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

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^pro) 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^pro inhibition with an IC₅₀ value of 116 nM and selectivity against SARS-CoV-2 M^pro when compared to PL^pro and RdRp. This new class of compounds could be used as potential leads for further optimization in anti COVID-19 drug discovery.