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

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• 作者：Lei Yuan ; Chunfeng Zhang ; Hongxin Sun ; Qingyin Liu ; Jian Huang ; Lei Sheng ; Bin Lin ; Jinhui Wang ; Lixia Chen ; ^{syzyclx@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Andrographolide ; Δ8 ; 17-Alkene exo-to-endo isomerization ; Semi-synthesis ; Structure modification ; Anti-influenza virus activity
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 February 2016
• 年：2016
• 卷：26
• 期：3
• 页码：769-773
• 全文大小：722 K

文摘

Two novel andrographolide analogues with the structural motif of Δ^8,17-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 Δ^8,9 and series II: olefin isomerizing to endocyclic Δ^7,8). 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 Δ^7,8-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.