Discovery of quinazolin-4-one-based non-covalent inhibitors targeting the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 Mpro)

Eur J Med Chem. 2023 Sep 5:257:115487. doi: 10.1016/j.ejmech.2023.115487. Epub 2023 May 24.

Abstract

The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a great threat to public health while various vaccines are available worldwide. Main protease (Mpro) has been validated as an effective anti-COVID-19 drug target. Using medicinal chemistry and rational drug design strategies, we identified a quinazolin-4-one series of nonpeptidic, noncovalent SARS-CoV-2 Mpro inhibitors based on baicalein, 5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one. In particular, compound C7 exhibits superior inhibitory activity against SARS-CoV-2 Mpro relative to baicalein (IC50 = 0.085 ± 0.006 and 0.966 ± 0.065 μM, respectively), as well as improved physicochemical and drug metabolism and pharmacokinetics (DMPK) properties. In addition, C7 inhibits viral replication in SARS-CoV-2-infected Vero E6 cells more effectively than baicalein (EC50 = 1.10 ± 0.12 and 5.15 ± 1.64 μM, respectively) with low cytotoxicity (CC50 > 50 μM). An X-ray co-crystal structure reveals a non-covalent mechanism of action, and a noncanonical binding mode not observed by baicalein. These results suggest that C7 represents a promising lead for development of more effective SARS-CoV-2 Mpro inhibitors and anti-COVID-19 drugs.

Keywords: Antiviral activity; Antiviral drugs; Noncovalent M(pro) inhibitors; SARS-CoV-2 M(pro).

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • COVID-19*
  • Humans
  • Pandemics
  • Peptide Hydrolases
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • SARS-CoV-2*

Substances

  • 4-hydroxyquinazoline
  • Antiviral Agents
  • Protease Inhibitors
  • Peptide Hydrolases