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Molecules 2017, 22(7), 1067; doi:10.3390/molecules22071067

Design, Synthesis and Evaluation of Hesperetin Derivatives as Potential Multifunctional Anti-Alzheimer Agents

Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 230000 Hefei, China
The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, 230000 Hefei, China
Institute for Liver Diseases, Anhui Medical University, 230000 Hefei, China
Author to whom correspondence should be addressed.
Received: 11 May 2017 / Revised: 15 June 2017 / Accepted: 25 June 2017 / Published: 26 June 2017
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In this study we designed and synthesized a series of new hesperetin derivatives on the basis of the structural characteristics of acetylcholinesterase (AChE) dual-site inhibitors. The activity of the novel derivatives was also evaluated. Results showed that the synthesized hesperetin derivatives displayed stronger inhibitory activity against AChE and higher selectivity than butyrylcholine esterase (BuChE) (selectivity index values from 68 to 305). The Lineweaver-Burk plot and molecular docking study showed that these compounds targeted both the peripheral anionic site (PAS) and catalytic active site (CAS) of AChE. The derivatives also showed a potent self-induced β-amyloid (Aβ) aggregation inhibition and a peroxyl radical absorbance activity. Moreover, compound 4f significantly protected PC12 neurons against H2O2-induced cell death at low concentrations. Cytotoxicity assay showed that the low concentration of the derivatives does not affect the viability of the SH-SY5Y neurons. Thus, these hesperetin derivatives are potential multifunctional agents for further development for the treatment of Alzheimer’s disease. View Full-Text
Keywords: hesperetin derivatives; acetylcholinesterase (AChE); butyrylcholine esterase (BuChE); β-amyloid (Aβ); multifunctional hesperetin derivatives; acetylcholinesterase (AChE); butyrylcholine esterase (BuChE); β-amyloid (Aβ); multifunctional

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Li, B.; Huang, A.-L.; Zhang, Y.-L.; Li, Z.; Ding, H.-W.; Huang, C.; Meng, X.-M.; Li, J. Design, Synthesis and Evaluation of Hesperetin Derivatives as Potential Multifunctional Anti-Alzheimer Agents. Molecules 2017, 22, 1067.

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