 2016, 21(8), 967; https://doi.org/10.3390/molecules21080967 - 23 Jul 2016

Cited by 6 | Viewed by 5890

Abstract

A simple synthetic route affording 27%–85% yields of benzo[6,7][1,5]diazocino[2,1-a]isoindol-12(14H)-one ring systems from readily available 3-(2-oxo-2-phenylethyl) isobenzofuran-1(3H)-ones and 2-(aminomethyl)aniline starting materials in toluene and catalysed by p-toluene-sulfonic acid is developed. The ¹H- and ¹³C-NMR spectra [...] Read more.

A simple synthetic route affording 27%–85% yields of benzo[6,7][1,5]diazocino[2,1-a]isoindol-12(14H)-one ring systems from readily available 3-(2-oxo-2-phenylethyl) isobenzofuran-1(3H)-ones and 2-(aminomethyl)aniline starting materials in toluene and catalysed by p-toluene-sulfonic acid is developed. The ¹H- and ¹³C-NMR spectra of the final products were assigned using a variety of one and two-dimensional NMR experiments. The distinction between the two potential isomers of the final products was made on the basis of heteronuclear multiple bond connectivity (HMBC) NMR spectra. Full article

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Open AccessArticle

Synthesis of New 3-Heteroarylindoles as Potential Anticancer Agents

by Abdou O. Abdelhamid, Sobhi M. Gomha, Nadia A. Abdelriheem and Saher M. Kandeel

Molecules 2016, 21(7), 929; https://doi.org/10.3390/molecules21070929 - 16 Jul 2016

Cited by 61 | Viewed by 6912

Abstract

2-(3-(1H-Indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-substituted-5-(substituted diazenyl)thiazoles and 2-(1H-indol-3-yl)-9-substituted-4,7-disubstituted pyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(7H)-ones were synthesized via reaction of hydrazonoyl halides with each of 3-(1H-indol-2-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide and 7-(1H-indol-3-yl)-2- thioxo-5-substituted-2,3-dihydropyrido[2,3-d]pyrimidin-4(1 [...] Read more.

2-(3-(1H-Indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-substituted-5-(substituted diazenyl)thiazoles and 2-(1H-indol-3-yl)-9-substituted-4,7-disubstituted pyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(7H)-ones were synthesized via reaction of hydrazonoyl halides with each of 3-(1H-indol-2-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide and 7-(1H-indol-3-yl)-2- thioxo-5-substituted-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones, respectively. Also, hydrazonoyl halides were reacted with N’-(1-(1H-indol-3-yl)ethylidene)-2-cyanoacetohydrazide to afford 1,3,4-thiadiazole derivatives. Structures of the new synthesis were elucidated on the basis of elemental analysis, spectral data, and alternative synthetic routes whenever possible. Fifteen of the new compounds have been evaluated for their antitumor activity against the MCF-7 human breast carcinoma cell line. The results indicated that many of the tested compounds showed moderate to high anticancer activity when compared with doxorubicin as a reference drug. Full article

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Open AccessArticle

Dyeing of Polyester with Disperse Dyes: Part 2. Synthesis and Dyeing Characteristics of Some Azo Disperse Dyes for Polyester Fabrics

by Alya M. Al-Etaibi, Huda S. Alnassar and Morsy Ahmed El-Apasery

Molecules 2016, 21(7), 855; https://doi.org/10.3390/molecules21070855 - 29 Jun 2016

Cited by 41 | Viewed by 8991

Abstract

The goal of this study was to utilize carrier for accelerating the rate of dyeing not only to enhance dyeing of polyester fabrics dyed with disperse dyes 3a,b, but also to save energy. Both the color strength expressed as dye [...] Read more.

The goal of this study was to utilize carrier for accelerating the rate of dyeing not only to enhance dyeing of polyester fabrics dyed with disperse dyes 3a,b, but also to save energy. Both the color strength expressed as dye uptake and the fastness properties of the dyed fabrics were evaluated. Full article

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Open AccessArticle

Dual Behavior of Iodine Species in Condensation of Anilines and Vinyl Ethers Affording 2-Methylquinolines

by Song Thi Le, Chisa Yasuoka, Haruyasu Asahara and Nagatoshi Nishiwaki

Molecules 2016, 21(7), 827; https://doi.org/10.3390/molecules21070827 - 25 Jun 2016

Cited by 7 | Viewed by 7696

Abstract

A metal-free, mild and efficient method for the synthesis of 2-methylquinolines was successfully developed by condensation of anilines with vinyl ethers in the presence of catalytic amount of iodine. Modification of both pyridine and benzene moieties was easily achieved by changing only the [...] Read more.

A metal-free, mild and efficient method for the synthesis of 2-methylquinolines was successfully developed by condensation of anilines with vinyl ethers in the presence of catalytic amount of iodine. Modification of both pyridine and benzene moieties was easily achieved by changing only the vinyl ether and aniline. In this reaction, the iodine species was revealed to show dual behavior; molecular iodine serves as an oxidant, while its reduced form, hydrogen iodide, activates the vinyl ether. The redox reaction between these iodine species enables the use of a catalytic amount of iodine in this synthetic method. Full article

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Open AccessArticle

Synthesis of Bioactive 2-(Arylamino)thiazolo[5,4-f]-quinazolin-9-ones via the Hügershoff Reaction or Cu- Catalyzed Intramolecular C-S Bond Formation

by Damien Hédou, Carole Dubouilh-Benard, Nadège Loaëc, Laurent Meijer, Corinne Fruit and Thierry Besson

Molecules 2016, 21(6), 794; https://doi.org/10.3390/molecules21060794 - 18 Jun 2016

Cited by 9 | Viewed by 7274

Abstract

A library of thirty eight novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives (series 8, 10, 14 and 17) was prepared via the Hügershoff reaction and a Cu catalyzed intramolecular C-S bond formation, helped by microwave-assisted technology when required. The efficient [...] Read more.

A library of thirty eight novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives (series 8, 10, 14 and 17) was prepared via the Hügershoff reaction and a Cu catalyzed intramolecular C-S bond formation, helped by microwave-assisted technology when required. The efficient multistep synthesis of the key 6-amino-3-cyclopropylquinazolin-4(3H)-one (3) has been reinvestigated and performed on a multigram scale from the starting 5-nitroanthranilic acid. The inhibitory potency of the final products was evaluated against five kinases involved in Alzheimer’s disease and showed that some molecules of the 17 series described in this paper are particularly promising for the development of novel multi-target inhibitors of kinases. Full article

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Open AccessReview

Synthesis of Linearly Fused Benzodipyrrole Based Organic Materials

by Maarten Vlasselaer and Wim Dehaen

Molecules 2016, 21(6), 785; https://doi.org/10.3390/molecules21060785 - 17 Jun 2016

Cited by 34 | Viewed by 10600

Abstract

The objective of this review is to give an overview of the synthetic methods to prepare different indolo[3,2-b]carbazoles and similar systems with a potential use in electro-optical devices such as OLEDs (organic light emitting diode), OPVs (organic photovoltaic) and OFETs (organic [...] Read more.

The objective of this review is to give an overview of the synthetic methods to prepare different indolo[3,2-b]carbazoles and similar systems with a potential use in electro-optical devices such as OLEDs (organic light emitting diode), OPVs (organic photovoltaic) and OFETs (organic field effect transistor). Some further modifications to the core units and their implications for specific applications are also discussed. Full article

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Open AccessArticle

Design, Synthesis and Antifungal Activity of Novel Benzofuran-Triazole Hybrids

by Zhen Liang, Hang Xu, Ye Tian, Mengbi Guo, Xin Su and Chun Guo

Molecules 2016, 21(6), 732; https://doi.org/10.3390/molecules21060732 - 7 Jun 2016

Cited by 43 | Viewed by 6287

Abstract

A series of novel benzofuran-triazole hybrids was designed and synthesized by click chemistry, and their structures were characterized by HRMS, FTIR and NMR. The in vitro antifungal activity of target compounds was evaluated using the microdilution broth method against five strains of pathogenic [...] Read more.

