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Advances in Synthesis and Biological Activity of Novel Derivatives Based on Five-Membered Heterocyclic Scaffolds and Their Intermediates—Second Edition

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Chemistry".

Deadline for manuscript submissions: 31 January 2025 | Viewed by 6080

Special Issue Editors

Dr. Theodora Venera Apostol

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Guest Editor
Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, 020956 Bucharest, Romania
Interests: organic chemistry; heterocycle chemistry; medicinal chemistry; organic synthesis and structure elucidation; 1,3-oxazole; N-acyl-α-amino acid; α-acylamino ketone; diphenyl sulfone scaffold
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. George Mihai Nitulescu

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Guest Editor
Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, 6 Traian Vuia Street, 020956 Bucharest, Romania
Interests: the design and synthesis of new anticancer agents; the design and synthesis of new antimicrobial compounds; studies and structural analysis; the isolation and analysis of natural compounds with anticancer effects; computer-assisted drug design studies
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Laura Ileana Socea

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Guest Editor
Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, 020956 Bucharest, Romania
Interests: organic chemistry; organic synthesis and structural analysis; medicinal chemistry; 5H-dibenzo[a,d][7]annulene; hydrazone; hydrazinecarbothioamide; 1,2,4-triazole; 1,3,4-oxadiazole
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Five-membered heterocyclic compounds (imidazoles, pyrazoles, oxazoles, thiazoles, triazoles, oxadiazoles, thiadiazoles, etc.) are very important in pharmaceutical and medicinal chemistry, as it is known that representatives of this class are the basis of many drugs with various therapeutic actions, including antimicrobial, antiviral, anticancer, anti-inflammatory, analgesic, and antidiabetic activities. Currently, this field is being studied extensively by a large number of researchers in order to discover and develop new pharmaceutical agents and bioactive molecules. Thus, recent progress in synthetic approaches to nitrogen-, oxygen-, and sulfur-containing five-membered heterocycles includes different synthesis protocols, such as multi-step strategies, multi-component pathways, photocatalysis, click reactions, and microwave-assisted or green synthesis, with pharmacologically potent derivatives reported.

This Special Issue aims to provide a summary of the recent advances in the synthesis and biological activity of novel derivatives based on five-membered heterocyclic scaffolds and their intermediates (N-acyl-α-amino acids, α-acylamino ketones, acyl hydrazones, acyl thioureas, hydrazinecarbothioamides, isocyanates, isothiocyanates, etc.). We invite you to contribute original research articles and/or reviews of the current scientific literature to this Special Issue of Molecules focused on the design, obtainment, and biological activity assessment of new pentatomic heterocyclic scaffolds and their intermediates.

Dr. Theodora Venera Apostol
Prof. Dr. George Mihai Nitulescu
Prof. Dr. Laura Ileana Socea
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • bioactive heterocycles
  • heterocyclic scaffolds
  • bioisosteric heterocyclic skeletons
  • azoles
  • pyrazole
  • oxazole
  • triazole
  • oxadiazole
  • drug design
  • in silico studies

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Related Special Issue

Published Papers (7 papers)

