2. Academic Validation
  3. 2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs) as human immunodeficiency virus type 1 integrase inhibitors: Influence of the alkylcarboxamide substitution of position 4

2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs) as human immunodeficiency virus type 1 integrase inhibitors: Influence of the alkylcarboxamide substitution of position 4

  • Eur J Med Chem. 2016 Jul 19:117:256-68. doi: 10.1016/j.ejmech.2016.03.083.
Muriel Billamboz 1,  Virginie Suchaud 1,  Fabrice Bailly 2,  Cedric Lion 3,  Marie-Line Andréola 4,  Frauke Christ 5,  Zeger Debyser 5,  Philippe Cotelle 1
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Université Lille Nord de France, F-59000 Lille, France; UMR CNRS 8576, Unité de Glycobiologie Structurale et Fonctionnelle, F-59655 Villeneuve d'Ascq, France.
  • 4 Laboratoire MFP, UMR 5234 CNRS, Université Bordeaux Segalen, FR Transbiomed, 146 Rue Léo Saignat, F-33076 Bordeaux, France.
  • 5 Molecular Medicine, K.U. Leuven and IRC KULAK, Kapucijnenvoer 33, B-3000 Leuven, Flanders, Belgium.
PMID: 27105029 DOI: 10.1016/j.ejmech.2016.03.083
Abstract

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.

Keywords

2-hydroxyisoquinoline-1,3(2H,4H)-diones; Antiretroviral; HIV-1 integrase; Two-metal binding pharmacophore.

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