A series of novel benzofuran-triazole hybrids was designed and synthesized by click chemistry, and their structures were characterized by HRMS, FTIR and NMR. The in vitro antifungal activity of target compounds was evaluated using the microdilution broth method against five strains of pathogenic fungi. The result indicated that the target compounds exhibited moderate to satisfactory activity. Furthermore, molecular docking was performed to investigate the binding affinities and interaction modes between the target compound and N-myristoyltransferase. Based on the results, preliminary structure activity relationships (SARs) were summarized to serve as a foundation for further investigation. Full article

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Open AccessArticle

Synthesis, Spectroscopic, X-ray Diffraction and DFT Studies of Novel Benzimidazole Fused-1,4-Oxazepines

by Abdulrahman I. Almansour, Natarajan Arumugam, Raju Suresh Kumar, Saied M. Soliman, Mohammad Altaf and Hazem A. Ghabbour

Molecules 2016, 21(6), 724; https://doi.org/10.3390/molecules21060724 - 3 Jun 2016

Cited by 12 | Viewed by 6501

Abstract

A series of benzimidazole-tethered oxazepine heterocyclic hybrids has been synthesized in good to excellent yields from an N-alkylated benzimidazole 2-carboxaldehyde, which in turn was accomplished from o-phenylenediamine in three good yielding steps. The calculated molecular structure of compounds 2-methyl-4-(2-((phenylimino)methyl)-1H-benzo-[ [...] Read more.

A series of benzimidazole-tethered oxazepine heterocyclic hybrids has been synthesized in good to excellent yields from an N-alkylated benzimidazole 2-carboxaldehyde, which in turn was accomplished from o-phenylenediamine in three good yielding steps. The calculated molecular structure of compounds 2-methyl-4-(2-((phenylimino)methyl)-1H-benzo-[d]imidazol-1-yl)-butan-2-ol 9 and 10 3,3-dimethyl-N-phenyl-1,2,3,5-tetrahydrobenzo-[4,5]imidazo[2,1-c][1,4]oxazepin-5-amine using the B3LYP/6–31 G(d, p) method were found to agree well with their X-ray structures. The charge distributions at the different atomic sites were computed using the natural bond orbital (NBO) method. The regions of electrophilic and nucleophilic reactivity were shown using a molecular electrostatic potential (MEP) map. In addition, the frontier molecular orbitals of these compounds were discussed at the same level of theory. Nonlinear optical (NLO) properties have also been investigated by computational hyperpolarizability studies, and it was found that Compound 9 is the best candidate for NLO applications. Full article

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Open AccessArticle

Synthesis of Novel UV Absorbers Bisindolylmethanes and Investigation of Their Applications on Cotton-Based Textile Materials

by Hikmet Nil Ergindemir, Acelya Aker, Agamirze Hamitbeyli and Nuket Ocal

Molecules 2016, 21(6), 718; https://doi.org/10.3390/molecules21060718 - 3 Jun 2016

Cited by 10 | Viewed by 5362

Abstract

Nowadays modified textiles, especially UV-protective, antibacterial and antimicrobial ones, have become the focus of great interest. In this study, several new UV absorbers, bis(indolyl)methane derivatives, were synthesized and grafted onto polyvinyl alcohol polymer (PVA). Their application properties on cotton-based textile materials were determined; [...] Read more.

Nowadays modified textiles, especially UV-protective, antibacterial and antimicrobial ones, have become the focus of great interest. In this study, several new UV absorbers, bis(indolyl)methane derivatives, were synthesized and grafted onto polyvinyl alcohol polymer (PVA). Their application properties on cotton-based textile materials were determined; the UV protection factor values of the modified fabrics were measured (UPF); and the antibacterial features of the fabrics were tested. Full article

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Open AccessArticle

Hydrazino-methoxy-1,3,5-triazine Derivatives’ Excellent Corrosion Organic Inhibitors of Steel in Acidic Chloride Solution

by Ayman El-Faham, Sameh M. Osman, Hamad A. Al-Lohedan and Gamal A. El-Mahdy

Molecules 2016, 21(6), 714; https://doi.org/10.3390/molecules21060714 - 1 Jun 2016

Cited by 31 | Viewed by 10630

Abstract

The corrosion inhibition performance of 2-hydrazino-4,6-dimethoxy-1,3,5-tirazine (DMeHT), 2,4-dihydrazino-6-methoxy-1,3,5-triaizine (DHMeT), and 2,4,6-tridydrazino-1,3,5-triaizne (TH₃) on steel corrosion in acidic media was examined using electrochemical techniques. The results showed 2,4-Ddihydrazino-6-methoxy-1,3,5-triaizine (DHMeT) gave the best corrosion protection performance among the other hydrazino derivatives even at [...] Read more.

The corrosion inhibition performance of 2-hydrazino-4,6-dimethoxy-1,3,5-tirazine (DMeHT), 2,4-dihydrazino-6-methoxy-1,3,5-triaizine (DHMeT), and 2,4,6-tridydrazino-1,3,5-triaizne (TH₃) on steel corrosion in acidic media was examined using electrochemical techniques. The results showed 2,4-Ddihydrazino-6-methoxy-1,3,5-triaizine (DHMeT) gave the best corrosion protection performance among the other hydrazino derivatives even at a low concentration of 25 ppm (95%). The number of hydrazino groups play an important role in the corrosion inhibition, where the two hydrazine groups increased the electrostatic interactions between the protonated tested compounds, the negatively charged steel surface resulted from the adsorption of the chloride anions, and the presence of the methoxy group made the compound more reliable for formation of film protection on the surface of steel through the lone pair of oxygen atoms. Electrochemical Impedance Spectroscopy (EIS) measurements suggested that the corrosion process of steel in presence of the hydrazino-s-triazine derivatives (TH₃, DMeHT and DHMeT) were being controlled by the charge transfer reaction. Polarization curves indicated that the examined TH₃, DMeHT and DHMeT behaved as mixed type inhibitors. Full article

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Open AccessArticle

Synthesis and Characterization of New 3-(4-Arylpiperazin-1-yl)-2-hydroxypropyl 4-Propoxybenzoates and Their Hydrochloride Salts

by Pavlina Marvanova, Tereza Padrtova, Tomas Pekarek, Jiri Brus, Jiri Czernek, Petr Mokry, Otakar Humpa, Michal Oravec and Josef Jampilek

Molecules 2016, 21(6), 707; https://doi.org/10.3390/molecules21060707 - 1 Jun 2016

Cited by 8 | Viewed by 5652

Abstract

Five new 3-(4-arylpiperazin-1-yl)-2-hydroxypropyl 4-propoxybenzoates were designed and synthesized as potential dual antihypertensive agents. The compounds were prepared as free bases and subsequently transformed to hydrochloride salts. The position of protonation of nitrogen atoms in the piperazine ring of hydrochloride salts was determined by [...] Read more.

Five new 3-(4-arylpiperazin-1-yl)-2-hydroxypropyl 4-propoxybenzoates were designed and synthesized as potential dual antihypertensive agents. The compounds were prepared as free bases and subsequently transformed to hydrochloride salts. The position of protonation of nitrogen atoms in the piperazine ring of hydrochloride salts was determined by means of ¹³C-CP/MAS and ¹⁵N-CP/MAS NMR and IR spectroscopy. Using these solid-state analytical techniques, it was found that both nitrogen atoms were protonated when excess hydrogen chloride was used for preparation of salts. On the other hand, when the equimolar amount of hydrogen chloride was used, piperazine nitrogen substituted by aryl was protonated. Full article

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Open AccessArticle

A Convenient Synthesis of 3,7′-Bisindole Derivatives

by Teng Liu, Hong-You Zhu, Da-Yun Luo, Sheng-Jiao Yan and Jun Lin

Molecules 2016, 21(5), 638; https://doi.org/10.3390/molecules21050638 - 17 May 2016

Cited by 8 | Viewed by 5495

Abstract

An efficient and convenient method to synthesize highly functionalized 3,7′-bisindole derivatives has been developed via a Michael addition and cyclic condensation reaction of heterocyclic ketene aminals (HKAs) with 2-(1H-indol-3-yl)cyclohexa-2,5-diene-1,4-dione derivatives in ethanol-based solvents at room temperature. This strategy provides an efficient, [...] Read more.

