Previously, isatin (2,3‐dioxoindole) derivatives were observed to inhibit rhinovirus 3C protease. 176  Due to the structural similarity between the rhinovirus 3C protease and SARS‐CoV‐1 Mpro, these derivatives were tested against SARS‐CoV‐1 Mpro. Among them, 106 (IC50, 0.95 µM) and 107 (IC50, 0.98 µM) exhibited the best SARS‐CoV‐1 Mpro inhibitory activity in the low micromolar range. 176  SAR studies suggested that the inhibition efficiency was mainly reliant on hydrophobic and electronic properties of the isatin core substitution pattern. Docking studies revealed that the molecules fit well in the active site of the protease. Both carbonyl groups of the isatin core engaged in H‐bonds with NH of Gly143, Ser144, Cys145, and His41. Compounds 106 and 107  176  were more selective for SARS‐CoV‐1 Mpro than other proteases like papain (106, 103 µM; 107, 87.24 µM), chymotrypsin (106, ~1 mM; 107, 10.4 µM), and trypsin (106, 362 µM; 107, 243 µM; Figure 28).