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Introduction of a new, lean propargylic vector to a known class of TR inhibitors resulted in the strongest reported competitive inhibitor of\n                    <jats:italic>Trypanosoma<\/jats:italic>\n                    (\n                    <jats:italic>T<\/jats:italic>\n                    .)\n                    <jats:italic>brucei<\/jats:italic>\n                    TR, with an inhibition constant\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>i<\/jats:sub>\n                    of 73\u2005n\n                    <jats:sc>m<\/jats:sc>\n                    , which is fully selective against human glutathione reductase (hGR). The best ligands exhibited in vitro IC\n                    <jats:sub>50<\/jats:sub>\n                    values (half\u2010maximal inhibitory concentration) against the HAT pathogen,\n                    <jats:italic>T. brucei rhodesiense<\/jats:italic>\n                    , in the mid\u2010nanomolar range, reaching down to 50\u2005n\n                    <jats:sc>m.<\/jats:sc>\n                    X\u2010Ray co\u2010crystal structures confirmed the binding mode of the ligands and revealed the presence of a HEPES buffer molecule in the large active site. Extension of the propargylic vector, guided by structure\u2010based design, to replace the HEPES buffer molecule should give inhibitors with low nanomolar\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>i<\/jats:sub>\n                    and IC\n                    <jats:sub>50<\/jats:sub>\n                    values for in vivo studies.\n                  <\/jats:p>","DOI":"10.1002\/chem.201901664","type":"journal-article","created":{"date-parts":[[2019,8,13]],"date-time":"2019-08-13T05:54:52Z","timestamp":1565675692000},"page":"11416-11421","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Targeting a Large Active Site: Structure\u2010Based Design of Nanomolar Inhibitors of\n                    <i>Trypanosoma brucei<\/i>\n                    Trypanothione Reductase"],"prefix":"10.1002","volume":"25","author":[{"given":"Raoul","family":"De\u2005Gasparo","sequence":"first","affiliation":[{"name":"Laboratorium f\u00fcr Organische Chemie ETH Zurich  Vladimir-Prelog-Weg 3 8093 Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2858-9123","authenticated-orcid":false,"given":"Ondrej","family":"Halgas","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Medical Biophysics University of Toronto  Medical Sciences Building, 5318, 1 King's College Circle Toronto ON M5S 1A8 Canada"},{"name":"The Campbell Family Institute for Cancer Research University Health Network  101 College Street Toronto ON M5G 1L7 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dora","family":"Harangozo","sequence":"additional","affiliation":[{"name":"Laboratorium f\u00fcr Organische Chemie ETH Zurich  Vladimir-Prelog-Weg 3 8093 Zurich 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 and Medical Biophysics University of Toronto  Medical Sciences Building, 5318, 1 King's College Circle Toronto ON M5S 1A8 Canada"},{"name":"The Campbell Family Institute for Cancer Research University Health Network  101 College Street Toronto ON M5G 1L7 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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