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

A novel series of potent, selective HIV-1 N-acylthiocarbamate (ATC) nonnucleoside reverse transcriptase inhibitors (NNRTIs) is described. The title compds. were synthesized through a highly convergent, one-pot procedure. In cell-based assays, the lead compd. (I) prevented the HIV-1 multiplication with an EC50 of 8 μM. The lead optimization strategy was developed by single or multiple modifications of the three mol. portions, in which I was notionally divided. Mol. 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 compds. retained low potency against HIV-1 strains carrying mutations (K103R, Y181C, and K103N/Y181C) responsible for NNRTI resistance. The hypothetical docking model of RT/I and RT/II, derived from X-ray crystallog. structure of a PETT deriv. in complex with HIV-1 RT, revealed that the model structures of ATCs do not approx. the NNRTI butterfly-like conformation. Anal. of these hypothetical complexes helps to rationalize some SARs and resistance data.