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
  • 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.