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Design, Synthesis, and Biological Evaluation of Novel Chromanone Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease

Li, Xinnan; Li, Tiantian; Zhan, Feiyan; Cheng, Feiyue; Lu, Li; Zhang, Bocheng; Li, Junda; Hu, Zhaoxin; Zhou, Shengnan; Jia, Yilin; Allen, Stephanie; White, Lisa; Phillips, James; Zhu, Zheying; Xu, Jinyi; Yao, Hequan


Xinnan Li

Tiantian Li

Feiyan Zhan

Feiyue Cheng

Li Lu

Bocheng Zhang

Junda Li

Zhaoxin Hu

Shengnan Zhou

Yilin Jia

Professor of Pharmaceutical Biophysics

James Phillips

Associate Professor in International Pharmacy and Traditional Medicines

Jinyi Xu

Hequan Yao


Based on a multitarget strategy, a series of novel chromanone-1-benzyl-1,2,3,6-tetrahydropyridin hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). The optimal compound C10 possessed excellent dual AChE/MAO-B inhibition both in terms of potency and equilibrium (AChE: IC50 = 0.58 ± 0.05 μM; MAO-B: IC50 = 0.41 ± 0.04 μM). Further molecular modeling and kinetic investigations revealed that compound C10 was a dual-binding inhibitor bound to both the catalytic anionic site and peripheral anionic site of AChE. In addition, compound C10 exhibited low neurotoxicity and potently inhibited AChE enzymatic activity. Furthermore, compound C10 more effectively protected against mitochondrial dysfunction and oxidation than donepezil, strongly inhibited AChE-induced amyloid aggregation, and moderately reduced glutaraldehyde-induced phosphorylation of tau protein in SH-SY5Y cells. Moreover, compound C10 displayed largely enhanced improvements in cognitive behaviors and spatial memory in a scopolamine-induced AD mice model with better efficacy than donepezil. Overall, the multifunctional profiles of compound C10 suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.


Li, X., Li, T., Zhan, F., Cheng, F., Lu, L., Zhang, B., …Yao, H. (2022). Design, Synthesis, and Biological Evaluation of Novel Chromanone Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease. ACS Chemical Neuroscience, 13(23), 3488-3501.

Journal Article Type Article
Acceptance Date Nov 3, 2022
Online Publication Date Nov 16, 2022
Publication Date Dec 7, 2022
Deposit Date Nov 29, 2022
Publicly Available Date Nov 17, 2023
Journal ACS Chemical Neuroscience
Print ISSN 1948-7193
Electronic ISSN 1948-7193
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 13
Issue 23
Pages 3488-3501
Keywords Cell Biology; Cognitive Neuroscience; Physiology; Biochemistry; General Medicine
Public URL
Publisher URL
Additional Information This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical Neuroiscience after peer review and technical editing by the publisher. To access the final edited and published work see