title: Pentacyclic nitrofurans that rapidly kill nifurtimox-resistant trypanosomes.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN, USA Avista Pharma Solutions, Durham, NC, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Bruhn
authors.affiliation: Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee, Scotland, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Wyllie
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Adaris
authors.initials: A
authors.lastname: Rodríguez-Cortés
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Angela K
authors.initials: AK
authors.lastname: Carrillo
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.lastname: Rakesh
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.affiliation: Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee, Scotland, UK.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Fairlamb
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN, USA richard.lee@stjude.org.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004351:Drug Resistance; D006801:Humans; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D009547:Nifurtimox / Q000494:pharmacology*; D009581:Nitrofurans / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000648:ultrastructure
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D009581:Nitrofurans; D014344:Trypanocidal Agents; D009547:Nifurtimox