title: The semi-synthesis of novel andrographolide analogues and anti-influenza virus activity evaluation of their derivatives.
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.
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Chunfeng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Hongxin
authors.initials: H
authors.lastname: Sun
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Qingyin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Sheng
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Lin
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: syzyclx@163.com.
authors.forename: Lixia
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004285:Dogs; D053122:Influenza A Virus, H3N2 Subtype / Q000502:physiology*; D020128:Inhibitory Concentration 50; D007536:Isomerism; D061985:Madin Darby Canine Kidney Cells; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004224:Diterpenes; C030419:andrographolide
keywords: Andrographolide; Anti-influenza virus activity; Semi-synthesis; Structure modification; Δ(8,17)-Alkene exo-to-endo isomerization