Structure‐Activity Relationships, Tolerability and Efficacy of Microtubule‐Active 1,2,4‐Triazolo[1,5‐a]pyrimidines as Potential Candidates to Treat Human African Trypanosomiasis

We describe the structure-activity relationships, tolerability, and efficacy of microtubule-targeting 1,2,4-triazolo[1,5-a]pyrimidines (TPDs) against the neglected pathogen, Trypanosoma brucei – the causative agent of human African trypanosomiasis (HAT). We identified viable candidates that reduce blood parasitemia within 24 h and extend the survival of T. brucei-infected mice compared to control animals. This evidence suggests that TPDs may be potential alternative treatments for HAT.

Abstract

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,β-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 significantly decreased blood parasitemia within 24 h. Further, two once-weekly doses at 10 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.

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