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MT\u2010targeting 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 \u03b1,\u03b2\u2010tubulin heterodimers, respectively. Evaluation of the activity of 123 TPD congeners against cultured\n                    <jats:italic>Trypanosoma brucei<\/jats:italic>\n                    enabled a robust quantitative structure\u2010activity relationship (QSAR) model and the prioritization of two congeners for\n                    <jats:italic>in\u2005vivo<\/jats:italic>\n                    pharmacokinetics (PK), tolerability and efficacy studies. Treatment of\n                    <jats:italic>T.\u2005brucei<\/jats:italic>\n                    \u2010infected mice with tolerable doses of TPDs significantly decreased blood parasitemia within 24\u2005h. Further, two once\u2010weekly doses at 10\u2005mg\/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\u2010active TPDs may provide alternative treatments for human African trypanosomiasis.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202300193","type":"journal-article","created":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T22:27:50Z","timestamp":1689028070000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Structure\u2010Activity Relationships, Tolerability and Efficacy of Microtubule\u2010Active 1,2,4\u2010Triazolo[1,5\u2010\n                    <i>a<\/i>\n                    ]pyrimidines as Potential Candidates to Treat Human African Trypanosomiasis**"],"prefix":"10.1002","volume":"18","author":[{"given":"Ludovica","family":"Monti","sequence":"first","affiliation":[{"name":"Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences University of California, San Diego  9500 Gilman Drive 92093 La Jolla CA USA"},{"name":"Present affiliation: Chemistry Department Molecular Sciences Research Hub Imperial College London  82 Wood Lane W12\u20090BZ London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence J.","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences University of California, San Diego  9500 Gilman Drive 92093 La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmine","family":"Varricchio","sequence":"additional","affiliation":[{"name":"Cardiff School of Pharmacy and Pharmaceutical Sciences Cardiff University  CF103NB Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bobby","family":"Lucero","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences University of California, San Diego  9500 Gilman Drive 92093 La Jolla CA USA"},{"name":"Department of Chemistry &amp; Biochemistry University of California, San Diego  9500 Gilman Drive 92093 La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thibault","family":"Alle","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences University of California, San Diego  9500 Gilman Drive 92093 La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqian","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences University of California, San Diego  9500 Gilman Drive 92093 La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ido","family":"Ben\u2010Shalom","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences University of California, San Diego  9500 Gilman Drive 92093 La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Gilson","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences University of California, San Diego  9500 Gilman Drive 92093 La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt R.","family":"Brunden","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research Perelman School of Medicine University of Pennsylvania  3600 Spruce Street 19104-6323 Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Brancale","sequence":"additional","affiliation":[{"name":"Cardiff School of Pharmacy and Pharmaceutical Sciences Cardiff University  CF103NB Cardiff UK"},{"name":"Present affiliation: Vysok\u00e1 \u0161kola chemicko-technologick\u00e1 v Praze Department of Organic Chemistry  Technick\u00e1 5 16628 Prague 6 Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conor R.","family":"Caffrey","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences University of California, San Diego  9500 Gilman Drive 92093 La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2718-3850","authenticated-orcid":false,"given":"Carlo","family":"Ballatore","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences University of California, San Diego  9500 Gilman Drive 92093 La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,7,24]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.idc.2018.10.003","volume":"33","author":"Bottieau E.","year":"2019","journal-title":"Infect. 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