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We used <jats:italic>Trypanosoma brucei<\/jats:italic> as a protozoal model organism to test synthetically modified derivatives, resulting in simplified but equally active compounds <jats:bold>2<\/jats:bold> (ZHAWOC6025) and <jats:bold>4<\/jats:bold> (ZHAWOC6027), which were subsequently modified in all regions of the molecule to gain an in\u2010depth SAR understanding. The antiprotozoal SAR matched SAR in phospholipid liposomes, where membrane integrity, leaking, and dynamics were studied. The mode of action is discussed based on a structure\u2013activity analysis of derivatives in efficacy, ultrastructural studies in <jats:italic>T. brucei<\/jats:italic>, and artificial membrane models, mimicking membrane stability and membrane potential. The main site of antiprotozoal action of natural and synthetic leucinostatins lies in the destabilization of the inner mitochondrial membrane, as demonstrated by ultrastructural analysis, electron microscopy and mitochondrial staining. Long\u2010time sublethal exposure of <jats:italic>T. brucei<\/jats:italic> (200 passages) and siRNA screening of 12\u2032000 mutants showed no signs of resistance development to the synthetic derivatives.<\/jats:p>","DOI":"10.1002\/anie.202102153","type":"journal-article","created":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T19:12:21Z","timestamp":1616008341000},"page":"15613-15621","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Antiprotozoal Structure\u2013Activity Relationships of Synthetic Leucinostatin Derivatives and Elucidation of their Mode of Action"],"prefix":"10.1002","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6998-0516","authenticated-orcid":false,"given":"Michael","family":"Brand","sequence":"first","affiliation":[{"name":"Institute of Chemistry and Biotechnology Center for Organic and Medicinal Chemistry Zurich University of Applied Sciences (ZHAW)  Einsiedlerstrasse 31 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