Next, the same group studied the SARs for compound 158 further. This led to the discovery of compound 165 with high PLpro inhibitory activity of SARS‐CoV‐1 (IC50, 0.32 µM) and antiviral activity (EC50, 9.1 µM) in Vero cells. 199  The mode of action of 165 was found to be a noncovalent, competitive inhibition of PLpro. Unlike the previous series, the stereochemistry at the α‐methyl group did not make a significant difference in inhibition of PLpro. For example, both (S)‐ and (R)‐methyl inhibitors, 165 (IC50, 0.32 µM; EC50, 9.1 µM and 166 (IC50, 0.56 µM; EC50, 9.1 µM), respectively, shared equipotent inhibitory activity in enzymatic and cell‐based assays.