Chiral resolution and molecular modeling investigation of rac-2-cyclopentylthio-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methylpyrimidin-4(3H)-one (MC-1047), a potent anti-HIV-1 reverse transcriptase agent of the DABO class

Chirality. 2001 Feb;13(2):75-80. doi: 10.1002/1520-636X(2001)13:2<75::AID-CHIR1001>3.0.CO;2-W.

Abstract

rac-2-Cyclopentylthio-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methylpyrimidin-4(3H)-one (MC-1047) is a potent inhibitor of HIV-1 multiplication in acutely infected cells. MC-1047 racemate has been resolved by chiral HPLC using, as chiral stationary phase (CSP), a commercially available (R,R)-Whelk-01 column. The optical purity and the circular dichroism (CD) of the two resolved enantiomers were determined and their biological activities tested in in vitro assays. Molecular modeling inspection of the binding of (R) and (S) enantiomers to the non-nucleoside binding site (NNBS) of reverse transcriptase (RT) using the defined model of F(2)-S-DABO/RT complex indicates the (R) enantiomer as the more active isomer.

MeSH terms

  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / isolation & purification*
  • Anti-HIV Agents / pharmacology
  • Cell Line
  • Circular Dichroism
  • HIV-1 / drug effects
  • Humans
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Pyrimidinones / chemistry*
  • Pyrimidinones / isolation & purification*
  • Pyrimidinones / pharmacology
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / isolation & purification*
  • Reverse Transcriptase Inhibitors / pharmacology

Substances

  • 2-cyclopentylthio-6-(1-(2,6-difluorophenyl)ethyl)-3,4-dihydro-5-methylpyrimidin-4(3H)-one
  • Anti-HIV Agents
  • Pyrimidinones
  • Reverse Transcriptase Inhibitors