The semi-synthesis of novel andrographolide analogues and anti-influenza virus activity evaluation of their derivatives

• Published in: Bioorganic & medicinal chemistry letters 2016-02, Vol.26 (3), p.769-773
• Main Authors: Yuan, Lei, Zhang, Chunfeng, Sun, Hongxin, Liu, Qingyin, Huang, Jian, Sheng, Lei, Lin, Bin, Wang, Jinhui, Chen, Lixia
• Format: Article
• Language: English
• Subjects: Andrographolide; Animals; Anti-influenza virus activity; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Diterpenes - chemical synthesis; Diterpenes - chemistry; Diterpenes - pharmacology; Dogs; Influenza A Virus, H3N2 Subtype - physiology; Inhibitory Concentration 50; Isomerism; Madin Darby Canine Kidney Cells; Semi-synthesis; Structure modification; Structure-Activity Relationship; Virus Replication - drug effects; Δ8,17-Alkene exo-to-endo isomerization
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.12.100

[Display omitted] Two novel andrographolide analogues with the structural motif of Δ8,17-alkene exo-to-endo isomerization, AI78 and AI89, were semi-synthesized firstly. Two series of derivatives were designed and synthesized based on the synthetic pathway (including series I: olefin isomerizing to endocyclic Δ8,9 and series II: olefin isomerizing to endocyclic Δ7,8). The anti-influenza virus activity in vitro for all derivatives was evaluated. Among the compounds synthesized, compound 38 with benzyl amino group showed the greatest potency against H3N2 and was approximately 1.5-fold more potent than that of Lianbizhi, andrographolide analogue used clinically in China. Adamantyl derivative, 43, presented the lowest toxicity, with a higher TC50 and TI values than Lianbizhi. The structure–activity relationships studies of the synthetic analogues indicated that the endocyclic Δ7,8-double bond is preferable for anti-viral effect. Furthermore, the introduction of the fatty amino attached to the rigid skeleton at C-17 is beneficial for activity.