Knowledge of the proposed chemical mechanism of action and cytochrome P450 metabolism of antimalarial trioxanes like artemisinin allows rational design of new antimalarial peroxides

Evidence is reviewed elucidating the mechanism of iron-induced triggering of antimalarial trioxanes. As prodrugs, trioxanes undergo homolytic, inner-sphere, reductive cleavage by ferrous iron to form sequentially oxy radicals, carbon radicals, high-valent iron-oxo species, epoxides, aldehydes, and dicarbonyl compounds. One or more of these reactive intermediates and neutral alkylating agents likely kill the malaria parasites. Several new, orally active antimalarial peroxides have been designed rationally based on this fundamental mechanistic paradigm. Incorporating metabolism-blocking substituents also provides some new, potent, semisynthetic artemisinin derivatives.