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15 pages, 2316 KiB

Open AccessArticle

Domino Multicomponent Approach for the Synthesis of Functionalized Spiro-Indeno[1,2-b]quinoxaline Heterocyclic Hybrids and Their Antimicrobial Activity, Synergistic Effect and Molecular Docking Simulation

by Abdulrahman I. Almansour, Natarajan Arumugam, Raju Suresh Kumar, Dhaifallah M. Al-thamili, Govindasami Periyasami, Karuppiah Ponmurugan, Naif Abdullah Al-Dhabi, Karthikeyan Perumal and Dhanaraj Premnath

Molecules 2019, 24(10), 1962; https://doi.org/10.3390/molecules24101962 - 22 May 2019

Cited by 19 | Viewed by 2849

Abstract

An expedient synthesis of hitherto unexplored novel hybrid heterocycles comprising dispiropyrrolidine, N-styrylpiperidone and indeno[1,2-b]quinoxaline units has been developed via domino multicomponent 1,3-dipolar cycloaddition strategy employing a new class of azomethine ylide in ionic liquid, 1-butyl-3-methylimidazolium bromide. This domino protocol involves, [...] Read more.

An expedient synthesis of hitherto unexplored novel hybrid heterocycles comprising dispiropyrrolidine, N-styrylpiperidone and indeno[1,2-b]quinoxaline units has been developed via domino multicomponent 1,3-dipolar cycloaddition strategy employing a new class of azomethine ylide in ionic liquid, 1-butyl-3-methylimidazolium bromide. This domino protocol involves, 1,3-dipolar cycloaddition and concomitant enamine reaction affording the dispiropyrrolidine tethered N-styrylpiperidone hybrid heterocycles in moderate to good yield in a single step. These compounds were evaluated for their antimicrobial activity against bacterial and fungal pathogens, therein compounds 8f, 8h, and 8l displayed significant activity against tested microbial pathogens. The synergistic effect revealed that the combination of compound 8h with streptomycin and vancomycin exhibited potent synergistic activity against E. coli ATCC 25922. In addition, molecular docking simulation has also been studied for the most active compound. Full article

(This article belongs to the Special Issue Design and Synthesis of Bioactive Compounds)

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11 pages, 3822 KiB

Open AccessArticle

Synthesis, Docking and Biological Evaluation of a Novel Class of Imidazothiazoles as IDO1 Inhibitors

by Marta Serafini, Enza Torre, Silvio Aprile, Alberto Massarotti, Silvia Fallarini and Tracey Pirali

Molecules 2019, 24(10), 1874; https://doi.org/10.3390/molecules24101874 - 15 May 2019

Cited by 19 | Viewed by 3082

Abstract

IDO1, a key dioxygenase in tryptophan-kynurenine metabolism, appeared in the last 10 years at the vanguard of druggable targets in cancer therapy due to its well-established role both in immune escape and inflammatory neovascularization. Among the pool of IDO1 inhibitors that have entered [...] Read more.

IDO1, a key dioxygenase in tryptophan-kynurenine metabolism, appeared in the last 10 years at the vanguard of druggable targets in cancer therapy due to its well-established role both in immune escape and inflammatory neovascularization. Among the pool of IDO1 inhibitors that have entered clinical trials, none have reached approval. The identification of novel inhibitors endowed with better clinical profile, together with the further comprehension of the interactions with residues in IDO1 active site, are still a need. In this context, we have synthesized a novel class of imidazothiazole derivatives as IDO1 inhibitors and identified three compounds with inhibitory potency in the low micromolar range. This report strengthens the role played by pocket C in the active site of IDO1, providing novel directions in the design of IDO1 inhibitors. Full article

(This article belongs to the Special Issue Design and Synthesis of Bioactive Compounds)

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14 pages, 10130 KiB

Open AccessArticle

Synthesis of diN-Substituted Glycyl-Phenylalanine Derivatives by Using Ugi Four Component Reaction and Their Potential as Acetylcholinesterase Inhibitors

by Luis Prent-Peñaloza, Alexander F. De la Torre, José L. Velázquez-Libera, Margarita Gutiérrez and Julio Caballero

Molecules 2019, 24(1), 189; https://doi.org/10.3390/molecules24010189 - 06 Jan 2019

Cited by 3 | Viewed by 4574

Abstract

Ugi four component reaction (Ugi-4CR) isocyanide-based multicomponent reactions were used to synthesize diN-substituted glycyl-phenylalanine (diNsGF) derivatives. All of the synthesized compounds were characterized by spectroscopic and spectrometric techniques. In order to evaluate potential biological applications, the synthesized compounds were tested in computational models [...] Read more.

