Probing Structure–Function Relationships of Serine Hydrolases and Proteases with Carbamate and Thiocarbamate Inhibitors

Benzene-1,3-di-N-n-octylcarbamate (1), benzene-1-hydroxyl-3-N-n-octylcarbamate (2), benzene-1,3-di-N-n-ocztylthiocarbamate (3), and benzene-1-hydroxyl-3-N-n-octylthiocarbamate (4) are synthesized from 1,3-benzene-diol and are characterized as the pseudo-substrate inhibitors of acetylcholinesterase, butyrylcholinesterase, cholesterol esterase, lipase, trypsin, and chymotrypsin. For these six enzyme inhibitions by 1–4, the pKi values are linearly correlated with their log ki values – Brønsted plots. Therefore, 1–4 inhibit these enzymes through a common mechanism. Moreover, both pKi and log ki values for the inhibitions by 1,3, and 4 are linearly correlated with both pKi and log ki values for the inhibitions by 2, respectively. Thus, the pKi values for the inhibitions by 2 are defined as the nucleophilicity constants of these enzymes (nenzyme). The log k2 values for the inhibitions by 1–4 are also linearly correlated with the nenzyme values. Therefore, the nucleophilicity for serine hydrolases and proteases toward 1–4 also applies the Swain–Scott correlations.