RESUMEN
Tubulin and microtubules (MTs) are potential protein targets to treat parasitic infections and our previous studies have shown that the triazolopyrimidine (TPD) class of MT-active compounds hold promise as antitrypanosomal agents. MT-targeting TPDs include structurally related but functionally diverse congeners that interact with mammalian tubulin at either one or two distinct interfacial binding sites; namely, the seventh and vinca sites, which are found within or between α,ß-tubulin heterodimers, respectively. Evaluation of the activity of 123 TPD congeners against cultured Trypanosoma brucei enabled a robust quantitative structure-activity relationship (QSAR) model and the prioritization of two congeners for inâ vivo pharmacokinetics (PK), tolerability and efficacy studies. Treatment of T.â brucei-infected mice with tolerable doses of TPDs significantly decreased blood parasitemia within 24â h. Further, two once-weekly doses at 10â mg/kg of a candidate TPD significantly extended the survival of infected mice relative to infected animals treated with vehicle. Further optimization of dosing and/or the dosing schedule of these CNS-active TPDs may provide alternative treatments for human African trypanosomiasis.
Asunto(s)
Tripanocidas , Trypanosoma brucei brucei , Tripanosomiasis Africana , Humanos , Ratones , Animales , Tripanosomiasis Africana/tratamiento farmacológico , Tubulina (Proteína)/metabolismo , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Pirimidinas/química , Microtúbulos/metabolismo , Relación Estructura-Actividad , Trypanosoma brucei brucei/metabolismo , Tripanocidas/farmacología , Tripanocidas/uso terapéutico , Tripanocidas/química , Mamíferos/metabolismoRESUMEN
Tubulin and microtubules (MTs) are potential protein targets to treat parasitic infections and our previous studies have shown that the triazolopyrimidine (TPD) class of MT- active compounds hold promise as antitrypanosomal agents. MT-targeting TPDs include structurally related but functionally diverse congeners that interact with mammalian tubulin at either one or two distinct interfacial binding sites; namely, the seventh and vinca sites, which are found within or between α,ß-tubulin heterodimers, respectively. Evaluation of the activity of 123 TPD congeners against cultured Trypanosoma brucei enabled a robust quantitative structure-activity relationship (QSAR) model and the prioritization of two congeners for in vivo pharmacokinetics (PK), tolerability and efficacy studies. Treatment of T. brucei -infected mice with tolerable doses of TPDs 3 and 4 significantly decreased blood parasitemia within 24 h. Further, two once-weekly doses of 4 at 10 mg/kg significantly extended the survival of infected mice relative to infected animals treated with vehicle. Further optimization of dosing and/or the dosing schedule of these CNS-active TPDs may provide alternative treatments for human African trypanosomiasis.