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.
Kuojun Zhang  1 ,  Tianyu Wang  1 ,  Maotian Li  2 ,  Mu Liu  3 ,  He Tang  1 ,  Lin Wang  1 ,  Ke Ye  1 ,  Jiamei Yang  1 ,  Sheng Jiang  1 ,  Yibei Xiao  1 ,  Youhua Xie  4 ,  Meiling Lu  5 ,  Xiangyu Zhang  6
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2. Department of Pharmacology, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, China.
  • 3. Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Diseases and Biosecurity, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China.
  • 4. Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Diseases and Biosecurity, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China. Electronic address: [email protected].
  • 5. Department of Pharmacology, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 6. Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
PMID: 37257212 DOI: 10.1016/j.ejmech.2023.115487
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).