Fluorination of Naturally Occurring N6-Benzyladenosine Remarkably Increased Its Antiviral Activity and Selectivity
Vladimir E. Oslovsky,
Mikhail S. Drenichev,
Liang Sun,
Nikolay N. Kurochkin,
Vladislav E. Kunetsky,
Carmen Mirabelli,
Johan Neyts,
Pieter Leyssen,
Sergey N. Mikhailov
Affiliations
Vladimir E. Oslovsky
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
Mikhail S. Drenichev
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
Liang Sun
Laboratory for Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven-University of Leuven, Minderbroedersstraat 10, Leuven 3000, Belgium
Nikolay N. Kurochkin
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
Vladislav E. Kunetsky
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
Carmen Mirabelli
Laboratory for Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven-University of Leuven, Minderbroedersstraat 10, Leuven 3000, Belgium
Johan Neyts
Laboratory for Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven-University of Leuven, Minderbroedersstraat 10, Leuven 3000, Belgium
Pieter Leyssen
Laboratory for Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven-University of Leuven, Minderbroedersstraat 10, Leuven 3000, Belgium
Sergey N. Mikhailov
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
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.
