Easy access to α-ketoamides as SARS-CoV-2 and MERS M(pro) inhibitors via the PADAM oxidation route

SARS-CoV-2 caused worldwide the current outbreak called COVID-19. Despite multiple countermeasures implemented, there is an urgent global need for new potent and efficient antiviral drugs against this pathogen. In this context, the main protease (M(pro)) of SARS-CoV-2 is an essential viral enzyme and plays a pivotal role in viral replication and transcription. Its specific cleavage of polypeptides after a glutamine residue has been considered as a key element to design novel antiviral drugs. Herein, we reported the design, synthesis and structure-activity relationships of novel α-ketoamides as covalent reversible inhibitors of M(pro), exploiting the PADAM oxidation route. The reported compounds showed μM to nM activities in enzymatic and in the antiviral cell-based assays against SARS-CoV-2 M(pro). In order to assess inhibitors’ binding mode, two co-crystal structures of SARS-CoV-2 M(pro) in complex with our inhibitors were solved, which confirmed the covalent binding of the keto amide moiety to the catalytic Cys145 residue of M(pro). Finally, in order to interrogate potential broad-spectrum properties, we assessed a selection of compounds against MERS M(pro) where they showed nM inhibitory potency, thus highlighting their potential as broad-spectrum coronavirus inhibitors.