The aldehyde inhibitor 9b with a P3-indole capping group also showed moderate inhibition of M pro . This prompted us to focus on analogs of 9b with an altered warhead structure, and the nitrile 11b as well as the Michael acceptor 12b were also evaluated with respect to their antiviral activity. Although 11b and 12b were found to be more than 100-fold weaker CatL inhibitors than 9b, one of the analogs, i.e., 11b, exhibited antiviral activity. This result was unexpected and indicated that potent in vitro activity against CatL was not a prerequisite for activity in the cellular antiviral test system. A correlation between the CatL and antiviral data for the other three nitrile inhibitors 11d,e,g was also not evident, since in the case of 11g, the highly efficient CatL inhibition (Ki = 9.56 nM) was not accompanied by strong effects against viral infection, whereas the rather weak CatL inhibitor 11e was potent in the antiviral assay exhibiting an EC50 value of 35.1 nM. This compound might act through interference with another biological target, which must be investigated in future studies.