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Various synthetic tetralone derivatives were studied as potential scaffolds for antileishmanial and antitrypanosomal activities. The compounds were studied for their effectiveness against multiple kinetoplastid protozoan pathogens: <jats:italic>Leishmania major<\/jats:italic>, <jats:italic>Leishmania mexicana,<\/jats:italic> and bloodstream trypomastigotes of <jats:italic>Trypanosoma brucei brucei<\/jats:italic>. Two different strains of <jats:italic>T. b. brucei<\/jats:italic> were used. The first strain was the wild\u2010type <jats:italic>Trypanosoma brucei<\/jats:italic> (s427\u2010WT), and the second strain was the multidrug resistant (MDR) strain B48, which was produced by deleting the TbAT1 gene from s427WT and subsequent adaptation to high levels of resistance to diamidines and organo\u2010arsenical drugs. Compounds <jats:bold>4c, 7c, 9b<\/jats:bold>, and <jats:bold>11b<\/jats:bold> showed activity against two strains of <jats:italic>Trypanosoma<\/jats:italic> and two different <jats:italic>Leishmania<\/jats:italic> species, establishing them as versatile leads with broad anti\u2010kinetoplastid activity. Compound <jats:bold>4c<\/jats:bold>, a tetralone derivative with a bromo\u2010containing trimethoxybenzylidene moiety and methyl\u2010substituted cyclohexanone ring, was identified as the most potent inhibitor for both <jats:italic>T. b. brucei<\/jats:italic> strains, with EC<jats:sub>50<\/jats:sub> values of 0.19 and 0.22\u2009\u00b5M for WT and B48, respectively, showing the absence of cross\u2010resistance with the diamidine and arsenical trypanocide classes. In addition, compound <jats:bold>4c<\/jats:bold> exhibited more potency than both controls, eflornithine and pentamidine, against the MDR strain. We conclude that tetralone derivates could be a valuable starting point for the discovery of new antiparasitic drugs.<\/jats:p>","DOI":"10.1002\/ddr.70055","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T05:33:32Z","timestamp":1738128812000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Antileishmanial and Antitrypanosomal Trends of Synthetic Tetralone Derivatives"],"prefix":"10.1002","volume":"86","author":[{"given":"Abdulsalam A. 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