Modification of the length and structure of the linker of N6-benzyladenosine modulates its selective antiviral activity against enterovirus 71

• Published in: European journal of medicinal chemistry 2016-03, Vol.111, p.84-94
• Main Authors: Drenichev, Mikhail S., Oslovsky, Vladimir E., Sun, Liang, Tijsma, Aloys, Kurochkin, Nikolay N., Tararov, Vitali I., Chizhov, Alexander O., Neyts, Johan, Pannecouque, Christophe, Leyssen, Pieter, Mikhailov, Sergey N.
• Format: Article
• Language: English
• Subjects: Enterovirus 71; N6-benzyladenosine derivatives; SAR; Synthesis and antiviral activity
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.01.036

Very recently, we demonstrated that N6-isopentenyladenosine, a cytokinin nucleoside, exerts a potent and selective antiviral effect on the replication of human enterovirus 71. The present study is devoted to the structure optimization of another natural compound: N6-benzyladenosine. We mainly focused on the exploration of the size and nature of the linker between the adenine and the phenyl ring, as well as on the necessity of the D-ribose residue. More than 30 analogues of N6-benzyladenosine were prepared and their antiviral properties were evaluated. Two main methodologies were used for preparation: N6-acetyl-2′,3′,5′-tri-O-acetyladenosine can be regioselectively alkylated either by alkyl halides under base promoted conditions or by alcohols in Mitsunobu reactions. After deacylation with 4 M PrNH2 in MeOH at room temperature for one day, the desired products were obtained in overall high yields. Analysis of the structure-activity relationship clearly shows that the optimal size of the linker is limited to 2 or 3 atoms (compounds 4–7). 2′-Deoxyadenosine derivatives did not elicit any inhibitory or cytotoxic effect, while 5′-deoxynucleosides still induced some cell protective antiviral activity. Based on these observations, it can be hypothesized that there may be another mechanism that is at the base of the antiviral activity of these compounds against enterovirus 71 besides a possible 5′-triphosphorylation followed by a putative inhibitory effect on RNA synthesis. [Display omitted] •N6-Benzyladenosine analogs were prepared and tested for antienteroviral activity.•Their activity is greatly dependent on the size and structure of the linker.•N6-Phenylpropenyladenosine exhibits the highest selectivity index.•The selectivity index was improved in about 50 times.