Ugi four component reaction (Ugi-4CR) isocyanide-based multicomponent reactions were used to synthesize diN-substituted glycyl-phenylalanine (diNsGF) derivatives. All of the synthesized compounds were characterized by spectroscopic and spectrometric techniques. In order to evaluate potential biological applications, the synthesized compounds were tested in computational models that predict the bioactivity of organic molecules by using only bi-dimensional molecular information. The diNsGF derivatives were predicted as cholinesterase inhibitors. Experimentally, all of the synthesized diNsGF derivatives showed moderate inhibitory activities against acetylcholinesterase (AChE) and poor activities against butyrylcholinesterase (BuChE). Compound 7a has significant activity and selectivity against AChE, which reveals that the diNsGF scaffold could be improved to reach novel candidates by combining other chemical components of the Ugi-4CR in a high-throughput combinatorial screening experiment. Molecular docking experiments of diNsGF derivatives inside AChE suggest that these compounds placed the phenylalanine group at the peripheral site of AChE. The orientations and chemical interactions of diNsGF derivatives were analyzed, and the changeable groups were identified for future exploration of novel candidates that could lead to the improvement of diNsGF derivative inhibitory activities. Full article

(This article belongs to the Special Issue Design and Synthesis of Bioactive Compounds)

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16 pages, 3054 KiB

Open AccessArticle

Preparation of Enantiomeric β-(2′,5′-Dimethylphenyl)Bromolactones, Their Antiproliferative Activity and Effect on Biological Membranes

by Witold Gładkowski, Aleksandra Włoch, Aleksandra Pawlak, Angelika Sysak, Agata Białońska, Marcelina Mazur, Paweł Mituła, Gabriela Maciejewska, Bożena Obmińska-Mrukowicz and Halina Kleszczyńska

Molecules 2018, 23(11), 3035; https://doi.org/10.3390/molecules23113035 - 20 Nov 2018

Cited by 9 | Viewed by 3272

Abstract

Three novel enantiomeric pairs of bromolactones possesing a 2,5-dimethylphenyl substituent at the β-position of the lactone ring have been synthesized from corresponding enantiomeric (E)-3-(2′,5′-dimethylphenyl)hex-4-enoic acids (4) by kinetically controlled bromolactonization with N-bromosuccinimide (NBS). γ-Bromo-δ-lactones (5) were [...] Read more.

Three novel enantiomeric pairs of bromolactones possesing a 2,5-dimethylphenyl substituent at the β-position of the lactone ring have been synthesized from corresponding enantiomeric (E)-3-(2′,5′-dimethylphenyl)hex-4-enoic acids (4) by kinetically controlled bromolactonization with N-bromosuccinimide (NBS). γ-Bromo-δ-lactones (5) were isolated as the major products. Absolute configurations of stereogenic centers of γ-bromo-δ-lactones (5) were assigned based on X-ray analysis; configurations of cis δ-bromo-γ-lactones (6) and trans δ-bromo-γ-lactones (7) were determined based on mechanism of bromolactonization. Synthesized compounds exhibited significant antiproliferative activity towards the four canine cancer cell lines (D17, CLBL-1, CLB70, and GL-1) and one human cancer line (Jurkat). Classifying the compounds in terms of activity, the most active were enantiomers of trans δ-bromo-γ-lactones (7) followed by enantiomers of cis isomer (6) and enantiomeric γ-bromo-δ-lactones (5). Higher activity was observed for all stereoisomers with S configuration at C-4 in comparison with their enantiomers with 4R configuration. Synthesized compounds did not induce hemolysis of erythrocytes. The results of the interaction of bromolactones with red blood cell membranes suggest that these compounds incorporate into biological membranes, concentrating mainly in the hydrophilic part of the bilayer but have practically no influence on fluidity in the hydrophobic region. The differences in interactions with the membrane between particular enantiomers were observed only for γ-lactones: stronger interactions were found for enantiomer 4R,5R,6S of cis γ-lactone (6) and for enantiomer 4S,5R,6S of trans γ-lactone (7). Full article

(This article belongs to the Special Issue Design and Synthesis of Bioactive Compounds)

