title: Esters and amides of 6-(chloromethyl)-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.
abstract: 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 alpha-chymotrypsin and human leukocyte elastase. Both series behaved as time-dependent inhibitors of alpha-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 alpha-chymotrypsin yet reported (kinact/KI = 760,000 M-1 S-1 at pH 7.5 and 25 degrees 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 alpha-chymotrypsin inhibitors.
authors.affiliation: Laboratorie de Chimie Pharmaceutique, Université de Liège, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Pochet
authors.forename: C
authors.initials: C
authors.lastname: Doucet
authors.forename: M
authors.initials: M
authors.lastname: Schynts
authors.forename: N
authors.initials: N
authors.lastname: Thierry
authors.forename: N
authors.initials: N
authors.lastname: Boggetto
authors.forename: B
authors.initials: B
authors.lastname: Pirotte
authors.forename: K Y
authors.initials: KY
authors.lastname: Jiang
authors.forename: B
authors.initials: B
authors.lastname: Masereel
authors.forename: P
authors.initials: P
authors.lastname: de Tullio
authors.forename: J
authors.initials: J
authors.lastname: Delarge
authors.forename: M
authors.initials: M
authors.lastname: Reboud-Ravaux
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D002918:Chymotrypsin / Q000037:antagonists & inhibitors*; D006801:Humans; D007700:Kinetics; D019272:Leukocyte Elastase; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001578:Benzopyrans; D015842:Serine Proteinase Inhibitors; D002918:Chymotrypsin; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase