title: Magnesium chelating 2-hydroxyisoquinoline-1,3(2H,4H)-diones, as inhibitors of HIV-1 integrase and/or the HIV-1 reverse transcriptase ribonuclease H domain: discovery of a novel selective inhibitor of the ribonuclease H function.
abstract: 2-Hydroxyisoquinoline-1,3(2H,4H)-dione was recently discovered as a scaffold for the inhibition of HIV-1 integrase and the ribonuclease H function of HIV-1 reverse transcriptase. First, we investigate its interaction with Mg(2+) and Mn(2+) using different spectroscopic techniques and report that 2-hydroxyisoquinoline-1,3(2H,4H)-dione forms a 1:1 complex with Mg(2+) but a 1:2 complex with Mn(2+). The complex formation requires enolization of the ligand. ESR spectroscopy shows a redox reaction between the ligand and Mn(2+) producing superoxide anions. Second, 2-hydroxyisoquinoline-1,3(2H,4H)-dione, its magnesium complex, and its 4-methyl and 2-hydroxy-4-methoxycarbonylisoquinoline-1,3(2H,4H)-diones were tested as inhibitors of HIV-1 integrase, reverse transcriptase ribonuclease H, and DNA polymerase functions. Their antiviral activities were evaluated and 2-hydroxy-4-methoxycarbonyl-isoquinoline-1,3(2H,4H)-dione was found to inhibit the viral replication of HIV-1 in MT-4 cells. Cross-resistance was measured for this compound on three different viral strains. Experimental data suggest that the antiviral activity of 2-hydroxy-4-methoxycarbonylisoquinoline-1,3(2H,4H)-dione is probably due to the RNase H inhibition.
authors.affiliation: Université Lille Nord de France, F-59000 Lille, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Billamboz
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bailly
authors.forename: Cédric
authors.initials: C
authors.lastname: Lion
authors.forename: Nadia
authors.initials: N
authors.lastname: Touati
authors.forename: Hervé
authors.initials: H
authors.lastname: Vezin
authors.forename: Christina
authors.initials: C
authors.lastname: Calmels
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Andréola
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: D020134:Catalytic Domain; D002460:Cell Line; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D024882:Drug Resistance, Viral; D004578:Electron Spin Resonance Spectroscopy; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007536:Isomerism; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008274:Magnesium; D009682:Magnetic Resonance Spectroscopy; D054309:Ribonuclease H, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D002614:Chelating Agents; D056831:Coordination Complexes; D019428:HIV Integrase Inhibitors; D007546:Isoquinolines; D054309:Ribonuclease H, Human Immunodeficiency Virus; D008274:Magnesium