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The mode of action of this prodrug involves an initial activation reaction catalyzed by a type I nitroreductase (NTR), an enzyme found predominantly in prokaryotes, leading to the formation of a cytotoxic unsaturated open-chain nitrile metabolite. Here, we evaluate the trypanocidal activities of a library of other 5-nitrofurans against the bloodstream form of<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">T. brucei<\/jats:named-content>as a preliminary step in the identification of additional nitroaromatic compounds that can potentially partner with eflornithine. Biochemical screening against the purified enzyme revealed that all 5-nitrofurans were effective substrates for<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">T. brucei<\/jats:named-content>NTR (TbNTR), with the preferred compounds having apparent<jats:italic>k<\/jats:italic><jats:sub>cat<\/jats:sub>\/<jats:italic>K<jats:sub>m<\/jats:sub><\/jats:italic>values approximately 50-fold greater than those of nifurtimox. For several compounds,<jats:italic>in vitro<\/jats:italic>reduction by this nitroreductase yielded products characterized by mass spectrometry as either unsaturated or saturated open-chain nitriles. When tested against the bloodstream form of<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">T. brucei<\/jats:named-content>, many of the derivatives displayed significant growth-inhibitory properties, with the most potent compounds generating 50% inhibitory concentrations (IC<jats:sub>50<\/jats:sub>s) around 200 nM. The antiparasitic activities of the most potent agents were demonstrated to be NTR dependent, as parasites having reduced levels of the enzyme displayed resistance to the compounds, while parasites overexpressing TbNTR showed hypersensitivity. We conclude that other members of the 5-nitrofuran class of nitroheterocycles have the potential to treat human African trypanosomiasis, perhaps as an alternative partner prodrug to nifurtimox, in the next generation of eflornithine-based combinational therapies.<\/jats:p>","DOI":"10.1128\/aac.02046-12","type":"journal-article","created":{"date-parts":[[2013,1,19]],"date-time":"2013-01-19T03:57:28Z","timestamp":1358567848000},"page":"1638-1647","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":35,"title":["Evaluating 5-Nitrofurans as Trypanocidal Agents"],"prefix":"10.1128","volume":"57","author":[{"given":"Christopher","family":"Bot","sequence":"first","affiliation":[{"name":"Queen Mary Pre-Clinical Drug Discovery Group, School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda S.","family":"Hall","sequence":"additional","affiliation":[{"name":"Queen Mary Pre-Clinical Drug Discovery Group, School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guzm\u00e1n","family":"\u00c1lvarez","sequence":"additional","affiliation":[{"name":"Grupo de Qu\u00edmica Medicinal, Facultad de Ciencias-Facultad de Qu\u00edmica, Universidad de la Rep\u00fablica, Montevideo, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossanna","family":"Di Maio","sequence":"additional","affiliation":[{"name":"Grupo de Qu\u00edmica Medicinal, Facultad de Ciencias-Facultad de Qu\u00edmica, Universidad de la Rep\u00fablica, Montevideo, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Grupo de Qu\u00edmica Medicinal, Facultad de Ciencias-Facultad de Qu\u00edmica, Universidad de la Rep\u00fablica, Montevideo, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo","family":"Cerecetto","sequence":"additional","affiliation":[{"name":"Grupo de Qu\u00edmica Medicinal, Facultad de Ciencias-Facultad de Qu\u00edmica, Universidad de la Rep\u00fablica, Montevideo, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shane R.","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"Queen Mary Pre-Clinical Drug Discovery Group, School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(98)00416-4"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60829-1"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1462399409001252"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-6851(01)00332-2"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-3156.2001.00775.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/S0022-3565(25)07878-4","article-title":"The chemotherapeutic properties of 5-nitro-2-furaldehyde semicarbazone (Furacin)","volume":"86","author":"Dodd MC","year":"1946","unstructured":"DoddMC. 1946. 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