Xanthones as antimalarial agents; studies of a possible mode of action

Marina V. Ignatushchenko, R. W. Winter, Hans Peter Bächinger, David J. Hinrichs, Michael Riscoe

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Abstract

We recently demonstrated that 2,3,4,5,6-pentahydroxyxanthone (X5) inhibits the in vitro growth of both chloroquine-sensitive and multidrug-resistant strains of P. falciparum. To study the molecular basis of its antimalarial action, we tested X5 and selected hydroxyxanthone analogs as inhibitors of in vitro heme polymerization in a low ionic strength phosphate solution at mildly acidic pH. We found that addition of 1 Eq. of X5 resulted in complete inhibition of polymerization in this system whereas addition of up to 40 Eqs. of standard antimalarial compounds (chloroquine, primaquine, quinacrine, artemisinin and methylene blue) had no such effect although these compounds did co-precipitate with heme. The antimalarial potency of the hydroxyxanthones correlated well with their ability to inhibit in vitro hems polymerization in our assay, suggesting that these compounds exert their antimalarial action by preventing hemozoin formation. Based on the observed structure-activity relationships, we propose a model displaying possible interactions between hydroxyxanthones and heme.

Original languageEnglish (US)
Pages (from-to)67-73
Number of pages7
JournalFEBS Letters
Volume409
Issue number1
DOIs
Publication statusPublished - Jun 2 1997

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Keywords

  • Chemotherapy
  • Digestive vacuole
  • Heme polymerization
  • Malaria
  • Plasmodium falciparum
  • Xanthone

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Ignatushchenko, M. V., Winter, R. W., Bächinger, H. P., Hinrichs, D. J., & Riscoe, M. (1997). Xanthones as antimalarial agents; studies of a possible mode of action. FEBS Letters, 409(1), 67-73. https://doi.org/10.1016/S0014-5793(97)00405-5