6-Substituted 2-Oxo-2H-1-benzopyran-3-carboxylic Acid as a Core Structure for Specific Inhibitors of Human Leukocyte Elastase

Abstract

Pyridyl esters of 6-substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid were designed as mechanism-based inhibitors of human leukocyte elastase. Compounds of series 4 specifically inhibited this enzyme. Several of the tested compounds (series 2 and 3) acted as powerful time-dependent inhibitors of both human leukocyte elastase and alpha-chymotrypsin; some compounds of these series inhibited thrombin. Trypsin was not inhibited. A transient inactivation was observed for human leukocyte elastase (k(i)/K(I) = 107 000 M(-1). s(-1) for 4c) and thrombin (k(i)/K(I) = 7 200 M(-1).s(-1) for 3b) as demonstrated by spontaneous or hydroxylamine-accelerated reactivation, irrespective of the nature of the substituent at the 6-position. Conversely, alpha-chymotrypsin was irreversibly inhibited by 6-chloromethyl derivatives (k(i)/K(I) = 107 400 M(-1). s(-1) for 3b). The presence of a latent alkylating function at the 6-position (chloromethyl group) was required for leading to this inactivation. In the absence of such an alkylating function (series 4), human leukocyte elastase was specifically inhibited suggesting that this new series of human leukocyte elastase inhibitors may be of potential therapeutic interest in degradative and degenerative processes involving this enzyme.

Coumarinic derivatives as mechanism-based inhibitors of α-chymotrypsin and human leukocyte elastase

“…It should also be speculated that HLE attacks at the exocyclic ester group instead of the lactone. 34 Optimized geometries of the ligand After optimization, 37 revealed two minimal energetic geometries with respect to the dihedral angle C 2 -C 3 -C 14 -X 16 value (Table 5). These minima correspond to two conformations (a and b) characterized by an opposite value for this dihedral angle.…”

Synthesis, hydrolysis, biochemical and theoretical evaluation of 1,4-bis(alkoxycarbonyl)azetidin-2-ones as potential elastase inhibitors

“…A similar observation has been reported occasionally in the case of one ester of 6-chloromethyl-2-oxo-2H-1-benzopyran-3-carboxylic acid tested against HLE; the enzyme reacted with the exocyclic ester. 42 Geometry optimization of compound 6a showed a particular conformation of the N1 side-chain due to the repulsion between the C5 and C6 carbonyls which occurs when C2 suffers nucleophilic attack from the a face. Considering the three potentially sensitive carbonyl functions (C2, C5 and C6), ab initio calculations were performed to determine the energetic barriers required to reach the transition state structures of hydrolysis in a model of enzymic cavity.…”

A cost-effective and green aqueous synthesis of 3-substituted coumarins catalyzed by potassium phthalimide

“…3-Cyanocoumarins, on the other hand, can be transferred to the useful compounds such as amides that exhibit specific inhibitory effects on the α-chemotripsin [8] and leukocyte elastase [9]. Coumarin-3-carbonitriles and 2-iminocoumarin-3-carbonitriles are also important intermediates, which are required for the preparation of 3-(4-oxo-3,4-dihydrothieno [2,3-d]pyrimidin-2-yl)-2-iminocoumarins [10], 3-imino-benzopyrano [2,3-c]isoxazoles [11] as well as 2-(2-iminocoumarin-3-yl)quinazoline-4(3H)-thiones [12].…”