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18 pages, 2981 KiB

Open AccessArticle

Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer’s Disease

by Wenhao Wu, Xintong Liang, Guoquan Xie, Langdi Chen, Weixiong Liu, Guolin Luo, Peiquan Zhang, Lihong Yu, Xuehua Zheng, Hong Ji, Chao Zhang and Wei Yi

Molecules 2018, 23(10), 2540; https://doi.org/10.3390/molecules23102540 - 05 Oct 2018

Cited by 12 | Viewed by 3531

Abstract

A series of novel ligustrazine derivatives 8a–r were designed, synthesized, and evaluated as multi-targeted inhibitors for anti-Alzheimer’s disease (AD) drug discovery. The results showed that most of them exhibited a potent ability to inhibit both ChEs, with a high selectivity towards [...] Read more.

A series of novel ligustrazine derivatives 8a–r were designed, synthesized, and evaluated as multi-targeted inhibitors for anti-Alzheimer’s disease (AD) drug discovery. The results showed that most of them exhibited a potent ability to inhibit both ChEs, with a high selectivity towards AChE. In particular, compounds 8q and 8r had the greatest inhibitory abilities for AChE, with IC₅₀ values of 1.39 and 0.25 nM, respectively, and the highest selectivity towards AChE (for 8q, IC₅₀ BuChE/IC₅₀ AChE = 2.91 × 10⁶; for 8r, IC₅₀ BuChE/IC₅₀ AChE = 1.32 × 10⁷). Of note, 8q and 8r also presented potent inhibitory activities against Aβ aggregation, with IC₅₀ values of 17.36 µM and 49.14 µM, respectively. Further cellular experiments demonstrated that the potent compounds 8q and 8r had no obvious cytotoxicity in either HepG2 cells or SH-SY5Y cells, even at a high concentration of 500 μM. Besides, a combined Lineweaver-Burk plot and molecular docking study revealed that these compounds might act as mixed-type inhibitors to exhibit such effects via selectively targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChEs. Taken together, these results suggested that further development of these compounds should be of great interest. Full article

(This article belongs to the Special Issue Design and Synthesis of Bioactive Compounds)

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19 pages, 6172 KiB

Open AccessArticle

Design, Synthesis, and Antiproliferative Evaluation of Novel Coumarin/2-Cyanoacryloyl Hybrids as Apoptosis Inducing Agents by Activation of Caspase-Dependent Pathway

by Yu-Ying Zhang, Qian-Qian Zhang, Jia-Li Song, Liang Zhang, Cheng-Shi Jiang and Hua Zhang

Molecules 2018, 23(8), 1972; https://doi.org/10.3390/molecules23081972 - 07 Aug 2018

Cited by 12 | Viewed by 3648

Abstract

A series of novel coumarin/2-cyanoacryloyl hybrids were prepared and evaluated for their in vitro anticancer activity. Among them, two analogs 5p and 5q showed promising antiproliferative activity against a panel of cancer cell lines, including A549, H157, HepG2, MCF7, MG63, and U2OS. Particularly, [...] Read more.

A series of novel coumarin/2-cyanoacryloyl hybrids were prepared and evaluated for their in vitro anticancer activity. Among them, two analogs 5p and 5q showed promising antiproliferative activity against a panel of cancer cell lines, including A549, H157, HepG2, MCF7, MG63, and U2OS. Particularly, 5q showed the most potent activity towards MG63 cells with an IC₅₀ value of 5.06 ± 0.25 μM. Morphological observation and 4,6-diamidino-2-phenylindole (DAPI) staining assay showed that 5q-treated MG63 cells displayed significant apoptosis characteristics. Moreover, flow cytometric detection of phosphatidylserine externalization revealed that 5q induced MG63 apoptosis in a dose-dependent manner. Real-time PCR and western blot assay further confirmed that 5q had strong effects to induce MG63 cell apoptosis, suggesting that the action was associated with down-regulation of the anti-apoptotic protein Bcl-2, upregulation of pro-apoptotic protein Bax, and induced activation of caspase-3, 8, and 9. The present results provide a new chemotype for anticancer drug development and continuing investigation into candidates with coumarin/2-cyanoacryloyl scaffold is warranted. Full article

(This article belongs to the Special Issue Design and Synthesis of Bioactive Compounds)

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Review

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34 pages, 6557 KiB

Open AccessReview

NAD Analogs in Aid of Chemical Biology and Medicinal Chemistry

by Anais Depaix and Joanna Kowalska

Molecules 2019, 24(22), 4187; https://doi.org/10.3390/molecules24224187 - 19 Nov 2019

Cited by 17 | Viewed by 6723

Abstract

Nicotinamide adenine dinucleotide (NAD) serves as an essential redox co-factor and mediator of multiple biological processes. Besides its well-established role in electron transfer reactions, NAD serves as a substrate for other biotransformations, which, at the molecular level, can be classified as protein post-translational [...] Read more.

