Pyrazolidinone-based peptidomimetic SARS-CoV-2 Mpro inhibitors.

The main protease (Mpro) of SARS-CoV-2 is an attractive drug target for COVID-19 treatment as it plays an integral role in the proliferation of coronavirus. Herein, we describe the investigation of ß- and γ-lactams as electrophilic "warheads" for covalent binding to Cys145 of the Mpro active site. The highest inhibitory activity (IC50 = 45 ± 3 µM) was achieved using a pyrazolidinone warhead attached to the targeting dipeptide. Importantly, the synergy of the warhead and the targeting dipeptide is crucial for the successful inhibition of Mpro.