8i4s

Publication Abstract from PubMed

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 (M(pro)) 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 M(pro) 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 M(pro) relative to baicalein (IC(50) = 0.085 +/- 0.006 and 0.966 +/- 0.065 muM, 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 (EC(50) = 1.10 +/- 0.12 and 5.15 +/- 1.64 muM, respectively) with low cytotoxicity (CC(50) ＞ 50 muM). 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 M(pro) inhibitors and anti-COVID-19 drugs.

Discovery of quinazolin-4-one-based non-covalent inhibitors targeting the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 M(pro)).,Zhang K, Wang T, Li M, Liu M, Tang H, Wang L, Ye K, Yang J, Jiang S, Xiao Y, Xie Y, Lu M, Zhang X Eur J Med Chem. 2023 Sep 5;257:115487. doi: 10.1016/j.ejmech.2023.115487. Epub , 2023 May 24. PMID:37257212^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.