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.

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