Pentacyclic nitrofurans that rapidly kill nifurtimox-resistant trypanosomes.
J Antimicrob Chemother
; 71(4): 956-63, 2016 Apr.
Article
em En
| MEDLINE
| ID: mdl-26682963
ABSTRACT
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.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Tripanossomicidas
/
Trypanosoma brucei brucei
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Nifurtimox
/
Nitrofuranos
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article