Synthesis and structure-activity relationship studies of water-soluble β-cyclodextrin-glycyrrhetinic acid conjugates as potential anti-influenza virus agents

Abstract

Glycyrrhetinic acid (GA) is a major constituent of the herb Glycyrrhiza glabra, and many of its derivatives demonstrate a broad spectrum of antiviral activities. In the current study, 18 water-soluble β-cyclodextrin (CD)-GA conjugates, in which GA was covalently coupled to the primary face of β-CD using 1,2,3-triazole moiety along with varying lengths of linker, were synthesized via copper-catalyzed azide-alkyl cycloaddition reaction. Benefited from the attached β-CD moiety, all these conjugates showed lower hydrophobicity (Alog P) compared with their parent compound GA. With the exception of per- O-methylated β-CD-GA conjugate ( 35), all other conjugates showed no significant cytotoxicity to MDCK cells, and these conjugates were then screened against A/WSN/33 (H1N1) virus using the cytopathic effect assay. The preliminary results indicated that six conjugates showed promising antiviral activity, and the C-3 and C-30 of GA could tolerate some modifications. Our findings suggested that GA could be used as a lead compound for the development of potential anti-influenza virus agents.

Graphical abstract

Highlights

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  Triterpene natural products are proposed as a new class of compounds for blocking influenza virus entry.

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  A total of 18 β-cyclodextrin-glycyrrhetinic acid conjugates were designed and synthesized via click chemistry.

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  The structure-activity relationship of their anti-influenza A/WSN/33 (H1N1) viruses was summarized.