Introduction of the 4-(4-bromophenyl)benzenesulfonyl group to hydrazide analogs of Ilomastat leads to potent gelatinase B (MMP-9) inhibitors with improved selectivity.
Hydrazide derivatives of Ilomastat, carrying either aryl groups or distinct alkyl and arylsulfonyl moieties were synthesized and evaluated for their MMP inhibitory activity. Potent and selective MMP-9 inhibition (IC(50)=3 nM) was observed for compound 3m (arylsulfonyl group: 4-(4-Br-C6H4)-C6H4-SO(2)-). Interaction with the S2 enzyme subsite is mainly responsible for the inhibitory properties of this derivative as confirmed by molecular docking computation.
Ledour
Gwennaël
G
Université de Reims-Champagne-Ardenne, CNRS UMR 6229, Institut de Chimie Moléculaire de Reims, Faculté de Pharmacie, IFR53 Biomolécules, 51 rue de Cognacq-Jay, 51096 Reims Cedex, France.
Moroy
Gautier
G
Rouffet
Matthieu
M
Bourguet
Erika
E
Guillaume
Dominique
D
Decarme
Martine
M
Elmourabit
Haquima
H
Augé
Franck
F
Alix
Alain J P
AJ
Laronze
Jean-Yves
JY
Bellon
Georges
G
Hornebeck
William
W
Sapi
Janos
J
D000465:Algorithms; D001554:Benzene / Q000737:chemistry / Q000494:pharmacology*; D006834:Hydrazines / Q000138:chemical synthesis / Q000494:pharmacology*; D006877:Hydroxamic Acids; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000737:chemistry / Q000494:pharmacology*
D006834:Hydrazines; D006877:Hydroxamic Acids; D007211:Indoles; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013451:Sulfonic Acids; C119203:ilomastat; D001554:Benzene