Synthesis, antiviral evaluation, molecular docking study and cytotoxicity of 5′-phosphorylated 1,2,3-triazolyl nucleoside analogues with thymine and 6-methyl uracil moieties

• Published in: Medicinal chemistry research Vol. 32; no. 8; pp. 1770 - 1803
• Main Authors: Garifullin, Bulat F., Tatarinov, Dmitry A., Andreeva, Olga V., Belenok, Mayya G., Strobykina, Irina Yu, Khabibulina, Leysan R., Shepelina, Anna V., Zarubaev, Vladimir V., Slita, Alexander V., Volobueva, Alexandrina S., Voloshina, Alexandra D., Lyubina, Anna P., Saifina, Liliya E., Semenov, Vyacheslav E., Kataev, Vladimir E.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-08-2023; Springer Nature B.V
• Subjects: Antiviral activity; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Chemical synthesis; Comparative analysis; Cytotoxicity; DNA-directed RNA polymerase; Inorganic Chemistry; Kinases; Medicinal Chemistry; Molecular docking; Nucleoside analogs; Nucleosides; Original Research; Pharmacology/Toxicology; Phosphonates; Prodrugs; RNA-directed RNA polymerase; Structure-activity relationships; Thymine; Uracil; Nucleotides; Click chemistry; Influenza virus; Nucleoside analogues; Antivirals
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-023-03112-z

A comparative analysis of in vitro antiviral activity (in terms of the concentration of semi-maximal inhibition, IC
50
) against influenza virus A/PR/8/34 (H1N1) of a large series of parent 1,2,3-triazolyl nucleoside analogues (with uracil, thymine, 6-methyluracil, quinazoline-2,4-dione moieties as nucleic bases) and their prodrug forms with masked 5ʹ-phosphate groups (diethyl phosphate, diphenyl phosphate, phosphoramidate) and negatively charged
H
-phosphonate and monophosphate groups was carried out. Obtained structure-activity relationships were interpreted based on the assumption that the synthesized parent 1,2,3-triazolyl nucleoside analogues and their prodrug forms, by analogy with the literature data, are metabolized by cellular kinases to their active 5ʹ-triphosphate forms that inhibit the activity of viral RNA-dependent RNA polymerase (RdRp). A correlation was found between the experimental values of IC
50
and the theoretical values of the binding energies of 5ʹ-triphosphate derivatives of the parent 1,2,3-triazolyl nucleoside analogues in the active site of RdRp.
Graphical Abstract