Compound 29 was only weakly active against SARS‐CoV‐1 Mpro (IC50, 800 µM) also in cellular antiviral assays. 130  However, systematic structural modifications led to a series of analogs that show moderate to good activity. 131  For example, compound 30 (Figure 11), in which the P1‐lactam was replaced by a phenyl ring, showed moderate activity. Compound 31, in which the larger P2 p‐fluorophenyl was replaced with a phenyl group, was even more effective. By taking 29 as a lead, Ghosh et al. designed new molecules mainly focusing on the replacement of the large P2 p‐fluorobenzyl group. Two of the resulting structures with P2‐benzyl (32) and prenyl (33) moieties showed decent inhibitory potencies at both enzymatic (K inact, 0.014 and 0.045 min−1, respectively) and cell‐based (IC50, 45 and 70 µM) assays. 132  Besides, no cytotoxicity was observed for these compounds up to 100 µM concentration. However, 32 and 33 were inactive at MERS‐CoV Mpro. 133  The same research group further modified the molecule with the introduction of P4 Boc‐serine, to establish additional hydrogen bond interactions as described in compound 34 (IC50, 75 µM). Unfortunately, the activity of the resulting compound was not improved. Further modification of the isobutyl group in compound 34 to isoprenyl group in compound 35 displayed potent activity with K i = 3.6 µM (Figure 11). 14