This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
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 Google Scholar
Google Scholar
Right arrow Articles by Rodenko, B.
Right arrow Articles by Koomen, G.-J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rodenko, B.
Right arrow Articles by Koomen, G.-J.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, November 2007, p. 3796-3802, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00425-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

2,N6-Disubstituted Adenosine Analogs with Antitrypanosomal and Antimalarial Activities{triangledown} ,{dagger}

Boris Rodenko,1 Alida M. van der Burg,1 Martin J. Wanner,1 Marcel Kaiser,2 Reto Brun,2 Matthew Gould,3 Harry P. de Koning,3* and Gerrit-Jan Koomen1

Van't Hoff Institute for Molecular Sciences, Universiteit van Amsterdam, Nieuwe Achtergracht 129, NL-1018 WS Amsterdam, The Netherlands,1 Antiparasite Chemotherapy, Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland,2 Institute of Biomedical and Life Sciences, Division of Infection and Immunity, University of Glasgow, Glasgow G12 8TA, United Kingdom3

Received 28 March 2007/ Returned for modification 22 June 2007/ Accepted 4 August 2007

A library of 2,N6-disubstituted adenosine analogs was synthesized and the analogs were tested for their antiprotozoal activities. It was found that 2-methoxy and 2-histamino and N6-m-iodobenzyl substitutions generally produced analogs with low levels of antiprotozoal activity. The best antiplasmodial activity was achieved with large aromatic substitutions, such as N6-2,2-diphenylethyl and naphthylmethyl, which could indicate a mechanism of action through aromatic stacking with heme in the digestive vacuole of Plasmodium spp. The activities against Trypanosoma cruzi trypomastigotes and Leishmania donovani amastigotes were generally low; but several analogs, particularly those with cyclopentylamino substitutions, displayed potent activities against Trypanosoma brucei rhodesiense and T. b. brucei bloodstream forms in vitro. The most active were 2-cyclopentylamino-N6-cyclopentyladenosine (compound NA42) and 2-cyclopentylamino-N6-cyclopentyladenine (compound NA134), with the nucleobase an order of magnitude more potent than the nucleoside, at 26 ± 4 nM. It was determined that the mode of action of these purines was trypanostatic, with the compounds becoming trypanocidal only at much higher concentrations. Those 2,N6-disubstituted purines tested for their effects on purine transport in T. b. brucei displayed at best a moderate affinity for the transporters. It is highly probable that the large hydrophobic substitutions, which bestow high calculated octanol-water coefficient values on the analogs, allow them to diffuse across the membrane. Consistent with this view, the analogs were as effective against a T. b. brucei strain lacking the P2 nucleoside transporter as they were against the parental strain. As the analogs were not toxic to human cell lines, the purine analogs are likely to act on a trypanosome-specific target.

* Corresponding author. Mailing address: Institute of Biomedical and Life Sciences, Division of Infection and Immunity, University of Glasgow, Glasgow G12 8TA, United Kingdom. Phone and fax: 44-141-3303753. E-mail: H.de-Koning{at}bio.gla.ac.uk

{triangledown} Published ahead of print on 13 August 2007.

{dagger} Supplemental material for the article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, November 2007, p. 3796-3802, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00425-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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