An efficient and convenient method to synthesize highly functionalized 3,7′-bisindole derivatives has been developed via a Michael addition and cyclic condensation reaction of heterocyclic ketene aminals (HKAs) with 2-(1H-indol-3-yl)cyclohexa-2,5-diene-1,4-dione derivatives in ethanol-based solvents at room temperature. This strategy provides an efficient, environmentally friendly approach for easy access to various novel 3,7′-bisindole derivatives in moderate to good yields. Full article

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Open AccessArticle

Sulforaphane Analogues with Heterocyclic Moieties: Syntheses and Inhibitory Activities against Cancer Cell Lines

by Ye-Hui Shi, Dong-Fang Dai, Jing Li, Yan-Wei Dong, Yin Jiang, Huan-Gong Li, Yuan Gao, Chuan-Ke Chong, Hui-Ying Li, Xiao-Qian Chu, Cheng Yang, Quan Zhang, Zhong-Sheng Tong, Cui-Gai Bai and Yue Chen

Molecules 2016, 21(4), 514; https://doi.org/10.3390/molecules21040514 - 21 Apr 2016

Cited by 12 | Viewed by 6743

Abstract

Recent studies have shown that sulforaphane (SFN) selectively inhibits the growth of ALDH⁺ breast cancer stem-like cells.Herein, a series of SFN analogues were synthesized and evaluated against breast cancer cell lines MCF-7 and SUM-159, and the leukemia stem cell-like cell line KG-1a. [...] Read more.

Recent studies have shown that sulforaphane (SFN) selectively inhibits the growth of ALDH⁺ breast cancer stem-like cells.Herein, a series of SFN analogues were synthesized and evaluated against breast cancer cell lines MCF-7 and SUM-159, and the leukemia stem cell-like cell line KG-1a. These SFN analogues were characterized by the replacement of the methyl group with heterocyclic moieties, and the replacement of the sulfoxide group with sulfide or sulfone. A growth inhibitory assay indicated that the tetrazole analogs 3d, 8d and 9d were significantly more potent than SFN against the three cancer cell lines. Compound 14c, the water soluble derivative of tetrazole sulfide 3d, demonstrated higher potency against KG-1a cell line than 3d. SFN, 3d and 14c significantly induced the activation of caspase-3, and reduced the ALDH⁺ subpopulation in the SUM159 cell line, while the marketed drug doxrubicin(DOX) increased the ALDH⁺ subpopulation. Full article

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Open AccessArticle

A Green Ultrasound Synthesis, Characterization and Antibacterial Evaluation of 1,4-Disubstituted 1,2,3-Triazoles Tethering Bioactive Benzothiazole Nucleus

by Nadjet Rezki

Molecules 2016, 21(4), 505; https://doi.org/10.3390/molecules21040505 - 18 Apr 2016

Cited by 39 | Viewed by 5532

Abstract

The synthesis of N-(benzo[d]thiazol-2-yl)-2-(4-substituted-1H-1,2,3-triazol-1-yl)acetamides 5a–r via the 1,3-dipolar cycloaddition reaction between 2-azido-N-(benzo[d]thiazol-2-yl)acetamide derivatives 3a–c and different alkynes were performed in the presence and absence of ultrasound irradiation. The synthesis was carried out using t [...] Read more.

The synthesis of N-(benzo[d]thiazol-2-yl)-2-(4-substituted-1H-1,2,3-triazol-1-yl)acetamides 5a–r via the 1,3-dipolar cycloaddition reaction between 2-azido-N-(benzo[d]thiazol-2-yl)acetamide derivatives 3a–c and different alkynes were performed in the presence and absence of ultrasound irradiation. The synthesis was carried out using t-BuOH/H₂O (1:1, v/v) as reaction solvents and CuSO₄·5H₂O/sodium ascorbate as the catalyst. The copper catalyst was implemented to provide the regioselective 1,4-disubstituted 1,2,3-triazoles 5a–r. Significant reductions in reaction times with comparably higher yields were observed when the reactions were carried out under ultrasound irradiation. The structures of the newly synthesized 1,2,3-triazoles were elucidated by IR, NMR, MS, and elemental analyses. They were also screened for their antimicrobial activity against three gram-positive (Streptococcus pneumonia, Bacillus subtilis, and Staphylococcus aureus), three gram-negative (Pseudomonas aeuroginosa, Escherichia coli, and Klebsiella pneumonia), and two fungal strains (Aspergillus fumigates and Candida albicans). Most of the tested compounds displayed promising antimicrobial activities at a Minimum Inhibition Concentration (MIC) of 4–16 μg/mL. Full article

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Scheme 1

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Open AccessReview

Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues

by Mohsine Driowya, Aziza Saber, Hamid Marzag, Luc Demange, Rachid Benhida and Khalid Bougrin

Molecules 2016, 21(4), 492; https://doi.org/10.3390/molecules21040492 - 14 Apr 2016

Cited by 38 | Viewed by 15844

Abstract

This review describes the formation of six-membered heterocyclic compounds and their fused analogues under microwave activation using modern organic transformations including cyclocondensation, cycloaddition, multicomponents and other modular reactions. The review is divided according to the main heterocycle types in order of increasing complexity, [...] Read more.

This review describes the formation of six-membered heterocyclic compounds and their fused analogues under microwave activation using modern organic transformations including cyclocondensation, cycloaddition, multicomponents and other modular reactions. The review is divided according to the main heterocycle types in order of increasing complexity, starting with heterocyclic systems containing one, two and three heteroatoms and their fused analogues. Recent microwave applications are reviewed, with special focus on the chemistry of bioactive compounds. Selected examples from the 2006 to 2015 literature are discussed. Full article

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Open AccessArticle

Investigation of the Pyridinium Ylide—Alkyne Cycloaddition as a Fluorogenic Coupling Reaction

by Simon Bonte, Ioana Otilia Ghinea, Rodica Dinica, Isabelle Baussanne and Martine Demeunynck

Molecules 2016, 21(3), 332; https://doi.org/10.3390/molecules21030332 - 10 Mar 2016

Cited by 15 | Viewed by 8154

Abstract

The cycloaddition of pyridinium ylides with alkynes was investigated under mild conditions. A series of 13 pyridinium salts was prepared by alkylation of 4-substituted pyridines. Their reactivity with propiolic ester or amide in various reaction conditions (different temperatures, solvents, added bases) was studied, [...] Read more.

The cycloaddition of pyridinium ylides with alkynes was investigated under mild conditions. A series of 13 pyridinium salts was prepared by alkylation of 4-substituted pyridines. Their reactivity with propiolic ester or amide in various reaction conditions (different temperatures, solvents, added bases) was studied, and 11 indolizines, with three points of structural variation, were, thus, isolated and characterized. The highest yields were obtained when electron-withdrawing groups were present on both the pyridinium ylide, generated in situ from the corresponding pyridinium salt, and the alkyne (X, Z = ester, amide, CN, carbonyl, etc.). Electron-withdrawing substituents, lowering the acid dissociation constant (pKa) of the pyridinium salts, allow the cycloaddition to proceed at pH 7.5 in aqueous buffers at room temperature. Full article

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Open AccessArticle

Hydrazonoyl Chlorides as Precursors for Synthesis of Novel Bis-Pyrrole Derivatives

by Nabila Abdelshafy Kheder

Molecules 2016, 21(3), 326; https://doi.org/10.3390/molecules21030326 - 9 Mar 2016

Cited by 18 | Viewed by 5388

Abstract

A convenient synthesis of some novel bis-pyrrole derivatives via hydrazonoyl halides is described. Antimicrobial evaluation of some selected examples of the synthesized products was carried out. The bis-pyrrole derivative having chloro substituents showed good activity against all of the used microbes. The molecular [...] Read more.

A convenient synthesis of some novel bis-pyrrole derivatives via hydrazonoyl halides is described. Antimicrobial evaluation of some selected examples of the synthesized products was carried out. The bis-pyrrole derivative having chloro substituents showed good activity against all of the used microbes. The molecular docking of the bis-pyrrole derivatives was performed by the Molecular Operating Environment (MOE) program. Full article

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Open AccessArticle

Synthesis of Naphthalene-Based Push-Pull Molecules with a Heteroaromatic Electron Acceptor

by David Šarlah, Amadej Juranovič, Boris Kožar, Luka Rejc, Amalija Golobič and Andrej Petrič

Molecules 2016, 21(3), 267; https://doi.org/10.3390/molecules21030267 - 2 Mar 2016

Cited by 10 | Viewed by 9620

Abstract

Naphthalene derivatives bearing electron-accepting and electron-donating groups at the 2,6-positions belong to the family of D-π-A push-pull dyes. It has been found that these compounds, e.g., 2-(1-(6-((2-(fluoro)ethyl)(methyl)amino)naphthalen-2-yl)ethylidene)malononitrile (FDDNP), show not only interesting optical properties, such as solvatochromism, but they have the potential to [...] Read more.