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Research

16 pages, 1986 KiB  
Article
C3-Alkylation of Imidazo[1,2-a]pyridines via Three-Component Aza-Friedel–Crafts Reaction Catalyzed by Y(OTf)3
by Kai Yang, Cai-Bo Chen, Zhao-Wen Liu, Zhen-Lin Li, Yu Zeng and Zhao-Yang Wang
Molecules 2024, 29(15), 3463; https://doi.org/10.3390/molecules29153463 - 24 Jul 2024
Viewed by 588
Abstract
As an important class of nitrogen-containing fused heterocyclic compounds, imidazo[1,2-a]pyridines often exhibit significant biological activities, such as analgesic, anticancer, antiosteoporosis, anxiolytic, etc. Using Y(OTf)3 as a Lewis acid catalyst, a simple and efficient method has been developed for the synthesis of C [...] Read more.
As an important class of nitrogen-containing fused heterocyclic compounds, imidazo[1,2-a]pyridines often exhibit significant biological activities, such as analgesic, anticancer, antiosteoporosis, anxiolytic, etc. Using Y(OTf)3 as a Lewis acid catalyst, a simple and efficient method has been developed for the synthesis of C3-alkylated imidazo[1,2-a]pyridines through the three-component aza-Friedel–Crafts reaction of imidazo[1,2-a]pyridines, aldehydes, and amines in the normal air atmosphere without the protection of inert gas and special requirements for anhydrous and anaerobic conditions. A series of imidazo[1,2-a]pyridine derivatives were obtained with moderate to good yields, and their structures were confirmed by 1H NMR, 13C NMR, and HRMS. Furthermore, this conversion has the advantages of simple operation, excellent functional group tolerance, high atomic economy, broad substrate scope, and can achieve gram-level reactions. Notably, this methodology may be conveniently applied to the further design and rapid synthesis of potential biologically active imidazo[1,2-a]pyridines with multifunctional groups. Full article
(This article belongs to the Special Issue Advances in Synthesis and Biological Activity of Novel Derivatives Based on Five-Membered Heterocyclic Scaffolds and Their Intermediates—Second Edition)
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14 pages, 2272 KiB  
Article
Polymethylenetetrazole: Synthesis, Characterization, and Energetic Properties
by Ljubica Brenjo, Aleksandar Oklješa, Matija Tomšič, Berta Barta Holló, Jovica Nešić, Elvira Tóth and Črtomir Podlipnik
Molecules 2024, 29(14), 3389; https://doi.org/10.3390/molecules29143389 - 18 Jul 2024
Viewed by 676
Abstract
The tetrazole moiety remains one of the most interesting scaffolds in the development of new high-energy density materials (HEDMs) because of its desired characteristics, such as high nitrogen content and heat of formation (HOF). The combination of several heterocycles with high HOF seems [...] Read more.
The tetrazole moiety remains one of the most interesting scaffolds in the development of new high-energy density materials (HEDMs) because of its desired characteristics, such as high nitrogen content and heat of formation (HOF). The combination of several heterocycles with high HOF seems to be a promising strategy for obtaining energetic materials with superior properties. Herein, we report the synthesis and characterization of a tetrazole polymer, polymethylenetetrazole (PMT), as a potential HEDM. The compound was characterized using NMR, IR, and Raman spectroscopy. Its weight average molecular mass was obtained by static light scattering (SLS), and its physical properties by powder XRD analysis. The density, sensitivity to friction (FS), and impact (IS) of the compound were determined as well. The results of the thermal and energetic properties of PMT suggest that this polymer could be an insensitive explosive. Full article
(This article belongs to the Special Issue Advances in Synthesis and Biological Activity of Novel Derivatives Based on Five-Membered Heterocyclic Scaffolds and Their Intermediates—Second Edition)
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40 pages, 4858 KiB  
Article
Design, Synthesis, and Characterization of Novel Thiazolidine-2,4-Dione-Acridine Hybrids as Antitumor Agents
by Monika Garberová, Zuzana Kudličková, Radka Michalková, Monika Tvrdoňová, Danica Sabolová, Slávka Bekešová, Michal Gramblička, Ján Mojžiš and Mária Vilková
Molecules 2024, 29(14), 3387; https://doi.org/10.3390/molecules29143387 - 18 Jul 2024
Viewed by 815
Abstract
