title: Design, synthesis, and biological evaluation of a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones as dual inhibitors of human immunodeficiency virus type 1 integrase and the reverse transcriptase RNase H domain.
abstract: We report herein the synthesis of a series of 19 2-hydroxyisoquinoline-1,3(2H,4H)-dione derivatives variously substituted at position 7 aimed at inhibiting selectively two-metal ion catalytic active sites. The compounds were tested against HIV-1 reverse transcriptase (RT) polymerase, HIV-1 RT ribonuclease H (RNase H), and HIV-1 integrase (IN). Most compounds displayed poor inhibition of RT polymerase even at 50 microM. The majority of the synthesized compounds inhibited RNase H and IN at micromolar concentrations, and some of them were weakly selective for IN. Surprisingly, two new hits were discovered, which displayed a high selectivity for IN with submicromolar IC50 values. These enzymatic inhibitory properties may be related to the metal binding abilities of the compounds. Physicochemical studies were consistent with a 1/1 stoichiometry of the magnesium complexes in solution, and the metal complexation was strictly dependent on the enolization abilities of the compounds. Unfortunately, all tested compounds exhibited high cellular cytotoxicity in cell culture which limits their applications as antiviral agents.
authors.affiliation: Laboratoire de Chimie Organique et Macromoléculaire, UMR CNRS 8009, Université de Lille 1, 59655 Villeneuve d'Ascq, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Billamboz
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bailly
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Barreca
authors.forename: Laura
authors.initials: L
authors.lastname: De Luca
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Mouscadet
authors.forename: Christina
authors.initials: C
authors.lastname: Calmels
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Andréola
authors.forename: Myriam
authors.initials: M
authors.lastname: Witvrouw
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Philippe
authors.initials: P
authors.lastname: Cotelle
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry; D002384:Catalysis; D020134:Catalytic Domain; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D015497:HIV-1 / Q000201:enzymology* / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000494:pharmacology*; D008956:Models, Chemical; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016914:Ribonuclease H / Q000737:chemistry*
chemical_list: D000998:Antiviral Agents; D007546:Isoquinolines; D018894:Reverse Transcriptase Inhibitors; D016914:Ribonuclease H