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CNSL is a waste product from cashew nut processing factories, with great potential as a source of drug precursors. The synthesized compounds were tested against <jats:italic>Trypanosoma brucei brucei<\/jats:italic>, including three multidrug\u2010resistant strains, <jats:italic>T.\u2005congolense<\/jats:italic>, and a human cell line. The most potent activity was found against <jats:italic>T.\u2005b.\u2005brucei<\/jats:italic>, the causative agent of HAT. Shorter\u2010chain derivatives <jats:bold>20<\/jats:bold> (2\u2010(3\u2010(8\u2010hydroxyoctyl)phenoxy)\u20105\u2010methoxynaphthalene\u20101,4\u2010dione) and <jats:bold>22<\/jats:bold> (5\u2010hydroxy\u20102\u2010(3\u2010(8\u2010hydroxyoctyl)phenoxy)naphthalene\u20101,4\u2010dione) were more active than <jats:bold>4<\/jats:bold>, displaying rapid micromolar trypanocidal activity, and no human cytotoxicity. Preliminary studies probing their mode of action on trypanosomes showed ATP depletion, followed by mitochondrial membrane depolarization and mitochondrion ultrastructural damage. This was accompanied by reactive oxygen species production. We envisage that such compounds, obtained from a renewable and inexpensive material, might be promising bio\u2010based sustainable hits for anti\u2010trypanosomatid drug discovery.<\/jats:p>","DOI":"10.1002\/cmdc.201800790","type":"journal-article","created":{"date-parts":[[2019,1,21]],"date-time":"2019-01-21T11:49:13Z","timestamp":1548071353000},"page":"621-635","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Discovery of Sustainable Drugs for Neglected Tropical Diseases: Cashew Nut Shell Liquid (CNSL)\u2010Based Hybrids Target Mitochondrial Function and ATP Production in <i>Trypanosoma brucei<\/i>"],"prefix":"10.1002","volume":"14","author":[{"given":"Michela","family":"Cerone","sequence":"first","affiliation":[{"name":"Department of Pharmacy and Biotechnology Alma Mater Studiorum \u2013 University of Bologna  Via Belmeloro 6 40126 Bologna Italy"},{"name":"Institute of Infection, Immunity and Inflammation 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