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.
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.
Billamboz
Muriel
M
Laboratoire de Chimie Organique et Macromoléculaire, UMR CNRS 8009, Université de Lille 1, 59655 Villeneuve d'Ascq, France.
Bailly
Fabrice
F
Barreca
Maria Letizia
ML
De Luca
Laura
L
Mouscadet
Jean-François
JF
Calmels
Christina
C
Andréola
Marie-Line
ML
Witvrouw
Myriam
M
Christ
Frauke
F
Debyser
Zeger
Z
Cotelle
Philippe
P
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*
D000998:Antiviral Agents; D007546:Isoquinolines; D018894:Reverse Transcriptase Inhibitors; D016914:Ribonuclease H