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.

Cardiff School of Pharmacy and Pharmaceutical Sciences Cardiff University CF103NB Cardiff UK

Center for Discovery and Innovation in Parasitic Diseases Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San Diego 9500 Gilman Drive 92093 La Jolla CA USA

Center for Neurodegenerative Disease Research Perelman School of Medicine University of Pennsylvania 3600 Spruce Street 19104 6323 Philadelphia PA USA

Department of Chemistry and Biochemistry University of California San Diego 9500 Gilman Drive 92093 La Jolla CA USA

Present affiliation Chemistry Department Molecular Sciences Research Hub Imperial College London 82 Wood Lane W12 0BZ London UK

Present affiliation Vysoká škola chemicko technologická Praha Department of Organic Chemistry Technická 5 16628 Prague 6 Czech Republic

bioRxiv. 2023 Mar 11:2023.03.11.532093. doi: 10.1101/2023.03.11.532093. PubMed

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