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.
Highlights
Alzheimer’s disease (AD) is a chronic neurodegenerative brain disorder that is characterized by cognitive impairment, memory loss, and dementia [1]
Inhibitors that exhibit high synapses selectivityofand activity excellent donepezil [13]. These results indicate that AChE inhibitors that exhibit high selectivity and high development prospects in the research and development of AD drugs
The introduction of the side chain in the hesperetin parent decreased the radical capturing capacity. These results indicate that the phenolic hydroxy in the hesperetin was responsible for the radical scavenging ability
Summary
Alzheimer’s disease (AD) is a chronic neurodegenerative brain disorder that is characterized by cognitive impairment, memory loss, and dementia [1]. The pathogenesis of AD remains unknown, many hypotheses have been developed. Brain cholinergic neuron damage, amyloid-β (Aβ) cascade, and oxidative stress hypotheses are widely recognized and are speculated to be the dominant causes of AD pathogenesis [3,4,5]. According to the cholinergic hypothesis, acetylcholinesterase (AChE) inhibitors, such as tacrine, donepezil, rivastigmine, and galantamine, are commonly used in clinical practice to treat AD [6]. AChE inhibitors are not ideal for the treatment of AD. They can improve a patient’s neuropsychiatric symptoms, but cannot prevent or slow down AD development. The latest research has shown that AChE possibly plays multiple functions in AD development because its peripheral anionic
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