Design and synthesis of antimalarial endoperoxides related to artemisinin

The malaria parasite is becoming increasingly resistant to traditional quinoline drugs. This, coupled with forced climate change and its attendant implications necessitate the development of improved malaria drug therapies. The most promising candidates for new chemotherapeutics are artemisinin and its derivatives. Artemisinin is a 1,2,4-trioxane sesquiterpene lactone natural product isolated from Artemisia annua. It has been used for thousands of years as a crude extract in Chinese folk medicine. We have designed and synthesized over 70 new endoperoxides related to artemisinin and assayed their antimalarial potency in vitro.; A series of 26 cyclic peroxy ketals was synthesized. These were usually available in two steps from commercial materials. As a result of iron(II)-induced degradation studies a tentative mechanism of action was set forth. Structure-activity correlations were developed which led us to synthesize seven examples with activities within an order of magnitude of artemisinin's.; The effects of incorporation of sulfide and sulfone moieties into synthetic 1,2,4-trioxane molecules were investigated. Enhanced activity was observed for sulfone over sulfide. The series culminated with one example which was approximately half as active as artemisinin. The yields for the synthesis of the most active sulfone trioxanes were low. Several examples of synthetic C3-unsaturated 1,2,4-trioxanes were generated. The antimalarial activity of these trioxanes was unimpressive.; Several semisynthetic derivatives of artemisinin were synthesized via the addition of 2-lithiothiazole to the lactone. The thiazole group was converted to an aldehyde which underwent various transformations. The resultant C10-deoxo C9,10-unsaturated compounds showed promising antimalarial efficacy, and some examples were more potent than artemisinin. Dimeric derivatives of this system were also prepared. These displayed promising preliminary biological testing results in antiproliferative and antitumor assays. C10-peroxy substituted semisynthetic derivatives of artemisinin were prepared via a glycosylation-type reaction with hydroperoxides. These generally showed superior activity to artemisinin. The generation of 1,2,4-trioxanes from glycals was also attempted. The initial results were discouraging.