Drug design, synthesis and biological evaluation of new antiretroviral agents

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of AIDS/HIV-1 infection. Our recent studies showed that indolylarylsulfones (IASs) bearing a cyclic moiety at the 2-carboxamide nitrogen linked through a short spacer group were endowed with potent antiretroviral activity.1,2 Based on the results previously obtained, we aimed to expand the SAR studies by the introduction of new aryl or heteroaryl portions to the indole nucleus. Interestingly, for the first time IASs endowed with one asymmetric centre have shown significant differences in term of antiretroviral potency. In particular, the R-enantiomer proved to be exceptionally potent and uniformly superior to the S-enantiomer against the whole viral panel. Docking studies showed that the methyl group of the R-enantiomer pointed toward the cleft created by the K103N mutation, in contrast the corresponding group of (S) counterpart. By calculating the solvent accessible surface, we observed that the exposed area of the RT in complex with S-enantiomer was larger than the area of the (R) complex.3