| Abstract
| - Eleven novel dispiro-1,2,4,5-tetraoxanes 3 bearing unsaturated and polar functional groupswere designed to enhance the oral antimalarial activity of the prototype tetraoxane 2 (WR148999). With the exception of 3g and 3h, tetraoxanes 3 were available via the peroxidationof corresponding cyclohexanone derivatives in H2SO4/CH3CN. Tetraoxanes 3g and 3h wereprepared by hydrolysis of ester tetraoxanes 3e and 3i, respectively. Five of the 11 tetraoxaneswere inactive, but six tetraoxanes had IC50 values of 6−26 nM against the K1 and NF54 strainsof Plasmodium falciparum compared to corresponding IC50 values of 28 and 39 nM for 2, and10 and 12 nM for artemisinin (1). Ester tetraoxane 3e was the most active in vitro, some 2-foldmore potent than 1. However, none of the six tetraoxanes active in vitro were as effective aseither 1 or 2 in vivo; at single doses of 100 mg/kg most possessed little to no vivo activity inmice infected with Plasmodium berghei. Unsaturated tetraoxane 3a was uniquely more activewhen administered per os (po) than subcutan (sc). For this series of tetraoxanes, the discrepancybetween vitro and vivo activities underscores the limitations of conclusions drawn solely fromin vitro antimalarial data and illustrates a practical benefit of complementary single-dose invivo antimalarial screens.
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