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Although artemisinin-based combination therapy demonstrates high efficacy in controlled clinical settings, its real-world effectiveness is often compromised by suboptimal patient adherence. Specifically, the artemether\u2013lumefantrine regimen, administered twice daily over 3\u00a0days, has been associated with reduced compliance due to its complexity. Simplified therapeutic regimens that enhance adherence could, therefore, play a critical role in reinvigorating progress toward malaria elimination. Over the past decade, substantial progress has been made in the discovery and development of new chemical entities for malaria treatment, although the most advanced candidate still requires a 3-day dosing regimen. Treatment shortening most likely requires multiple drug combinations. Multi-drug regimens, such as artemether\u2013lumefantrine\u2013amodiaquine appear to be well tolerated, but these are under development to address emerging resistance to lumefantrine and will be unlikely to improve compliance. Sulfadoxine\u2013pyrimethamine was originally developed as a single-dose curative treatment for malaria, and although use was curtailed early due to rapid selection for resistance, it continues to be deployed as a single therapy or in combination with other medicines, in treatment and in prevention. Combining with artemisinin-based combinations would be an option for potential treatment shortening. Of the registered antimalarial treatments, only a few of the artemisinin-based combinations are suitable. Mefloquine is excluded for tolerability concerns, amodiaquine because of its use in seasonal malaria chemoprevention, and lumefantrine and piperaquine due to concerns of emerging resistance. Pyronaridine\u2013artesunate emerges as a promising candidate for association with sulfadoxine\u2013pyrimethamine. A four-drug, single-dose antimalarial regimen would transform compliance, and play a major role in disease elimination. However, to ensure its success it will be important to assess the safety and tolerability of the novel association and understand its efficacy in regions with evolving resistance to sulfadoxine\u2013pyrimethamine. Clinical studies need to assess the risk for selection of strains with novel resistance mechanisms against artesunate or pyronaridine. Importantly, a comprehensive clinical evaluation will generate valuable real-world insights into community acceptance and operational feasibility. This information will be an important foundation for future design of single dose malaria therapies involving new chemical entities.<\/jats:p>","DOI":"10.1186\/s12936-025-05559-4","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T12:42:54Z","timestamp":1759236174000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Making the most of existing antimalarial medicines: a single dose cure with sulfadoxine\u2013pyrimethamine plus artesunate\u2013pyronaridine"],"prefix":"10.1186","volume":"24","author":[{"given":"Ghyslain","family":"Mombo-Ngoma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Ramharter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rella","family":"Zoleko Manego","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertrand","family":"Lell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quique","family":"Bassat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Aide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oumou","family":"Maiga Ascofare","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy N. 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