Structure-based Design, Parallel Synthesis, SAR and Molecular Modelling Studies of Thiocarbamates, New Potent Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitor Isosteres of Phenethylthiazolylthiourea (PETT) Derivatives.

Description

Thiocarbamates (TCs) has been identified as a novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), isosteres of phenethylthiazolylthiourea (PETT) derivatives. Assuming as a lead compound O-[2-(phthalimido)ethyl]-phenylthiocarbamate, one of the precursors of the previously described acylthiocarbamates (Ranise, A.; et al. J. Med. Chem. 2003, 46, 768-781), two targeted solution-phase TC libraries were prepared by parallel synthesis. The lead optimization strategy led to para-substituted TCs which were active against wild-type HIV-1 in MT-4-based assays at nanomolar concentrations (EC50 range: 0.04-0.01 microM). Most of the TCs showed good selectivity indices, since no cytotoxic effect was detected at concentrations as high as 100 microM. Furthermore a number of TCs significantly reduced the multiplication of the Y181C mutant, but they were inactive against K103R and K103N + Y181C mutants. The docking model predictions were consistent with in vitro biological assays of the anti-HIV-1 activity of the TCs and related compounds synthesized.

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