Indolylarylsulfones with potent anti-HIV-1 activity

Acquired immune deficiency syndrome (AIDS) pandemic remains among the leading causes of death worldwide. 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. We designed and synthesized a series of chiral indolylarylsulfones (IASs) as new HIV-1 NNRTIs. The new IASs 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 at semipreparative level into their pure enantiomers. The (R)-8 enantiomer bearing the chiral (a-methylbenzyl) was superior to the (S)-counterpart. IAS derivatives bearing the (S) alanine unit, (S)-23, (S,R)-25, (S)-31, and (S)-33, were remarkably more potent than the corresponding (R)-enantiomers. Compound 23 protected hippocampal neuronal cells from the excitotoxic insult, while efavirenz did not contrast the neurotoxic effect of glutamate. The present results highlight the chiral IASs as new NNRTIs with improved resistance profile against the mutant HIV-1 strains and reduced neurotoxic effects.