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 Stewart, M. L.
Right arrow Articles by Barrett, M. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stewart, M. L.
Right arrow Articles by Barrett, M. P.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, May 2004, p. 1733-1738, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1733-1738.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Trypanocidal Activity of Melamine-Based Nitroheterocycles

Mhairi L. Stewart,1 Gorka Jimenez Bueno,2 Alessandro Baliani,2 Burkhard Klenke,2 Reto Brun,3 Janice M. Brock,1 Ian H. Gilbert,2 and Michael P. Barrett1*

Division of Infection and Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ,1 Welsh School of Pharmacy, Cardiff University, Cardiff CF10 3XF, United Kingdom,2 Swiss Tropical Institute, CH-4002 Basel, Switzerland3

Received 24 September 2003/ Returned for modification 31 October 2003/ Accepted 21 January 2004

A series of nitroheterocyclic compounds were designed with linkages to melamine or benzamidine groups that are known substrates of the P2 aminopurine and other transporters in African trypanosomes of the brucei group. Several compounds showed in vitro trypanotoxicity with 50% inhibitory concentrations in the submicromolar range. Although most compounds interacted with the P2 transporter, as judged by their ability to inhibit adenosine transport via this carrier, uptake through this route was not necessary for activity since TbAT1-null mutant parasites, deficient in this transporter, retained sensitivity to these drugs. One compound, a melamine-linked nitrofuran, also showed pronounced activity against parasites in mice. Studies into the mode of action of this compound indicated that neither reductive, nor oxidative, stress were related to its trypanocidal activity ruling out a genotoxic effect in T. brucei, distinguishing it from some other, mammalian cell toxic, trypanocidal nitroheterocycles.

* Corresponding author. Mailing address: Institute of Biomedical and Life Sciences, Division of Infection and Immunity, University of Glasgow, The Joseph Black Building, Glasgow G12 8QQ, United Kingdom. Phone: (44) 141-330-6904. Fax: (44) 141-330-6904. E-mail: m.barrett{at}bio.gla.ac.uk.

Antimicrobial Agents and Chemotherapy, May 2004, p. 1733-1738, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1733-1738.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Arrighi, R. B. G., Ebikeme, C., Jiang, Y., Ranford-Cartwright, L., Barrett, M. P., Langel, U., Faye, I. (2008). Cell-Penetrating Peptide TP10 Shows Broad-Spectrum Activity against both Plasmodium falciparum and Trypanosoma brucei brucei. Antimicrob. Agents Chemother. 52: 3414-3417 [Abstract] [Full Text]  
  • Wilkinson, S. R., Taylor, M. C., Horn, D., Kelly, J. M., Cheeseman, I. (2008). A mechanism for cross-resistance to nifurtimox and benznidazole in trypanosomes. Proc. Natl. Acad. Sci. USA 105: 5022-5027 [Abstract] [Full Text]  
  • Stewart, M. L., Boussard, C., Brun, R., Gilbert, I. H., Barrett, M. P. (2005). Interaction of Monobenzamidine-Linked Trypanocides with the Trypanosoma brucei P2 Aminopurine Transporter. Antimicrob. Agents Chemother. 49: 5169-5171 [Abstract] [Full Text]  
  • Geiser, F., Luscher, A., de Koning, H. P., Seebeck, T., Maser, P. (2005). Molecular Pharmacology of Adenosine Transport in Trypanosoma brucei: P1/P2 Revisited. Mol. Pharmacol. 68: 589-595 [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»