Tetraoxane antimalarials and their reaction with Fe(II)
(2006) Journal of Medicinal Chemistry — Vol. 49, n° 13, p. 3790-3799 (2006)
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- Mixed tetraoxanes 5a and 13 synthesized from cholic acid and 4-oxocyclohexanecarboxylic acid were as active as artemisinin against chloroquine-susceptible, chloroquine-resistant, and multidrug-resistant Plasmodium falciparum strains (IC50, IC90). Most active 13 is metabolically stable in in vitro metabolism studies. In vivo studies on tetraoxanes with a C(4'') methyl group afforded compound 15, which cured 4/5 mice at 600 and 200 mg, kg(-1), day(-1), and 2/5 mice at 50 mg, kg(-1), day(-1), showing no toxic effects. Tetraoxane 19 was an extremely active antiproliferative with LC50 of 17 nM and maximum tolerated dose of 400 mg/kg. In Fe(II)-induced scission of tetraoxane antimalarials only RO center dot radicals were detected by EPR experiments. This finding and the indication of Fe(IV)=O species led us to propose that RO center dot radicals are probably capable of inducing the parasite's death. Our results suggest that C radicals are possibly not the only lethal species derived from peroxide prodrug antimalarials, as currently believed.
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Opsenica, I., Terzic, N., Opsenica, D., Angelovski, G., Lehnig, M., Eilbracht, P., Tinant, B., Juranic, Z., Smith, K. S., Yang, Y. S., Diaz, D. S., Smith, P. L., Milhous, W. K., Dokovic, D., & Solaja, B. A. (2006). Tetraoxane antimalarials and their reaction with Fe(II). Journal of Medicinal Chemistry, 49(13), 3790-3799. https://doi.org/10.1021/jm050966r (Original work published 2006)