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15 pages, 1641 KiB

Open AccessArticle

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 1498

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

Open AccessArticle

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 1 | Viewed by 1832

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

Open AccessReview

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 17 | Viewed by 3987

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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