Xinyu Zong, Xiaoyang Li, Shiyu Liu, Guanxuan Jin, Kan Yang, Chunnong Wang, Longfei Li, Fei Cao, Wan Li
Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmacy, Hebei University, Baoding, 071002, Hebei, People's Republic of China.
Department of Pharmacy, Air Force Medical Center, PLA, Air Force Medical University, Beijing, 100142, China.
Mol Divers. 2025 Aug 13. doi: 10.1007/s11030-025-11308-1.
COVID-19, caused by SARS-CoV-2, has led to a global health crisis. The main protease (M) 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 IC 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.
由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的2019冠状病毒病（COVID-19）已导致全球健康危机。主要蛋白酶（M）对于病毒复制至关重要，这使其成为开发抗COVID-19治疗药物的一个有前景的靶点。在本文中，一系列新型的2-芳基硫烷基甲基-6-溴吲哚衍生物（I、II、III和IV）被设计为2019新型冠状病毒主要蛋白酶抑制剂。通过取代、甲基化和酰化反应高效合成了所设计的化合物，并通过电喷雾质谱（ESI-MS）、核磁共振（NMR）和X射线晶体衍射进行了表征。生物活性测定表明，化合物III2对2019新型冠状病毒主要蛋白酶具有优异的抑制活性，半数抑制浓度（IC）值为1.6 μM。小鼠急性毒性结果表明，化合物III2属于低毒化合物，在小鼠组织中未观察到明显的病理变化。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新型冠状病毒主要蛋白酶的结合模式。
