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

Guo-Ning Zhang; Jianyuan Zhao; Quanjie Li; Minghua Wang; Mei Zhu; Juxian Wang; Shan Cen; Yucheng Wang

doi:10.1016/j.ejmech.2021.113622

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. Epub 2021 Jun 10.

Authors

Guo-Ning Zhang¹, Jianyuan Zhao¹, Quanjie Li¹, Minghua Wang¹, Mei Zhu¹, Juxian Wang², Shan Cen³, Yucheng Wang⁴

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.

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.

MeSH terms

Acetamides / chemical synthesis*
Acetamides / pharmacology
Adenosine Monophosphate / analogs & derivatives
Adenosine Monophosphate / pharmacology
Adenosine Monophosphate / standards
Alanine / analogs & derivatives
Alanine / pharmacology
Alanine / standards
Antiviral Agents / chemical synthesis*
Antiviral Agents / pharmacology
COVID-19 Drug Treatment*
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology
Humans
Inhibitory Concentration 50
Molecular Docking Simulation
Molecular Structure
Protein Binding
RNA, Viral / antagonists & inhibitors*
RNA-Dependent RNA Polymerase / antagonists & inhibitors*
SARS-CoV-2 / drug effects*
SARS-CoV-2 / genetics
Structure-Activity Relationship

Substances

Acetamides
Antiviral Agents
Enzyme Inhibitors
RNA, Viral
remdesivir
Adenosine Monophosphate
RNA-Dependent RNA Polymerase
Alanine