This study focuses on the synthesis and structural characterization of new compounds that integrate thiazolidine-2,4-dione, acridine moiety, and an acetamide linker, aiming to leverage the synergistic effects of these pharmacophores for enhanced therapeutic potential. The newly designed molecules were efficiently synthesized through a [...] Read more.
This study focuses on the synthesis and structural characterization of new compounds that integrate thiazolidine-2,4-dione, acridine moiety, and an acetamide linker, aiming to leverage the synergistic effects of these pharmacophores for enhanced therapeutic potential. The newly designed molecules were efficiently synthesized through a multi-step process and subsequently transformed into their hydrochloride salts. Comprehensive spectroscopic techniques, including nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), infrared (IR) spectroscopy, and elemental analysis, were employed to determine the molecular structures of the synthesized compounds. Biological evaluations were conducted to assess the therapeutic potential of the new compounds. The influence of these derivatives on the metabolic activity of various cancer cell lines was assessed, with IC50 values determined via MTT assays. An in-depth analysis of the structure–activity relationship (SAR) revealed intriguing insights into their cytotoxic profiles. Compounds with electron-withdrawing groups generally exhibited lower IC50 values, indicating higher potency. The presence of the methoxy group at the linking phenyl ring modulated both the potency and selectivity of the compounds. The variation in the acridine core at the nitrogen atom of the thiazolidine-2,4-dione core significantly affects the activity against cancer cell lines, with the acridin-9-yl substituent enhancing the compounds’ antiproliferative activity. Furthermore, compounds in their hydrochloride salt forms demonstrated better activity against cancer cell lines compared to their free base forms. Compounds 12c·2HCl (IC50 = 5.4 ± 2.4 μM), 13d (IC50 = 4.9 ± 2.9 μM), and 12f·2HCl (IC50 = 4.98 ± 2.9 μM) demonstrated excellent activity against the HCT116 cancer cell line, and compound 7d·2HCl (IC50 = 4.55 ± 0.35 μM) demonstrated excellent activity against the HeLa cancer cell line. Notably, only a few tested compounds, including 7e·2HCl (IC50 = 11.00 ± 2.2 μM), 7f (IC50 = 11.54 ± 2.06 μM), and 7f·2HCl (IC50 = 9.82 ± 1.92 μM), showed activity against pancreatic PATU cells. This type of cancer has a very high mortality due to asymptomatic early stages, the occurrence of metastases, and frequent resistance to chemotherapy. Four derivatives, namely, 7e·2HCl, 12d·2HCl, 13c·HCl, and 13d, were tested for their interaction properties with BSA using fluorescence spectroscopic studies. The values for the quenching constant (Ksv) ranged from 9.59 × 104 to 10.74 × 104 M−1, indicating a good affinity to the BSA protein. Full article
(This article belongs to the Special Issue Advances in Synthesis and Biological Activity of Novel Derivatives Based on Five-Membered Heterocyclic Scaffolds and Their Intermediates—Second Edition)
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17 pages, 2054 KiB  
Article
Synthesis and In Silico Analysis of New Polyheterocyclic Molecules Derived from [1,4]-Benzoxazin-3-one and Their Inhibitory Effect against Pancreatic α-Amylase and Intestinal α-Glucosidase
by Mohamed Ellouz, Aziz Ihammi, Abdellah Baraich, Ayoub Farihi, Darifa Addichi, Saliha Loughmari, Nada Kheira Sebbar, Mohamed Bouhrim, Ramzi A. Mothana, Omar M. Noman, Bruno Eto, Fatiha Chigr and Mohammed Chigr
Molecules 2024, 29(13), 3086; https://doi.org/10.3390/molecules29133086 - 28 Jun 2024
Viewed by 674
Abstract
This study focuses on synthesizing a new series of isoxazolinyl-1,2,3-triazolyl-[1,4]-benzoxazin-3-one derivatives 5a–5o. The synthesis method involves a double 1,3-dipolar cycloaddition reaction following a “click chemistry” approach, starting from the respective [1,4]-benzoxazin-3-ones. Additionally, the study aims to evaluate the antidiabetic potential [...] Read more.
