Two sets of tricyclic 1,2,4-trioxanes containing the ABC (10, 11) and ACD ring portions (21, 22, 32, 33, 37, and 38) of artemisinin (1) were synthesized by successive photo-oxygenation of appropriate enol-ether precursors to 1,2-dioxanes and inter- and intramolecular reaction with a carbonyl compound or oxo-substituted side-chain. The structures of 10, 21, and 22 were determined by X-ray analysis. The anti-malarial activity of all trioxanes, except 37 and 38, was evaluated in vitro against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum parasites. Trioxanes 11 and 21 were as active as artemisinin (1). It was found that neither the lactone function nor rings B and D of 1 were essential for activity. A possible pharmacophore for artemisinin-like activity, which embodies a spirocyclopentane group attached to C(3) of 1,2,4-trioxane, was proposed.