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.

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Abstract

A library of 2,N<sup>6</sup>-disubstituted adenosine analogs was synthesized and the analogs were tested for their antiprotozoal activities. It was found that 2-methoxy and 2-histamino and <i>N</i><sup>6</sup>-<i>m</i>-iodobenzyl substitutions generally produced analogs with low levels of antiprotozoal activity. The best antiplasmodial activity was achieved with large aromatic substitutions, such as <i>N</i><sup>6</sup>-2,2-diphenylethyl and naphthylmethyl, which could indicate a mechanism of action through aromatic stacking with heme in the digestive vacuole of <i>Plasmodium</i> spp. The activities against <i>Trypanosoma</i> <i>cruzi</i> trypomastigotes and <i>Leishmania</i> <i>donovani</i> amastigotes were generally low; but several analogs, particularly those with cyclopentylamino substitutions, displayed potent activities against <i>Trypanosoma</i> <i>brucei</i> <i>rhodesiense</i> and <i>T</i>. <i>b</i>. <i>brucei</i> bloodstream forms in vitro. The most active were 2-cyclopentylamino-<i>N</i><sup>6</sup>-cyclopentyladenosine (compound NA42) and 2-cyclopentylamino-<i>N</i><sup>6</sup>-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,N<sup>6</sup>-disubstituted purines tested for their effects on purine transport in <i>T</i>. <i>b</i>. <i>brucei</i> 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 <i>T</i>. <i>b</i>. <i>brucei</i> 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: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
Journal Name:Antimicrobial Agents and Chemotherapy
Journal Abbr.:Antimicrob Agents Chemother
Publisher:American Society for Microbiology
ISSN:0066-4804
ISSN (Online):1098-6596

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