The structural simplification of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) O-(2-phthalimidoethyl)-N-(hetero)aroyl-N-arylthiocarbamates led to design of (hetero)aroyl esters of 2-(N-phthalimido)ethanol as a potential new class of anti-HIV-1 agents. The setup of a soln.-phase parallel synthesis method allowed the rapid prepn. of a high no. of analogs. In cell-based assays, 20 of 34 esters showed anti-HIV-1 activity ranging from nanomolar to micromolar concns. The most potent esters had only a minor effect or were ineffective in enzyme assay against HIV-1 reverse transcriptase. Variations on the O-(2-phthalimidoethyl) moiety led to compds. devoid of antiretroviral activity, but cytotoxic, in particular those bearing the 4-chloro-3-nitrobenzoyl moiety. The most cytotoxic compd. displayed a CC50 value of 1.6 μM.
(Hetero)aroyl esters of 2-(N-phthalimido)ethanol and analogues: parallel synthesis, anti-HIV-1 activity and cytotoxicity
CESARINI, SARA;SPALLAROSSA, ANDREA;RANISE, ANGELO;SCHENONE, SILVIA;
2010-01-01
Abstract
The structural simplification of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) O-(2-phthalimidoethyl)-N-(hetero)aroyl-N-arylthiocarbamates led to design of (hetero)aroyl esters of 2-(N-phthalimido)ethanol as a potential new class of anti-HIV-1 agents. The setup of a soln.-phase parallel synthesis method allowed the rapid prepn. of a high no. of analogs. In cell-based assays, 20 of 34 esters showed anti-HIV-1 activity ranging from nanomolar to micromolar concns. The most potent esters had only a minor effect or were ineffective in enzyme assay against HIV-1 reverse transcriptase. Variations on the O-(2-phthalimidoethyl) moiety led to compds. devoid of antiretroviral activity, but cytotoxic, in particular those bearing the 4-chloro-3-nitrobenzoyl moiety. The most cytotoxic compd. displayed a CC50 value of 1.6 μM.
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