Thiocarbamates as non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 2: Parallel synthesis, molecular modelling and structure-activity relationship studies on analogues of O-(2-phenylethyl)-N-phenylthiocarbamate

Bioorg Med Chem. 2008 Apr 1;16(7):4173-85. doi: 10.1016/j.bmc.2007.12.046. Epub 2007 Dec 25.

Abstract

To acquire further insight into the structure-activity relationship (SAR) of the thiocarbamates (TCs) described in the preceding work, 57 analogues of the lead compound O-(2-phenylethyl)-N-phenylthiocarbamate I were prepared by parallel solution-phase synthesis. We varied the 2-phenylethyl moiety (mono-substitution on the phenyl ring and modification of the ethyl linker), keeping constant the N-phenyl ring substitutions which have given the best results in the previous series. Most of the new TCs inhibited wild-type HIV-1 at micro- and nanomolar concentrations in MT-4 cell-based assays. Some TCs were also active at micromolar concentrations against the Y181C and/or K103N/Y181C resistant mutants. The SARs were rationalized by docking simulations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • HIV-1 / drug effects*
  • HIV-1 / enzymology*
  • Models, Molecular*
  • Molecular Structure
  • Nucleosides / chemistry
  • 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