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

Abstract

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.

Keywords: 1,2,3-triazole; antivirals; click chemistry; influenza virus; nucleoside analogues; nucleotides.

Figure 1

The most well-known antiviral cyclic nucleoside analogues.

Figure 2

Schematic representation of the most known prodrugs.

Scheme 1

Synthesis of pyrimidine derivatives containing a ω-alkyne substituent at the N-1 atom.

Scheme 2

Synthesis of 2,3,5-tri-O-acetyl-β-D-ribofuranosyl azide 4c.

Scheme 3

Synthesis of 1,2,3-triazolyl nucleoside analogues.

Scheme 4

Synthesis of 5′-diethyl- and 5′-diphenylphosphates of 1,2,3-triazolyl nucleoside analogues.

Scheme 5

Synthesis of 5′-phosphoramidates of 1,2,3-triazolyl nucleoside analogues.

Scheme 6

Synthesis of 5′-H-phosphonates of 1,2,3-triazolyl nucleoside analogues.

Scheme 7

Synthesis of 5′- phosphates of 1,2,3-triazolyl nucleoside analogues.

Scheme 7

Synthesis of 5′- phosphates of 1,2,3-triazolyl nucleoside analogues.

Figure 3

Parent 1,2,3-triazolyl nucleoside analogues 33a,b and 34a,b and their 5′-triphosphate derivatives 35a,b and 36a,b.

Figure 4

Molecular docking simulations of the optimized docking model of compounds 35a,b and 36a,b in the PA-Nter (PDB code 4AWK) active site of the RdRp of influenza virus A (H1N1) were obtained in the lowest-energy conformations.