Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility

Bioorg Med Chem Lett. 2013 Sep 15;23(18):5213-6. doi: 10.1016/j.bmcl.2013.06.091. Epub 2013 Jul 8.

Abstract

Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.

Keywords: Anti-HIV agent; Drug solubility; NNRTI.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Cell Line, Transformed
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • HIV-1 / drug effects*
  • Humans
  • Hydrazines / chemical synthesis
  • Hydrazines / chemistry
  • Hydrazines / pharmacology*
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Solubility
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • Hydrazines