2,N⁶-disubstituted adenosine analogs with antitrypanosomal and antimalarial activities

Rodenko, B., van der Burg, A. M., Wanner, M. J., Kaiser, M., Brun, R., Gould, M., de Koning, H. P. and Koomen, G.-J. (2007) 2,N⁶-disubstituted adenosine analogs with antitrypanosomal and antimalarial activities. Antimicrobial Agents and Chemotherapy, 51(11), pp. 3796-3802. (doi: 10.1128/AAC.00425-07) (PMID:17698622) (PMCID:PMC2151466)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: De Koning, Professor Harry and Gould, Matthew and Rodenko, Dr Boris
• Authors: Rodenko, B., van der Burg, A. M., Wanner, M. J., Kaiser, M., Brun, R., Gould, M., de Koning, H. P., and Koomen, G.-J.
• Subjects: Q Science > QH Natural history > QH345 Biochemistry
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Antimicrobial Agents and Chemotherapy
• Journal Abbr.: Antimicrob Agents Chemother
• Publisher: American Society for Microbiology
• ISSN: 0066-4804
• ISSN (Online): 1098-6596
• Published Online: 13 August 2007