{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:38:19Z","timestamp":1768505899051,"version":"3.49.0"},"posted":{"date-parts":[[2023,3,11]]},"group-title":"Microbiology","reference-count":49,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,3,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  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 \u03b1,\u03b2-tubulin 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-activity relationship (QSAR) model and the prioritization of two congeners for\n                  <jats:italic>in vivo<\/jats:italic>\n                  pharmacokinetics (PK), tolerability and efficacy studies. Treatment of\n                  <jats:italic>T. brucei<\/jats:italic>\n                  -infected mice with tolerable doses of TPDs\n                  <jats:bold>3<\/jats:bold>\n                  and\n                  <jats:bold>4<\/jats:bold>\n                  significantly decreased blood parasitemia within 24 h. Further, two once-weekly doses of\n                  <jats:bold>4<\/jats:bold>\n                  at 10 mg\/kg 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.\n                <\/jats:p>","DOI":"10.1101\/2023.03.11.532093","type":"posted-content","created":{"date-parts":[[2023,3,11]],"date-time":"2023-03-11T23:30:10Z","timestamp":1678577410000},"source":"Crossref","is-referenced-by-count":1,"title":["Structure-Activity Relationships, Tolerability and Efficacy of Microtubule-Active 1,2,4-Triazolo[1,5-\n                  <i>a<\/i>\n                  ]pyrimidines as Potential Candidates to Treat Human African Trypanosomiasis"],"prefix":"10.64898","author":[{"given":"Ludovica","family":"Monti","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lawrence J.","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmine","family":"Varricchio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bobby","family":"Lucero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thibault","family":"Alle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenqian","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ido","family":"Bem-Shalom","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Gilson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kurt R.","family":"Brunden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Brancale","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Conor R.","family":"Caffrey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Ballatore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023031513100480000_2023.03.11.532093v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.idc.2018.10.003"},{"key":"2023031513100480000_2023.03.11.532093v1.2","doi-asserted-by":"publisher","DOI":"10.3390\/tropicalmed5010029"},{"key":"2023031513100480000_2023.03.11.532093v1.3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-031621-025153"},{"key":"2023031513100480000_2023.03.11.532093v1.4","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms10071298"},{"key":"2023031513100480000_2023.03.11.532093v1.5","unstructured":"https:\/\/dndi.org\/research-development\/portfolio\/fexinidazole\/."},{"key":"2023031513100480000_2023.03.11.532093v1.6","unstructured":"Groupe, S.-A. 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