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

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.

Figure optionsDownload as PowerPoint slide