The chemotherapy of rodent malaria. XLVIII. The activities of some synthetic 1,2,4-trioxanes against chloroquine-sensitive and chloroquine-resistant parasites. Part 1: Studies leading to the development of novelcis-fused cyclopenteno derivatives

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Abstract
The new Chinese antimalarial blood schizontocide, artemisinin, derived from the plant Artemisia annua, displays a high level of activity against polyresistant Plasmodium falciparum. Several synthetic 1,2,4-trioxanes were examined in a search for compounds that exhibit a similar type of action against drug-resistant parasites. This paper, the first of a series, describes the examination of these trioxanes against drug-sensitive and drug-resistant malaria parasites in a rodent model, using artemisinin and arteether as comparison standards. Cis-fused cyclohexeno-l,2,4-trioxanes (10–17) substituted with various side-chains revealed for the most part variable but weak antimalarial activity. On the other hand, cis-fused cyclopenteno-1,2,4-trioxanes (18–19) showed greater activity, 19 showing about l/30th of the activity of arteether against drug-sensitive Plasmodium berghei in vivo, thereby providing a clue to the structure—activity relationship.