The First 5′-Phosphorylated 1,2,3-Triazolyl Nucleoside Analogues with Uracil and Quinazoline-2,4-Dione Moieties: A Synthesis and Antiviral Evaluation

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 19; p. 6214
• Main Authors: Tatarinov, Dmitry A, Garifullin, Bulat F, Belenok, Mayya G, Andreeva, Olga V, Strobykina, Irina Yu, Shepelina, Anna V, Zarubaev, Vladimir V, Slita, Alexander V, Volobueva, Alexandrina S, Saifina, Liliya F, Shulaeva, Marina M, Semenov, Vyacheslav E, Kataev, Vladimir E
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 21-09-2022; MDPI
• Subjects: 1,2,3-triazole; Acquired immune deficiency syndrome; AIDS; Alcohol; Antiviral activity; antivirals; click chemistry; Dengue fever; Diketones; Evaluation; FDA approval; Hepatitis; Herpes viruses; HIV; Human immunodeficiency virus; Infections; Influenza; influenza virus; Metabolism; Metabolites; Methylene; Molecular biology; Molecular docking; Nucleoside analogs; nucleoside analogues; Nucleosides; nucleotides; Phosphates; Phosphonates; Phosphorylation; Physiological aspects; Triazoles; Uracil; Viral infections; Viruses; Russia
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27196214

A series of 5′-phosphorylated (dialkyl phosphates, diaryl phosphates, phosphoramidates, H-phosphonates, phosphates) 1,2,3-triazolyl nucleoside analogues in which the 1,2,3-triazole-4-yl-β-D-ribofuranose fragment is attached via a methylene group or a butylene chain to the N-1 atom of the heterocycle moiety (uracil or quinazoline-2,4-dione) was synthesized. All compounds were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1). Antiviral assays revealed three compounds, 13b, 14b, and 17a, which showed moderate activity against influenza virus A (H1N1) with IC50 values of 17.9 μM, 51 μM, and 25 μM, respectively. In the first two compounds, the quinazoline-2,4-dione moiety is attached via a methylene or a butylene linker, respectively, to the 1,2,3-triazole-4-yl-β-D-ribofuranosyl fragment possessing a 5′-diphenyl phosphate substituent. In compound 17a, the uracil moiety is attached via the methylene unit to the 1,2,3-triazole-4-yl-β-D-ribofuranosyl fragment possessing a 5′-(phenyl methoxy-L-alaninyl)phosphate substituent. The remaining compounds appeared to be inactive against influenza virus A/PR/8/34/(H1N1). The results of molecular docking simulations indirectly confirmed the literature data that the inhibition of viral replication is carried out not by nucleoside analogues themselves, but by their 5′-triphosphate derivatives.