ESTERS AND AMIDES OF (CHLOROMETHYL)1-2-OXO-2H-1-BENZOPYRAN-3-CARBOXYLIC ACID AS INHIBITORS OF ALPHA-CHYMOTRYPSIN - SIGNIFICANCE OF THE AROMATIC NATURE OF THE NOVEL ESTER-TYPE COUMARIN FOR STRONG INHIBITORY ACTIVITY

A series of esters and amides of -(chloromethyl)-2-oxo-2H-1-benzopyran -3-carboxylic acid were synthesized and evaluated in vitro for their i nhibitory activity toward bovine alpha-chymotrypsin and human leukocyt e elastase. Both series behaved as time-dependent inhibitors of alpha- chymotrypsin, but ester-type coumarins were clearly more efficient tha n the corresponding amides in inactivating the serine proteinase. The best inactivations were observed with ''aromatic'' esters, in particul ar with meta-substituted phenyl esters such as m-chlorophenyl chlorome thyl)-2-oxo-2H-1-benzopyran-3-carboxylate, which appears to be one of the most powerful inactivators of alpha-chymotrypsin yet reported (k(i nact)/K-I = 760 000 M(-1) s(-1) at pH 7.5 and 25 degrees C). Usually, the coumarin derivatives failed to inhibit significantly human leukocy te elastase. As a result, the reported series of aromatic coumarinic e sters behaves as a new chemical family of selective alpha-chymotrypsin inhibitors.