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

摘要

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 pK i values are linearly correlated with their log k i values – Brønsted plots. Therefore, 1–4 inhibit these enzymes through a common mechanism. Moreover, both pK i and log k i values for the inhibitions by 1,3, and 4 are linearly correlated with both pK i and log k i values for the inhibitions by 2, respectively. Thus, the pK i values for the inhibitions by 2 are defined as the nucleophilicity constants of these enzymes (n enzyme). The log k 2 values for the inhibitions by 1–4 are also linearly correlated with the n enzyme values. Therefore, the nucleophilicity for serine hydrolases and proteases toward 1–4 also applies the Swain–Scott correlations.