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Various drugs were used to treat malaria, including artemisinin and derivatives, antibiotics (tetracycline, doxycycline), quinolines (chloroquine, amodiaquine), and folate antagonists (sulfadoxine and pyrimethamine). Since the malarial parasites developed drug resistance, there is a need to develop new chemical entities with high efficacy and low toxicity. In this context, 1,2,4,5\u2010tetraoxanes emerged as an essential scaffold and have shown promising antimalarial activity. To improve activity and overcome resistance to various antimalarial drugs; 1,2,4,5\u2010tetraoxanes were fused with various aryl\/heteroaryl\/alicyclic\/spiro moieties (steroid\u2010based 1,2,4,5\u2010tetraoxanes, triazine\u2010based 1,2,4,5\u2010tetraoxanes, aminoquinoline\u2010based 1,2,4,5\u2010tetraoxanes, dispiro\u2010based 1,2,4,5\u2010tetraoxanes, piperidine\u2010based 1,2,4,5\u2010tetraoxanes and diaryl\u2010based 1,2,4,5\u2010tetraoxanes). The present review aims to focus on covering the relevant literature published during the past 30 years (1992\u20132022). We summarize the most significant in vitro, in vivo results and structure\u2013activity relationship studies of 1,2,4,5\u2010tetraoxane\u2010based hybrids as antimalarial agents. The structural evolution of different hybrids can provide the framework for the future development of 1,2,4,5\u2010tetraoxane\u2010based hybrids to treat malaria.<\/jats:p>","DOI":"10.1002\/med.22040","type":"journal-article","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T09:20:27Z","timestamp":1713172827000},"page":"2266-2290","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["1,2,4,5\u2010Tetraoxane derivatives\/hybrids as potent antimalarial endoperoxides: Chronological advancements, structure\u2212activity relationship (SAR) studies and future perspectives"],"prefix":"10.1002","volume":"44","author":[{"given":"Abdul Rahaman","family":"T. 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