| Summary: | A series of 1,2,3-triazolyl nucleoside analogues in which 1,2,3-triazol-4-yl-β-<span style="font-variant: small-caps;">d</span>-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 <i>N</i>-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, <b>2i</b>, <b>5i</b>, <b>11c</b>, which showed moderate activity against influenza virus A H1N1 with IC<sub>50</sub> 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-<span style="font-variant: small-caps;">d</span>-ribofuranosyl fragments are attached via butylene linkers to <i>N</i>-1 and <i>N</i>-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine, respectively). In nucleoside analogue <b>11c</b>, two 1,2,3-triazol-4-yl-2′,3′,5′-tri-<i>O</i>-acetyl-β-<span style="font-variant: small-caps;">d</span>-ribofuranose fragments are attached via propylene linkers to the C-5 and <i>N</i>-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 <b>2f</b> and <b>5f</b>, in which 1,2,3-triazol-4-yl-2′,3′,5′-tri-<i>O</i>-acetyl-β-<span style="font-variant: small-caps;">d</span>-ribofuranose fragments are attached to the C-5 and <i>N</i>-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine respectively). These compounds exhibited high antiviral potency against the coxsackie B3 virus with IC<sub>50</sub> 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 <b>2i</b>, <b>5i</b>, and <b>11c</b> 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 <b>2f</b> and <b>5f</b> against coxsackievirus B3, it can be explained by their interaction with the coat proteins VP1 and VP2.
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