Design, synthesis, and biological activity of a novel series of 2,5-disubstituted furans/pyrroles as HIV-1 fusion inhibitors targeting gp41

Bioorg Med Chem Lett. 2011 Nov 15;21(22):6895-8. doi: 10.1016/j.bmcl.2011.08.081. Epub 2011 Sep 5.

Abstract

Based on molecular docking analysis of earlier results, we designed a series of 2,5-disubstituted furans/pyrroles (5a-h) as HIV-1 entry inhibitors. Compounds were synthesized by Suzuki-Miyaura cross coupling, followed by a Knoevenagel condensation or Wittig reaction. Four of these compounds were found to be effective in inhibiting HIV-1 infection, with the best compounds being 5f and 5h, which exhibited significant inhibition on HIV-1(IIIB) infection at micromolar levels with low cytotoxicity. These compounds are also effective in blocking HIV-1 mediated cell-cell fusion and the gp41 six-helix bundle formation, suggesting that they are also HIV-1 fusion inhibitors targeting gp41 and have potential to be developed as a new class of anti-HIV-1 agents.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Design
  • Furans / chemical synthesis
  • Furans / chemistry
  • Furans / pharmacology
  • HIV Envelope Protein gp41 / antagonists & inhibitors*
  • HIV Envelope Protein gp41 / metabolism
  • HIV Fusion Inhibitors / chemical synthesis
  • HIV Fusion Inhibitors / chemistry*
  • HIV Fusion Inhibitors / pharmacology*
  • HIV Infections / drug therapy
  • HIV-1 / drug effects*
  • Humans
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry*
  • Pyrroles / pharmacology*

Substances

  • Furans
  • HIV Envelope Protein gp41
  • HIV Fusion Inhibitors
  • Pyrroles