Endoperoxides as potential antimalarial agents.

A number of mono- and bicyclic endoperoxides were prepared and tested for antimalarial activity in search of a simplified analogue of the 5-oxygen-substituted 1,2,4-trioxane ring structure of the naturally occurring antimalarial qinghaosu. The compounds were assayed in an in vitro system for antimalarial activity against chloroquine-susceptible and chloroquine-resistant strains of P. falciparum. The most active compound in this assay was 2-[((butyloxy)-carbonyl)oxy]-1,1,10-trimethyl-6,9-epidioxy-delta 7-octalin (17a), which showed an IC50 of 100 and 57 ng/mL, respectively. For comparison, qinghaosu exhibits a mean IC50 less than 3.4 ng/mL.