2. Academic Validation
  3. 4-Substituted 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as a Novel Class of HIV-1 Integrase Inhibitors

4-Substituted 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as a Novel Class of HIV-1 Integrase Inhibitors

  • ACS Med Chem Lett. 2013 May 17;4(7):606-11. doi: 10.1021/ml400009t.
Muriel Billamboz 1,  Virginie Suchaud 1,  Fabrice Bailly 1,  Cedric Lion 1,  Jonas Demeulemeester 2,  Christina Calmels 3,  Marie-Line Andréola 3,  Frauke Christ 2,  Zeger Debyser 2,  Philippe Cotelle 1
Affiliations

Affiliations

  • 1 Université Lille Nord de France , F-59000 Lille, France ; Université Lille 1 Sciences & Technologies , EA 4478 Chimie Moléculaire et Formulation, F-59655 Villeneuve d'Ascq, France.
  • 2 KU Leuven , Molecular Virology and Gene Therapy (VCTB+5), Kapucijnenvoer 33, B-3000 Leuven, Flanders, Belgium.
  • 3 UMR 5234 CNRS, Université Bordeaux Segalen , 146 Rue Léo Saignat, F-33076 Bordeaux, France.
PMID: 24900718 DOI: 10.1021/ml400009t
Abstract

A series of 2-hydroxy-1,3-dioxoisoquinoline-4-carboxamides featuring an N-hydroxyimide chelating functionality was evaluated for their inhibitory properties against human immunodeficiency virus type 1 integrase (HIV-1 IN). Several derivatives displayed low nanomolar IC50 values comparable to that of the clinically used raltegravir. A marked effect of one compound on both primary IN-catalyzed reactions, strand transfer (ST), and 3' processing (3'-P), emphasizes a novel IN inhibition mechanism establishing it as a potential new generation IN inhibitor. Substitution of the 2-hydroxyisoquinoline-1,3-dione scaffold at position 4 by carboxamido chains was beneficial for Antiviral activity since reproducible low micromolar anti-HIV activities were obtained for the first time within this scaffold.

Keywords

2-hydroxy-1,3-dioxoisoquinoline-4-carboxamide; 3′ processing; HIV; antiretroviral; integrase.

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