The structure and antimalarial activity of some 1,2,4-trioxanes, 1,2,4,5-tetroxanes, and bicyclic endoperoxides. Implications for the mode of action

The mode of antimalarial action of cis-fused cyclopenteno-1,2,4-trioxanes (7-13), dispiro-1,2,4,5-tetroxanes (14-17), and bridged bicyclic endoperoxides (18-22) was examined by systematically changing substituents at positions remote from the O-O bond. It is concluded that peroxides of high activity (7-11, 14-15, 18, and 19) are able to intimately dock on heme and rearrange efficiently to an ethyl radical which kills the parasite by alkylation. Dimethyl substituents on the spirocyclohexane ring in the trioxanes (12 and 13) and tetroxane (16) diminish activity by hampering either docking or the reactivity of a C-centered radical. Endoperoxides derived from methylnaphthalenes (20-22) are inactive owing to their inability to generate an ethyl radical.