Design, Synthesis, Derivatization, and Structure−Activity Relationships of Simplified, Tricyclic, 1,2,4-Trioxane Alcohol Analogues of the Antimalarial Artemisinin

Abstract

Novel C₄-(hydroxyalkyl)trioxanes 5d and 5e were designed and synthesized based on an understanding of the molecular mechanism of action of similar 1,2,4-trioxanes structurally related to the antimalarial natural product artemisinin (1). In vitro efficacies of these two new pairs of C₄-diastereomers against chloroquine-sensitive Plasmodium falciparum support conclusions about the importance to antimalarial activity of formation of a C₄ radical by a 1,5-hydrogen atom abstraction. Derivatives 6, 7, and 21 of C_4β-substituted trioxane alcohols 4a, 5d, and 5e were prepared, each in a single-step, high-yielding transformation. Four of these new analogues, 6a − c and 7, are potent in vitro antimalarials, having 140 to 50% of the efficacy of the natural trioxane artemisinin (1).