Ghosh et al. 197  contributed significantly to the development of SARS‐CoV‐1 PLpro inhibitors based on the naphthalene scaffold. Two lead compounds 157 and 158 (Figure 36) were identified by an HTS of a chemical library containing greater than 50 000 compounds. They both inhibit PLpro of SARS‐CoV‐1 at a moderate potency (IC50 20.1 and 59 µM, respectively). The (R)‐enantiomer of compound 157 was found to be a greater than twofold more potent inhibitor of PLpro when compared with its racemic mixture (157). Subsequent SAR studies highlighted the 2‐naphthyl substitution as an important structural requirement rather than at the position 1 of the naphthyl ring in addition to the presence of o‐methyl and m‐amino groups, in the other phenyl ring. Compound 159 displayed the best inhibitory activity of PLpro (IC50, 0.6 µM) and acts in a noncovalent reversible manner with a K i value of 0.49 µM. 198  Compound 159 also showed moderate antiviral activity in Vero cells with an EC50 value of 14.5 µM.