Discovery, characterization, and lead optimization of 7-azaindole non-nucleoside HIV-1 reverse transcriptase inhibitors

A library of 585 compounds built off a 7-azaindole core was evaluated for anti-HIV-1 activity, and ten hits emerged with submicromolar potency and therapeutic index >100. Of these, three were identified as non-nucleoside reverse transcriptase (RT) inhibitors and were assayed against relevant resistant mutants. Lead compound 8 inhibited RT with submicromolar potency (IC50 = 0.73 μM) and also maintained some activity against the clinically important RT mutants K103N and Y181C (IC50 = 9.2, 3.5 μM) in cell-free assays. Free energy perturbation guided lead optimization resulted in the development of a compound with a two-fold increase in potency against RT (IC50 = 0.36 μM). These data highlight the discovery of a unique scaffold with the potential to move forward as next-generation anti-HIV-1 agents.

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