Synthesis of 1,2,3-triazolyl nucleoside analogues and their antiviral activity
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ORIGINAL ARTICLE
Synthesis of 1,2,3‑triazolyl nucleoside analogues and their antiviral activity Olga V. Andreeva1 · Bulat F. Garifullin1 · Vladimir V. Zarubaev2 · Alexander V. Slita2 · Iana L. Yesaulkova2 · Liliya F. Saifina1 · Marina M. Shulaeva1 · Maya G. Belenok1 · Vyacheslav E. Semenov1 · Vladimir E. Kataev1 Received: 20 June 2020 / Accepted: 3 September 2020 © Springer Nature Switzerland AG 2020
Abstract Based on the fact that a search for influenza antivirals among nucleoside analogues has drawn very little attention of chemists, the present study reports the synthesis of a series of 1,2,3-triazolyl nucleoside analogues in which a pyrimidine fragment is attached to the ribofuranosyl-1,2,3-triazol-4-yl moiety by a polymethylene linker of variable length. Target compounds were prepared by the Cu alkyne-azide cycloaddition (CuAAC) reaction. Derivatives of uracil, 6-methyluracil, 3,6-dimethyluracil, thymine and quinazolin-2,4-dione with ω-alkyne substituent at the N1 (or N5) atom and azido 2,3,5-triO-acetyl-D-β-ribofuranoside were used as components of the CuAAC reaction. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. The best values of IC50 (inhibiting concentration) and SI (selectivity index) were demonstrated by the lead compound 4i in which the 1,2,3-triazolylribofuranosyl fragment is attached to the N1 atom of the quinazoline-2,4-dione moiety via a butylene linker (IC50 = 30 μM, SI = 24) and compound 8n in which the 1,2,3-triazolylribofuranosyl fragment is attached directly to the N5 atom of the 6-methyluracil moiety (IC50 = 15 μM, SI = 5). According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 4i and 8n against 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). Graphic abstract
Keywords Nucleoside analogues · 1,2,3-Triazole · Influenza virus · Coxsackievirus · Click chemistry Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11030-020-10141-y) contains supplementary material, which is available to authorized users. * Vyacheslav E. Semenov [email protected] Extended author information available on the last page of the article
Abbreviations PA Polymerase acidic protein RdRP RNA-dependent RNA polymerase PA-Nter N-terminal endonuclease domain LBD Ligand-binding domain
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Introduction Naturally occurring nucleosides represent a unique scaffold for drug design due to their involvement in numerous biological processes as well as the fact that they serve as essential building blocks for DNA and RNA synthesis [1]. Nucleosides play important roles in the replication and transcription of genetic information and, as such, have been utilized for decades for antibacterial or antiviral therapeutics [2, 3]. In the early 1960s, the idea appeared that various nucleoside derivatives (or analogues) can a
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