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Parthenin, like artemisinin, has an effect on<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Plasmodium<\/jats:named-content>blood stage development. We extended the evaluation of parthenin as a potential therapeutic for the transmissible stages of<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Plasmodium falciparum<\/jats:named-content>as it transitions between human and mosquito, with the aim of gaining potential mechanistic insight into the inhibitory activity of this compound. We posited that if parthenin targets different biological pathways in the parasite, this in turn could pave the way for the development of druggable compounds that could prevent the spread of artemisinin-resistant parasites. We examined parthenin's effect on male gamete activation and the ookinete-to-oocyst transition in the mosquito as well as on stage V gametocytes that are present in peripheral blood. Parthenin arrested parasite development for each of the stages tested. The broad inhibitory properties of parthenin on the evaluated parasite stages may suggest different mechanisms of action between parthenin and artemisinin. Parthenin's cytotoxicity notwithstanding, its demonstrated activity in this study suggests that structurally related SQLs with a better safety profile deserve further exploration. We used our battery of assays to test parthenolide, which has a more compelling safety profile. Parthenolide demonstrated activity nearly identical to that of parthenin against<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">P. falciparum<\/jats:named-content>, highlighting its potential as a possible transmission-blocking drug scaffold. We discuss the context of the evidence with respect to the next steps toward expanding the current antimalarial arsenal.<\/jats:p>","DOI":"10.1128\/aac.02002-15","type":"journal-article","created":{"date-parts":[[2016,1,20]],"date-time":"2016-01-20T03:58:43Z","timestamp":1453262323000},"page":"2108-2117","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":27,"title":["The Nonartemisinin Sesquiterpene Lactones Parthenin and Parthenolide Block Plasmodium falciparum Sexual Stage Transmission"],"prefix":"10.1128","volume":"60","author":[{"given":"Jared N.","family":"Balaich","sequence":"first","affiliation":[{"name":"W. 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