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<p>COVID-19, caused by SARS-CoV-2, has led to a global health crisis. The main protease (M<sup>pro</sup>) 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 (<b>I</b>, <b>II III</b> and <b>IV</b>) 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 <b>III2</b> had excellent inhibitory activity against 2019-nCoV main protease with IC<sub>50</sub> values of 1.6&#xa0;μM. Acute toxicity results in mice showed that compound <b>III2</b> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年8月13日

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

摘要

COVID-19, caused by SARS-CoV-2, has led to a global health crisis. The main protease (Mpro) 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.