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The known inhibitors of this enzyme behave poorly or have low activity in the parasite. In this work, we used symmetrical diarylideneketones derived from structures with trypanosomicidal activity. We obtained an enzymatic inhibitor with an IC<jats:sub>50<\/jats:sub> value of 86\u2005n<jats:sc>m<\/jats:sc> without inhibition effects on the mammalian enzyme. These molecules also affected cruzipain, another essential proteolytic enzyme of the parasite. This dual activity is important to avoid resistance problems. The compounds were studied in vitro against the epimastigote form of the parasite, and nonspecific toxicity to mammalian cells was also evaluated. As a proof of concept, three of the best derivatives were also assayed in vivo. Some of these derivatives showed higher in vitro trypanosomicidal activity than the reference drugs and were effective in protecting infected mice. In addition, these molecules could be obtained by a simple and economic green synthetic route, which is an important feature in the research and development of future drugs for neglected diseases.<\/jats:p>","DOI":"10.1002\/cmdc.201500385","type":"journal-article","created":{"date-parts":[[2015,10,24]],"date-time":"2015-10-24T07:58:36Z","timestamp":1445673516000},"page":"1328-1338","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Potent and Selective Inhibitors of <i>Trypanosoma cruzi<\/i> Triosephosphate Isomerase with Concomitant Inhibition of Cruzipain: Inhibition of Parasite Growth through Multitarget Activity"],"prefix":"10.1002","volume":"11","author":[{"given":"Elena","family":"Aguilera","sequence":"first","affiliation":[{"name":"Grupo de Qu\u00edmica Medicinal Facultad de Ciencias Universidad de la Rep\u00fablica  Igu\u00e1\u20054225 Montevideo 11600 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