Naphthalene derivatives bearing electron-accepting and electron-donating groups at the 2,6-positions belong to the family of D-π-A push-pull dyes. It has been found that these compounds, e.g., 2-(1-(6-((2-(fluoro)ethyl)(methyl)amino)naphthalen-2-yl)ethylidene)malononitrile (FDDNP), show not only interesting optical properties, such as solvatochromism, but they have the potential to label protein aggregates of different compositions formed in the brain of patients suffering from neurodegenerative diseases like Alzheimer’s (AD). In continuation of our research we set our goal to find new FDDNP analogs, which would inherit optical and binding properties but hopefully show better specificity for tau protein aggregates, which are characteristic for neurodegeneration caused by repetitive mild trauma. In this work we report on the synthesis of new FDDNP analogs in which the acceptor group has been formally replaced with an aromatic five- or six-membered heterocycle. The heterocyclic moiety was annealed to the central naphthalene ring either by classical ring closure reactions or by modern transition metal-catalyzed coupling reactions. The chemical characterization, NMR spectra, and UV/vis properties of all new compounds are reported. Full article

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Open AccessArticle

Conjugated Oligo-Aromatic Compounds Bearing a 3,4,5-Trimethoxy Moiety: Investigation of Their Antioxidant Activity Correlated with a DFT Study

by Huda. S. Kareem, Nurdiana Nordin, Thorsten Heidelberg, Azlina Abdul-Aziz and Azhar Ariffin

Molecules 2016, 21(2), 224; https://doi.org/10.3390/molecules21020224 - 17 Feb 2016

Cited by 17 | Viewed by 6928

Abstract

A series of heterocyclic compounds bearing the well-known free radical scavenging 3,4,5-trimethoxybenzyloxy group, was synthesized. The key compound 4-(3,4,5-trimethoxybenzyl-oxy)benzohydrazide was converted into thiosemicarbazide derivatives, which were subsequently cyclized with NaOH to provide 1,2,4-triazole derivatives. Alternative treatment of the acid hydrazide with carbon disulfide [...] Read more.

A series of heterocyclic compounds bearing the well-known free radical scavenging 3,4,5-trimethoxybenzyloxy group, was synthesized. The key compound 4-(3,4,5-trimethoxybenzyl-oxy)benzohydrazide was converted into thiosemicarbazide derivatives, which were subsequently cyclized with NaOH to provide 1,2,4-triazole derivatives. Alternative treatment of the acid hydrazide with carbon disulfide in the presence of KOH led to the corresponding 1,3,4-oxadiazole and various alkylated derivatives. The newly synthesized compounds were purified and the structures of the products were elucidated and confirmed on the basis of their analytical and spectral data. Their antioxidant activities were evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH^•) and Ferric Reducing Antioxidant Power (FRAP) assays. The thiosemicarbazide derivatives were highly active in both antioxidant assays with the lowest IC₅₀ value for DPPH radical scavenging. Theoretical calculations based on density functional theory (DFT) were performed to understand the relative importance of NH, SH and CH hydrogens on the radical scavenging activities of these compounds. Full article

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Open AccessArticle

Synthesis of Some Novel 2-Amino-5-arylazothiazole Disperse Dyes for Dyeing Polyester Fabrics and Their Antimicrobial Activity

by Hatem E. Gaffer, Moustafa M. G. Fouda and Mohamed E. Khalifa

Molecules 2016, 21(1), 122; https://doi.org/10.3390/molecules21010122 - 21 Jan 2016

Cited by 37 | Viewed by 5789

Abstract

The present work describes the synthesis of a series of four novel biologically active 2-amino-5-arylazothiazole disperse dyes containing the sulfa drug nucleus. The structures of the synthesized thiazole derivatives are confirmed using UV-spectrophotometry, infrared and nuclear magnetic resonance techniques and elemental analysis. The [...] Read more.

The present work describes the synthesis of a series of four novel biologically active 2-amino-5-arylazothiazole disperse dyes containing the sulfa drug nucleus. The structures of the synthesized thiazole derivatives are confirmed using UV-spectrophotometry, infrared and nuclear magnetic resonance techniques and elemental analysis. The synthesized dyes are applied to polyester fabrics as disperse dyes and their fastness properties to washing, perspiration, rubbing, sublimation, and light are evaluated. The synthesized compounds exhibit promising biological efficiency against selected Gram-positive and Gram-negative pathogenic bacteria as well as fungi. Full article

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Open AccessArticle

Syntheses of 4-Indolylquinoline Derivatives via Reductive Cyclization of Indolylnitrochalcone Derivatives by Fe/HCl

by Wen-Chang Chen, Chan-Chieh Lin, Veerababurao Kavala, Chun-Wei Kuo, Chia-Yu Huang and Ching-Fa Yao

Molecules 2015, 20(12), 22499-22519; https://doi.org/10.3390/molecules201219862 - 15 Dec 2015

Cited by 6 | Viewed by 5969

Abstract

An easy and efficient procedure for the synthesis of 4-indolylquinoline derivatives is described. This process involves two steps, the first of which is the Michael addition of indole to nitrochalcones promoted by sulfamic acid under solvent free conditions and the second step is [...] Read more.

An easy and efficient procedure for the synthesis of 4-indolylquinoline derivatives is described. This process involves two steps, the first of which is the Michael addition of indole to nitrochalcones promoted by sulfamic acid under solvent free conditions and the second step is a reductive cyclization of the indolylnitrochalcone intermediates to 4-indolylquinoline derivatives by Fe/HCl in ethanol. In both steps, the reactions are clean and the yields of products are high. Full article

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Open AccessArticle

Synthesis and Regioselective Reaction of Some Unsymmetrical Heterocyclic Chalcone Derivatives and Spiro Heterocyclic Compounds as Antibacterial Agents

by Maher A. El-Hashash, Sameh A. Rizk and Saad R. Atta-Allah

Molecules 2015, 20(12), 22069-22083; https://doi.org/10.3390/molecules201219827 - 10 Dec 2015

Cited by 33 | Viewed by 8416

Abstract

A number of novel heterocyclic chalcone derivatives can be synthesized by thermal and microwave tools. Treatment of 4-(4-Acetylamino- and/or 4-bromo-phenyl)-4-oxobut-2-enoic acids with hydrogen peroxide in alkaline medium were afforded oxirane derivatives 2. Reaction of the epoxide 2 with 2-amino-5-aryl-1,3,4-thiadiazole derivatives yielded chalcone [...] Read more.

A number of novel heterocyclic chalcone derivatives can be synthesized by thermal and microwave tools. Treatment of 4-(4-Acetylamino- and/or 4-bromo-phenyl)-4-oxobut-2-enoic acids with hydrogen peroxide in alkaline medium were afforded oxirane derivatives 2. Reaction of the epoxide 2 with 2-amino-5-aryl-1,3,4-thiadiazole derivatives yielded chalcone of imidazo[2,1-b]thiadiazole derivative 4 via two thermal routes. In one pot reaction of 4-bromoacetophenone, diethyloxalate, and 2-amino-5-aryl-1,3,4-thiadiazole derivatives in MW irradiation (W 250 and T 150 °C) under eco-friendly conditions afforded an unsuitable yield of the desired chalcone 4d. The chalcone derivatives 4 were used as a key starting material to synthesize some new spiroheterocyclic compounds via Michael and aza-Michael adducts. The chalcone 4f was similar to the aryl-oxo-vinylamide derivatives for the inhibition of tyrosine kinase and cancer cell growth. The electron-withdrawing substituents, such as halogens, and 2-amino-1,3,4-thiadiazole moeity decreasing the electron density, thereby decreasing the energy of HOMO, and the presence of imidazothiadiazole moiety should improve the antibacterial activity. Thus, the newly synthesized compounds were evaluated for their anti-bacterial activity against (ATCC 25923), (ATCC 10987), (ATCC 274,) and (SM514). The structure of the newly synthesized compounds was confirmed by elemental analysis and spectroscopic data. Full article

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Open AccessArticle

Eco-Friendly Synthesis of Some Thiosemicarbazones and Their Applications as Intermediates for 5-Arylazothiazole Disperse Dyes

by Hatem E. Gaffer and Mohamed E. Khalifa

Molecules 2015, 20(12), 21982-21991; https://doi.org/10.3390/molecules201219820 - 9 Dec 2015

Cited by 15 | Viewed by 6618

Abstract

The solid-solid reactions of thiosemicarbazide with 4-formylantipyrine, 2-acetylpyrrole and camphor were performed to afford the thiosemicarbazones 1–3 which underwent hetero-cyclization with phenacyl bromide to furnish the corresponding thiazole derivatives 4–6. The yields of the reactions are quantitative in [...] Read more.

