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

• Published in: Molecular diversity Vol. 25; no. 1; pp. 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: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-02-2021; Springer Nature B.V
• 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; Coxsackievirus; 1,2,3-Triazole; Click chemistry; Influenza virus; Nucleoside analogues
• ISSN: 1381-1991; 1573-501X
• DOI: 10.1007/s11030-020-10141-y

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