Antimalarial Activity of Artemisinin (Qinghaosu) and Related Trioxanes: Mechanism (s) of Action

Malaria is one of the most deadly infectious diseases known to mankind. The species of Plasmodium that cause malaria can develop resistance to chemotherapeutic drugs that is going in recent times. Artemisinin and its analogs comprise a rapidly expanding chemotherapeutic arsenal in the ongoing worldwide fight against the resurgent threat of malaria. The promise of artemisinin, its semisynthetic derivatives, and its fully synthetic analogs as a new class of nonalkaloidal, fast-acting antimalarials has stimulated extensive synthetic and mechanistic research into their novel mode of action. Artemisinin and its expanding array of structurally related 1,2,4-trioxanes are effective against both simple and complicated malaria. The desire to develop new, more potent agents related to this promising class of drugs has prompted researchers to elucidate the mechanism(s) of action of these relatively new antimalarials. The developing understanding is the mechanism of action in which the endoperoxide linkage is a trigger, activated by iron-induced reduction inside the malaria parasite that releases a cascade of reactive intermediates—cytotoxic free radicals, one or more high-valent iron-oxo intermediates, and electrophilic alkylating agents—that ultimately cause fatal damage to the parasites.