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=0.73μM) and also maintained some activity against the clinically important RT mutants K103N and Y181C (IC50=9.2, 3.5μM) 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=0.36μM). These data highlight the discovery of a unique scaffold with the potential to move forward as next-generation anti-HIV-1 agents.
['Stanton|Richard A|RA|', 'Lu|Xiao|X|', 'Detorio|Mervi|M|', 'Montero|Catherine|C|', 'Hammond|Emily T|ET|', 'Ehteshami|Maryam|M|', 'Domaoal|Robert A|RA|', 'Nettles|James H|JH|', 'Feraud|Michel|M|', 'Schinazi|Raymond F|RF|']
D000818:Animals D001665:Binding Sites D002470:Cell Survival D002522:Chlorocebus aethiops D004353:Drug Evaluation, Preclinical D054303:HIV Reverse Transcriptase D015497:HIV-1 D006801:Humans D007211:Indoles D062105:Molecular Docking Simulation D016297:Mutagenesis, Site-Directed D011485:Protein Binding D017434:Protein Structure, Tertiary D018894:Reverse Transcriptase Inhibitors D014709:Vero Cells
Reverse transcriptase FEP HIV NNRTI