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

Monti, Ludovica, Liu, Lawrence J., Varricchio, Carmine ORCID: https://orcid.org/0000-0002-1673-4768, Lucero, Bobby, Alle, Thibault, Yang, Wenqian, Bem‐Shalom, Ido, Gilson, Michael, Brunden, Kurt R., Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Caffrey, Conor R. and Ballatore, Carlo 2023. 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. ChemMedChem 18 (20) , e202300193. 10.1002/cmdc.202300193

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by-nc/4.0/
Publisher:	Wiley
ISSN:	1860-7179
Date of First Compliant Deposit:	25 July 2023
Date of Acceptance:	10 July 2023
Last Modified:	06 Jan 2024 05:11
URI:	https://orca.cardiff.ac.uk/id/eprint/161257

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