2. Academic Validation
  3. Discovery and optimization of 2-((1H-indol-3-yl)thio)-N-benzyl-acetamides as novel SARS-CoV-2 RdRp inhibitors

Discovery and optimization of 2-((1H-indol-3-yl)thio)-N-benzyl-acetamides as novel SARS-CoV-2 RdRp inhibitors

  • Eur J Med Chem. 2021 Nov 5:223:113622. doi: 10.1016/j.ejmech.2021.113622.
Guo-Ning Zhang 1,  Jianyuan Zhao 1,  Quanjie Li 1,  Minghua Wang 1,  Mei Zhu 1,  Juxian Wang 2,  Shan Cen 3,  Yucheng Wang 4
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.
  • 2 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. Electronic address: wangjuxian@imb.pumc.edu.cn.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. Electronic address: shancen@imb.pumc.edu.cn.
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. Electronic address: wangyucheng@imb.pumc.edu.cn.
PMID: 34147744 DOI: 10.1016/j.ejmech.2021.113622
Abstract

The emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the global pandemic coronavirus disease (COVID-19), but no specific Antiviral drug has been proven effective for controlling this pandemic to date. In this study, several 2-((indol-3-yl)thio)-N-benzyl-acetamides were identified as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors. After a two-round optimization, a new series of 2-((indol-3-yl)thio)-N-benzyl-acetamides was designed, synthesized, and evaluated for SARS-CoV-2 RdRp inhibitory effect. Compounds 6b2, 6b5, 6c9, 6d2, and 6d5 were identified as potent inhibitors with IC50 values of 3.35 ± 0.21 μM, 4.55 ± 0.2 μM, 1.65 ± 0.05 μM, 3.76 ± 0.79 μM, and 1.11 ± 0.05 μM, respectively; the IC50 of remdesivir (control) was measured as 1.19 ± 0.36 μM. All of the compounds inhibited RNA synthesis by SARS-CoV-2 RdRp. The most potent compound 6d5, which showed a stronger inhibitory activity against the human coronavirus HCoV-OC43 than remdesivir, is a promising candidate for further investigation.

Keywords

2-((Indol-3-yl)thio)-N-Benzyl-acetamides; COVID-19; RdRp inhibitor; SARS-CoV-2.

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