Chiral resolution, absolute configuration assignment and biological activity of racemic diarylpyrimidine CH(OH)-DAPY as potent nonnucleoside HIV-1 reverse transcriptase inhibitors

Eur J Med Chem. 2012 Jul;53:229-34. doi: 10.1016/j.ejmech.2012.04.004. Epub 2012 Apr 21.

Abstract

(+)-3a and (-)-3a were successfully separated from racemate (±)-3a by the chiral technique of supercritical fluid chromatography (SCF) with enantiomeric excess (ee%) >99% and purity >99%, and assigned for their absolute configuration as R and S, respectively, by the experimental electronic circular dichroism (ECD) spectrum and simulated ECD spectra calculated by time-dependent density functional theory (TDDFT) calculations. (+)-(R)-3a displayed excellent activity with an EC(50) of 5.3 nM against wild-type HIV-1, which was 12-fold more potent than (-)-(S)-3a. However, (-)-(S)-3a showed higher potency than (+)-(R)-3a against the double HIV-1 RT mutant (K103N+Y181C) as well as HIV-2 strain ROD. The possible reason for the difference of (R)- and (S)-3a in anti-HIV-1 activity was interpreted by molecular docking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / chemistry
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • HIV-2 / drug effects
  • Models, Molecular
  • Protein Conformation
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Stereoisomerism

Substances

  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase
  • pyrimidine