Dialkylimidazole inhibitors of Trypanosoma cruzi sterol 14α-demethylase as anti-Chagas disease agents

Bioorg Med Chem Lett. 2013 Dec 1;23(23):6492-9. doi: 10.1016/j.bmcl.2013.08.015. Epub 2013 Aug 12.

Abstract

New dialkylimidazole based sterol 14α-demethylase inhibitors were prepared and tested as potential anti-Trypanosoma cruzi agents. Previous studies had identified compound 2 as the most potent and selective inhibitor against parasite cultures. In addition, animal studies had demonstrated that compound 2 is highly efficacious in the acute model of the disease. However, compound 2 has a high molecular weight and high hydrophobicity, issues addressed here. Systematic modifications were carried out at four positions on the scaffold and several inhibitors were identified which are highly potent (EC50 <1 nM) against T. cruzi in culture. The halogenated derivatives 36j, 36k, and 36p, display excellent activity against T. cruzi amastigotes, with reduced molecular weight and lipophilicity, and exhibit suitable physicochemical properties for an oral drug candidate.

Keywords: CYP51; Chagas disease; Dialkylimidazole; Sterol 14-alpha demethylase; Trypanosoma cruzi.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-alpha Demethylase Inhibitors / administration & dosage
  • 14-alpha Demethylase Inhibitors / pharmacology
  • 14-alpha Demethylase Inhibitors / therapeutic use*
  • Animals
  • Chagas Disease / drug therapy*
  • Chagas Disease / parasitology
  • Imidazoles / pharmacology*
  • Models, Molecular
  • Trypanosoma cruzi / drug effects*
  • Trypanosoma cruzi / enzymology*

Substances

  • 14-alpha Demethylase Inhibitors
  • Imidazoles