Orally active antimalarial 3-substituted trioxanes: new synthetic methodology and biological evaluation

Journal of Medicinal Chemistry
G H PosnerT A Shapiro

Abstract

On the basis of a mechanistic understanding of the mode of action of artemisinin-like antimalarials, a series of structurally simple 3-aryl-1,2,4-trioxanes 5 was designed and was prepared in three to five operations from commercial reactants. The 3-aryl group was attached in each case as a nucleophile. In an electronically complementary fashion, 3-(fluoroalkyl)-trioxanes 6 were prepared via attachment of electrophilic fluoroalkyl esters. Both in vitro and in vivo antimalarial evaluations of these new trioxanes showed 12 beta-methoxy-3-aryltrioxanes 5g, 5j, 5k, and 51 to be highly potent, with crystalline fluorobenzyl ether trioxane 5k especially potent even when administered to rodents orally. As shown by rearrangement of hexamethyl Dewar benzene into hexamethylbenzene, iron-induced degradation of some of these 3-aryltrioxanes 5 involves generation of high-valent iron oxo species that might kill malaria parasites.

References

Apr 1, 1994·The American Journal of Tropical Medicine and Hygiene·G H PosnerR N Rossan
Jul 11, 1996·The New England Journal of Medicine·A L Kellermann, K H Todd
Jun 1, 1996·Microbiological Reviews·S R MeshnickS Kamchonwongpaisan

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Citations

Nov 19, 2002·International Journal for Parasitology·Kristina BorstnikGary H Posner
Jul 17, 2001·Bioorganic & Medicinal Chemistry Letters·M Jung, H Kim
Jul 15, 2000·Bioorganic & Medicinal Chemistry·G H PosnerT A Shapiro
Aug 1, 2014·Future Medicinal Chemistry·Daniel J Jansen, Ryan A Shenvi
Nov 17, 2006·Nature Chemical Biology·Adam R Renslo, James H McKerrow
May 30, 2009·Drug Discovery Today·K M Muraleedharan, Mitchell A Avery
Mar 26, 2010·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jian Li, Bing Zhou
Aug 24, 2010·Journal of Chemical Information and Modeling·Amit K GuptaAnil K Saxena
Oct 16, 2014·Organic Letters·Wei-Bo Han, Yikang Wu

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Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

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Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.