Synthesis, biological evaluation and molecular modeling of 2-Hydroxyisoquinoline-1,3-dione analogues as inhibitors of HIV reverse transcriptase associated ribonuclease H and polymerase

Eur J Med Chem. 2017 Jun 16:133:85-96. doi: 10.1016/j.ejmech.2017.03.059. Epub 2017 Mar 29.

Abstract

Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function not clinically validated as an antiviral target. 2-Hydroxyisoquinoline-1,3-dione (HID) is known to confer active site directed inhibition of divalent metal-dependent enzymatic functions, such as HIV RNase H, integrase (IN) and hepatitis C virus (HCV) NS5B polymerase. We report herein the synthesis and biochemical evaluation of a few C-5, C-6 or C-7 substituted HID subtypes as HIV RNase H inhibitors. Our data indicate that while some of these subtypes inhibited both the RNase H and polymerase (pol) functions of RT, potent and selective RNase H inhibition was achieved with subtypes 8-9 as exemplified with compounds 8c and 9c.

Keywords: 2-hydroxyisoquinoline-1,3-diones; HIV; Inhibitor; RNase H; Reverse transcriptase.

MeSH terms

  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology*
  • Catalytic Domain / drug effects
  • Drug Design
  • HIV Infections / drug therapy
  • HIV Infections / virology
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / enzymology*
  • Humans
  • Isoquinolines / chemistry*
  • Isoquinolines / pharmacology*
  • Molecular Docking Simulation
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Ribonuclease H / antagonists & inhibitors*
  • Ribonuclease H / metabolism

Substances

  • 2-hydroxyisoquinoline-1,3(2H,4H)-dione
  • Anti-HIV Agents
  • Isoquinolines
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase
  • Ribonuclease H