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Recent advances in chemical proteomics have shed light on the complex mechanism of action of semi\u2010synthetic artemisinin (ARTs), particularly their promiscuous alkylation of parasite proteins via previous heme\u2010mediated bioactivation of the endoperoxide bond. Alarmingly, the rise of resistance to ART in South East Asia and the synthetic limitations of the ART scaffold have pushed the course for the necessity of fully synthetic endoperoxide\u2010based antimalarials. Several classes of synthetic endoperoxide antimalarials have been described in literature utilizing various endoperoxide warheads including 1,2\u2010dioxanes, 1,2,4\u2010trioxanes, 1,2,4\u2010trioxolanes, and 1,2,4,5\u2010tetraoxanes. Two of these classes, the 1,2,4\u2010trioxolanes (arterolane\u00a0and artefenomel) and the 1,2,4,5\u2010tetraoxanes (N205 and\u00a0E209) based antimalarials, have been explored extensively and are still in active development. In contrast, the most recent publication pertaining to the development of the 1,2\u2010dioxane, Arteflene, and 1,2,4\u2010trioxanes fenozan\u201050F, DU1301, and PA1103\/SAR116242 was published in 2008. This review summarizes the synthesis, biological and clinical evaluation, and mechanistic studies of the most developed synthetic endoperoxide antimalarials, providing an update on those classes still in active development.\n                  <\/jats:p>","DOI":"10.1002\/med.21849","type":"journal-article","created":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T04:09:53Z","timestamp":1628222993000},"page":"3062-3095","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Artemisinin inspired synthetic endoperoxide drug candidates: Design, synthesis, and mechanism of action studies"],"prefix":"10.1002","volume":"41","author":[{"given":"Christopher M.","family":"Woodley","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Liverpool Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia S. 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