Pentacyclic nitrofurans that rapidly kill nifurtimox-resistant trypanosomes

J Antimicrob Chemother. 2016 Apr;71(4):956-63. doi: 10.1093/jac/dkv417. Epub 2015 Dec 18.


Objectives: In response to reports of Trypanosoma brucei resistance to the nitroaromatic drug nifurtimox, we evaluated the potential of antituberculosis nitrofuran isoxazolines as inhibitors of trypanosome growth.

Methods: The susceptibility of T. brucei brucei was assessed in vitro. The lowest effective concentration to inhibit growth (EC90) against drug-susceptible and -resistant parasites, time-kill kinetics, reversibility of inhibition and propensity for P-glycoprotein-mediated exclusion from the blood-brain barrier were determined.

Results: Nitrofuran isoxazolines were potent inhibitors of T. brucei brucei proliferation at nanomolar concentrations, with pentacyclic nitrofurans being 100-fold more potent than nifurtimox. Activity was sustained against nifurtimox-resistant parasites, suggesting the possibility of a unique mechanism of activation and potential for use in the treatment of drug-resistant infections. Exposure of parasites to the maximum concentrations of Compound 15 achieved in vivo with oral dosing yielded >2 logs of irreversible killing in <4 h, indicating rapid trypanocidal activity.

Conclusions: Pentacyclic nitrofuran isoxazolines warrant further development for the treatment of drug-susceptible and nifurtimox-resistant trypanosome infections.

Publication types

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

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / drug effects
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Animals
  • Cell Line
  • Drug Resistance
  • Humans
  • Kinetics
  • Microbial Sensitivity Tests
  • Nifurtimox / pharmacology*
  • Nitrofurans / chemical synthesis
  • Nitrofurans / pharmacology*
  • Nitrofurans / toxicity
  • Trypanocidal Agents / chemical synthesis
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma brucei brucei / drug effects*
  • Trypanosoma brucei brucei / ultrastructure


  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Nitrofurans
  • Trypanocidal Agents
  • Nifurtimox