Nicotinamide adenine dinucleotide (NAD) serves as an essential redox co-factor and mediator of multiple biological processes. Besides its well-established role in electron transfer reactions, NAD serves as a substrate for other biotransformations, which, at the molecular level, can be classified as protein post-translational modifications (protein deacylation, mono-, and polyADP-ribosylation) and formation of signaling molecules (e.g., cyclic ADP ribose). These biochemical reactions control many crucial biological processes, such as cellular signaling and recognition, DNA repair and epigenetic modifications, stress response, immune response, aging and senescence, and many others. However, the links between the biological effects and underlying molecular processes are often poorly understood. Moreover, NAD has recently been found to tag the 5′-ends of some cellular RNAs, but the function of these NAD-capped RNAs remains largely unrevealed. Synthetic NAD analogs are invaluable molecular tools to detect, monitor, structurally investigate, and modulate activity of NAD-related enzymes and biological processes in order to aid their deeper understanding. Here, we review the recent advances in the design and development of NAD analogs as probes for various cellular NAD-related enzymes, enzymatic inhibitors with anticancer or antimicrobial therapeutic potential, and other NAD-related chemical biology tools. We focus on research papers published within the last 10 years. Full article

(This article belongs to the Special Issue Design and Synthesis of Bioactive Compounds)

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11 pages, 2576 KiB

Open AccessFeature PaperReview

The Chemistry and Biology of Cyclophostin, the Cyclipostins and Related Compounds

by Christopher D. Spilling

Molecules 2019, 24(14), 2579; https://doi.org/10.3390/molecules24142579 - 16 Jul 2019

Cited by 7 | Viewed by 2491

Abstract

Cyclophostin, the cyclipostins and the salinipostins are structurally related cyclic enolphosphate natural products. This mini review describes their isolation, synthesis and biological activities. In addition, the synthesis and biological activities of monocyclic enolphosphate and mono and bicyclic enolphosphonate analogs are presented. Full article

(This article belongs to the Special Issue Design and Synthesis of Bioactive Compounds)

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30 pages, 14822 KiB

Open AccessFeature PaperReview

Development of the Inhibitors That Target the PD-1/PD-L1 Interaction—A Brief Look at Progress on Small Molecules, Peptides and Macrocycles

by Katarzyna Guzik, Marcin Tomala, Damian Muszak, Magdalena Konieczny, Aleksandra Hec, Urszula Błaszkiewicz, Marcin Pustuła, Roberto Butera, Alexander Dömling and Tad A. Holak

Molecules 2019, 24(11), 2071; https://doi.org/10.3390/molecules24112071 - 30 May 2019

Cited by 105 | Viewed by 15410

Abstract

Cancer immunotherapy based on antibodies targeting the immune checkpoint PD-1/PD-L1 pathway has seen unprecedented clinical responses and constitutes the new paradigm in cancer therapy. The antibody-based immunotherapies have several limitations such as high production cost of the antibodies or their long half-life. Small-molecule [...] Read more.

Cancer immunotherapy based on antibodies targeting the immune checkpoint PD-1/PD-L1 pathway has seen unprecedented clinical responses and constitutes the new paradigm in cancer therapy. The antibody-based immunotherapies have several limitations such as high production cost of the antibodies or their long half-life. Small-molecule inhibitors of the PD-1/PD-L1 interaction have been highly anticipated as a promising alternative or complementary therapeutic to the monoclonal antibodies (mAbs). Currently, the field of developing anti-PD-1/PD-L1 small-molecule inhibitors is intensively explored. In this paper, we review anti-PD-1/PD-L1 small-molecule and peptide-based inhibitors and discuss recent structural and preclinical/clinical aspects of their development. Discovery of the therapeutics based on small-molecule inhibitors of the PD-1/PD-L1 interaction represents a promising but challenging perspective in cancer treatment. Full article

(This article belongs to the Special Issue Design and Synthesis of Bioactive Compounds)

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