Extension into the entrance channel of HIV-1 reverse transcriptase--crystallography and enhanced solubility

Bioorg Med Chem Lett. 2013 Sep 15;23(18):5209-12. doi: 10.1016/j.bmcl.2013.06.093. Epub 2013 Jul 8.

Abstract

Non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-RT) are reported that feature extension into the entrance channel near Glu138. Complexes of the parent anilinylpyrimidine 1 and the morpholinoethoxy analog 2j with HIV-RT have received crystallographic characterization confirming the designs. Measurement of aqueous solubilities of 2j, 2k, the parent triazene 2a, and other NNRTIs demonstrate profound benefits for addition of the morpholinyl substituent.

Keywords: Anti-HIV agent; Crystal structures; 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*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • HIV Reverse Transcriptase / chemistry*
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects
  • Models, Molecular
  • Molecular Structure
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Solubility
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • Enzyme Inhibitors
  • Pyrimidines
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase