Mechanism-based thrombin inhibitors: design, synthesis, and molecular docking of a new selective 2-oxo-2H-1-benzopyran derivative.
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.
Frédérick
Raphaël
R
Department of Pharmacy, University of Namur, FUNDP, 61, Rue de Bruxelles, B-5000 Namur, Belgium. raphael.frederick@gmail.com
Robert
Séverine
S
Charlier
Caroline
C
Wouters
Johan
J
Masereel
Bernard
B
Pochet
Lionel
L
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
C523416:3-(5-chloro-2-(N-ethyloxoacetamido)phenoxycarbonyl)-6-chloromethylcoumarin; D001578:Benzopyrans; D003374:Coumarins; D013917:Thrombin