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We report here the synthesis and evaluation of four new\n            <jats:italic>N<\/jats:italic>\n            -hydroxy and 12 new\n            <jats:italic>N<\/jats:italic>\n            -alkoxy derivatives of bisimidazoline leads as potential agents for the treatment of late-stage sleeping sickness. These compounds, which have reduced basicity compared to the parent leads (i.e., are less ionized at physiological pH), were evaluated\n            <jats:italic>in vitro<\/jats:italic>\n            against\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Trypanosoma brucei rhodesiense<\/jats:named-content>\n            and\n            <jats:italic>in vivo<\/jats:italic>\n            in murine models of first- and second-stage sleeping sickness. Resistance profile, physicochemical parameters,\n            <jats:italic>in vitro<\/jats:italic>\n            BBB permeability, and microsomal stability also were determined. The\n            <jats:italic>N<\/jats:italic>\n            -hydroxy imidazoline analogues were the most effective\n            <jats:italic>in vivo<\/jats:italic>\n            , with 4-((1-hydroxy-4,5-dihydro-1\n            <jats:italic>H<\/jats:italic>\n            -imidazol-2-yl)amino)-\n            <jats:italic>N<\/jats:italic>\n            -(4-((1-hydroxy-4,5-dihydro-1\n            <jats:italic>H<\/jats:italic>\n            -imidazol-2-yl)amino)phenyl)benzamide (14d) showing 100% cures in the first-stage disease, while 15d, 16d, and 17d appeared to slightly improve survival. In addition, 14d showed weak activity in the chronic model of central nervous system infection in mice. No evidence of reduction of this compound with hepatic microsomes and mitochondria was found\n            <jats:italic>in vitro<\/jats:italic>\n            , suggesting that\n            <jats:italic>N<\/jats:italic>\n            -hydroxy imidazolines are metabolically stable and have intrinsic activity against\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">T. brucei<\/jats:named-content>\n            . In contrast to its unsubstituted parent compound, the uptake of 14d in\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">T. brucei<\/jats:named-content>\n            was independent of known drug transporters (i.e.,\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">T. brucei<\/jats:named-content>\n            AT1\/P2 and HAPT), indicating a lower predisposition to cross-resistance with other diamidines and arsenical drugs. Hence, the\n            <jats:italic>N<\/jats:italic>\n            -hydroxy bisimidazolines (14d in particular) represent a new class of promising antitrypanosomal agents.\n          <\/jats:p>","DOI":"10.1128\/aac.03958-14","type":"journal-article","created":{"date-parts":[[2014,11,25]],"date-time":"2014-11-25T04:28:59Z","timestamp":1416889739000},"page":"890-904","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":14,"title":["A New Nonpolar\n            <i>N<\/i>\n            -Hydroxy Imidazoline Lead Compound with Improved Activity in a Murine Model of Late-Stage Trypanosoma brucei brucei Infection Is Not Cross-Resistant with Diamidines"],"prefix":"10.1128","volume":"59","author":[{"given":"Carlos H.","family":"R\u00edos Mart\u00ednez","sequence":"first","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica, IQM-CSIC, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Miller","sequence":"additional","affiliation":[{"name":"Institut Necker-Enfants Malades, INSERM U1151, CNRS 8253, Paris, France"},{"name":"Universit\u00e9 Paris Descartes UMR_S 1151, Sorbonne Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayathiri","family":"Ganeshamoorthy","sequence":"additional","affiliation":[{"name":"Institut Cochin, Universit\u00e9 Paris Descartes, CNRS (UMR 8104), Paris, France"},{"name":"INSERM, U1016, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabienne","family":"Glacial","sequence":"additional","affiliation":[{"name":"Institut Cochin, Universit\u00e9 Paris Descartes, CNRS (UMR 8104), Paris, France"},{"name":"INSERM, U1016, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute, Basel, Switzerland"},{"name":"University of Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry P.","family":"de Koning","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthonius A.","family":"Eze","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Lagartera","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica, IQM-CSIC, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom\u00e1s","family":"Herraiz","sequence":"additional","affiliation":[{"name":"Instituto de Ciencia y Tecnolog\u00eda de Alimentos y Nutrici\u00f3n, ICTAN-CSIC, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Dardonville","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica, IQM-CSIC, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","volume-title":"Working to overcome the global impact of neglected tropical diseases: first WHO report on neglected tropical diseases","author":"WHO","year":"2010","unstructured":"WHO. 2010. 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