Synthesis and Antiviral Evaluation of Nucleoside Analogues Bearing One Pyrimidine Moiety and Two D-Ribofuranosyl Residues.

Olga V Andreeva,Marina M Shulaeva,Bulat F Garifullin,Vladimir E Kataev,Mayya G Belenok,Alexander V Slita,Vladimir V Zarubaev,Anna P Lyubina,Iana L Yesaulkova,Alexandrina S Volobueva,Alexandra D Voloshina,Liliya F Saifina,Maria A Man’Kova,Vyacheslav E Semenov

doi:10.3390/molecules26123678

Abstract

A series of 1,2,3-triazolyl nucleoside analogues in which 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via polymethylene linkers to both nitrogen atoms of the heterocycle moiety (uracil, 6-methyluracil, thymine, quinazoline-2,4-dione, alloxazine) or to the C-5 and N-3 atoms of the 6-methyluracil moiety was synthesized. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. Antiviral assays revealed three compounds, 2i, 5i, 11c, which showed moderate activity against influenza virus A H1N1 with IC50 values of 57.5 µM, 24.3 µM, and 29.2 µM, respectively. In the first two nucleoside analogues, 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via butylene linkers to N-1 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine, respectively). In nucleoside analogue 11c, two 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-d-ribofuranose fragments are attached via propylene linkers to the C-5 and N-3 atoms of the 6-methyluracil moiety. Almost all synthesized 1,2,3-triazolyl nucleoside analogues showed no antiviral activity against the coxsackie B3 virus. Two exceptions are 1,2,3-triazolyl nucleoside analogs 2f and 5f, in which 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-d-ribofuranose fragments are attached to the C-5 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine respectively). These compounds exhibited high antiviral potency against the coxsackie B3 virus with IC50 values of 12.4 and 11.3 µM, respectively, although both were inactive against influenza virus A H1N1. According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 2i, 5i, and 11c against the 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). As to the antiviral activity of nucleoside analogs 2f and 5f against coxsackievirus B3, it can be explained by their interaction with the coat proteins VP1 and VP2.

Highlights

Nucleoside analogues represent an efficient scaffold for the development of antiviral drugs
The strategy for the synthesis of the target nucleoside analogues (Figure 2) was based upon the copper-catalyzed alkyne–azide cycloaddition (CuAAC) reaction and was carried out according to a convergent scheme consisting of pyrimidine and carbohydrate routes completed with the formation of alkyne precursors related to alkynyl substituted pyrimidines and an azide precursor related to β-D-ribofuranose, respectively
One can conclude that antiviral activity of the 1,2,3-triazolyl nucleoside analogues 2i, 5i, 11c against the H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein of RNA-dependent RNA polymerase

Summary

Introduction

Nucleoside analogues represent an efficient scaffold for the development of antiviral drugs. Abacavir (Figure 1), in comparison with adenosine, underwent both a modification of the adenine moiety (an amino group appeared at the C-2 position and a cyclopropane ring was attached to the amino group at the C-6 atom) and the sugar residue (the D-ribofuranosyl moiety was replaced by a cyclopentene ring) [1,2]. We synthesized nucleoside analogues in which a 1,2,3-triazol-4-yl-β-Dribofuranosyl fragment was attached to the pyrimidine moiety (uracil, 6-methyluracil, thymine, quinazoline-2,4-dione) through a polymethylene linker of variable length [20,21]. We report on the synthesis and antiviral evaluation of novel nucleoside analogues in which a 1,2,3-triazol4-yl-β-D-ribofuranosyl fragment is attached via a polymethylene linker of variable length to Molecules 2021, 26, 3678 both nitrogen atoms of the pyrimidine moiety (uracil, 6-methyluracil, thymine, quinazoline2,4-dione, alloxazine) or to the C-5 and N-3 atoms of the 6-methyluracil moiety (Figure 2)

Chemistry

Antiviral Evaluation

Influenza Virus A H1N1

Coxsackievirus B3

Conclusions