The solid-solid reactions of thiosemicarbazide with 4-formylantipyrine, 2-acetylpyrrole and camphor were performed to afford the thiosemicarbazones 1–3 which underwent hetero-cyclization with phenacyl bromide to furnish the corresponding thiazole derivatives 4–6. The yields of the reactions are quantitative in all cases and the products do not require further purification. A series of 5-arylazo-2-(substituted ylidene-hydrazinyl)-thiazole dyes 7–9 was then prepared by diazo coupling of thiazole derivatives 4–6 with several diazonium chlorides. The synthesized dyes were applied as disperse dyes for dyeing polyester fabric. The dyed fabrics exhibit good washing, perspiration, sublimation and light fastness properties, with little variation in their moderate to good rubbing fastness. Full article

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Open AccessArticle

Utility of 3-Acetyl-6-bromo-2H-chromen-2-one for the Synthesis of New Heterocycles as Potential Antiproliferative Agents

by Sobhi M. Gomha, Yasser H. Zaki and Abdou O. Abdelhamid

Molecules 2015, 20(12), 21826-21839; https://doi.org/10.3390/molecules201219803 - 4 Dec 2015

Cited by 63 | Viewed by 8230

Abstract

Coumarin derivatives containing pyrazolo[1,5-a]pyrimidine, tetrazolo[1,5-a]pyrimidine, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-d]pyrimidine, 1,3,4-thiadiazoles and thiazoles were synthesized from 6-bromo-3-(3-(dimethylamino)acryloyl)-2H-chromen-2-one, methyl 2-(1-(6-bromo-2-oxo-2H-chromen-3-yl)ethylidene)hydrazine carbodithioate, 2-(1-(6-bromo-2-oxo-2H-chromen-3-yl)ethylidene) hydrazine carbothioamide and each of heterocyclic amine, hydrazonoyl chlorides and hydroximoyl [...] Read more.

Coumarin derivatives containing pyrazolo[1,5-a]pyrimidine, tetrazolo[1,5-a]pyrimidine, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-d]pyrimidine, 1,3,4-thiadiazoles and thiazoles were synthesized from 6-bromo-3-(3-(dimethylamino)acryloyl)-2H-chromen-2-one, methyl 2-(1-(6-bromo-2-oxo-2H-chromen-3-yl)ethylidene)hydrazine carbodithioate, 2-(1-(6-bromo-2-oxo-2H-chromen-3-yl)ethylidene) hydrazine carbothioamide and each of heterocyclic amine, hydrazonoyl chlorides and hydroximoyl chlorides. The structures of the newly synthesized compounds were elucidated on the basis of elemental analysis, spectral data, and alternative synthetic routes whenever possible. Moreover, selected newly synthesized products were evaluated for their antitumor activity against a liver carcinoma cancer cell line (HEPG2-1). The results revealed that pyrazolo[1,5-a]pyrimidine 7c, thiazole 23g and 1,3,4-thiadiazole 18a (IC₅₀ = 2.70 ± 0.28, 3.50 ± 0.23 and 4.90 ± 0.69 µM, respectively) have promising antitumor activity against liver carcinoma (HEPG2-1) while most of the tested compounds showed moderate activity. Full article

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Open AccessArticle

Synthesis and Antimicrobial Evaluation of a New Series of Heterocyclic Systems Bearing a Benzosuberone Scaffold

by Osama I. Abd El-Salam, Ali S. Alsayed, Korany A. Ali, Ahmed A. Abd Elwahab, Abd El-Galil E. Amr and Hassan M. Awad

Molecules 2015, 20(11), 20434-20447; https://doi.org/10.3390/molecules201119701 - 16 Nov 2015

Cited by 10 | Viewed by 5841

Abstract

A series of novel benzosuberone derivatives were synthesized and evaluated as antimicrobial agents by using substituted benzosuberone derivatives 1a,b as starting materials. Treatment of 1a,b with phenyl isothiocyanate in dimethylformamide was followed by treatment with cold HCl solution to [...] Read more.

A series of novel benzosuberone derivatives were synthesized and evaluated as antimicrobial agents by using substituted benzosuberone derivatives 1a,b as starting materials. Treatment of 1a,b with phenyl isothiocyanate in dimethylformamide was followed by treatment with cold HCl solution to afford the thioamides 4a,b, which was reacted with methyl iodide to obtain methylated products 5a,b. Cyclocondensation of 4a,b with chloroacetone 6 and phenacyl chloride 7 gave the corresponding thiophene derivatives 9a–c. Reaction of 4a,b with C-acetyl-N- arylhydrazonoyl chlorides 14a and 14b in boiling EtOH in the presence of triethylamine, afforded the corresponding 1,3,4-thiadiazoline derivatives 16a–d. The thioamides 4a,b were reacted with C-ethoxycarbonyl-N-arylhydrazonoyl chlorides 18a,b which afforded 1,3,4-thiadiazoline derivatives 19a–d. The benzosuberones 1a,b were treated with 3-mercaptopropanoic acid to give compounds 21a,b, which were cyclized to tricyclic thiopyran-4(5H)-one derivatives 22a,b. The latter compounds 22a,b were reacted with 3-mercaptopropanoic acid to give compounds 23a,b, which were cyclized tetracyclic ring systems 24a,b. Finally, compounds 24a,b were oxidized using hydrogen peroxide under reflux conditions to afford the oxidized form of the novel tetracyclic heterogeneous ring systems 25a,b. The newly synthesized compounds were screened for antimicrobial activities. The structures of new compounds were characterized by ¹H-NMR, ¹³C-NMR, IR, and EI-MS. Full article

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Open AccessArticle

Direct Aminolysis of Ethoxycarbonylmethyl 1,4-Dihydropyridine-3-carboxylates

by Brigita Vigante, Martins Rucins, Aiva Plotniece, Karlis Pajuste, Iveta Luntena, Brigita Cekavicus, Egils Bisenieks, Rufus Smits, Gunars Duburs and Arkadij Sobolev

Molecules 2015, 20(11), 20341-20354; https://doi.org/10.3390/molecules201119697 - 12 Nov 2015

Cited by 8 | Viewed by 8621

Abstract

The ethoxycarbonylmethyl esters of 1,4-dihydropyridines were directly converted into carbamoylmethyl esters in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) in good to excellent yields under mild conditions. The use of TBD is crucial for the successful aminolysis of ethoxycarbonylmethyl ester of 1,4-dihydropyridines with secondary amines [...] Read more.

The ethoxycarbonylmethyl esters of 1,4-dihydropyridines were directly converted into carbamoylmethyl esters in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) in good to excellent yields under mild conditions. The use of TBD is crucial for the successful aminolysis of ethoxycarbonylmethyl ester of 1,4-dihydropyridines with secondary amines as without it the reaction does not proceed at all. The aminolysis reaction proceeded regioselectively, as the alkyl ester conjugated with the 1,4-dihydropyridine cycle was not involved in the reaction. Screening of other N-containing bases, such as triethylamine (TEA), pyridine, 4-(N,N-dimethylamino)pyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), imidazole, tetramethyl guanidine (TMG) and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) as catalysts revealed no activity in the studied reaction. Full article

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Open AccessArticle

Synthesis of Novel β-Keto-Enol Derivatives Tethered Pyrazole, Pyridine and Furan as New Potential Antifungal and Anti-Breast Cancer Agents

by Smaail Radi, Said Tighadouini, Olivier Feron, Olivier Riant, Mohammed Bouakka, Redouane Benabbes and Yahia N. Mabkhot

Molecules 2015, 20(11), 20186-20194; https://doi.org/10.3390/molecules201119684 - 10 Nov 2015

Cited by 38 | Viewed by 8651

Abstract

Recently, a new generation of highly promising inhibitors bearing β-keto-enol functionality has emerged. Reported herein is the ﬁrst synthesis and use of novel designed drugs based on the β-keto-enol group embedded with heterocyclic moieties such as pyrazole, pyridine, and furan, prepared in a [...] Read more.

