Abstract
Recently, we demonstrated that the natural cytokinin nucleosides N6-isopentenyladenosine (iPR) and N6-benzyladenosine (BAPR) 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 BAPR and evaluated their activity on the replication of human enterovirus 71 in a cytopathic effect (CPE) reduction assay. The monofluorination of the BAPR-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, N6-trifluoromethylbenzyladenosine derivatives (9–11) exhibited also a very interesting profile, with low cytotoxicity observed. In particular, the analogue N6-(3-trifluoromethylbenzyl)-adenosine (10) with a four-fold gain in potency as compared to BAPR and the best SI in the class represents a promising candidate for further development.
Highlights
For many years, natural products (NPs) have been a leading source for the majority of the approved drugs, and their structures are a valuable source of inspiration for medicinal chemists [1].Interestingly, only 36% of the new chemical entities discovered between 1981 and 2010 were developed without inspiration from a natural product [2].Among natural products, the development of nucleosides is by far the most fruitful field of investigation
Our data revealed that the introduction of at least two fluorine atoms or a trifluoromethyl group on the phenyl ring of BAPR dramatically improved its selectivity by reducing the cytotoxicity, and in case of compound 10, by increasing the potency
After 2 days, the mixture was evaporated in a vacuum and the residue was purified by column chromatography on silica gel
Summary
Natural products (NPs) have been a leading source for the majority of the approved drugs, and their structures are a valuable source of inspiration for medicinal chemists [1]. Cytokinin nucleosides contain a hydrophilic ribofuranose moiety and a purine heterocyclic scaffold modified with a Molecules 2017, 22, 1219; doi:10.3390/molecules22071219 www.mdpi.com/journal/molecules. EV71 commonly hand-, foot-,disease and mouth disease (HFMD), a mild and family. EV71 commonly causes hand-,causes foot-, and mouth (HFMD), a mild and self-limiting self-limiting illness mostly affecting children under the In agesome of five. [20,21] These compounds were rather cytotoxic, a potent and selective antiviral effect on EV71 [20,21]. These compounds were rather with CC50 values in50the low micromolar range (4–8 μM).
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