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

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.

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