Potent and selective HIV-1 ribonuclease H inhibitors based on a 1-hydroxy-1,8-naphthyridin-2(1H)-one scaffold

Bioorg Med Chem Lett. 2010 Nov 15;20(22):6754-7. doi: 10.1016/j.bmcl.2010.08.135. Epub 2010 Sep 24.

Abstract

Optimization studies using an HIV RNase H active site inhibitor containing a 1-hydroxy-1,8-naphthyridin-2(1H)-one core identified 4-position substituents that provided several potent and selective inhibitors. The best compound was potent and selective in biochemical assays (IC(50)=0.045 μM, HIV RT RNase H; 13 μM, HIV RT-polymerase; 24 μM, HIV integrase) and showed antiviral efficacy in a single-cycle viral replication assay in P4-2 cells (IC(50)=0.19 μM) with a modest window with respect to cytotoxicity (CC(50)=3.3 μM).

MeSH terms

  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • HIV-1 / enzymology*
  • HeLa Cells
  • Humans
  • Naphthyridines / chemistry
  • Naphthyridines / pharmacology
  • Ribonuclease H / antagonists & inhibitors*

Substances

  • 1-hydroxy-1,8-naphthyridin-2(1H)-one
  • Anti-HIV Agents
  • Enzyme Inhibitors
  • Naphthyridines
  • Ribonuclease H