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Antimicrobial Agents and Chemotherapy, January 2002, p. 144-150, Vol. 46, No. 1
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.1.144-150.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Optimization of Xanthones for Antimalarial Activity: the 3,6-Bis-{omega}-Diethylaminoalkoxyxanthone Series

Jane Xu Kelly,1,2 Rolf Winter,1,2 David H. Peyton,1 David J. Hinrichs,2 and Michael Riscoe1,2*

Department of Chemistry, Portland State University, Portland, Oregon 97207-0751,1 Medical Research Service, Department of Veterans Affairs Medical Center, Portland, Oregon 972012

Received 1 March 2001/ Returned for modification 18 August 2001/ Accepted 10 October 2001

Hydroxyxanthones have been identified as novel antimalarial agents. The compounds are believed to exert their activity by complexation to heme and inhibition of hemozoin formation. Modification of the xanthone structure was pursued to improve their antimalarial activity. Attachment of R-groups bearing protonatable nitrogen atoms was conducted to enhance heme affinity through ionic interactions with the propionate side chains of the metalloporphyrin and to facilitate drug accumulation in the parasite food vacuole. A series of 3,6-bis-{omega}-diethylaminoalkoxyxanthones with side chains ranging from 2 to 8 carbon atoms were prepared and evaluated. Measurement of heme affinity for each of the derivatives revealed a strong correlation (R2 = 0.97) between affinity and antimalarial potency. The two most active compounds in the series contained 5- and 6-carbon side chains and exhibited low nanomolar 50% inhibitory concentration (IC50) values against strains of chloroquine-susceptible and multidrug-resistant Plasmodium falciparum in vitro. Both of these xanthones exhibit stronger heme affinity (8.26 x 105 and 9.02 x 105 M–1, respectively) than either chloroquine or quinine under similar conditions and appear to complex heme in a unique manner.

* Corresponding author. Mailing address: Medical Research Service, R&D-33, Veterans Affairs Medical Center, 3710 S.W. U.S. Veterans Hospital Road, Portland, OR 97201. Phone: (503) 721-7885. Fax: (503) 402-2817. Email: riscoem{at}ohsu.edu.

Antimicrobial Agents and Chemotherapy, January 2002, p. 144-150, Vol. 46, No. 1
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.1.144-150.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kelly, J. X., Smilkstein, M. J., Cooper, R. A., Lane, K. D., Johnson, R. A., Janowsky, A., Dodean, R. A., Hinrichs, D. J., Winter, R., Riscoe, M. (2007). Design, Synthesis, and Evaluation of 10-N-Substituted Acridones as Novel Chemosensitizers in Plasmodium falciparum. Antimicrob. Agents Chemother. 51: 4133-4140 [Abstract] [Full Text]  
  • Smilkstein, M., Sriwilaijaroen, N., Kelly, J. X., Wilairat, P., Riscoe, M. (2004). Simple and Inexpensive Fluorescence-Based Technique for High-Throughput Antimalarial Drug Screening. Antimicrob. Agents Chemother. 48: 1803-1806 [Abstract] [Full Text]  


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