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

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.