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

Citations Over TimeTop 10% of 2008 papers

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.

Related Papers

• Characterization and structural analysis of HIV-1 integrase conservation.(2009)
• → Evolution of Integrase Resistance During Failure of Integrase Inhibitor-Based Antiretroviral Therapy(2010)73 cited
• → Bovine Brain Ribonuclease Is the Functional Homolog of Human Ribonuclease 1(2014)31 cited
• → Synthesis and HIV-1 Integrase Inhibition Activity of some N-Arylindoles(2008)46 cited
• → Compensating effects on the cytotoxicity of ribonuclease A variants(2003)25 cited