Iron-mediated degradation kinetics of substituted dispiro-1,2,4-trioxolane antimalarials

Darren J. Creek, William N. Charman, Francis C.K. Chiu, Richard J. Prankerd, Kevin J. McCullough, Yuxiang Dong, Jonathan L. Vennerstrom, Susan A. Charman

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

The iron-mediated reactivity of various dispiro-1,2,4-trioxolanes was determined by automated kinetic analysis under standard reaction conditions. The active antimalarial compounds underwent peroxide bond cleavage by Fe(II) resulting in products indicative of carbon-centered radical formation. The rate of reaction was heavily influenced by the presence of spiro-substituted adamantane and cyclohexane rings, and was also significantly affected by cyclohexane ring substitution. Steric hindrance around the peroxide oxygen atoms appeared to be the major determinant of reaction rate, however polar substituents also affected reactivity by an independent mechanism. A wide range of reaction rates was observed within this class of peroxide antimalarials, however iron-mediated reactivity did not directly correlate with in vitro antimalarial activity.

Original languageEnglish (US)
Pages (from-to)2945-2956
Number of pages12
JournalJournal of Pharmaceutical Sciences
Volume96
Issue number11
DOIs
StatePublished - Nov 2007

Keywords

  • Anti-infectives
  • Kinetics
  • Malaria
  • Oxidation
  • Peroxide
  • Reduction
  • Structure-activity relationship

ASJC Scopus subject areas

  • Pharmaceutical Science

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    Creek, D. J., Charman, W. N., Chiu, F. C. K., Prankerd, R. J., McCullough, K. J., Dong, Y., Vennerstrom, J. L., & Charman, S. A. (2007). Iron-mediated degradation kinetics of substituted dispiro-1,2,4-trioxolane antimalarials. Journal of Pharmaceutical Sciences, 96(11), 2945-2956. https://doi.org/10.1002/jps.20958