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Recent Advances in Heterocyclic Chemistry in Drug Discovery

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

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 9644

Special Issue Editor


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Guest Editor
Department of Chemistry, Fudan University, Shanghai, China
Interests: drug design; small molecule drugs; methodologies for synthetic drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Heterocycles are common scaffolds of the vast majority of marketed drugs and drug candidates. New advances in synthetic methodologies that enable rapid access to a wide variety of heterocyclic compounds are of critical importance to medicinal chemists as they can readily generate bulk quantities of desired compounds to discover new and effective pharmaceuticals among heterocyclic compounds.

This Special Issue of Molecules will comprise original research articles and reviews in the field of heterocycle chemistry considering drug design, new synthetic methodologies, process chemistry, and biological activities of heterocyclic compounds.

Dr. Qiuqin He
Guest Editor

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Keywords

  • heterocycles
  • drug design
  • synthetic methodologies
  • process chemistry
  • biological activities

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Published Papers (3 papers)

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Research

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15 pages, 1641 KiB  
Article
N-Phenacyldibromobenzimidazoles—Synthesis Optimization and Evaluation of Their Cytotoxic Activity
by Anna Kowalkowska, Konrad Chojnacki, Maciej Multan, Jan K. Maurin, Edyta Łukowska-Chojnacka and Patrycja Wińska
Molecules 2022, 27(14), 4349; https://doi.org/10.3390/molecules27144349 - 7 Jul 2022
Cited by 1 | Viewed by 1805
Abstract
Antifungal N-phenacyl derivatives of 4,6- and 5,6-dibromobenzimidazoles are interesting substrates in the synthesis of new antimycotics. Unfortunately, their application is limited by the low synthesis yields and time-consuming separation procedure. In this paper, we present the optimization of the synthesis conditions and [...] Read more.
Antifungal N-phenacyl derivatives of 4,6- and 5,6-dibromobenzimidazoles are interesting substrates in the synthesis of new antimycotics. Unfortunately, their application is limited by the low synthesis yields and time-consuming separation procedure. In this paper, we present the optimization of the synthesis conditions and purification methods of N-phenacyldibromobenzimidazoles. The reactions were carried out in various base solvent-systems including K2CO3, NaH, KOH, t-BuOK, MeONa, NaHCO3, Et3N, Cs2CO3, DBU, DIPEA, or DABCO as a base, and MeCN, DMF, THF, DMSO, or dioxane as a solvent. The progress of the reaction was monitored using HPLC analysis. The best results were reached when the reactions were carried out in an NaHCO3–MeCN system at reflux for 24 h. Additionally, the cytotoxic activity of the synthesized compounds against MCF-7 (breast adenocarcinoma), A-549 (lung adenocarcinoma), CCRF-CEM (acute lymphoblastic leukemia), and MRC-5 (normal lung fibroblasts) was evaluated. We observed that the studied cell lines differed in sensitivity to the tested compounds with MCF-7 cells being the most sensitive, while A-549 cells were the least sensitive. Moreover, the cytotoxicity of the tested derivatives towards CCRF-CEM cells increased with the number of chlorine or fluorine substituents. Furthermore, some of the active compounds, i.e., 2-(5,6-dibromo-1H-benzimidazol-1-yl)-1-(3,4-dichlorophenyl)ethanone (4f), 2-(4,6-dibromo-1H-benzimidazol-1-yl)-1-(2,4,6-trichlorophenyl)ethanone (5g), and 2-(4,6-dibromo-1H-benzimidazol-1-yl)-1-(2,4,6-trifluorophenyl)ethanone (5j) demonstrated pro-apoptotic properties against leukemic cells with derivative 5g being the most effective. Full article
(This article belongs to the Special Issue Recent Advances in Heterocyclic Chemistry in Drug Discovery)
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17 pages, 4865 KiB  
Article
Design, Synthesis, Biological Evaluation, and Molecular Modeling of 2-Difluoromethylbenzimidazole Derivatives as Potential PI3Kα Inhibitors
by Xiangcong Wang, Moxuan Zhang, Ranran Zhu, Zhongshan Wu, Fanhong Wu, Zhonghua Wang and Yanyan Yu
Molecules 2022, 27(2), 387; https://doi.org/10.3390/molecules27020387 - 8 Jan 2022
Cited by 2 | Viewed by 2257
Abstract
PI3Kα is one of the potential targets for novel anticancer drugs. In this study, a series of 2-difluoromethylbenzimidazole derivatives were studied based on the combination of molecular modeling techniques 3D-QSAR, molecular docking, and molecular dynamics. The results showed that the best comparative molecular [...] Read more.
PI3Kα is one of the potential targets for novel anticancer drugs. In this study, a series of 2-difluoromethylbenzimidazole derivatives were studied based on the combination of molecular modeling techniques 3D-QSAR, molecular docking, and molecular dynamics. The results showed that the best comparative molecular field analysis (CoMFA) model had q2 = 0.797 and r2 = 0.996 and the best comparative molecular similarity indices analysis (CoMSIA) model had q2 = 0.567 and r2 = 0.960. It was indicated that these 3D-QSAR models have good verification and excellent prediction capabilities. The binding mode of the compound 29 and 4YKN was explored using molecular docking and a molecular dynamics simulation. Ultimately, five new PI3Kα inhibitors were designed and screened by these models. Then, two of them (86, 87) were selected to be synthesized and biologically evaluated, with a satisfying result (22.8 nM for 86 and 33.6 nM for 87). Full article
(This article belongs to the Special Issue Recent Advances in Heterocyclic Chemistry in Drug Discovery)
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Review

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31 pages, 7670 KiB  
Review
An Update on Synthesis of Coumarin Sulfonamides as Enzyme Inhibitors and Anticancer Agents
by Laila Rubab, Sumbal Afroz, Sajjad Ahmad, Saddam Hussain, Iram Nawaz, Ali Irfan, Fozia Batool, Katarzyna Kotwica-Mojzych and Mariusz Mojzych
Molecules 2022, 27(5), 1604; https://doi.org/10.3390/molecules27051604 - 28 Feb 2022
Cited by 24 | Viewed by 5007
Abstract
Coumarin is an important six-membered aromatic heterocyclic pharmacophore, widely distributed in natural products and synthetic molecules. The versatile and unique features of coumarin nucleus, in combination with privileged sulfonamide moiety, have enhanced the broad spectrum of biological activities. The research and development of [...] Read more.
Coumarin is an important six-membered aromatic heterocyclic pharmacophore, widely distributed in natural products and synthetic molecules. The versatile and unique features of coumarin nucleus, in combination with privileged sulfonamide moiety, have enhanced the broad spectrum of biological activities. The research and development of coumarin, sulfonamide-based pharmacology, and medicinal chemistry have become active topics, and attracted the attention of medicinal chemists, pharmacists, and synthetic chemists. Coumarin sulfonamide compounds and analogs as clinical drugs have been used to cure various diseases with high therapeutic potency, which have shown their enormous development value. The diversified and wide array of biological activities such as anticancer, antibacterial, anti-fungal, antioxidant and anti-viral, etc. were displayed by diversified coumarin sulfonamides. The present systematic and comprehensive review in the current developments of synthesis and the medicinal chemistry of coumarin sulfonamide-based scaffolds give a whole range of therapeutics, especially in the field of oncology and carbonic anhydrase inhibitors. In the present review, various synthetic approaches, strategies, and methodologies involving effect of catalysts, the change of substrates, and the employment of various synthetic reaction conditions to obtain high yields is cited. Full article
(This article belongs to the Special Issue Recent Advances in Heterocyclic Chemistry in Drug Discovery)
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