Discovery and structure-activity relationship studies of novel α-ketoamide derivatives targeting the SARS-CoV-2 main protease.

The SARS-CoV-2 main protease (M, also named 3CL) is a promising antiviral target against COVID-19 due to its functional importance in viral replication and transcription. Herein, we report the discovery of a series of α-ketoamide derivatives as a new class of SARS-CoV-2 M inhibitors. Structure-activity relationship (SAR) of these compounds was analyzed, which led to the identification of a potent M inhibitor (27h) with an IC value of 10.9 nM. The crystal structure of M in complex with 27h revealed that α-ketoamide warhead covalently bound to Cys145s of the protease. In an in vitro antiviral assay, 27h showed excellent activity with an EC value of 43.6 nM, comparable to the positive control, Nirmatrelvir. This compound displayed high target specificity for M against human proteases and low toxicity. It also possesses favorable pharmacokinetic properties. Overall, compound 27h could be a promising lead compound for drug discovery targeting SARS-CoV-2 M and deserves further in-depth studies.