Development of Potent and Effective SARS-CoV-2 Main Protease Inhibitors Based on Maleimide Analogs for the Potential Treatment of COVID-19

In the present work, we report a new series of potent SARS-CoV-2 Main Protease (Mpro) inhibitors based on maleimide derivatives. The inhibitory activities were tested in an enzymatic assay using recombinant Mpro (3CL Protease from coronavirus SARS-CoV-2). Within the set of new Mpro inhibitors, 6e demonstrated the highest activity in the enzymatic assay with an IC50 value of 8.52 +/- 0.44 mu M. The IC50 value for Nirmatrelvir (PF-07321332, used as a reference) was 0.84 +/- 0.37 mu M. The cytotoxic properties were determined in the MTT assay using MRC-5 and HEK-293 cell lines. In the course of the investigation, we found that the newly obtained maleimide derivatives are not substantially cytotoxic (IC50 values for most compounds were above 200 mu M).