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Among the hits were the antiemetic benzimidazole drug Lerisetron 1 (IC50 NF54 = 0.81 \u03bcM) and its methyl-substituted analogue 2 (IC50 NF54 = 0.098 \u03bcM). A medicinal chemistry hit to lead effort led to the identification of chloro-substituted analogue 3 with high potency against the drug-sensitive NF54 (IC50 NF54 = 0.062 \u03bcM) and multidrug-resistant K1 (IC50 K1 = 0.054 \u03bcM) strains of the human malaria parasite Plasmodium falciparum. Compounds 2 and 3 gratifyingly showed in vivo efficacy in both Plasmodium berghei and P. falciparum mouse models of malaria. Cardiotoxicity risk as expressed in strong inhibition of the human ether-a-go-go-related gene (hERG) potassium channel was identified as a major liability to address. This led to the synthesis and biological assessment of around 60 analogues from which several compounds with improved antiplasmodial potency, relative to the lead compound 3, were identified.<\/jats:p>","DOI":"10.1021\/acsomega.0c00327","type":"journal-article","created":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T14:12:36Z","timestamp":1584454356000},"page":"6967-6982","source":"Crossref","is-referenced-by-count":17,"title":["Lerisetron Analogues with Antimalarial Properties:\nSynthesis, Structure\u2013Activity Relationship Studies, and Biological\nAssessment"],"prefix":"10.1021","volume":"5","author":[{"given":"Rudolf","family":"Mueller","sequence":"first","affiliation":[{"name":"University of Cape Town , , ,","place":["Rondebosch, South Africa, 7701"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virsinha","family":"Reddy","sequence":"additional","affiliation":[{"name":"University of Cape Town , , ,","place":["Rondebosch, South Africa, 7701"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aloysius T.","family":"Nchinda","sequence":"additional","affiliation":[{"name":"University of Cape Town , , ,","place":["Rondebosch, South Africa, 7701"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanuel","family":"Mebrahtu","sequence":"additional","affiliation":[{"name":"University of Cape Town , , ,","place":["Rondebosch, South Africa, 7701"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dale","family":"Taylor","sequence":"additional","affiliation":[{"name":"University of Cape Town , , ,","place":["Observatory, South Africa, 7925"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Lawrence","sequence":"additional","affiliation":[{"name":"University of Cape Town , , ,","place":["Observatory, South Africa, 7925"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lloyd","family":"Tanner","sequence":"additional","affiliation":[{"name":"University of Cape Town , , ,","place":["Observatory, South Africa, 7925"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marine","family":"Barnabe","sequence":"additional","affiliation":[{"name":"University of Cape Town , , ,","place":["Observatory, South Africa, 7925"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles J.","family":"Eyermann","sequence":"additional","affiliation":[{"name":"University of Cape Town , , ,","place":["Rondebosch, South Africa, 7701"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zou","sequence":"additional","affiliation":[{"name":"Shanghai Blueray Biopharma Co. LTD , Block 3, 576 Libing Road , Pudong New District, ,","place":["Shanghai, China, 201301"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravinder R.","family":"Kondreddi","sequence":"additional","affiliation":[{"name":"PJS Pharma Pvt. Ltd. , Plot No. 103\/1, Phase II, IDA Cherlapally , ,","place":["Hyderabad, India, 500051"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh B.","family":"Lakshminarayana","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases , 5300 Chiron Way , , ,","place":["Emeryville, California, United States, 94608"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Rottmann","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute , , ,","place":["Basel, Switzerland, CH-4051"]},{"name":"University of Basel , ,","place":["Basel, Switzerland, 4002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie J.","family":"Street","sequence":"additional","affiliation":[{"name":"University of Cape Town , , ,","place":["Rondebosch, South Africa, 7701"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1327-4727","authenticated-orcid":true,"given":"Kelly","family":"Chibale","sequence":"additional","affiliation":[{"name":"University of Cape Town , , ,","place":["Rondebosch, South Africa, 7701"]},{"name":"University of Cape Town , , ,","place":["Rondebosch, South Africa, 7701"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,3,17]]},"reference":[{"key":"2026090207452833100_cit1","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1016\/S0140-6736(13)60024-0","article-title":"Malaria","volume":"383","author":"White","year":"2014","journal-title":"Lancet"},{"key":"2026090207452833100_cit2a","doi-asserted-by":"publisher","DOI":"10.2807\/1560-7917.es2013.18.40.20603","article-title":"Plasmodium knowlesi Infection\nImported to Germany, January 2013","author":"Orth","year":"2013","journal-title":"Euro Surveill."},{"key":"2026090207452833100_cit2b","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1038\/nrmicro.2016.79","article-title":"Plasmodium Species: Master Renovators\nof Their Host Cells","volume":"14","author":"de Koning-Ward","year":"2016","journal-title":"Nat. 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