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. Epub 2016 Jun 25.

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.

MeSH terms

  • Animals
  • Binding Sites
  • Cell Survival / drug effects
  • Chlorocebus aethiops
  • Drug Evaluation, Preclinical
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Humans
  • Indoles / chemistry*
  • Indoles / metabolism
  • Indoles / pharmacology
  • Indoles / toxicity
  • Molecular Docking Simulation
  • Mutagenesis, Site-Directed
  • Protein Binding
  • Protein Structure, Tertiary
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / metabolism
  • Reverse Transcriptase Inhibitors / pharmacology
  • Vero Cells

Substances

  • 7-azaindole dimer
  • Indoles
  • Reverse Transcriptase Inhibitors
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase