文献类型：期刊文献

英文题名：Multi-target directed ligands design of 1-O-Acetylbritannilactone derivatives: Dual anti-neuroinflammatory and acetylcholinesterase inhibitory activities

作者：Liang, Yan-Peng[1,2];Gao, Qian[3];Chen, Hong[3];Ma, Rui[1];Zhao, Xiao-Bo[1];Jin, Xiao-Jie[3];Zhang, Jian[3];Shi, Yan-Ping[1];Ha, Wei[1]

第一作者：Liang, Yan-Peng

通信作者：Shi, YP[1];Ha, W[1]

机构：[1]Chinese Acad Sci, Lanzhou Inst Chem Phys, Key Lab Nat Med Gansu Prov, Lanzhou 730000, Peoples R China;[2]Univ Chinese Acad Sci, Beijing 100049, Peoples R China;[3]Gansu Univ Chinese Med, Sch Pharm, Dunhuang Key Lab Med & Transformat, Minist Educ, Lanzhou 730000, Peoples R China

第一机构：Chinese Acad Sci, Lanzhou Inst Chem Phys, Key Lab Nat Med Gansu Prov, Lanzhou 730000, Peoples R China

通信机构：[1]corresponding author), Chinese Acad Sci, Lanzhou Inst Chem Phys, Key Lab Nat Med Gansu Prov, Lanzhou 730000, Peoples R China.

年份：2025

卷号：68

外文期刊名：PHYTOCHEMISTRY LETTERS

收录：;Scopus(收录号：2-s2.0-105010009387);WOS:【SCI-EXPANDED(收录号:WOS:001532833700001)】；

基金：This work was financially supported by the National Natural Science Foundation of China (U21A20407, 22274163, 22374160) , Major Sci-ence and Technology Program of Gansu Province (25ZDFA002) and Gansu Overseas Expertise Introduction Program (GSHZJH 12-2025-10) . The author would like to thank Prof. J. J. Tang from Northwest A & F University for their help in bioactivity evaluation experiments.

语种：英文

外文关键词：Alzheimer's disease; 1-O-acetylbritannilactone; Multi-target directed ligands; Acetylcholinesterase inhibition; Anti-neuroinflammatory

摘要：Alzheimer's disease, a progressive neurodegenerative disorder of the central nervous system, presents a complex pathological mechanism that limits the efficacy of conventional single-target drugs. Utilizing the unique advantages of natural products in multi-target intervention, this study employed the active component 1-O-acetylbritannilactone (ABL) from Inula britannica L. as the parent structure. Guided by the multi-target directed ligands (MTDLs) strategy, four novel derivatives (ABL-1 to ABL-4) were successfully designed and synthesized by introducing acetylcholinesterase (AChE) inhibitory pharmacophores into the ABL scaffold. In vitro pharmacological evaluation demonstrated that ABL-2, ABL-3, and ABL-4 not only preserved the anti-neuroinflammatory activity of the parent compound but also endowed compound ABL with AChE inhibitory potency. Notably, ABL-4 displayed the most promising dual efficacy profile, achieving an AChE inhibition rate of 40.09 +/- 0.73 % at 30 mu M and an anti-neuroinflammatory activity (EC50 = 8.43 +/- 0.5 mu M). Molecular docking simulations revealed that the dual-target synergistic mechanism of ABL derivatives arises from hydrogen bonding and it-it stacking interactions with key residues of both AChE and inducible nitric oxide synthase (iNOS). This work not only validates the feasibility of the MTDLs strategy in optimizing natural product scaffolds but also provides a structurally novel lead compound with significant potential for developing multi-target anti-AD therapeutics.