Fluorination of Naturally Occurring N6-Benzyladenosine Remarkably Increased Its Antiviral Activity and Selectivity

Abstract

Recently, we demonstrated that the natural cytokinin nucleosides <i>N</i>⁶-isopentenyladenosine (<b>iPR</b>) and <i>N</i>⁶-benzyladenosine (<b>BAPR</b>) exert a potent and selective antiviral effect on the replication of human enterovirus 71. In order to further characterize the antiviral profile of this class of compounds, we generated a series of fluorinated derivatives of <b>BAPR</b> and evaluated their activity on the replication of human enterovirus 71 in a cytopathic effect (CPE) reduction assay. The monofluorination of the <b>BAPR</b>-phenyl group changed the selectivity index (SI) slightly because of the concomitant high cell toxicity. Interestingly, the incorporation of a second fluorine atom resulted in a dramatic improvement of selectivity. Moreover, <i>N</i>⁶-trifluoromethylbenzyladenosines derivatives (<b>9</b>-<b>11</b>) exhibited also a very interesting profile, with low cytotoxicity observed. In particular, the analogue <i>N</i>⁶-(3-trifluoromethylbenzyl)-adenosine (<b>10</b>) with a four-fold gain in potency as compared to <b>BAPR</b> and the best SI in the class represents a promising candidate for further development.