Discovery of the potent covalent inhibitor with an acrylate warhead for SARS-CoV-2 3CL protease
Wen Shen, Xinyao Chen, Liping Zhou, Yan Cheng, Yan Zhang, Xiangrui Jiang, Haiguo Sun, Jingshan Shen · Bioorganic & Medicinal Chemistry Letters · 2024
• Compound 12b displayed potent 3CL pro inhibitory activity (IC 50 = 28.89 nM). • Compound 12b displayed potent antiviral activity against HCoV-OC43 and SARS-CoV-2 replicon. • Compound 12b displayed low cytotoxicity. COVID-19 has caused severe consequences in terms of public health and economy worldwide since its outbreak in December 2019. SARS-CoV-2 3C-like protease (3CL pro ), crucial for the viral replications, is an attractive target for the development of antiviral drugs. In this study, several kinds of Michael acceptor warheads were utilized to hunt for potent covalent inhibitors against 3CL pro . Meanwhile, novel 3CL pro inhibitors with the P3-3,5-dichloro-4-(2-(dimethylamino)ethoxy)phenyl moiety were designed and synthesized which may form salt bridge with residue Glu166. Among them, two compounds 12b and 12c exhibited high inhibitory activities against SARS-CoV-2 3CL pro . Further investigations suggested that 12b with an acrylate warhead displayed potent activity against HCoV-OC43 (EC 50 = 97 nM) and SARS-CoV-2 replicon (EC 50 = 45 nM) and low cytotoxicity (CC 50 > 10 μM) in Huh7 cells. Taken together, this study devised two series of 3CL pro inhibitors and provided the potent SARS-CoV-2 3CL pro inhibitor ( 12b ) which may be used for treating coronavirus infections.