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Artemisinins, used as first\u2010line malaria treatments, have attracted attention for their potential activity against\n                    <jats:italic>Leishmania<\/jats:italic>\n                    . The mechanisms by which artemisinins treat malaria were deeply investigated and are thought to involve peroxide cleavage with formation of radicals, alkylating molecular targets within\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    . However, the action of endoperoxides on\n                    <jats:italic>Leishmania<\/jats:italic>\n                    spp. remains poorly understood. To gain insight, we undertook the synthesis and structural characterization of 1,2,4\u2010trioxolanes, 1,2,4,5\u2010tetraoxanes, and respective deoxygenated controls. The compounds were evaluated in vitro against axenic and intracellular forms of\n                    <jats:italic>Leishmania donovani<\/jats:italic>\n                    and\n                    <jats:italic>Leishmania major<\/jats:italic>\n                    . Their selectivity indexes (SIs) were determined. Among 29 compounds, tetraoxanes\n                    <jats:bold>27<\/jats:bold>\n                    ,\n                    <jats:bold>29<\/jats:bold>\n                    ,\n                    <jats:bold>30<\/jats:bold>\n                    ,\n                    <jats:bold>32<\/jats:bold>\n                    , and\n                    <jats:bold>33<\/jats:bold>\n                    exhibited the highest potency against both\n                    <jats:italic>Leishmania<\/jats:italic>\n                    species, but most showed limited selectivity (SI\u2009&lt;\u200910) toward the parasite. Nevertheless,\n                    <jats:bold>33<\/jats:bold>\n                    demonstrated strong efficacy against\n                    <jats:italic>L. major<\/jats:italic>\n                    (SI of 13.7). Comparing peroxides versus their ether controls often revealed similar activities, suggesting involvement of other mechanisms beyond the iron\u2010dependent peroxide activation, unlike what is described for\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70454","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T01:35:11Z","timestamp":1788399311000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis, Structure, and Antileishmanial Activity of Novel 1,2,4\u2010Trioxolanes, 1,2,4,5\u2010Tetraoxanes and Their Respective Deoxygenated Controls"],"prefix":"10.1002","volume":"21","author":[{"given":"In\u00eas C. C.","family":"Costa","sequence":"first","affiliation":[{"name":"Center of Marine Sciences CCMAR Gambelas Campus,\u00a0University of Algarve  Faro Portugal"},{"name":"Department of Chemistry and Pharmacy Faculty of Sciences and Technology, Gambelas Campus University of Algarve  Faro Portugal"},{"name":"BioCIS: Biomol\u00e9cules Conception,\u00a0Isolement,\u00a0Synth\u00e8se University of Paris\u2010Saclay  Orsay France"},{"name":"University of Paris\u2010Saclay  Orsay France"},{"name":"Anses,\u00a0INRAe,\u00a0EnvA,\u00a0UMR BIPAR,\u00a0Laboratory of Animal Health  Maisons\u2010Alfort France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia S. M.","family":"Amado","sequence":"additional","affiliation":[{"name":"Center of Marine Sciences CCMAR Gambelas Campus,\u00a0University of Algarve  Faro Portugal"},{"name":"Department of Chemistry and Pharmacy Faculty of Sciences and Technology, Gambelas Campus University of Algarve  Faro Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe M.","family":"Loiseau","sequence":"additional","affiliation":[{"name":"BioCIS: Biomol\u00e9cules Conception,\u00a0Isolement,\u00a0Synth\u00e8se University of Paris\u2010Saclay  Orsay France"},{"name":"University of Paris\u2010Saclay  Orsay France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Cojean","sequence":"additional","affiliation":[{"name":"University of Paris\u2010Saclay  Orsay France"},{"name":"Anses,\u00a0INRAe,\u00a0EnvA,\u00a0UMR BIPAR,\u00a0Laboratory of Animal Health  Maisons\u2010Alfort France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 A.","family":"Paix\u00e3o","sequence":"additional","affiliation":[{"name":"CFisUC Department of Physics University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9447-2855","authenticated-orcid":false,"given":"Maria L. 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