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Antimicrob. Agents Chemother. doi:10.1128/AAC.00544-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Compounds structurally related to ellagic acid show improved antiplasmodial activity

Interdisciplinary Research Center, Justus-Liebig-University, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany; Max Planck Institute for Medical Research, Jahnstrasse 29, D-69120 Heidelberg, Germany; Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland

^* To whom correspondence should be addressed. Email: becker.katja{at}gmx.de.

	Abstract

The cancer chemopreventive agent ellagic acid (EA) is a known inhibitor of glutathione S-transferases (GSTs) and possesses antiplasmodial activities in the upper nanomolar range. In the recent drug development approach, the properties of the active site of Plasmodium falciparum (Pf) GST were exploited for inhibitor design by introducing one or two additional hydroxyl groups into EA yielding flavellagic acid (FEA) and coruleoellagic acid (CEA), respectively. Indeed, the inhibition of PfGST was improved with increasing hydrophilicity of the planar polyaromatic ring system. Studying the effects of the two compounds on central redox enzymes of Plasmodium revealed that also glutathione reductase and thioredoxin reductase are inhibited in the lower micromolar range. Both compounds had strong antiplasmodial activity in the lower nanomolar range and were particularly effective against chloroquine (CQ) resistant P. falciparum strains. Neither FEA nor CEA showed cytotoxic effects on human cells. This was supported by negligible changes in transcript levels and enzyme activities of redox enzymes in human A549 cells upon treatment with the compounds. In Plasmodium, however, CEA treatment resulted in a marked down-regulation of most antioxidant genes studied, and impaired mainly the trophozoite stage of the parasites. In addition, EA, CEA and FEA were found to strongly inhibit in vitro heme aggregation. In vitro and preliminary in vivo studies indicated that CEA is a slowly acting compound compared to CQ and is able to significantly improve survival of P. berghei infected mice. We conclude that FEA and CEA are promising antimalarial leads which deserve to be followed up.