Chemical modification of the plant isoprenoid cytokinin N6-isopentenyladenosine yields a selective inhibitor of human enterovirus 71 replication

• Ten new N6-substituted adenosines have been synthesized.
• N6-Isopenthenyladenosine exerts antiviral effect on the replication of EV71.
• The structure–activity relationship for N6-substituted adenosines has been studied.
• The allylation of N6-propargyladenosine in the presence of Cu(I) was developed.
• N6-(5-Hexene-2-yne-1-yl)adenosine exhibits the highest selectivity index.

In this study, we demonstrate that N6-isopentenyladenosine, which essentially is a plant cytokinin-like compound, exerts a potent and selective antiviral effect on the replication of human enterovirus 71 with an EC50 of 1.0 ± 0.2 μM and a selectivity index (SI) of 5.7. The synthesis of analogs with modification of the N6-position did not result in a lower EC50 value. However, in particular with the synthesis of N6-(5-hexene-2-yne-1-yl)adenosine (EC50 = 4.3 ± 1.5 μM), the selectivity index was significantly increased: because of a reduction in the adverse effect of this compound on the host cells, an SI > 101 could be calculated. With this study, we for the first time provide proof that a compound class that is based on the plant cytokinin skeleton offers an interesting starting point for the development of novel antivirals against mammalian viruses, in the present context in particular against enterovirus 71.

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