Discovery of highly potent SARS-CoV-2 M pro inhibitors based on benzoisothiazolone scaffold

• Published in: Bioorganic & medicinal chemistry letters 2022-02, Vol.58, p.128526
• Main Authors: Chen, Weixiong, Feng, Bo, Han, Sheng, Wang, Peipei, Chen, Wuhong, Zang, Yi, Li, Jia, Hu, Youhong
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Coronavirus 3C Proteases - antagonists & inhibitors; Coronavirus 3C Proteases - metabolism; COVID-19 Drug Treatment; Drug Discovery; Humans; Microbial Sensitivity Tests; Molecular Structure; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; SARS-CoV-2 - drug effects; SARS-CoV-2 - enzymology; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology
• ISSN: 1464-3405
• DOI: 10.1016/j.bmcl.2022.128526

The COVID-19 pandemic has drastically impacted global economies and public health. Although vaccine development has been successful, it was not sufficient against more infectious mutant strains including the Delta variant indicating a need for alternative treatment strategies such as small molecular compound development. In this work, a series of SARS-CoV-2 main protease (M ) inhibitors were designed and tested based on the active compound from high-throughput diverse compound library screens. The most efficacious compound (16b-3) displayed potent SARS-CoV-2 M inhibition with an IC value of 116 nM and selectivity against SARS-CoV-2 M when compared to PL and RdRp. This new class of compounds could be used as potential leads for further optimization in anti COVID-19 drug discovery.