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

Bioorg Med Chem Lett. 2016 Feb 1;26(3):769-773. doi: 10.1016/j.bmcl.2015.12.100.

Lei Yuan ¹, Chunfeng Zhang ¹, Hongxin Sun ¹, Qingyin Liu ¹, Jian Huang ¹, Lei Sheng ¹, Bin Lin ¹, Jinhui Wang ¹, Lixia Chen ²

Affiliations

1 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
2 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: [email protected].

PMID: 26791013 DOI: 10.1016/j.bmcl.2015.12.100

Abstract

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.

Keywords

Andrographolide; Anti-influenza virus activity; Semi-synthesis; Structure modification; Δ(8,17)-Alkene exo-to-endo isomerization.

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