This study focuses on synthesizing a new series of isoxazolinyl-1,2,3-triazolyl-[1,4]-benzoxazin-3-one derivatives 5a–5o. The synthesis method involves a double 1,3-dipolar cycloaddition reaction following a “click chemistry” approach, starting from the respective [1,4]-benzoxazin-3-ones. Additionally, the study aims to evaluate the antidiabetic potential of these newly synthesized compounds through in silico methods. This synthesis approach allows for the combination of three heterocyclic components: [1,4]-benzoxazin-3-one, 1,2,3-triazole, and isoxazoline, known for their diverse biological activities. The synthesis procedure involved a two-step process. Firstly, a 1,3-dipolar cycloaddition reaction was performed involving the propargylic moiety linked to the [1,4]-benzoxazin-3-one and the allylic azide. Secondly, a second cycloaddition reaction was conducted using the product from the first step, containing the allylic part and an oxime. The synthesized compounds were thoroughly characterized using spectroscopic methods, including 1H NMR, 13C NMR, DEPT-135, and IR. This molecular docking method revealed a promising antidiabetic potential of the synthesized compounds, particularly against two key diabetes-related enzymes: pancreatic α-amylase, with the two synthetic molecules 5a and 5o showing the highest affinity values of 9.2 and 9.1 kcal/mol, respectively, and intestinal α-glucosidase, with the two synthetic molecules 5n and 5e showing the highest affinity values of −9.9 and −9.6 kcal/mol, respectively. Indeed, the synthesized compounds have shown significant potential as antidiabetic agents, as indicated by molecular docking studies against the enzymes α-amylase and α-glucosidase. Additionally, ADME analyses have revealed that all the synthetic compounds examined in our study demonstrate high intestinal absorption, meet Lipinski’s criteria, and fall within the required range for oral bioavailability, indicating their potential suitability for oral drug development. Full article
(This article belongs to the Special Issue Advances in Synthesis and Biological Activity of Novel Derivatives Based on Five-Membered Heterocyclic Scaffolds and Their Intermediates—Second Edition)
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20 pages, 4350 KiB  
Article
Synthesis and Biological Evaluation of New Compounds with Nitroimidazole Moiety
by Katarzyna Dziduch, Sara Janowska, Sylwia Andrzejczuk, Paulina Strzyga-Łach, Marta Struga, Marcin Feldo, Oleg Demchuk and Monika Wujec
Molecules 2024, 29(13), 3023; https://doi.org/10.3390/molecules29133023 - 26 Jun 2024
Viewed by 1158
Abstract
Heterocyclic compounds, particularly those containing azole rings, have shown extensive biological activity, including anticancer, antibacterial, and antifungal properties. Among these, the imidazole ring stands out due to its diverse therapeutic potential. In the presented study, we designed and synthesized a series of imidazole [...] Read more.
Heterocyclic compounds, particularly those containing azole rings, have shown extensive biological activity, including anticancer, antibacterial, and antifungal properties. Among these, the imidazole ring stands out due to its diverse therapeutic potential. In the presented study, we designed and synthesized a series of imidazole derivatives to identify compounds with high biological potential. We focused on two groups: thiosemicarbazide derivatives and hydrazone derivatives. We synthesized these compounds using conventional methods and confirmed their structures via nuclear magnetic resonance spectroscopy (NMR), MS, and elemental analysis, and then assessed their antibacterial and antifungal activities in vitro using the broth microdilution method against Gram-positive and Gram-negative bacteria, as well as Candida spp. strains. Our results showed that thiosemicarbazide derivatives exhibited varied activity against Gram-positive bacteria, with MIC values ranging from 31.25 to 1000 µg/mL. The hydrazone derivatives, however, did not display significant antibacterial activity. These findings suggest that structural modifications can significantly influence the antimicrobial efficacy of imidazole derivatives, highlighting the potential of thiosemicarbazide derivatives as promising candidates for further development in antibacterial therapies. Additionally, the cytotoxic activity against four cancer cell lines was evaluated. Two derivatives of hydrazide-hydrazone showed moderate anticancer activity. Full article
(This article belongs to the Special Issue Advances in Synthesis and Biological Activity of Novel Derivatives Based on Five-Membered Heterocyclic Scaffolds and Their Intermediates—Second Edition)
