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

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Eur J Med Chem


. 2021 Jun 10;223:113622.
doi: 10.1016/j.ejmech.2021.113622. Online ahead of print.
Discovery and optimization of 2-((1H-indol-3-yl)thio)-N-benzyl-acetamides as novel SARS-CoV-2 RdRp inhibitors


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

• 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.