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
  • 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: [email protected].
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.