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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

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journal contribution
posted on 24.03.2011, 00:00 by Muriel Billamboz, Fabrice Bailly, Cédric Lion, Nadia Touati, Hervé Vezin, Christina Calmels, Marie-Line Andréola, Frauke Christ, Zeger Debyser, Philippe Cotelle
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 Mg2+ and Mn2+ using different spectroscopic techniques and report that 2-hydroxyisoquinoline-1,3(2H,4H)-dione forms a 1:1 complex with Mg2+ but a 1:2 complex with Mn2+. The complex formation requires enolization of the ligand. ESR spectroscopy shows a redox reaction between the ligand and Mn2+ 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.