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Among tested compounds, two <jats:bold>13\u2009g<\/jats:bold> and <jats:bold>14\u2009g<\/jats:bold> exhibited promising inhibitory activity on <jats:italic>Pf<\/jats:italic>3D7 with IC<jats:sub>50<\/jats:sub> values of 0.28 and 0.09\u2005\u03bcM, respectively. Neither of the hits exhibited cytotoxicity on HepG2 cells up to 150\u2005\u03bcM and Vero cells up to 20\u2005\u03bcM. Compounds\u2005<jats:bold>13\u2009g<\/jats:bold> and <jats:bold>14\u2009g<\/jats:bold> were also evaluated against chloroquine\u2010resistant <jats:italic>Pf<\/jats:italic>Dd2 and displayed IC<jats:sub>50<\/jats:sub> values of 0.11 and 0.10\u2005\u03bcM, respectively. Next, <jats:bold>13\u2009g<\/jats:bold> and <jats:bold>14\u2009g<\/jats:bold> were administered to the <jats:italic>Plasmodium berghei<\/jats:italic> mice model at 30\u2005mg\/kg intraperitoneally for four consecutive doses, which showed 25\u2009% and 50\u2009% reduction in the parasitemia load, respectively. The efficacy of hits <jats:bold>13\u2009g<\/jats:bold> and <jats:bold>14\u2009g<\/jats:bold> was improved along with mean survival time when administered in combination with artesunate. On liver\u2010stage parasites, compounds <jats:bold>13\u2009g<\/jats:bold> and <jats:bold>14\u2009g<\/jats:bold> showed &gt;80\u2009% inhibition at 1\u2005\u03bcM. Compound\u2005<jats:bold>14\u2009g<\/jats:bold> was also tested for toxicity in mice at 100\u2005mg\/kg dose, which revealed no abnormality in mice organs. Preliminary pharmacokinetic studies of compound\u2005<jats:bold>14\u2009g<\/jats:bold> exhibited absorption and maintained a presence in the body for more than six hours.<\/jats:p>","DOI":"10.1002\/cmdc.202400616","type":"journal-article","created":{"date-parts":[[2024,11,9]],"date-time":"2024-11-09T02:23:32Z","timestamp":1731119012000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Synthesis and Evaluation of Fluorinated Piperazine\u2010Hydroxyethylamine Analogues as Potential Antiplasmodial Candidates"],"prefix":"10.1002","volume":"20","author":[{"given":"Charu","family":"Upadhyay","sequence":"first","affiliation":[{"name":"Department of Chemistry Miranda House University of Delhi  Delhi 110007"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreya","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"Infectious Diseases Laboratory National Institute of Immunology  New Delhi 110067"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumit","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Chemistry Miranda House University of Delhi  Delhi 110007"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kapil","family":"Vashisht","sequence":"additional","affiliation":[{"name":"HeteroChem InnoTech Hansraj College Campus University of Delhi, Malka Ganj  Delhi 110007"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xujie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Key Laboratory of Chemical Biology (Ministry of Education) School of Pharmaceutical Sciences Chelloo College of Medicine Shandong University  44 West Culture Road 250012 Jinan Shandong PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic","family":"Gagnon","sequence":"additional","affiliation":[{"name":"Centre de Recherche du CHU de Qu\u00e9bec-Universit\u00e9 Laval D\u00e9partement de Microbiologie-Infectiologie et d'Immunologie Universit\u00e9 Laval  Quebec G1 V 0 A6 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pooja","family":"Singh","sequence":"additional","affiliation":[{"name":"Infectious Diseases Laboratory National Institute of Immunology  New Delhi 110067"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhan","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Key Laboratory of Chemical Biology (Ministry of Education) School of Pharmaceutical Sciences Chelloo College of Medicine Shandong University  44 West Culture Road 250012 Jinan Shandong PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dave","family":"Richard","sequence":"additional","affiliation":[{"name":"Centre de Recherche du CHU de Qu\u00e9bec-Universit\u00e9 Laval D\u00e9partement de Microbiologie-Infectiologie et d'Immunologie Universit\u00e9 Laval  Quebec G1 V 0 A6 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2133-8847","authenticated-orcid":false,"given":"Brijesh","family":"Rathi","sequence":"additional","affiliation":[{"name":"HeteroChem InnoTech Hansraj College Campus University of Delhi, Malka Ganj  Delhi 110007"},{"name":"H.G. 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