title: Discovery, characterization, and lead optimization of 7-azaindole non-nucleoside HIV-1 reverse transcriptase inhibitors.
abstract: 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.
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Stanton
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Lu
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Mervi
authors.initials: M
authors.lastname: Detorio
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Montero
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Emily T
authors.initials: ET
authors.lastname: Hammond
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Ehteshami
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Domaoal
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Nettles
authors.affiliation: PROVEPHARM, 22 rue Marc Donadille, F-13013 Marseille, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Feraud
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: rschina@emory.edu.
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
mesh_terms: D000818:Animals; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004353:Drug Evaluation, Preclinical; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D062105:Molecular Docking Simulation; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D014709:Vero Cells
chemical_list: C023422:7-azaindole dimer; D007211:Indoles; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: FEP; HIV; NNRTI; Reverse transcriptase