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

Abstract

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.

• Authors: Bo Li, Ai-Ling Huang, Yi-Long Zhang, Zeng Li, Hai-Wen Ding, Cheng Huang, Xiao-Ming Meng, Jun Li
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 22 Issue 7 (Jun 26 2017) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 28672874 (Publication Type: Journal Article)

Chemical References

• Amyloid beta-Peptides
• Antioxidants
• GPI-Linked Proteins
• Neuroprotective Agents
• Protein Aggregates
• Hydrogen Peroxide
• Hesperidin
• ACHE protein, human
• Acetylcholinesterase
• hesperetin

Topics

• Acetylcholinesterase
• Amyloid beta-Peptides (chemistry, drug effects)
• Animals
• Antioxidants (chemical synthesis, chemistry, pharmacology)
• Catalytic Domain
• Cell Line
• Drug Design
• GPI-Linked Proteins (antagonists & inhibitors)
• Hesperidin (chemical synthesis, chemistry, pharmacology)
• Humans
• Hydrogen Peroxide (adverse effects)
• Models, Molecular
• Molecular Docking Simulation
• Molecular Structure
• Neuroprotective Agents (chemical synthesis, chemistry, pharmacology)
• PC12 Cells
• Protein Aggregates (drug effects)
• Rats
• Structure-Activity Relationship