2. Academic Validation
  3. Discovery, characterization, and lead optimization of 7-azaindole non-nucleoside HIV-1 reverse transcriptase inhibitors

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

  • Bioorg Med Chem Lett. 2016 Aug 15;26(16):4101-5. doi: 10.1016/j.bmcl.2016.06.065.
Richard A Stanton 1,  Xiao Lu 1,  Mervi Detorio 1,  Catherine Montero 1,  Emily T Hammond 1,  Maryam Ehteshami 1,  Robert A Domaoal 1,  James H Nettles 1,  Michel Feraud 2,  Raymond F Schinazi 3
Affiliations

Affiliations

  • 1 Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 2 PROVEPHARM, 22 rue Marc Donadille, F-13013 Marseille, France.
  • 3 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.
PMID: 27390064 DOI: 10.1016/j.bmcl.2016.06.065
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.

Keywords

FEP; HIV; NNRTI; Reverse transcriptase.

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