Esters and amides of 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid as inhibitors of α-chymotrypsin : Significance of the aromatic nature of the novel ester-type coumarin for strong inhibitory activity

A series of esters and amides of 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid were synthesized and evaluated in vitro for their inhibitory activity toward bovine α-chymotrypsin and human leukocyte elastase. Both series behaved as time-dependent inhibitors of α-chymotrypsin, but ester-type coumarins were clearly more efficient than the corresponding amides in inactivating the serine proteinase. The best inactivations were observed with “aromatic” esters, in particular with meta-substituted phenyl esters such as m-chlorophenyl 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylate, which appears to be one of the most powerful inactivators of α-chymotrypsin yet reported (kinact/KI = 760 000 M-1 s-1 at pH 7.5 and 25 °C). Usually, the coumarin derivatives failed to inhibit significantly human leukocyte elastase. As a result, the reported series of aromatic coumarinic esters behaves as a new chemical family of selective α-chymotrypsin inhibitors.