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Antimicrobial Agents and Chemotherapy, February 2009, p. 622-630, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00544-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Compounds Structurally Related to Ellagic Acid Show Improved Antiplasmodial Activity{triangledown}

Nicole Sturm,1 Ying Hu,1 Herbert Zimmermann,2 Karin Fritz-Wolf,1,2 Sergio Wittlin,3 Stefan Rahlfs,1 and Katja Becker1*

Interdisciplinary Research Center, Justus-Liebig-University, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany,1 Max Planck Institute for Medical Research, Jahnstrasse 29, D-69120 Heidelberg, Germany,2 Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland3

Received 28 April 2008/ Returned for modification 21 May 2008/ Accepted 7 November 2008

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 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 P. falciparum GST was improved with the increasing hydrophilicity of the planar polyaromatic ring system. Studying the effects of the two compounds on the central redox enzymes of Plasmodium revealed that glutathione reductase and thioredoxin reductase also 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 downregulation 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, compared to CQ, CEA is a slowly acting compound and is able to significantly improve the survival of Plasmodium berghei-infected mice. We conclude that FEA and CEA are promising antimalarial compounds that deserve to be studied further.

* Corresponding author. Mailing address: Interdisciplinary Research Center, Justus-Liebig-University, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany. Phone: 49-(0)641-9939120. Fax: 49-(0)641-9939129. E-mail: becker.katja{at}gmx.de

{triangledown} Published ahead of print on 17 November 2008.

Antimicrobial Agents and Chemotherapy, February 2009, p. 622-630, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00544-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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