Synthesis of potent analogs of the antimalarial 1,2,4-trioxane natural product artemisinin, and, mechanistic studies directed towards elucidation of the mechanism(s) of antimalarial action of artemisinin and its 1,2,4-trioxane analogs

We have designed and synthesized analogs of the antimalarial drug artemisinin and have studied the mechanism(s) of action of this 1,2,4-trioxane natural product and its analogs. Artemisinin is the active component of a tea of Artemisia annua leaves used to treat fever for millennia in Chinese herbal medicine. Its discovery and development in the 1970's and 1980's has dramatically improved malaria chemotherapy in endemic areas of China, southeast Asia, Africa, and South America. This drug and its closely-related semi-synthetic analogs are especially effective in treating multidrug-resistant strains of the parasites that cause the most severe complications of the disease, P. falciparum.; We have constructed a number of 4- and 3-substituted tricyclic 1,2,4-trioxanes. 4-Alkylated analogs provided evidence that, after iron(II)-initiated homolysis of the peroxide bond, formation of a carbon radical by 1,5-hydrogen atom abstraction is important in the antimalarial mechanism of action of 1,2,4-trioxanes. Also, we found that hydroxyalkyl substitution is more effective at enhancing antimalarial efficacy when at C-8a than when at C-4. We have synthesized a series of 3-aryl trioxanes that included four very promising analogs that are orally-active in mice. Degradation of a 3-phenyl trioxane produced the first example of an antimalarial diketone.; We have conducted a series of model degradation experiments on artemisinin and its analogs. These experiments clearly showed for the first time, through reporter reactions, the intermediacy of high-valent iron-oxo species during iron(II) decomposition of artemisinin. We were able to show that this reactive oxidizing agent is formed even in aqueous mixtures of organic solvent. Overall, the structure-activity and mechanistic information garnered from this work may be used to develop future, potent trioxane antimalarials.