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.

• Klíčová slova
• Triazolopyrimidines, Trypanosoma brucei, drug discovery, human African trypanosomiasis, microtubules,
• MeSH
• lidé MeSH
• mikrotubuly metabolismus   MeSH
• myši MeSH
• pyrimidiny farmakologie   terapeutické užití   chemie   MeSH
• savci metabolismus   MeSH
• trypanocidální látky * farmakologie   terapeutické užití   chemie   MeSH
• Trypanosoma brucei brucei * metabolismus   MeSH
• trypanozomóza africká * farmakoterapie   MeSH
• tubulin metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• pyrimidiny MeSH
• trypanocidální látky * MeSH
• tubulin MeSH