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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.



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