This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Auparakkitanon, S.
Right arrow Articles by Wilairat, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Auparakkitanon, S.
Right arrow Articles by Wilairat, P.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, December 2003, p. 3708-3712, Vol. 47, No. 12
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.12.3708-3712.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Antimalarial 9-Anilinoacridine Compounds Directed at Hematin

Saranya Auparakkitanon,1 Wilai Noonpakdee,1 Raymond K. Ralph,2 William A. Denny,3 and Prapon Wilairat1*

Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand,1 Cancer Research and Developmental Biology, School of Biological Sciences,2 Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand3

Received 2 June 2003/ Returned for modification 15 July 2003/ Accepted 26 August 2003

Antimalarial 9-anilinoacridines are potent inhibitors of parasite DNA topoisomerase II both in vitro and in situ. 3,6-Diamino substitution on the acridine ring greatly improves parasiticidal activity against Plasmodium falciparum by targeting DNA topoisomerase II. A series of 9-anilinoacridines were investigated for their abilities to inhibit ß-hematin formation, to form drug-hematin complexes, and to enhance hematin-induced lysis of red blood cells. Inhibition of ß-hematin formation was minimal with 3,6-diamino analogs of 9-anilinoacridine and greatest with analogs with a 3,6-diCl substitution together with an electron-donating group in the 1'-anilino position. On the other hand, the presence of a 1'-N(CH3)2 group in the anilino ring produced compounds that strongly inhibited ß-hematin formation but which did not appear to be sensitive to the nature of the substitutions in the acridine nucleus. The derivatives bound hematin, and Job's plots of UV-visible absorbance changes in drug-hematin complexes at various molar ratios indicated a stoichiometric ratio of 1:2. The drugs enhanced hematin-induced red blood cell lysis at low concentrations (<4 µM). These studies open up the novel possibility of development of 9-anilinoacridine antimalarials that target not only DNA topoisomerase II but also ß-hematin formation, which should help delay the rapid onset of resistance to drugs acting at only a single site.

* Corresponding author. Mailing address: Department of Biochemistry, Faculty of Science, Mahidol University, Rama 6 Rd., Bangkok 10400, Thailand. Phone: (662) 245-5195. Fax: (662) 248-0375. E-mail: scpwl{at}mahidol.ac.th.

Antimicrobial Agents and Chemotherapy, December 2003, p. 3708-3712, Vol. 47, No. 12
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.12.3708-3712.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Omodeo-Sale, F., Cortelezzi, L., Basilico, N., Casagrande, M., Sparatore, A., Taramelli, D. (2009). Novel Antimalarial Aminoquinolines: Heme Binding and Effects on Normal or Plasmodium falciparum-Parasitized Human Erythrocytes. Antimicrob. Agents Chemother. 53: 4339-4344 [Abstract] [Full Text]  
  • Biagini, G. A., Fisher, N., Berry, N., Stocks, P. A., Meunier, B., Williams, D. P., Bonar-Law, R., Bray, P. G., Owen, A., O'Neill, P. M., Ward, S. A. (2008). Acridinediones: Selective and Potent Inhibitors of the Malaria Parasite Mitochondrial bc1 Complex. Mol. Pharmacol. 73: 1347-1355 [Abstract] [Full Text]  
  • Caffrey, C. R., Steverding, D., Swenerton, R. K., Kelly, B., Walshe, D., Debnath, A., Zhou, Y.-M., Doyle, P. S., Fafarman, A. T., Zorn, J. A., Land, K. M., Beauchene, J., Schreiber, K., Moll, H., Ponte-Sucre, A., Schirmeister, T., Saravanamuthu, A., Fairlamb, A. H., Cohen, F. E., McKerrow, J. H., Weisman, J. L., May, B. C. H. (2007). Bis-Acridines as Lead Antiparasitic Agents: Structure-Activity Analysis of a Discrete Compound Library In Vitro. Antimicrob. Agents Chemother. 51: 2164-2172 [Abstract] [Full Text]  
  • Auparakkitanon, S., Chapoomram, S., Kuaha, K., Chirachariyavej, T., Wilairat, P. (2006). Targeting of hematin by the antimalarial pyronaridine.. Antimicrob. Agents Chemother. 50: 2197-2200 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»