2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs) as human immunodeficiency virus type 1 integrase inhibitors: Influence of the alkylcarboxamide substitution of position 4.
Herein, we report further insight into the biological activities displayed by the 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) scaffold. Previous studies have evidenced the marked fruitful effect of substitution of this two-metal binding pharmacophore at position 4 by phenyl and benzyl carboxamido chains. Strong human immunodeficiency virus type 1 integrase (HIV-1 IN) inhibitors in the low nanomolar range with micromolar (even down to low nanomolar) anti-HIV activities were obtained. Keeping this essential 4-carboxamido function, we investigated the influence of the replacement of phenyl and benzyl groups by various alkyl chains. This study shows that the recurrent halogenobenzyl pharmacophore found in the INSTIs can be efficiently replaced by an n-alkyl group. With an optimal length of six carbons, we observed a biological profile and a high barrier to resistance equivalent to those of a previously reported hit compound bearing a 4-fluorobenzyl group.
Université Lille Nord de France, F-59000 Lille, France; Centre de Recherches Jean-Pierre Aubert UMR-S1172, Faculté des Sciences Pharmaceutiques et Biologiques, 3 rue du Professeur Laguesse, BP83, F-59006 Lille, France.
Muriel
M
Billamboz
Université Lille Nord de France, F-59000 Lille, France; Centre de Recherches Jean-Pierre Aubert UMR-S1172, Faculté des Sciences Pharmaceutiques et Biologiques, 3 rue du Professeur Laguesse, BP83, F-59006 Lille, France.
Virginie
V
Suchaud
Université Lille Nord de France, F-59000 Lille, France; Centre de Recherches Jean-Pierre Aubert UMR-S1172, Faculté des Sciences Pharmaceutiques et Biologiques, 3 rue du Professeur Laguesse, BP83, F-59006 Lille, France. Electronic address: fabrice.bailly@univ-lille1.fr.
Fabrice
F
Bailly
Université Lille Nord de France, F-59000 Lille, France; UMR CNRS 8576, Unité de Glycobiologie Structurale et Fonctionnelle, F-59655 Villeneuve d'Ascq, France.
Cedric
C
Lion
Laboratoire MFP, UMR 5234 CNRS, Université Bordeaux Segalen, FR Transbiomed, 146 Rue Léo Saignat, F-33076 Bordeaux, France.
Marie-Line
ML
Andréola
Molecular Medicine, K.U. Leuven and IRC KULAK, Kapucijnenvoer 33, B-3000 Leuven, Flanders, Belgium.
Frauke
F
Christ
Molecular Medicine, K.U. Leuven and IRC KULAK, Kapucijnenvoer 33, B-3000 Leuven, Flanders, Belgium.
Zeger
Z
Debyser
Université Lille Nord de France, F-59000 Lille, France; Centre de Recherches Jean-Pierre Aubert UMR-S1172, Faculté des Sciences Pharmaceutiques et Biologiques, 3 rue du Professeur Laguesse, BP83, F-59006 Lille, France.
Philippe
P
Cotelle
D000478:Alkylation; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000187:drug effects; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
C558516:2-hydroxyisoquinoline-1,3(2H,4H)-dione; D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D007546:Isoquinolines
2-hydroxyisoquinoline-1,3(2H,4H)-diones; Antiretroviral; HIV-1 integrase; Two-metal binding pharmacophore