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Drugs used for treatment against HAT first stage have limited effectiveness, and the second stage drugs have been reported to be toxic, expensive, and have time\u2010consuming administration, and parasitic resistance has developed against these drugs. The aim of this study was to evaluate the anti\u2010trypanosomal activity of nitrofurantoin\u2010triazole hybrids against <jats:italic>T. b. gambiense<\/jats:italic> and <jats:italic>T. b. rhodesiense<\/jats:italic> parasites in vitro. This study screened 19 synthesized nitrofurantoin\u2010triazole (NFT) hybrids on two strains of human trypanosomes, and cytotoxicity was evaluated on Madin\u2010Darby bovine kidney (MDBK) cells. The findings in this study showed that an increase in the chain length and the number of carbon atoms in some n\u2010alkyl hybrids influenced the increase in anti\u2010trypanosomal activity against <jats:italic>T. b. gambiense<\/jats:italic> and <jats:italic>T. b. rhodesiense<\/jats:italic>. The short\u2010chain n\u2010alkyl hybrids showed decreased activity compared to the long\u2010chain n\u2010alkyl hybrids, with increased activity against both <jats:italic>T. b. gambiense<\/jats:italic> and <jats:italic>T. b. rhodesiense<\/jats:italic>. Incorporation of additional electron\u2010donating substituents in some NFT hybrids showed increased anti\u2010trypanosomal activity than to electron\u2010withdrawing substituents in NFT hybrids. All 19 NFT hybrids tested displayed better anti\u2010trypanosomal activity against <jats:italic>T. b. gambiense<\/jats:italic> than <jats:italic>T. b. rhodesiense<\/jats:italic>. The NFT hybrid no. 16 was among the best performing hybrids against both <jats:italic>T. b. gambiense<\/jats:italic> (0.08\u2009\u00b1\u20090.04\u2009\u03bcM) and <jats:italic>T. b.rhodesiense<\/jats:italic> (0.11\u2009\u00b1\u20090.06\u2009\u03bcM), and its activity might be influenced by the introduction of fluorine in the para\u2010position on the benzyl ring. Remarkably, the NFT hybrids in this study displayed weak to moderate cytotoxicity on MDBK cells. All of the NFT hybrids in this study had selectivity index values ranging from 18 to greater than 915, meaning that they were up to 10\u2013100 times fold selective in their anti\u2010trypanosomal activity. The synthesized NFT hybrids showed strong selectivity &gt;10 to <jats:italic>T. b. gambiense<\/jats:italic> and <jats:italic>T. b. rhodesiense<\/jats:italic>, which indicates that they qualify from the initial selection criteria for potential hit drugs.<\/jats:p>","DOI":"10.1111\/fcp.12940","type":"journal-article","created":{"date-parts":[[2023,7,22]],"date-time":"2023-07-22T02:32:51Z","timestamp":1689993171000},"page":"72-83","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["In vitro anti\u2010trypanosomal activity of synthetic nitrofurantoin\u2010triazole hybrids against <i>Trypanosoma<\/i> species causing human African trypanosomosis"],"prefix":"10.1111","volume":"38","author":[{"given":"Anna","family":"Seetsi","sequence":"first","affiliation":[{"name":"Unit for Environmental Sciences and Management North\u2010West University  Potchefstroom South 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Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0473-8075","authenticated-orcid":false,"given":"Tsepo","family":"Ramatla","sequence":"additional","affiliation":[{"name":"Unit for Environmental Sciences and Management North\u2010West University  Potchefstroom South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oriel","family":"Thekisoe","sequence":"additional","affiliation":[{"name":"Unit for Environmental Sciences and Management North\u2010West University  Potchefstroom South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,7,21]]},"reference":[{"issue":"1","key":"e_1_2_12_2_1","first-page":"257","article-title":"Epidemiology of human African trypanosomiasis","volume":"6","author":"Franco JR","year":"2014","journal-title":"Clin 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