Design, synthesis, and biological evaluation of novel trifluoromethyl indoles as potent HIV-1 NNRTIs with an improved drug resistance profile

Org Biomol Chem. 2014 Jun 7;12(21):3446-58. doi: 10.1039/c3ob42186d. Epub 2014 Apr 22.

Abstract

A novel series of trifluoromethyl indole derivatives have been designed, synthesized and evaluated for anti-HIV-1 activities in MT-2 cells. The hydrophobic constant, acute toxicity, carcinogenicity and mutagenicity were predicted. Trifluoromethyl indoles 10i and 10k showed extremely promising activities against WT HIV-1 with IC50 values at the low nanomolar level, similar to efavirenz, better than nevirapine, and also possessed higher potency towards the drug-resistant mutant strain Y181C than nevirapine. Preliminary SAR and docking studies of detailed binding mode provided some insights for discovery of more potent NNRTIs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / chemistry
  • Alkynes
  • Benzoxazines / chemistry
  • Benzoxazines / pharmacology
  • Carcinogens / toxicity
  • Catalysis
  • Cell Line
  • Cyclopropanes
  • Drug Design*
  • Drug Resistance, Viral / drug effects*
  • HIV Reverse Transcriptase / chemistry
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Ligands
  • Models, Molecular
  • Mutagens / toxicity
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*

Substances

  • Aldehydes
  • Alkynes
  • Benzoxazines
  • Carcinogens
  • Cyclopropanes
  • Indoles
  • Ligands
  • Mutagens
  • Mutant Proteins
  • Reverse Transcriptase Inhibitors
  • 3-hydroxybutanal
  • HIV Reverse Transcriptase
  • efavirenz