Structural and theoretical studies of [6-bromo-1-(4-fluorophenylmethyl)-4(1H)-quinolinon-3-yl)]-4-hydroxy-2-oxo-3-butenoïc acid as HIV-1 integrase inhibitor.
Ethyl [6-bromo-1-(4-fluorophenylmethyl)-4(1H)-quinolinon-3-yl]-4-hydroxy-2-oxo-3-butenoate 1 and [6-bromo-1-(4-fluorophenylmethyl)-4(1H)-quinolinon-3-yl)]-4-hydroxy-2-oxo-3-butenoïc acid 2 were synthesized as potential HIV-1 integrase inhibitors and evaluated for their enzymatic and antiviral activity, acidic compound 2 being more potent than ester compound 1. X-ray diffraction analyses and theoretical calculations show that the diketoacid chain of compound 2 is preferentially coplanar with the quinolinone ring (dihedral angle of 0-30 degrees ). Docking studies suggest binding modes in agreement with structure-activity relationships.
Vandurm
Pierre
P
Laboratoire de Chimie Biologique Structurale, Facultés Universitaires Notre-Dame de la Paix, B-5000 Namur, Belgium. pierre.vandurm@fundp.ac.be
Cauvin
Christine
C
Guiguen
Allan
A
Georges
Benoît
B
Le Van
Kiet
K
Martinelli
Valérie
V
Cardona
Christelle
C
Mbemba
Gladys
G
Mouscadet
Jean-François
JF
Hevesi
László
L
Van Lint
Carine
C
Wouters
Johan
J
D042462:4-Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002087:Butyrates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008968:Molecular Conformation; D011485:Protein Binding; D011789:Quantum Theory; D013329:Structure-Activity Relationship
C543995:(6-bromo-1-(4-fluorophenylmethyl)-4(1H)-quinolinon-3-yl)-4-hydroxy-2-oxo-3-butenoic acid; D042462:4-Quinolones; D002087:Butyrates; D019428:HIV Integrase Inhibitors; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1