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These protozoa possess a unique redox metabolism based on trypanothione and trypanothione reductase (TR), making TR a promising drug target. We report the optimization of properties and potency of cyclohexylpyrrolidine inhibitors of TR by structure\u2010based design. The best inhibitors were freely soluble and showed competitive inhibition constants (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>) against <jats:italic>Trypanosoma<\/jats:italic> (<jats:italic>T<\/jats:italic>.) <jats:italic>brucei<\/jats:italic> TR and <jats:italic>T.\u2005cruzi<\/jats:italic> TR and in\u2005vitro activities (half\u2010maximal inhibitory concentration, IC<jats:sub>50<\/jats:sub>) against these parasites in the low micromolar range, with high selectivity against human glutathione reductase. X\u2010ray co\u2010crystal structures confirmed the binding of the ligands to the hydrophobic wall of the \u201cmepacrine binding site\u201d with the new, solubility\u2010providing vectors oriented toward the surface of the large active site.<\/jats:p>","DOI":"10.1002\/cmdc.201800067","type":"journal-article","created":{"date-parts":[[2018,4,6]],"date-time":"2018-04-06T17:58:12Z","timestamp":1523037492000},"page":"957-967","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Biological Evaluation and X\u2010ray Co\u2010crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma"],"prefix":"10.1002","volume":"13","author":[{"given":"Raoul","family":"De\u2005Gasparo","sequence":"first","affiliation":[{"name":"Laboratorium f\u00fcr Organische Chemie ETH Z\u00fcrich  Vladimir-Prelog-Weg 3 8093 Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke","family":"Brodbeck\u2010Persch","sequence":"additional","affiliation":[{"name":"Laboratorium f\u00fcr Organische Chemie ETH Z\u00fcrich  Vladimir-Prelog-Weg 3 8093 Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Bryson","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry, Medical Biophysics, and Molecular Genetics University of Toronto  Medical Sciences Building, #5358, 1 King's College Circle Toronto ON M5S\u20051A8 Canada"},{"name":"The Campbell Family Institute for Cancer Research University Health Network  101 College Street Toronto ON M5G\u20051L7 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina B.","family":"Hentzen","sequence":"additional","affiliation":[{"name":"Laboratorium f\u00fcr Organische Chemie ETH Z\u00fcrich  Vladimir-Prelog-Weg 3 8093 Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute  Socinstrasse 57 4002 Basel Switzerland"},{"name":"University of Basel  Petersplatz 1 4003 Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1162-7242","authenticated-orcid":false,"given":"Emil F.","family":"Pai","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry, Medical Biophysics, and Molecular Genetics University of Toronto  Medical Sciences Building, #5358, 1 King's College Circle Toronto ON M5S\u20051A8 Canada"},{"name":"The Campbell Family Institute for Cancer Research University Health Network  101 College Street Toronto ON M5G\u20051L7 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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