ChemInform Abstract: 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.

Abstract

Esters and Amides of 6-(Chloromethyl)-2-oxo-2H-1-benzopyran-3carboxylic Acid as Inhibitors of α-Chymotrypsin: Significance of the "Aromatic" Nature of the Novel Ester-Type Coumarin for Strong Inhibitory Activity. -The title compounds (30 examples) are synthesized and tested in vitro for their inhibitory activity towards bovine α-chymotrypsin and human leukocyte elastase. The best inactivations are observed with aromatic esters, in particular with m-substituted phenyl esters, such as (VIc), which appears to be one of the most powerful inactivators of α-chymotrypsin hitherto reported.-(POCHET, L.; DOUCET, C.; SCHYNTS, M.; THIERRY, N.; BOGGETTO, N.; PIROTTE, B.; JIANG, K. Y.; MASEREEL, B.; DE TULLIO, P.; DELARGE, J.; REBOUD-RAVAUX, M.; J. Med. Chem. 39 (1996) 13, 2579-2585; Lab. Chim. Pharm., Univ. Liege, B-4000 Liege, Belg.; EN)

Toward the First Class of Suicide Inhibitors of Kallikreins Involved in Skin Diseases

“…On the other hand, cycloalkyl (cyclododecyl; X = CH 2 Cl) ester and amide derived from 6-(chloromethyl)-2-oxo-2 H -1-benzopyran-3-carboxylic acid were found inactive on the selected KLKs and matriptase. It was also the case for the corresponding methyl and allyl amides. Methyl and ethyl esters (X = CH 2 Cl) were poorly active: IC 50 = 54 ± 2 μM against KLK5 and 27 ± 2 μM against KLK7 for the methyl compound; IC 50 = 21 ± 1 μM against KLK7 for the ethyl compound.…”

“…The synthesis of several tested compounds was previously described. − New 2-oxo-2 H -1-benzopyran-3-carboxylic acid derivatives bearing a fluoromethyl or a bromomethyl group at the 6-position were obtained according to the chemical pathway described in Scheme . The reaction of the appropriate di(halo)phenyl ester of malonic acid 2 with 5-hydroxymethylsalicylaldehyde , in the conditions of the Knoevenagel reaction provided the (halo)phenyl 6-(hydroxymethyl)-2-oxo-2 H -1-benzopyran-3-carboxylates 3 .…”

“…The synthesis of several tested compounds was previously described. − New 2-oxo-2 H -1-benzopyran-3-carboxylic acid derivatives bearing a fluoromethyl or a bromomethyl group at the 6-position were obtained according to the chemical pathway described in Scheme . The reaction of the appropriate di(halo)phenyl ester of malonic acid 2 with 5-hydroxymethylsalicylaldehyde , in the conditions of the Knoevenagel reaction provided the (halo)phenyl 6-(hydroxymethyl)-2-oxo-2 H -1-benzopyran-3-carboxylates 3 . The latter 6-(hydroxymethyl)-substituted intermediates were converted into the final 6-(fluoromethyl)- ( 4a ) or 6-(bromomethyl)-substituted (halo)phenyl 2-oxo-2 H -1-benzopyran-3-carboxylates ( 4b - e ) after reaction with the Ishikawa’s reagent ( 56 ) (fluorination) or with thionyl bromide (bromination).…”

“…The isoquinol-1-yl ester of 2-oxo-2 H -1-benzopyran-3-carboxylic acid ( 56 ) resulted from the reaction of 1-hydroxyisoquinoline with the acid chloride of the commercially available 2-oxo-2 H -1-benzopyran-3-carboxylic acid. Other unpublished monosubstituted phenyl esters of 6-(chloromethyl)-2-oxo-2 H -1-benzopyran-3-carboxylic acid (compounds 18 , 19 , 28 , 29 , 30 , 33 ) were synthesized from the reaction of 6-(chloromethyl)-2-oxo-2 H -1-benzopyran-3-carbonyl chloride with the appropriate phenol according to a previously described process …”

“…Our former studies on coumarin-3-carboxylic acid derivatives as potent inhibitors of some serine proteases − prompted us to obtain new families of nonpeptidic inhibitors susceptible to selectively target KLKs. This study was also extended to matriptase, an activator of pro-KLK5 that is considered an initiator of the KLK cascades in the skin …”