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

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.

First Macrocyclic 1,2,3-Triazolyl Uridine Analogues

“…Compounds 3, 5-9 were prepared as described earlier. [36,38] Their spectral data were in keeping with published ones. [36,38] Synthesis Azido 5-mesyloxy-2,3-O-isopropylidene--D-ribofuranoside (10).…”

“…Recently, we synthesized a series of 1,2,3-triazole nucleoside analogues [35,36] and being interested in the work on the synthesis of macrocyclic nucleoside analogues, [31][32][33][34] we also decided to prepare several macrocycles, but to use for this aim not the ring-closing metathesis strategy, [33] but the strategy of a copper-catalyzed 1,3-dipolar cycloaddition. [37] Herein, we report on the synthesis of a 29-membered macrocycle formed from one uracil molecule, two Dribofuranose molecules and four 1,2,3-triazole molecules as well as a 58-membered macrocycle formed from two uracil molecules, four D-ribofuranose molecules and eight 1,2,3-triazole molecules.…”

Conformationally Locked Carbocyclic Nucleosides Built on a 4′-Hydroxymethyl-3′-hydroxybicyclo[4.1.0]heptane Template. Stereoselective Synthesis and Antiviral Activity

“…Interestingly, another precedent using CNAs pointed out that the use of cyclopentenyl derivatives showed higher activity against coxsackie B4 than the corresponding saturated counterparts . Recently, other non-CNAs have been described with important antiviral activity toward the closely related coxsackie B3 virus. , In one of these works, the use of 1,2,3-triazole-based non-natural nucleobases proved to be effective to improve the antiviral activity . However, in other cases, the use of non-natural nucleobases in linear CNAs has not led to significant antiviral activity against coxsackie B4 virus. , Despite all these precedents, at present, there is no approved specific treatment for coxsackie virus infections.…”

“… 52 Recently, other non-CNAs have been described with important antiviral activity toward the closely related coxsackie B3 virus. 53 , 54 In one of these works, the use of 1,2,3-triazole-based non-natural nucleobases proved to be effective to improve the antiviral activity. 54 However, in other cases, the use of non-natural nucleobases in linear CNAs has not led to significant antiviral activity against coxsackie B4 virus.…”

“… 53 , 54 In one of these works, the use of 1,2,3-triazole-based non-natural nucleobases proved to be effective to improve the antiviral activity. 54 However, in other cases, the use of non-natural nucleobases in linear CNAs has not led to significant antiviral activity against coxsackie B4 virus. 55 , 56 Despite all these precedents, at present, there is no approved specific treatment for coxsackie virus infections.…”