Synthesis and antimalarial activity of sixteen dispiro-1,2,4,5-tetraoxanes: Alkyl-substituted 7,8,15,16-tetraoxadispiro[5.2.5.2]hexadecanes

Sixteen alkyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15,16-tetraoxadi spiro[5.2.5.2]hexadecanes) were synthesized to explore dispiro-1,2,4,5-tetr aoxane SAR and to identify tetraoxanes with better oral antimalarial activi ty than prototype tetraoxane 1 (WR 148999). The tetraoxanes were prepared e ither by peroxidation of the corresponding cyclohexanone derivatives in H2S O4/CH3CN or by ozonolysis of the corresponding cyclohexanone methyl oximes. Those tetraoxanes with alkyl substituents at the 1 and 10 positions were f ormed as single stereoisomers, whereas the five tetraoxanes formed without the stereochemical control provided by alkyl groups at the 1 and 10 positio ns were isolated as mixtures of diastereomers. Three of the sixteen tetraox anes were inactive (IC50's > 1000 nM), but five (2, 6, 10, 11, 12) had IC50 's between 10 and 30 nM against the chloroquine-sensitive D6 and chloroquin e-resistant W2 clones of Plasmodium falciparum compared to corresponding IC 50's of 55 and 32 nM for 1 and 8.4 and 7.3 nM for artemisinin. We suggest t hat tetraoxanes 13, 16, and 17 were inactive and tetraoxanes 4 and 7 were w eakly active due to steric effects preventing or hindering peroxide bond ac cess to parasite heme. Tetraoxanes 1, 10, 11, and 14, along with artemisini n and arteether as controls, were administered po b.i.d. (128 mg/kg/day) to P. berghei-infected mice on days 3, 4, and 5 post-infection. At this dose, tetraoxanes 10, 11, and 14 cured between 40% and 60% of the infected anima ls. In comparison, artemisinin and tetraoxane 1 produced no cures, whereas arteether cured 100% of the infected animals. There was no apparent relatio nship between tetraoxane structure and in vitro neurotoxicity, nor was ther e any correlation between antimalarial activity and neurotoxicity for these seventeen tetraoxanes.