New indolylarylsulfones as highly potent and broad spectrum HIV-1 non-nucleoside reverse transcriptase inhibitors

• New indolylarylsulfones were prepared and evaluated as HIV-1 NNRTIs.
• Against the NL4-3 HIV-1 WT strain, compounds 4–15 were superior to reference drugs NVP and EFV.
• Several compounds inhibited the K103N HIV-1 mutant strain in the nanomolar range of concentration and were superior to EFV.
• Against the Y181C and L100I HIV-1 mutant strains, some compounds were superior to EFV.
• Enantiomer 24 was more potent than 25 against the whole viral panel.

New indolylarylsulfone HIV-1 NNRTIs were synthesized to evaluate unexplored substitutions of the benzyl/phenylethyl group linked at the indole-2-carboxamide. Against the NL4-3 HIV-1 WT strain, 17 out 20 compounds were superior to NVP and EFV. Several compounds inhibited the K103N HIV-1 mutant strain at nanomolar concentration and were superior to EFV. Some derivatives were superior to EFV against the Y181C and L100I HIV-1 mutant strains. Against the NL4-3 HIV-1 strain, the enantiomers 24 and 25 showed small differences of activity. In contrast, 24 turned out significantly more potent than 25 against the whole panel of mutant HIV-1 strains. The docking studies suggested that the difference in the observed inhibitory activities of 24 and 25 against the K03N mutation could be due to a kinetic rather than affinity differences.

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