Synthesis, Structure, and Antimalarial Activity of Tricyclic 1,2,4‐Trioxanes Related to Artemisinin

Abstract

Abstract 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.