Parallel one-pot synthesis and structure-activity relationship study of symmetric formimidoester disulfides as a novel class of potent non-nucleoside HIV-1 reverse transcriptase inhibitors

Description

The mol. duplication of non-nucleoside reverse transcriptase inhibitor (NNRTI) O-(2-phthalimidoethyl)-N-arylthiocarbamates (C-TCs) led to the identification of sym. formimidoester disulfides (DSs) as a novel class of potent NNRTIs. The lead compd. 1 [dimer of the isothiocarbamic form of TC O-(2-phthalimidoethyl)-N-phenylthiocarbamate] turned out to prevent the wild-type HIV-1 multiplication in MT-4 cell culture with an EC50 value of 0.35 μM. In order to perform a structure-activity relationship (SAR) study, we prepd. 40 analogs of 1 by an unprecedented one-pot method of soln.-phase parallel synthesis. The SAR strategy was focused on the variation of the N-aryl portion (mono-, di- and trisubstitution of the Ph ring and its replacement with a 1-naphthyl, cyclopropyl or benzyl group) and of the 2-phthalimidoethyl moiety (introduction of a Me on the phthalimide substructure, replacement of the phthalimide moiety with a Ph ring and elongation of the Et linker). Most DSs proved to inhibit the wild-type HIV-1 replication in cell-based assays and 15 of them were active at nanomolar concns. The most potent congeners (11, 15, 16, 17, 18, 19, 20 and 32, EC50: 10-70 nM) shared the N-para-substituted Ph moiety. Compd. 17 tested in enzyme assay against recombinant wild-type reverse transcriptase displayed an IC50 value of 0.74 μM. Compds. 19 and 33 were active at micromolar concns. against the clin. relevant Y181C and/or K103R resistant mutants.

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