Recently, a new generation of highly promising inhibitors bearing β-keto-enol functionality has emerged. Reported herein is the ﬁrst synthesis and use of novel designed drugs based on the β-keto-enol group embedded with heterocyclic moieties such as pyrazole, pyridine, and furan, prepared in a one-step procedure by mixed Claisen condensation. All the newly synthesized compounds were characterized by FT-IR, ¹H-NMR, ¹³C-NMR, ESI/LC-MS, elemental analysis, and evaluated for their in vitro antiproliferative activity against breast cancer (MDA-MB241) human cell lines and fungal strains (Fusarium oxysporum f.sp albedinis FAO). Three of the synthesized compounds showed potent activity against fungal strains with IC₅₀ values in the range of 0.055–0.092 µM. The results revealed that these compounds showed better IC₅₀ values while compared with positive controls. Full article

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Open AccessArticle

Efficient Syntheses of 1,2,3-Triazoloamide Derivatives Using Solid- and Solution-Phase Synthetic Approaches

by Doohyun Lee, Daehun Kim, Seungyeon Lee, Taegeum Kim, Joobin Kim, Sohee Kim, Kwang-Hyeon Liu, Sangkyu Lee, Jong-Sup Bae, Kyung-Sik Song, Chang-Woo Cho, Youn Kyung Son, Dong Jae Baek and Taeho Lee

Molecules 2015, 20(11), 19984-20013; https://doi.org/10.3390/molecules201119673 - 5 Nov 2015

Cited by 9 | Viewed by 7791

Abstract

Efficient synthetic routes for the preparation of secondary and tertiary 1,2,3-triazoloamide derivatives were developed. A secondary α-1,2,3-triazoloamide library was constructed and expanded by a previously developed solid-phase synthetic route and a tertiary 1,2,3-triazoloamide library was constructed by a parallel solution-phase synthetic route. The [...] Read more.

Efficient synthetic routes for the preparation of secondary and tertiary 1,2,3-triazoloamide derivatives were developed. A secondary α-1,2,3-triazoloamide library was constructed and expanded by a previously developed solid-phase synthetic route and a tertiary 1,2,3-triazoloamide library was constructed by a parallel solution-phase synthetic route. The synthetic routes rely on amide formation with secondary amines and chloro-acid chlorides; S_N2 reaction with sodium azide; and the selective [3 + 2] Hüisgen cycloaddition with appropriate terminal alkynes. The target secondary and tertiary 1,2,3-triazoloamide derivatives were obtained with three-diversity points in excellent overall yields and purities using the reported solid- and solution-phase synthetic routes, respectively. Full article

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Open AccessArticle

Novel 2-Thioxanthine and Dipyrimidopyridine Derivatives: Synthesis and Antimicrobial Activity

by Samar El-kalyoubi, Fatmah Agili and Shaker Youssif

Molecules 2015, 20(10), 19263-19276; https://doi.org/10.3390/molecules201019263 - 22 Oct 2015

Cited by 11 | Viewed by 6021 | Correction

Abstract

Several fused imidazolopyrimidines were synthesized starting from 6-amino-1-methyl-2-thiouracil (1) followed by nitrosation, reduction and condensation with different aromatic aldehydes to give Schiff’s base. The dehydrocyclization of Schiff’s bases using iodine/DMF gave Compounds 5a–g. The methylation of 5a– [...] Read more.

Several fused imidazolopyrimidines were synthesized starting from 6-amino-1-methyl-2-thiouracil (1) followed by nitrosation, reduction and condensation with different aromatic aldehydes to give Schiff’s base. The dehydrocyclization of Schiff’s bases using iodine/DMF gave Compounds 5a–g. The methylation of 5a–g using a simple alkylating agent as dimethyl sulfate ((CH₃)₂SO₄) gave either monoalkylated imidazolopyrimidine 6a–g at room temperature or dialkylated derivatives 7a–g on heating 6a–g with ((CH₃)₂SO₄). On the other hand, treatment of 1 with different aromatic aldehydes in absolute ethanol in the presence of conc. hydrochloric acid at room temperature and/or reflux with acetic acid afforded bis-5,5́-diuracylmethylene 8a–e, which cyclized on heating with a mixture of acetic acid/HCl (1:1) to give 9a–e. Compounds 9a–e can be obtained directly by refluxing of Compound 1 with a mixture of acetic acid/HCl. The synthesized new compounds were screened for antimicrobial activity, and the MIC was measured. Full article

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Open AccessArticle

Synthesis of Some Novel Heterocyclic and Schiff Base Derivatives as Antimicrobial Agents

by Mohamed E. Azab, Sameh A. Rizk and Abd El-Galil E. Amr

Molecules 2015, 20(10), 18201-18218; https://doi.org/10.3390/molecules201018201 - 7 Oct 2015

Cited by 26 | Viewed by 9528

Abstract

Treatment of 2,3-diaryloxirane-2,3-dicarbonitriles 1a–c with different nitrogen nucleophiles, e.g., hydrazine, methyl hydrazine, phenyl hydrazine, hydroxylamine, thiosemicarbazide, and/or 2-amino-5-phenyl-1,3,4-thiadiazole, afforded pyrazole, isoxazole, pyrrolotriazine, imidazolothiadiazole derivatives 2–5, respectively. Reacting pyrazoles 2a–c with aromatic aldehydes and/or methyl glycinate produced [...] Read more.

Treatment of 2,3-diaryloxirane-2,3-dicarbonitriles 1a–c with different nitrogen nucleophiles, e.g., hydrazine, methyl hydrazine, phenyl hydrazine, hydroxylamine, thiosemicarbazide, and/or 2-amino-5-phenyl-1,3,4-thiadiazole, afforded pyrazole, isoxazole, pyrrolotriazine, imidazolothiadiazole derivatives 2–5, respectively. Reacting pyrazoles 2a–c with aromatic aldehydes and/or methyl glycinate produced Schiff’s bases 7a–d and pyrazolo[3,4-b]-pyrazinone derivative 8, respectively. Treating 7 with ammonium acetate and/or hydrazine hydrate, furnished the imidazolopyrazole and pyrazolotriazine derivatives 9 and 10, respectively. Reaction of 8 with chloroacetic acid and/or diethyl malonate gave tricyclic compound 11 and triketone 12, respectively. On the other hand, compound 1 was reacted with active methylene precursors, e.g., acetylacetone and/or cyclopentanone producing adducts 14a,b which upon fusion with ammonium acetate furnished the 3-pyridone derivatives 15a,b, respectively. Some of newly synthesized compounds were screened for activity against bacterial and fungal strains and most of the newly synthesized compounds showed high antimicrobial activities. The structures of the new compounds were elucidated using IR, ¹H-NMR, ¹³C-NMR and mass spectroscopy. Full article

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Open AccessReview

Heterocyclic Anticancer Compounds: Recent Advances and the Paradigm Shift towards the Use of Nanomedicine’s Tool Box

by Pedro Martins, João Jesus, Sofia Santos, Luis R. Raposo, Catarina Roma-Rodrigues, Pedro Viana Baptista and Alexandra R. Fernandes

Molecules 2015, 20(9), 16852-16891; https://doi.org/10.3390/molecules200916852 - 16 Sep 2015

Cited by 563 | Viewed by 20222

Abstract

The majority of heterocycle compounds and typically common heterocycle fragments present in most pharmaceuticals currently marketed, alongside with their intrinsic versatility and unique physicochemical properties, have poised them as true cornerstones of medicinal chemistry. Apart from the already marketed drugs, there are many [...] Read more.

The majority of heterocycle compounds and typically common heterocycle fragments present in most pharmaceuticals currently marketed, alongside with their intrinsic versatility and unique physicochemical properties, have poised them as true cornerstones of medicinal chemistry. Apart from the already marketed drugs, there are many other being investigated for their promising activity against several malignancies. In particular, anticancer research has been capitalizing on the intrinsic versatility and dynamic core scaffold of these compounds. Nevertheless, as for any other promising anticancer drugs, heterocyclic compounds do not come without shortcomings. In this review, we provide for a concise overview of heterocyclic active compounds and families and their main applications in medicine. We shall focus on those suitable for cancer therapy while simultaneously addressing main biochemical modes of action, biological targets, structure-activity relationships as well as intrinsic limitation issues in the use of these compounds. Finally, considering the advent of nanotechnology for effective selective targeting of drugs, we shall discuss fundamental aspects and considerations on nanovectorization of such compounds that may improve pharmacokinetic/pharmacodynamic properties of heterocycles. Full article

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Open AccessArticle

Fluorination Effects on NOS Inhibitory Activity of Pyrazoles Related to Curcumin

by Carla I. Nieto, María Pilar Cabildo, María Pilar Cornago, Dionisia Sanz, Rosa M. Claramunt, María Carmen Torralba, María Rosario Torres, José Elguero, José A. García, Ana López and Darío Acuña-Castroviejo

Molecules 2015, 20(9), 15643-15665; https://doi.org/10.3390/molecules200915643 - 28 Aug 2015

Cited by 20 | Viewed by 7025

Abstract

A series of new (E)-3(5)-[β-(aryl)-ethenyl]-5(3)-phenyl-1H-pyrazoles bearing fluorine atoms at different positions of the aryl group have been synthesized starting from the corresponding β-diketones. All compounds have been characterized by elemental analysis, DSC as well as NMR (¹H, [...] Read more.

