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The few drugs available have drawbacks including suboptimal efficacy, adverse effects, drug resistance, and difficult routes of administration. New drugs are needed. A series of 20 novel quinolone compounds with affordable synthetic routes was made and evaluated <jats:italic>in\u2005vitro<\/jats:italic> against <jats:italic>Trypanosoma brucei<\/jats:italic> and HEK293 cells. Of the 20\u2005compounds, 12 had sub\u2010micromolar potencies against the parasite (EC<jats:sub>50<\/jats:sub> values=0.051\u20130.57\u2005\u03bcM), and most were non\u2010toxic to HEK293 cells (CC<jats:sub>50<\/jats:sub> values&gt;5\u2005\u03bcM). Two of the most potent compounds presented sub\u2010micromolar activities against other trypanosome (sub)species (<jats:italic>T. cruzi<\/jats:italic> and <jats:italic>T. b. rhodesiense<\/jats:italic>). Although aqueous solubility is poor, both compounds possess good logD values (2\u20133), and either robust or poor microsomal stability profiles. These varying attributes will be addressed in future reports.<\/jats:p>","DOI":"10.1002\/cmdc.202300667","type":"journal-article","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T23:36:03Z","timestamp":1707348963000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Tractable Quinolone Hydrazides Exhibiting Sub\u2010Micromolar and Broad Spectrum Antitrypanosomal Activities"],"prefix":"10.1002","volume":"19","author":[{"given":"Kgothatso A.","family":"Chirwa","sequence":"first","affiliation":[{"name":"Centre of Excellence for Pharmaceutical Sciences North-West University  Potchefstroom 2520 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karol R.","family":"Francisco","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation in Parasitic Diseases University of California  San Diego 9500 Gilman Drive La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phelelisiwe S.","family":"Dube","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Pharmaceutical Sciences North-West University  Potchefstroom 2520 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayoung","family":"Park","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation in Parasitic Diseases University of California  San Diego 9500 Gilman Drive La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesetja J.","family":"Legoabe","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Pharmaceutical Sciences North-West University  Potchefstroom 2520 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thaiz Rodrigues","family":"Teixeira","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation in Parasitic Diseases University of California  San Diego 9500 Gilman Drive La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conor R.","family":"Caffrey","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation in Parasitic Diseases University of California  San Diego 9500 Gilman Drive La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6282-043X","authenticated-orcid":false,"given":"Richard M.","family":"Beteck","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Pharmaceutical Sciences North-West University  Potchefstroom 2520 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,23]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-3156.2001.00775.x"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0031182020000645"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756-3305-1-3"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00246-11"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2017.02.016"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7MD00280G"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp0806684"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-398457-9.00004-4"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pep.2017.06.011"},{"key":"e_1_2_8_10_1","first-page":"257","volume":"6","author":"Franco J. 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