To revisit M pro inhibitory activity, we did not identify an inhibitor that was active in the nanomolar range. This finding was in sharp contrast to the outstanding activity against cathepsins that we observed for certain representatives. Only the aldehydes 9b (Figure ) and 9c displayed moderate M pro inhibitory activities that were accompanied by their extremely strong potency against cathepsins. Considering the capability of cathepsins to proteolytically activate coronaviral spike proteins via the endosomal pathway, the most promising compounds were subjected to an investigation of their antiviral activity. ) was investigated for potential cytotoxicity on Calu-3 cells at a high concentration of 10 μM. None of the compounds exhibited cytotoxicity at the given concentration. Calu-3 cells, which were infected with SARS-CoV-2, were used to test the antiviral activity of the selected compounds (9a-c, 11b,d,e,g, 12b). Figure illustrates the activity against SARS-CoV-2, Pango lineage B.1.513. We employed molnupiravir, a recognized and authorized SARS-CoV-2 inhibitor, as a positive control. The cells were incubated 1 hour before infection with SARS-CoV-2 at a multiplicity of infection (MOI) of 0.01 and 24 hours postinfection (p.i.) with 10-fold serial dilutions (10-0.001 µM) of each inhibitor. Viral titers of Calu-3 cell culture supernatants were determined by titration on Vero E6 cells 24 h p.i. and are expressed as plaque-forming units (PFU) per milliliter. From these data, EC50 values were calculated (Table ).