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15 pages, 4212 KiB  
Article
Exploring the Antitumor Efficacy of N-Heterocyclic Nitrilotriacetate Oxidovanadium(IV) Salts on Prostate and Breast Cancer Cells
by Katarzyna Chmur, Aleksandra Tesmar, Magdalena Zdrowowicz, Damian Rosiak, Jarosław Chojnacki and Dariusz Wyrzykowski
Molecules 2024, 29(12), 2924; https://doi.org/10.3390/molecules29122924 - 19 Jun 2024
Viewed by 610
Abstract
The crystal structures of two newly synthesized nitrilotriacetate oxidovanadium(IV) salts, namely [QH][VO(nta)(H2O)](H2O)2 (I) and [(acr)H][VO(nta)(H2O)](H2O)2 (II), were determined. Additionally, the cytotoxic effects of four N-heterocyclic nitrilotriacetate oxidovanadium(IV) salts—1,10-phenanthrolinium, [(phen)H][VO(nta)(H [...] Read more.
The crystal structures of two newly synthesized nitrilotriacetate oxidovanadium(IV) salts, namely [QH][VO(nta)(H2O)](H2O)2 (I) and [(acr)H][VO(nta)(H2O)](H2O)2 (II), were determined. Additionally, the cytotoxic effects of four N-heterocyclic nitrilotriacetate oxidovanadium(IV) salts—1,10-phenanthrolinium, [(phen)H][VO(nta)(H2O)](H2O)0.5 (III), 2,2′-bipyridinium [(bpy)H][VO(nta)(H2O)](H2O) (IV), and two newly synthesized compounds (I) and (II)—were evaluated against prostate cancer (PC3) and breast cancer (MCF-7) cells. All the compounds exhibited strong cytotoxic effects on cancer cells and normal cells (HaCaT human keratinocytes). The structure–activity relationship analysis revealed that the number and arrangement of conjugated aromatic rings in the counterion had an impact on the antitumor effect. The compound (III), the 1,10-phenanthrolinium analogue, exhibited the greatest activity, whereas the acridinium salt (II), with a different arrangement of three conjugated aromatic rings, showed the lowest toxicity. The increased concentrations of the compounds resulted in alterations to the cell cycle distribution with different effects in MCF-7 and PC3 cells. In MCF-7 cells, compounds I and II were observed to block the G2/M phase, while compounds III and IV were found to arrest the cell cycle in the G0/G1 phase. In PC3 cells, all compounds increased the rates of cells in the G0/G1 phase. Full article
(This article belongs to the Special Issue Advances in Synthesis and Biological Activity of Novel Derivatives Based on Five-Membered Heterocyclic Scaffolds and Their Intermediates—Second Edition)
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14 pages, 2757 KiB  
Article
Room Temperature Diels–Alder Reactions of 4-Vinylimidazoles
by Brandon B. Fulton, Alexia J. Hartzell, H. V. Rasika Dias and Carl J. Lovely
Molecules 2024, 29(8), 1902; https://doi.org/10.3390/molecules29081902 - 22 Apr 2024
Viewed by 921
Abstract
In the course of studying Diels–Alder reactions of 4-vinylimidazoles with N-phenylmaleimide, it was discovered that they engage in cycloaddition at room temperature to give high yields of the initial cycloadduct as a single stereoisomer. In certain cases, the product precipitated out of [...] Read more.
In the course of studying Diels–Alder reactions of 4-vinylimidazoles with N-phenylmaleimide, it was discovered that they engage in cycloaddition at room temperature to give high yields of the initial cycloadduct as a single stereoisomer. In certain cases, the product precipitated out of the reaction mixture and could be isolated by simple filtration, thereby avoiding issues with aromatization observed during chromatographic purification. Given these results, intramolecular variants using doubly activated dienophiles were also investigated at room temperature. Amides underwent cycloaddition at room temperature in modest yields, but the initial adducts were not isolable with Nimid-benzyl-protected systems. Attempts to extend these results to the corresponding esters and hydroxamate were less successful with these substrates only undergoing cycloaddition at elevated temperatures in lower yields. Density functional theory calculations were performed to evaluate the putative transition states for both the inter- and intramolecular variants to rationalize experimental observations. Full article
(This article belongs to the Special Issue Advances in Synthesis and Biological Activity of Novel Derivatives Based on Five-Membered Heterocyclic Scaffolds and Their Intermediates—Second Edition)
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