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A screen of the Jumpstarter library against\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    identified W482 with a pyrimidine\u20102,4\u2010diamine scaffold. Structure\u2010activity relationships reveal the importance of the pyrimidine core and its endocyclic nitrogen, while alternative amines are tolerated in the 4\u2010position. Bulky and hydrophobic carboxamides or substituted phenyl ureas display the most potent antiplasmodial activity. Resistance selection and whole genome sequencing reveal an amplification of the gene encoding the ABCI3 transporter protein W482\u2010resistant parasites. W482 is found to exhibit greater activity against parasites with reduced expression of ABCI3, confirming that resistance is related to the transporter. W482 arrests\u00a0asexual parasites at the ring to trophozoite transition stage and exhibits a fast\u2010killing profile with a lag phase of 24\u2009h. Improving the antiparasitic activity alongside metabolic stability and solubility remains a challenge in the future development of the pyrimidine\u20102,4\u2010diamine class.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202500739","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T03:43:31Z","timestamp":1765597411000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exploration and Characterization of the Antimalarial Activity of Pyrimidine\u20102,4\u2010Diamines for which Resistance is Mediated by the ABCI3 Transporter"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8428-5370","authenticated-orcid":false,"given":"Mahta","family":"Mansouri","sequence":"first","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research  Parkville 3052 Australia"},{"name":"Department of Medical Biology The University of Melbourne  Parkville 3010 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9386-0648","authenticated-orcid":false,"given":"Madeline G.","family":"Dans","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research  Parkville 3052 Australia"},{"name":"Department of Medical Biology The University of Melbourne  Parkville 3010 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijun","family":"Low","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research  Parkville 3052 Australia"},{"name":"Department of Medical Biology The University of Melbourne  Parkville 3010 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8460-8920","authenticated-orcid":false,"given":"Katie","family":"Loi","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research  Parkville 3052 Australia"},{"name":"Department of Medical Biology The University of Melbourne  Parkville 3010 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5561-6636","authenticated-orcid":false,"given":"Kate E.","family":"Jarman","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research  Parkville 3052 Australia"},{"name":"Department of Medical Biology The University of Melbourne  Parkville 3010 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyn S.","family":"Penington","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research  Parkville 3052 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7297-8660","authenticated-orcid":false,"given":"Deyun","family":"Qiu","sequence":"additional","affiliation":[{"name":"Research School of Biology Australian National University  Canberra 2601 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0050-9101","authenticated-orcid":false,"given":"Adele M.","family":"Lehane","sequence":"additional","affiliation":[{"name":"Research School of Biology Australian National University  Canberra 2601 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5071-5819","authenticated-orcid":false,"given":"Benigno","family":"Crespo","sequence":"additional","affiliation":[{"name":"Global Health Medicines R &amp;D, GSK  Tres Cantos 28760 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1854-2882","authenticated-orcid":false,"given":"Franciso\u2010Javier","family":"Gamo","sequence":"additional","affiliation":[{"name":"Global Health Medicines R &amp;D, GSK  Tres Cantos 28760 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6745-233X","authenticated-orcid":false,"given":"Delphine","family":"Baud","sequence":"additional","affiliation":[{"name":"MMV Medicines for Malaria Venture  1215 Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7010-5348","authenticated-orcid":false,"given":"Stephen","family":"Brand","sequence":"additional","affiliation":[{"name":"MMV Medicines for Malaria Venture  1215 Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul F.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Emerging Science &amp; 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