Relationship between antimalarial activity and heme alkylation for spiro- and dispiro-1,2,4-trioxolane antimalarials

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

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

The reaction of spiro- and dispiro-1,2,4-trioxolane antimalarials with heme has been investigated to provide further insight into the mechanism of action for this important class of antimalarials. A series of trioxolanes with various antimalarial potencies was found to be unreactive in the presence of Fe(III) hemin, but all were rapidly degraded by reduced Fe(II) heme. The major reaction product from the heme-mediated degradation of biologically active trioxolanes was an alkylated heme adduct resulting from addition of a radical intermediate. Under standardized reaction conditions, a correlation (R2 = 0.88) was found between the extent of heme alkylation and in vitro antimalarial activity, suggesting that heme alkylation may be related to the mechanism of action for these trioxolanes. Significantly less heme alkylation was observed for the clinically utilized artemisinin derivatives compared to the equipotent trioxolanes included in this study.

Original languageEnglish (US)
Pages (from-to)1291-1296
Number of pages6
JournalAntimicrobial Agents and Chemotherapy
Volume52
Issue number4
DOIs
StatePublished - Apr 2008

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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