Thiocarbamates as non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 1: Parallel synthesis, molecular modelling and structure-activity relationship studies on O-[2-(hetero)arylethyl]-N-phenylthiocarbamates

Bioorg Med Chem. 2008 Apr 1;16(7):4160-72. doi: 10.1016/j.bmc.2007.12.050. Epub 2007 Dec 25.

Abstract

In order to expand the structure-activity relationship (SAR) studies on Thiocarbamates (TCs), a recently discovered class of potent non-nucleoside HIV-1 reverse transcriptase inhibitors, 38 analogues of the lead O-[2-(2-pyridyl)ethyl]-N-phenylthiocarbamate 1 were prepared by parallel solution-phase synthesis. The SAR strategy was focused on the variation (mono- and disubstitution) of the N-phenyl ring and the replacement of the 2-pyridyl with 4-pyridyl, 2-thienyl and phenyl rings. The majority of the new TCs proved to prevent the wild-type HIV-1 multiplication in MT-4 cell culture and the most potent congeners displayed an EC(50) value of 100 nM. Two TCs were active also at micromolar concentrations against the Y181C- and/or K103N/Y181C-resistant mutants. Docking simulations helped to rationalize the SARs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • HIV-1 / drug effects*
  • HIV-1 / enzymology*
  • HIV-1 / genetics
  • Models, Molecular*
  • Molecular Structure
  • Mutation / genetics
  • Nucleosides / chemistry
  • RNA-Directed DNA Polymerase / genetics
  • RNA-Directed DNA Polymerase / metabolism
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Thiocarbamates / chemical synthesis*
  • Thiocarbamates / chemistry
  • Thiocarbamates / pharmacology*

Substances

  • Nucleosides
  • Reverse Transcriptase Inhibitors
  • Thiocarbamates
  • RNA-Directed DNA Polymerase