Antiviral Agent Synthesis

Viruses are one of the main health problems around the world due to their ability to cause diseases and the low effectiveness of antiviral drugs. During the past few years, there have been considerable efforts to develop antiviral drugs that specifically target various human-infecting viruses such as Coronaviruses (CoVs), human immunodeficiency virus (HIV), herpes, hepatitis, and influenza^[1]. Click chemistry has drawn much attention and has become a powerful tool for the synthesis of antiviral agents because of its convenience and effectiveness in the construction of heteroatom links (C-X-C).

Applications

• Anti-HIV agent synthesis by CuAAC click reaction

CuAAC click reaction is a proven protocol for synthesizing triazole products which could serve for the synthesis of novel anti-HIV agents. In 2013, Wu and co-workers reported the synthesis of a series of 4' [1,2,3] triazole-2'-deoxy-2'-fluoro-β-D-arabinofuranosylcytosines via CuAAC click reaction between 1-(4'-azido-2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) cytosine and appropriate alkynes in high yields (Scheme 1). Most of the synthesized compounds demonstrated potent anti-HIV-1 activity with no cytotoxicity observed at the highest tested concentration up to 25 μΜ^[2]. It is envisioned that click chemistry will make more contributions to anti-HIV agent synthesis in the future.

Scheme 1. The synthesis of 4' [1,2,3] triazole-2'-deoxy-2'-fluoro-
β-D-arabinofuranosylcytosines by CuAAC click reaction.

• Anti-IV agent synthesis by CuAAC click reaction

CuAAC click reaction is also used in the synthesis of anti-influenza virus (IV) agents. Su and co-workers^[3] reported the preparation of a series of oleanolic acid (OA)-saccharide conjugates via the CuAAC click reaction (Scheme 2), and the anti-influenza activity of these compounds was evaluated in vitro. Among them, compound 11b, an OA-glucose conjugate, showed a significantly increased anti-influenza activity with an IC50 of 5.47 mM, and no obvious cytotoxic effect on Madin-Daby canine kidney (MDCK) cells was observed at 100 mM.

Scheme 2. The synthesis of OA-saccharide conjugates (11b) via the CuAAC click reaction.

What Can We Do?

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References

1. Kaur, J.; et al. An overview of recent advances in biomedical applications of click chemistry. Bioconjugate Chemistry. 2021, 8(32): 1455-1471.
2. Wu, J.; et al. Design, synthesis, and biological evaluation of new 2'-deoxy-2'-fluoro-4'-triazole cytidine nucleosides as potent antiviral agents. European Journal of Medicinal Chemistry. 2013, 63: 739-745.
3. Su, Y.; et al. Design, synthesis of oleanolic acid-saccharide conjugates using click chemistry methodology and study of their anti-influenza activity. European Journal of Medicinal Chemistry. 2019, 182: 111622.