Design, synthesis, SAR, and molecular modeling studies of acylthiocarbamates: a novel series of potent non-nucleoside HIV-1 reverse transcriptase inhibitors structurally related to phenethylthiazolylthiourea derivatives

J Med Chem. 2003 Feb 27;46(5):768-81. doi: 10.1021/jm0209984.


A novel series of potent, selective HIV-1 N-acylthiocarbamate (ATC) nonnucleoside reverse transcriptase inhibitors (NNRTIs) is described. The title compounds were synthesized through a highly convergent, one-pot procedure. In cell-based assays, the lead compound (17c) prevented the HIV-1 multiplication with an EC(50) of 8 microM. The lead optimization strategy was developed by single or multiple modifications of the three molecular portions, in which 17c was notionally divided. Molecular modeling studies led to the synthesis of O-(2-phthalimidoethyl)-N-(p-substituted phenyl)-N-acylthiocarbamates, which showed in vitro activities against HIV-1 in the low nanomolar range. Nevertheless, the title compounds retained low potency against HIV-1 strains carrying mutations (K103R, Y181C, and K103N/Y181C) responsible for NNRTI resistance. The hypothetical docking model of RT/17c and RT/25c, derived from X-ray crystallographic structure of a PETT derivative in complex with HIV-1 RT, revealed that the model structures of ATCs do not approximate the NNRTI butterfly-like conformation. Analysis of these hypotetical complexes helps to rationalize some SARs and resistance data.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Computer-Aided Design
  • HIV Reverse Transcriptase / chemistry*
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects
  • Humans
  • Ligands
  • Models, Molecular
  • Mutation
  • Quantitative Structure-Activity Relationship
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Thiazoles / chemistry*
  • Thiocarbamates / chemical synthesis*
  • Thiocarbamates / chemistry
  • Thiocarbamates / pharmacology
  • Thiourea / chemistry*
  • Virus Replication


  • Ligands
  • Reverse Transcriptase Inhibitors
  • Thiazoles
  • Thiocarbamates
  • HIV Reverse Transcriptase
  • Thiourea