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

• Published in: Molecules (Basel, Switzerland) Vol. 22; no. 7; p. 1067
• Main Authors: Li, Bo, Huang, Ai-Ling, Zhang, Yi-Long, Li, Zeng, Ding, Hai-Wen, Huang, Cheng, Meng, Xiao-Ming, Li, Jun
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26-06-2017; MDPI
• Subjects: Acetylcholinesterase; acetylcholinesterase (AChE); Alzheimer's disease; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - drug effects; Animals; Antioxidants; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Binding sites; butyrylcholine esterase (BuChE); Catalytic Domain; Cell death; Cell Line; Citrus fruits; Cytotoxicity; Dementia; Design; Drug Design; Drug dosages; Esterase; Ethanol; GPI-Linked Proteins - antagonists & inhibitors; hesperetin derivatives; Hesperidin; Hesperidin - chemical synthesis; Hesperidin - chemistry; Hesperidin - pharmacology; Humans; Hydrocarbons; Hydrogen peroxide; Hydrogen Peroxide - adverse effects; Hypotheses; Laboratories; Low concentrations; Medical treatment; Models, Molecular; Molecular docking; Molecular Docking Simulation; Molecular Structure; multifunctional; Nervous system; Neurons; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Pathogenesis; PC12 Cells; Peroxyl radicals; Protein Aggregates - drug effects; R&D; Rats; Research & development; Selectivity; Structure-Activity Relationship; Viability; β-Amyloid; β-amyloid (Aβ); multifunctional; hesperetin derivatives; β-amyloid (Aβ); acetylcholinesterase (AChE); butyrylcholine esterase (BuChE)
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules22071067

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
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.