DESIGN, SYNTHESIS, DERIVATIZATION, AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF SIMPLIFIED, TRICYCLIC, 1,2,4-TRIOXANE ALCOHOL ANALOGS OF THE ANTIMALARIAL ARTEMISININ

Novel C-4-(hydroxyalkyl)trioxanes 5d and 5e were designed and synthesi zed based on an understanding of the molecular mechanism of action of similar 1,2,4-trioxanes structurally related to the antimalarial natur al product artemisinin (1). In vitro efficacies of these two new pairs of C-4-diastereomers against chloroquine-sensitive Plasmodium falcipa rum support conclusions about the importance to antimalarial activity of formation of a C-4 radical by a 1,5-hydrogen atom abstraction, Deri vatives 6, 7, and 21 of C-4 beta-substituted trioxane alcohols 4a, 5d, and 5e were prepared, each in a single-step, high-yielding transforma tion. Four of these new analogues, 6a-c and 7, are potent in vitro ant imalarials, having 140 to 50% of the efficacy of the natural trioxane artemisinin (1).