Synthesis of 1,2,3-triazolyl nucleoside analogues and their antiviral activity

Based on the fact that a search for influenza antivirals among nucleoside analogues has drawn very little attention of chemists, the present study reports the synthesis of a series of 1,2,3-triazolyl nucleoside analogues in which a pyrimidine fragment is attached to the ribofuranosyl-1,2,3-triazol-4...

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Published in:Molecular diversity 2021-02, Vol.25 (1), p.473-490
Main Authors: Andreeva, Olga V., Garifullin, Bulat F., Zarubaev, Vladimir V., Slita, Alexander V., Yesaulkova, Iana L., Saifina, Liliya F., Shulaeva, Marina M., Belenok, Maya G., Semenov, Vyacheslav E., Kataev, Vladimir E.
Format: Article
Language:English
Subjects:
Acquired immune deficiency syndrome
AIDS
Animals
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Biochemistry
Biomedical and Life Sciences
Cancer
Cell Death - drug effects
Chemistry
Chemists
Chlorocebus aethiops
Dogs
Drug resistance
Enterovirus - drug effects
HIV
Human immunodeficiency virus
Influenza
Influenza A Virus, H1N1 Subtype - drug effects
Life Sciences
Madin Darby Canine Kidney Cells
Molecular Docking Simulation
Nucleosides - chemical synthesis
Nucleosides - chemistry
Nucleosides - pharmacology
Organic Chemistry
Original
Original Article
Pharmacy
Polymer Sciences
RNA polymerase
Thermodynamics
Triazoles - chemical synthesis
Triazoles - chemistry
Triazoles - pharmacology
Vero Cells
Viruses
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Summary:Based on the fact that a search for influenza antivirals among nucleoside analogues has drawn very little attention of chemists, the present study reports the synthesis of a series of 1,2,3-triazolyl nucleoside analogues in which a pyrimidine fragment is attached to the ribofuranosyl-1,2,3-triazol-4-yl moiety by a polymethylene linker of variable length. Target compounds were prepared by the Cu alkyne-azide cycloaddition (CuAAC) reaction. Derivatives of uracil, 6-methyluracil, 3,6-dimethyluracil, thymine and quinazolin-2,4-dione with ω-alkyne substituent at the N 1 (or N 5) atom and azido 2,3,5-tri- O -acetyl-D-β-ribofuranoside were used as components of the CuAAC reaction. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. The best values of IC 50 (inhibiting concentration) and SI (selectivity index) were demonstrated by the lead compound 4i in which the 1,2,3-triazolylribofuranosyl fragment is attached to the N 1 atom of the quinazoline-2,4-dione moiety via a butylene linker (IC 50  = 30 μM, SI = 24) and compound 8n in which the 1,2,3-triazolylribofuranosyl fragment is attached directly to the N 5 atom of the 6-methyluracil moiety (IC 50  = 15 μM, SI = 5). According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 4i and 8n against H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRP). Graphic abstract
ISSN:1381-1991
1573-501X
DOI:10.1007/s11030-020-10141-y