Design, synthesis and SARS-CoV‑2 main protease inhibitory activities of 2-arylthiomethyl-6-bromoindole derivatives.

IF 3.8 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2025-08-13 DOI:10.1007/s11030-025-11308-1

Zong Xinyu, Li Xiaoyang, Liu Shiyu, Jin Guanxuan, Yang Kan, Wang Chunnong, Li Longfei, Cao Fei, Li Wan

引用次数: 0

Abstract

COVID-19, caused by SARS-CoV-2, has led to a global health crisis. The main protease (M^pro) is essential for viral replication, making it a promising target for the development of anti-COVID-19 therapeutics. In this paper, series of novel 2-arylsulfanylmethyl-6-bromoindole derivatives (I, II III and IV) were designed as 2019-nCoV main protease inhibitors. The designed compounds were efficiently synthesized by substitution, methylation and acylation reactions and were determined by ESI-MS, NMR and crystal X-ray diffraction. The bioassay showed that compound III2 had excellent inhibitory activity against 2019-nCoV main protease with IC₅₀ values of 1.6 μM. Acute toxicity results in mice showed that compound III2 belongs to low-toxicity compound, and no significant pathological changes were observed in mouse tissues. Molecular docking and molecular dynamics simulations revealed the binding mode of 2-arylthiomethyl-6-bromoindole derivatives with 2019-nCoV main protease.

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2-芳基硫甲基-6-溴吲哚衍生物的设计、合成及其对SARS-CoV - 2主要蛋白酶的抑制活性

由SARS-CoV-2引起的COVID-19已引发全球卫生危机。主要蛋白酶（Mpro）对病毒复制至关重要，使其成为开发抗covid -19疗法的有希望的靶点。本文设计了一系列新型2-芳基磺酰甲基-6-溴吲哚衍生物（I、II、III和IV）作为2019-nCoV主要蛋白酶抑制剂。设计的化合物通过取代、甲基化和酰化反应高效合成，并通过ESI-MS、NMR和晶体x射线衍射进行了鉴定。生物实验结果表明，化合物III2对新型冠状病毒主要蛋白酶具有良好的抑制活性，IC50值为1.6 μM。小鼠急性毒性实验结果显示化合物III2属于低毒化合物，小鼠组织未见明显病理改变。分子对接和分子动力学模拟揭示了2-芳基硫甲基-6-溴吲哚衍生物与2019-nCoV主蛋白酶的结合模式。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;