Coumarinic derivatives as mechanism-based inhibitors of alpha-chymotrypsinand human leukocyte elastase

Novel coumarinic derivatives were synthesized and tested for their inhibito ry potency toward alpha-CT and HLE. Cycloalkyl esters and amides were found to be essentially inactive on both enzymes. On the opposite, aromatic este rs strongly inactivated alpha-CT whereas HLE was less efficiently inhibited with dichlorophenyl ester derivatives (k(inact)/K-I=4000 M-1 s(-1) for 36) . Representative examples of amide, eater, thioester and ketone derivatives were prepared in order to evaluate the influence of the link between the c oumarinic ring and the phenyl side chain. The irreversible inactivation of alpha-CT by 6-chloromethyl derivatives should be due to alkylation of a his tidine residue as suggested by the amino acid analysis of the modified chym otrypsin. Conversely the inhibition of HLE was transient. Intrinsic reactiv ity of coumarins has been calculated using a model of a nucleophilic reacti on between the ligand and the couple methanol-water, From this calculation, it appears that differences in the inhibitory potency expressed by these m olecules cannot only be explained by differences in the reactivity of the l actonic carbonyl group toward the nucleophilic attack. (C) 2000 Elsevier Sc ience Ltd. All rights reserved.