Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides: Charting a workable structure-activity relationship using simple prototypes

Yuxiang Dong, Jacques Chollet, Hugues Matile, Susan A. Charman, Francis C.K. Chiu, William N. Charman, Bernard Scorneaux, Heinrich Urwyler, Josefina Santo Tomas, Christian Scheurer, Christopher Snyder, Arnulf Dorn, Xiaofang Wang, Jean M. Karle, Yuanqing Tang, Sergio Wittlin, Reto Brun, Jonathan L. Vennerstrom

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

This paper describes the discovery of synthetic 1,2,4-trioxolane antimalarials and how we established a workable structure-activity relationship in the context of physicochemical, biopharmaceutical, and toxicological profiling. An achiral dispiro-1,2,4-trioxolane (3) in which the trioxolane is flanked by a spiroadamantane and spirocyclohexane was rapidly identified as a lead compound. Nonperoxidic 1,3-dioxolane isosteres of 3 were inactive as were trioxolanes without the spiroadamantane. The trioxolanes were substantially less effective in a standard oral suspension formulation compared to a solubilizing formulation and were more active when administered subcutaneously than orally, both of which suggest substantial biopharmaceutical liabilities. Nonetheless, despite their limited oral bioavailability, the more lipophilic trioxolanes generally had better oral activity than their more polar counterparts. In pharmacokinetic experiments, four trioxolanes had high plasma clearance values, suggesting a potential metabolic instability. The toxicological profiles of two trioxolanes were comparable to that of artesunate.

Original languageEnglish (US)
Pages (from-to)4953-4961
Number of pages9
JournalJournal of Medicinal Chemistry
Volume48
Issue number15
DOIs
StatePublished - Jul 28 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Dong, Y., Chollet, J., Matile, H., Charman, S. A., Chiu, F. C. K., Charman, W. N., Scorneaux, B., Urwyler, H., Santo Tomas, J., Scheurer, C., Snyder, C., Dorn, A., Wang, X., Karle, J. M., Tang, Y., Wittlin, S., Brun, R., & Vennerstrom, J. L. (2005). Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides: Charting a workable structure-activity relationship using simple prototypes. Journal of Medicinal Chemistry, 48(15), 4953-4961. https://doi.org/10.1021/jm049040u