Synthesis of 1,2,3-triazolyl nucleoside analogues and their antiviral activity
| Autor: | Iana L Yesaulkova, Vladimir E. Kataev, Olga V. Andreeva, Vladimir V. Zarubaev, Alexander V. Slita, B. F. Garifullin, Maya G. Belenok, M. M. Shulaeva, Liliya F. Saifina, Vyacheslav E. Semenov |
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| Rok vydání: | 2020 |
| Předmět: |
Pyrimidine
Stereochemistry 1 2 3-Triazole Substituent 010402 general chemistry Antiviral Agents 01 natural sciences Catalysis Madin Darby Canine Kidney Cells Inorganic Chemistry chemistry.chemical_compound Dogs Influenza A Virus H1N1 Subtype Nucleoside analogues Chlorocebus aethiops Drug Discovery Animals Coxsackievirus Moiety Physical and Theoretical Chemistry Vero Cells Molecular Biology Polymerase Enterovirus Cell Death biology Click chemistry 010405 organic chemistry Organic Chemistry Nucleosides Uracil General Medicine Triazoles 0104 chemical sciences Thymine Molecular Docking Simulation chemistry biology.protein Thermodynamics Original Article Influenza virus Nucleoside Linker Information Systems |
| Zdroj: | Molecular Diversity |
| ISSN: | 1573-501X 1381-1991 |
| Popis: | 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 N1 (or N5) 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 IC50 (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 N1 atom of the quinazoline-2,4-dione moiety via a butylene linker (IC50 = 30 μM, SI = 24) and compound 8n in which the 1,2,3-triazolylribofuranosyl fragment is attached directly to the N5 atom of the 6-methyluracil moiety (IC50 = 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 Electronic supplementary material The online version of this article (10.1007/s11030-020-10141-y) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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