A series of new (E)-3(5)-[β-(aryl)-ethenyl]-5(3)-phenyl-1H-pyrazoles bearing fluorine atoms at different positions of the aryl group have been synthesized starting from the corresponding β-diketones. All compounds have been characterized by elemental analysis, DSC as well as NMR (¹H, ¹³C, ¹⁹F and ¹⁵N) spectroscopy in solution and in solid state. Three structures have been solved by X-ray diffraction analysis, confirming the tautomeric forms detected by solid state NMR. The in vitro study of their inhibitory potency and selectivity on the activity of nNOS and eNOS (calcium-calmodulin dependent) as well as iNOS (calcium-calmodulin independent) isoenzymes is presented. A qualitative structure–activity analysis allowed the establishment of a correlation between the presence/ absence of different substituents with the inhibition data proving that fluorine groups enhance the biological activity. (E)-3(5)-[β-(3-Fluoro-4-hydroxyphenyl)-ethenyl]-5(3)-phenyl-1H-pyrazole (13), is the best inhibitor of iNOS, being also more selective towards the other two isoforms. Full article

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Open AccessReview

Synthesis and Consecutive Reactions of α-Azido Ketones: A Review

by Sadia Faiz, Ameer Fawad Zahoor, Nasir Rasool, Muhammad Yousaf, Asim Mansha, Muhammad Zia-Ul-Haq and Hawa Z. E. Jaafar

Molecules 2015, 20(8), 14699-14745; https://doi.org/10.3390/molecules200814699 - 13 Aug 2015

Cited by 34 | Viewed by 12038

Abstract

This review paper covers the major synthetic approaches attempted towards the synthesis of α-azido ketones, as well as the synthetic applications/consecutive reactions of α-azido ketones. Full article

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Open AccessArticle

Synthesis and Photophysical Properties of Polycarbo-Substituted Quinazolines Derived from the 2-Aryl-4-chloro-6-iodoquinazolines

by Malose Jack Mphahlele, Hugues Kamdem Paumo, Lydia Rhyman and Ponnadurai Ramasami

Molecules 2015, 20(8), 14656-14683; https://doi.org/10.3390/molecules200814656 - 13 Aug 2015

Cited by 15 | Viewed by 6158

Abstract

The reactivity of the 2-aryl-4-chloro-6-iodoquinazolines towards palladium catalyzed sequential (Sonogashira/Suzuki-Miyaura) and one-pot two-step cross-coupling (bis-Sonogashira, and successive Sonogashira/Stille) reactions to afford novel unsymmetrical polycarbo-substituted quinazolines has been evaluated. In contrast to the chloro-bromo substituted quinazolines in which selectivity has been previously found to [...] Read more.

The reactivity of the 2-aryl-4-chloro-6-iodoquinazolines towards palladium catalyzed sequential (Sonogashira/Suzuki-Miyaura) and one-pot two-step cross-coupling (bis-Sonogashira, and successive Sonogashira/Stille) reactions to afford novel unsymmetrical polycarbo-substituted quinazolines has been evaluated. In contrast to the chloro-bromo substituted quinazolines in which selectivity has been previously found to generally favor substitution at the more activated C(4)-Cl bond over the weaker Csp²-Br bond, substitution in the case of the chloro-iodo derivatives favors cross-coupling through the intrinsically more reactive Csp²-I bond. The electronic absorption and emission properties of the prepared 2,3-diaryl-6-(phenylethynyl)quinazolines were studied in solvents of different polarity (dichloromethane, toluene, DMF, methanol) and CH₂Cl₂-TFA mixture using UV-Vis and emission spectroscopic techniques complemented with density functional theory method to establish the effect of substituents on intramolecular charge transfer properties. Full article

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Open AccessReview

Recent Developments and Biological Activities of N-Substituted Carbazole Derivatives: A Review

by Maryam Bashir, Afifa Bano, Abdul Subhan Ijaz and Bashir Ahmad Chaudhary

Molecules 2015, 20(8), 13496-13517; https://doi.org/10.3390/molecules200813496 - 23 Jul 2015

Cited by 169 | Viewed by 12729

Abstract

Carbazoles represent an important class of heterocycles. These have been reported to exhibit diverse biological activities such as antimicrobial, antitumor, antiepileptic, antihistaminic, antioxidative, anti-inflammatory, antidiarrhoeal, analgesic, neuroprotective and pancreatic lipase inhibition properties. A series of carbazole derivatives such as N-substituted carbazoles, benzocarbazoles, [...] Read more.

Carbazoles represent an important class of heterocycles. These have been reported to exhibit diverse biological activities such as antimicrobial, antitumor, antiepileptic, antihistaminic, antioxidative, anti-inflammatory, antidiarrhoeal, analgesic, neuroprotective and pancreatic lipase inhibition properties. A series of carbazole derivatives such as N-substituted carbazoles, benzocarbazoles, furocarbazoles, pyrrolocarbazoles, indolocarbazoles, imidazocarbazoles, etc. have been synthesized. The N-substituted derivatives have gained the attention of researchers due to their therapeutic potential against neurological disorders and cell proliferation. Herein an attempt is made to review the medicinal importance of recently synthesized N-substituted carbazoles. Full article

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Open AccessArticle

Heterocycles 38. Biocatalytic Synthesis of New Heterocyclic Mannich Bases and Derivatives

by Denisa Leonte, László Csaba Bencze, Csaba Paizs, Florin Dan Irimie and Valentin Zaharia

Molecules 2015, 20(7), 12300-12313; https://doi.org/10.3390/molecules200712300 - 6 Jul 2015

Cited by 8 | Viewed by 7958

Abstract

This paper describes the biocatalytic synthesis of new Mannich bases containing various heterocyclic rings (thiazole, furane, thiophene, pyridine) by applying the lipase catalyzed trimolecular condensation of the corresponding heterocyclic aldehydes with acetone and primary aromatic amines, in mild and eco-friendly reaction conditions. The [...] Read more.

This paper describes the biocatalytic synthesis of new Mannich bases containing various heterocyclic rings (thiazole, furane, thiophene, pyridine) by applying the lipase catalyzed trimolecular condensation of the corresponding heterocyclic aldehydes with acetone and primary aromatic amines, in mild and eco-friendly reaction conditions. The obtained Mannich bases were acylated to their corresponding N-acetyl derivatives. All compounds were characterized by ¹H-NMR, ¹³C-NMR and MS spectrometry. Full article

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Open AccessArticle

Uses of 3-(2-Bromoacetyl)-2H-chromen-2-one in the Synthesis of Heterocyclic Compounds Incorporating Coumarin: Synthesis, Characterization and Cytotoxicity

by Rafat M. Mohareb and Nadia Y. MegallyAbdo

Molecules 2015, 20(6), 11535-11553; https://doi.org/10.3390/molecules200611535 - 23 Jun 2015

Cited by 18 | Viewed by 7797

Abstract

In this work, 3-bromoacetylcoumarin was used as the key starting material for the synthesis of pyran, pyridine, thiophene, thiazole and pyrazole derivatives through its reaction with different reagents. The structures of the newly synthesized compounds were confirmed on the basis of their spectral [...] Read more.

