SYNTHESIS AND ANTIMALARIAL ACTIVITIES OF STRUCTURALLY SIMPLIFIED 1,2,4-TRIOXANES RELATED TO ARTEMISININ

Eleven derivatives of the clinically useful, antimalarial, 1,2,4-trioxane artemisinin have been synthesized in only several steps from commercial cyclohexanones. Of these simple, tricyclic 1,2,4-trioxanes, 10 showed considerable in vitro antimalarial activity, with one being as potent as artemisinin. Some structure-activity relationship generalizations are made from this series of artemisinin analogs. Triethylsilyl hydrotrioxide (Et(3)SiOOOH), prepared in situ from ozone and triethylsilane, is shown to be a mild, fast-acting, and effective dioxetane-forming reagent with vinyl ethers and with a vinyl thioether on relatively small (50-100 mg) scale.