Understanding molecular mechanism(s) of action of artemisinin and 1,2,4-trioxanes: Designer trioxanes and endoperoxides as antimalarial drugs

Malaria has distinguished itself among present infectious diseases as a major public health concern worldwide. Its rapidly developing resistance against various classical chemotherapies has prompted researchers to find other non-classical alternatives to combat the disease. Chemists and biologists have worked together in discovering a new non-alkaloidal class of potent antimalarial agents in artemisinin, a sesquiterpene lactone endoperoxide. From various studies, artemisinin and its related analogs exert their antimalarial activity by generating cytotoxic intermediates from their encounter with heme. Heme is a by-product toxic to malaria parasites formed from parasitic metabolism of the human host's erythrocytic hemoglobin. Evidence suggests that these cytotoxic intermediates include radicals, high-valent iron-oxo species and one or more electrophilic epoxides all of which are potent alkylating agents and oxidants conceivably responsible for protein alkylation or oxidative damage to biomolecules crucial to the parasite's survival.; Based on our current understanding of molecular mechanism(s) of action, we have designed and synthesized a series of semi-synthetic deoxoartemisinin analogs, other simplified 1,2,4-trioxanes, and simple non-trioxane endoperoxides to further investigate structure-activity relationships. Some of our rationally designed analogs show very promising in vitro and in vivo antimalarial activity and relatively low toxicity. Our semi-synthetic 10-deoxoartemisinin analogs can be synthesized in only a few steps from artemether. Interestingly, many of our antimalarially active trioxane and artemisinin-based dimers are potent antiproliferative and antitumor agents. One of our deoxoartemisinin dimers has been shown not only to inhibit the growth of, but also to kill, human cancer cells. Taken together, these series of novel, rationally designed trioxane and artemisinin-based analogs provide an expanding arsenal of chemotherapies to bring malaria under control and potentially to fight against cancer.