Design, synthesis, and biological evaluation of new 2′-deoxy-2′-fluoro-4′-triazole cytidine nucleosides as potent antiviral agents

• A series of 2′-deoxy-2′-fluoro-4′-triazole cytidine nucleosides were prepared.
• Compounds 9–17 were obtained via Cu(I)-mediated [3 + 2] cycloaddition reactions.
• Compounds 9, 10 and 13 exhibited extremely potent antiviral activity.
• No cytotoxicity observed at the highest tested concentration up to 25 μM.
• A preliminary structure–activity relationship was obtained.

A series of 4′-[1,2,3]triazole-2′-deoxy-2′-fluoro-β-d-arabinofuranosylcytosines (9–17) were prepared by Cu(I)-mediated [3 + 2] cycloaddition reactions (CuAAC) of 1-(4′-azido-2′-deoxy-2′-fluoro-β-d-arabinofuranosyl)cytosine (1) with appropriate alkynes in good yields. Their structures were fully established by 1H NMR, 13C NMR, HRMS, and elemental analysis. Most of these nucleoside analogs exhibited potent anti-HIV-1 activity with no cytotoxicity observed at the highest tested concentration up to 25 μM. Among them, compounds 9, 10 and 13 exhibited extremely potent antiviral activity, thus had a great potential for further development as novel nucleoside reverse transcriptase inhibitors (NRTIs) for the treatment of HIV-1 infection. Besides, the anti-HBV activity of compounds 10, 11 and 17 had been investigated.

A series of 4′-[1,2,3]triazole-2′-deoxy-2′-fluoro-β-d-arabinofuranosylcytosines were prepared, most of which exhibited potent anti-HIV-1 activity with no cytotoxicity observed at the highest tested concentration up to 25 μM.Figure optionsDownload as PowerPoint slide