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.
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Jefford et al. (1993) studied this question.