Anti-plasmodial polyvalent interactions in Artemisia annua L. aqueous extract--possible synergistic and resistance mechanisms

PLoS One. 2013 Nov 14;8(11):e80790. doi: 10.1371/journal.pone.0080790. eCollection 2013.

Abstract

Artemisia annua hot water infusion (tea) has been used in in vitro experiments against P. falciparum malaria parasites to test potency relative to equivalent pure artemisinin. High performance liquid chromatography (HPLC) and mass spectrometric analyses were employed to determine the metabolite profile of tea including the concentrations of artemisinin (47.5±0.8 mg L(-1)), dihydroartemisinic acid (70.0±0.3 mg L(-1)), arteannuin B (1.3±0.0 mg L(-1)), isovitexin (105.0±7.2 mg L(-1)) and a range of polyphenolic acids. The tea extract, purified compounds from the extract, and the combination of artemisinin with the purified compounds were tested against chloroquine sensitive and chloroquine resistant strains of P. falciparum using the DNA-intercalative SYBR Green I assay. The results of these in vitro tests and of isobologram analyses of combination effects showed mild to strong antagonistic interactions between artemisinin and the compounds (9-epi-artemisinin and artemisitene) extracted from A. annua with significant (IC50 <1 μM) anti-plasmodial activities for the combination range evaluated. Mono-caffeoylquinic acids, tri-caffeoylquinic acid, artemisinic acid and arteannuin B showed additive interaction while rosmarinic acid showed synergistic interaction with artemisinin in the chloroquine sensitive strain at a combination ratio of 1:3 (artemisinin to purified compound). In the chloroquine resistant parasite, using the same ratio, these compounds strongly antagonised artemisinin anti-plasmodial activity with the exception of arteannuin B, which was synergistic. This result would suggest a mechanism targeting parasite resistance defenses for arteannuin B's potentiation of artemisinin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / pharmacology*
  • Artemisia annua / chemistry*
  • Artemisinins / pharmacology
  • Cinnamates / pharmacology
  • Depsides / pharmacology
  • Drug Synergism
  • Plant Extracts / chemistry*
  • Plant Extracts / pharmacology*
  • Plasmodium falciparum / drug effects*
  • Rosmarinic Acid

Substances

  • Antimalarials
  • Artemisinins
  • Cinnamates
  • Depsides
  • Plant Extracts
  • artemisitene
  • arteannuin B
  • artemisinin

Grants and funding

This study was funded by Engineering and Physical Sciences Research Council (EPSRC, UK) and SensaPharm Ltd via an Industrial CASE PhD studentship. The award was allocated competitively by Chemistry Innovation Knowledge Transfer Network (CIKTN, UK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.