Indolylarylsulfones as novel potent anti-HIV-1 agents

Acquired Immune Deficiency Syndrome (AIDS) is a leading cause of death worldwide. HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) are key highly active antiretroviral therapy drugs in the clinical management of AIDS/HIV-1 infections. Our recent studies showed that indolylarylsulfones (IASs) bearing a cyclic moiety on the 2-carboxamide nitrogen, linked through a short spacer group, are endowed with potent antiretroviral activity. The new IASs 8-37 showed potent inhibition of the HIV-1 WT NL4-3 strain and of the mutant K103N, Y181C, Y188L and K103N-Y181C HIV-1 strains. Six racemic mixtures, 8, 23-25, 31 and 33, were separated into their pure enantiomers. Overall, the (R)-8 enantiomer bearing the chiral (α- methylbenzyl) was superior to the (S)-counterpart. IAS derivatives bearing the (S)-alanine unit, (S)-23 and (S,R)-25, were remarkably more potent than the corresponding (R)-enantiomers. Moreover, the use of compound 23 resulted in the protection hippocampal neuronal cells from the excitotoxic insult, while efavirenz did not contrast the neurotoxic effect of glutamate. These results highlight the chiral IASs as new NNRTIs with improved resistance profile against the mutant HIV-1 strains and reduced neurotoxic effects.