In this work, 3-bromoacetylcoumarin was used as the key starting material for the synthesis of pyran, pyridine, thiophene, thiazole and pyrazole derivatives through its reaction with different reagents. The structures of the newly synthesized compounds were confirmed on the basis of their spectral data and elemental analyses. All of the synthesized compounds were screened for their in vitro anticancer activity against six human cancer cell lines, namely: human gastric cancer (NUGC), human colon cancer (DLD1), human liver cancer (HA22T and HEPG2), nasopharyngeal carcinoma (HONE1), human breast cancer (MCF) and normal fibroblast cells (WI38). The IC₅₀ values (the sample concentration that produces 50% reduction in cell growth) in nanomolars (nM)) showed most of the compounds exhibited significant cytotoxic effect. Among these derivatives, compound 6d showed almost equipotent cytotoxic activity against NUGC (IC₅₀ = 29 nM) compared to the standard CHS 828 (IC₅₀ = 25 nM). Full article

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Open AccessArticle

Synthesis, Characterization, Antimicrobial Screening and Free-Radical Scavenging Activity of Some Novel Substituted Pyrazoles

by Nagwa Mohamed Mahrous Hamada and Nadia Yousef Megally Abdo

Molecules 2015, 20(6), 10468-10486; https://doi.org/10.3390/molecules200610468 - 8 Jun 2015

Cited by 39 | Viewed by 7992

Abstract

The present work deals with the synthesis of acetoxysulfonamide pyrazole derivatives, substituted 4,5-dihydropyrazole-1-carbothioamide and 4,5-dihydropyrazole-1-isonicotinoyl derivatives starting from substituted vanillin chalcones. Acetoxysulfonamide pyrazole derivatives were prepared from the reaction of chalcones with p-sulfamylphenylhydrazine followed by treatment with acetic anhydride. At the same [...] Read more.

The present work deals with the synthesis of acetoxysulfonamide pyrazole derivatives, substituted 4,5-dihydropyrazole-1-carbothioamide and 4,5-dihydropyrazole-1-isonicotinoyl derivatives starting from substituted vanillin chalcones. Acetoxysulfonamide pyrazole derivatives were prepared from the reaction of chalcones with p-sulfamylphenylhydrazine followed by treatment with acetic anhydride. At the same time 4,5-dihydropyrazole-1-carbothioamide and 4,5-dihydropyrazole-1-isonicotinoyl derivatives were prepared from the reaction of chalcones with either thiosemicarbazide or isonicotinic acid hydrazide, respectively. The synthesized compounds were structurally characterized on the basis of IR, ¹H-NMR, ¹³C-NMR spectral data and microanalyses. All of the newly isolated compounds were tested for their antimicrobial activities. The antimicrobial screening using the agar well-diffusion method revealed that the chloro derivatives are the most active ones. Moreover, the antioxidant and anti-inflammatory activity of these chloro derivatives are also studied using the DPPH radical scavenging and NO radical scavenging methods, respectively. Full article

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Open AccessArticle

Synthesis, In-Vitro Antibacterial, Antifungal, and Molecular Modeling of Potent Anti-Microbial Agents with a Combined Pyrazole and Thiophene Pharmacophore

by Yahia Nasser Mabkhot, Nahed Ahmed Kaal, Seham Alterary, Salim S. Al-Showiman, Assem Barakat, Hazem A. Ghabbour and Wolfgang Frey

Molecules 2015, 20(5), 8712-8729; https://doi.org/10.3390/molecules20058712 - 14 May 2015

Cited by 29 | Viewed by 6686

Abstract

Ethyl 5-acetyl-4-methyl-2-(phenylamino)thiophene-3-carboxylate (2) and there derivatives 3a–c, 4, 6a–c and 9a–f were synthesized. The structure of compound 2 was deduced by ¹H-NMR, ¹³C-NMR, FT-IR, MS, microanalysis, and single-crystal X-ray crystallography. The [...] Read more.

Ethyl 5-acetyl-4-methyl-2-(phenylamino)thiophene-3-carboxylate (2) and there derivatives 3a–c, 4, 6a–c and 9a–f were synthesized. The structure of compound 2 was deduced by ¹H-NMR, ¹³C-NMR, FT-IR, MS, microanalysis, and single-crystal X-ray crystallography. The compound crystallized in the monoclinic system, with space group P2₁/c and cell coordinates a = 8.5752(16) Å, b = 21.046(4) Å, c = 8.2941(12) Å, β = 101.131(6)°, V = 1468.7(4) Å³, and Z = 4. Compounds 2, 3a–c, 4, 5a–c and 9a–f were subjected into in vitro antimicrobial activity tests. Compounds 3a and 3c were more potent than standard drug amphotericin B, showing MIC values of 23.8 ± 0.42 and 24.3 ± 0.68, respectively, against Aspergillus fumigatus while the standard drug MIC was 23.7 ± 0.1. Compound 3c was also more potent (MIC 24.8 ± 0.64) than the standard drug amphotericin B (MIC 19.7 ± 0.2) against Syncephalastrum racemosum. Compounds 4 and 9f also showed promising anti-microbial activity. Molecular modeling was performed for the most active compounds. Full article

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Open AccessArticle

Synthesis, Molecular Structure and Spectroscopic Investigations of Novel Fluorinated Spiro Heterocycles

by Mohammad Shahidul Islam, Abdullah Mohammed Al-Majid, Assem Barakat, Saied M. Soliman, Hazem A. Ghabbour, Ching Kheng Quah and Hoong-Kun Fun

Molecules 2015, 20(5), 8223-8241; https://doi.org/10.3390/molecules20058223 - 7 May 2015

Cited by 8 | Viewed by 6992

Abstract

This paper describes an efficient and regioselective method for the synthesis of novel fluorinated spiro-heterocycles in excellent yield by cascade [5+1] double Michael addition reactions. The compounds 7,11-bis(4-fluorophenyl)-2,4-dimethyl- 2,4-diazaspiro[5.5] undecane-1,3,5,9-tetraone (3a) and 2,4-dimethyl-7,11-bis (4-(trifluoromethyl)phenyl)-2,4-diazaspiro[5.5]undecane-1,3,5,9-tetraone (3b) were characterized [...] Read more.

This paper describes an efficient and regioselective method for the synthesis of novel fluorinated spiro-heterocycles in excellent yield by cascade [5+1] double Michael addition reactions. The compounds 7,11-bis(4-fluorophenyl)-2,4-dimethyl- 2,4-diazaspiro[5.5] undecane-1,3,5,9-tetraone (3a) and 2,4-dimethyl-7,11-bis (4-(trifluoromethyl)phenyl)-2,4-diazaspiro[5.5]undecane-1,3,5,9-tetraone (3b) were characterized by single-crystal X-ray diffraction, FT-IR and NMR techniques. The optimized geometrical parameters, infrared vibrational frequencies and NMR chemical shifts of the studied compounds have also been calculated using the density functional theory (DFT) method, using Becke-3-Lee-Yang-Parr functional and the 6-311G(d,p) basis set. There is good agreement between the experimentally determined structural parameters, vibrational frequencies and NMR chemical shifts of the studied compounds and those predicted theoretically. The calculated natural atomic charges using NBO method showed higher polarity of 3a compared to 3b.The calculated electronic spectra are also discussed based on the TD-DFT calculations. Full article

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Synthesis, Crystal Structures and Spectroscopic Properties of Triazine-Based Hydrazone Derivatives; A Comparative Experimental-Theoretical Study

by Muhammad Nadeem Arshad, Aisha Bibi, Tariq Mahmood, Abdullah M. Asiri and Khurshid Ayub

Molecules 2015, 20(4), 5851-5874; https://doi.org/10.3390/molecules20045851 - 3 Apr 2015

Cited by 91 | Viewed by 9656

Abstract

We report here a comparative theoretical and experimental study of four triazine-based hydrazone derivatives. The hydrazones are synthesized by a three step process from commercially available benzil and thiosemicarbazide. The structures of all compounds were determined by using the UV-Vis., FT-IR, NMR ( [...] Read more.

We report here a comparative theoretical and experimental study of four triazine-based hydrazone derivatives. The hydrazones are synthesized by a three step process from commercially available benzil and thiosemicarbazide. The structures of all compounds were determined by using the UV-Vis., FT-IR, NMR (¹H and ¹³C) spectroscopic techniques and finally confirmed unequivocally by single crystal X-ray diffraction analysis. Experimental geometric parameters and spectroscopic properties of the triazine based hydrazones are compared with those obtained from density functional theory (DFT) studies. The model developed here comprises of geometry optimization at B3LYP/6-31G (d, p) level of DFT. Optimized geometric parameters of all four compounds showed excellent correlations with the results obtained from X-ray diffraction studies. The vibrational spectra show nice correlations with the experimental IR spectra. Moreover, the simulated absorption spectra also agree well with experimental results (within 10–20 nm). The molecular electrostatic potential (MEP) mapped over the entire stabilized geometries of the compounds indicated their chemical reactivates. Furthermore, frontier molecular orbital (electronic properties) and first hyperpolarizability (nonlinear optical response) were also computed at the B3LYP/6-31G (d, p) level of theory. Full article

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