Novel indolylarylsulfone derivatives as covalent HIV-1 reverse transcriptase inhibitors specifically targeting the drug-resistant mutant Y181C

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used in combination therapies against HIV-1. However, emergent and transmitted drug resistance compromise their efficacy the clinical setting. Y181C is selected patients receiving nevirapine, etravirine rilpivirine, together with K103N most prevalent NNRTI-associated mutation HIV-infected patients. Herein, we report on design, synthesis biological evaluation of a novel series indolylarylsulfones bearing acrylamide or ethylene sulfonamide reactive groups as warheads to inactivate Cys181-containing HIV-1 RT via Michael addition reaction. Compounds I-7 I-9 demonstrated higher selectivity towards mutant than wild-type RT, nucleotide incorporation inhibition assays. The larger size NNRTI binding pocket enzyme facilitates better fit for active compounds, while stacking interactions Phe227 Pro236 contribute inhibitor binding. Mass spectrometry data were consistent covalent modification although off-target reactivity constitutes major limitation further development described inhibitors.