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Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of <jats:italic>Pf<\/jats:italic>. The clinical candidate (compound <jats:bold>12<\/jats:bold>) is efficacious in a mouse model of <jats:italic>Pf<\/jats:italic> malaria with an ED<jats:sub>99<\/jats:sub> &lt;30\u2009mg\u2009kg<jats:sup>\u22121<\/jats:sup> and displays good <jats:italic>in vivo<\/jats:italic> safety margins in guinea pigs and rats. With a predicted half-life of 36\u2009h in humans, a single dose of 260\u2009mg might be sufficient to maintain therapeutic blood concentration for 4\u20135 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of <jats:italic>Pf<\/jats:italic> malaria in combination with other agents in clinical development.<\/jats:p>","DOI":"10.1038\/ncomms7715","type":"journal-article","created":{"date-parts":[[2015,3,31]],"date-time":"2015-03-31T10:45:45Z","timestamp":1427798745000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate"],"prefix":"10.1038","volume":"6","author":[{"given":"Shahul","family":"Hameed P.","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh","family":"Solapure","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas","family":"Patil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp P.","family":"Henrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela A.","family":"Magistrado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sowmya","family":"Bharath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kannan","family":"Murugan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavithra","family":"Viswanath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayashree","family":"Puttur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhishek","family":"Srivastava","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0614-901X","authenticated-orcid":false,"given":"Eknath","family":"Bellale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijender","family":"Panduga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gajanan","family":"Shanbag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Disha","family":"Awasthy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudhir","family":"Landge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sapna","family":"Morayya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna","family":"Koushik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramanatha","family":"Saralaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anandkumar","family":"Raichurkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8408-2298","authenticated-orcid":false,"given":"Nikhil","family":"Rautela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nilanjana","family":"Roy Choudhury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anisha","family":"Ambady","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radha","family":"Nandishaiah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jitendar","family":"Reddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. 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