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Here, a series of novel bis\u2010tetrahydropyran 1,4\u2010triazole analogues based on the framework of chamuvarinin, a polyketide natural product isolated from the <jats:italic>annonaceae<\/jats:italic> plant species are detailed. The analogues synthesized display low micromolar trypanocidal activities towards both bloodstream and insect forms of <jats:italic>Trypanosoma brucei<\/jats:italic>, the causative agent of African sleeping sickness, also known as Human African Trypanosomiasis (HAT). A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4\u2010triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure\u2013activity relationship studies. Together, the biological potency and calculated lipophilicity values indicate that while there is room for improvement, these derivatives may represent a promising novel class of anti\u2010HAT agents.<\/jats:p>","DOI":"10.1002\/cmdc.201402272","type":"journal-article","created":{"date-parts":[[2014,8,21]],"date-time":"2014-08-21T19:29:22Z","timestamp":1408649362000},"page":"2548-2556","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Non\u2010natural Acetogenin Analogues as Potent <i>Trypanosoma brucei<\/i> Inhibitors"],"prefix":"10.1002","volume":"9","author":[{"given":"Gordon J.","family":"Florence","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew L.","family":"Fraser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eoin R.","family":"Gould","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth F. 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