A series of ribo‐ and deoxyribonucleosides bearing 2‐aminopurine as a nucleobase with 7,8‐difluoro‐ 3,4‐dihydro‐3‐methyl‐2H‐[1,4]benzoxazine (conjugated directly or through an aminohexanoyl spacer) was synthesized using an enzymatic transglycosylation reaction. Nucleosides 3‐6 were resistant to deamination under action of adenosine deaminase (ADA) Escherichia coli and ADA from calf intestine. The antiviral activity of the modified nucleosides was evaluated against herpes simplex virus type 1 (HSV‐1, strain L2). It has been shown that at sub‐toxic concentrations, nucleoside (S)‐4‐[2‐amino‐9‐(β‐D‐ribofuranosyl)‐purin‐6‐yl]‐7,8‐difluoro‐3,4‐dihydro‐3‐methyl‐2H‐[1,4]benzoxazine exhibit significant antiviral activity (SI > 32) on the model of HSV‐1 in vitro, including an acyclovir‐resistant virus strain (HSV‐1, strain L2/R).
Novel conjugates of 2‐aminopurine and purine containing fragments of chiral heterocyclic amines attached at position 6 of purine core via a linker, fragment of omega‐amino acid, have been synthesized and evaluated in vitro for their anti‐herpetic activity in the Vero E6 cells; as a result, a new group of compounds possessing high inhibitory activity against herpes simplex virus type 1, including acyclovir‐resistant (TK–) strain has been revealed. The anti‐herpetic activity of the synthesized compounds is substantially dependent on the stereo configuration of the fragment of heterocyclic amine.
A series of 5,6-disubstituted benzimidazole nucleosides, obtained earlier, did not show any significant antiviral activity at relatively low cytotoxicity in vitro. In the course of our research we have succeeded in introducing an additional fluorine atom into the benzimidazole ring system. A new series of 4,6-difluorobenzimidazoles, bearing various groups (fluoro-, methoxy-, ethoxy-, morpholino-, and pyrrolidino-) in the 5-position of the benzene ring, have been synthesized. All these compounds proved to be substrates for recombinant E. coli purine nucleoside phosphorylase (PNP) in the transglycosylation reaction. Effective methods for the synthesis of ribo-and 2′-deoxyribonucleosides with high yields (60-90%) have been described, and the formation of regioisomeric N3-nucleosides of benzimidazoles have been detected. The biological activity of the nucleosides obtained against herpes simplex virus type 1 (HSV-1) has been elucidated. All compounds show a low cytotoxicity in the cell culture Vero E6. 4,5,6-Trifluoro-1-(β-D-ribofuranosyl)benzimidazole and 5-methoxy-4,6-difluoro-1-(β-D-2′-deoxyribofuranosyl)benzimidazole proved to inhibit completely the progression of the virus cytopathic effect (CPE) at a multiplicity of infection (MOI) of 0.01 PFU/cell.
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