title: Mechanism-based thrombin inhibitors: design, synthesis, and molecular docking of a new selective 2-oxo-2H-1-benzopyran derivative.
abstract: New 2-oxo-2H-1-benzopyran derivatives were prepared to optimize 2a,b, initially developed as mechanism-based alpha-chymotrypsin (alpha-CT) inhibitors, into potent and selective thrombin (THR) inhibitors. From this study, 22, characterized by a 2-(N-ethyl-2'-oxoacetamide)-5'-chlorophenyl ester side chain, was shown to be a good THR inhibitor (ki/KI = 3455 M(-1) x s(-1)), displaying an excellent selectivity profile against other serine proteases such as factor Xa, trypsin, and alpha-CT. Docking analysis of this compound into the different protein structures revealed the molecular basis responsible for its potency and selectivity.
authors.affiliation: Department of Pharmacy, University of Namur, FUNDP, 61, Rue de Bruxelles, B-5000 Namur, Belgium. raphael.frederick@gmail.com
authors.forename: Raphaël
authors.initials: R
authors.lastname: Frédérick
authors.forename: Séverine
authors.initials: S
authors.lastname: Robert
authors.forename: Caroline
authors.initials: C
authors.lastname: Charlier
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
authors.forename: Bernard
authors.initials: B
authors.lastname: Masereel
authors.forename: Lionel
authors.initials: L
authors.lastname: Pochet
mesh_terms: D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: C523416:3-(5-chloro-2-(N-ethyloxoacetamido)phenoxycarbonyl)-6-chloromethylcoumarin; D001578:Benzopyrans; D003374:Coumarins; D013917:Thrombin