Synthesis and evaluation of multi-target-directed ligands for the treatment of Alzheimer’s disease based on the fusion of donepezil and melatonin

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• 作者：Jin Wang ; Zhi-Min Wang ; Xue-Mei Li ; Fan Li ; Jia-Jia Wu ; Ling-Yi Kong ; ^{cpu_lykong@126.com" class="auth_mail" title="E-mail the corresponding author} ; Xiao-Bing Wang ; ^{xbwang@cpu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AchE ; Acetylcholinesterase ; BuChE ; Butyrylcholinesterase ; AD ; Alzheimer&rsquo ; s disease ; Aβ ; β-Amyloid ; CAS ; Catalytic anionic site ; PAS ; Peripheral anionic site ; BBB ; Blood&ndash ; brain barrier ; AβOs ; Soluble Aβ oligomers ; CNS ; Central nervous system ; NFTS ; Neurofibrillary tangles ; ChEs ; Cholinesterases ; ChEIs ; Cholinesterase inhibitors ; CDI ; 1 ; 1&prime ; -Carbonyldiimidazole ; ORAC ; Oxygen radical absorbance capacity ; PAMPA ; Parallel artificial membrane permeation assay
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 September 2016
• 年：2016
• 卷：24
• 期：18
• 页码：4324-4338
• 全文大小：2223 K

文摘

A novel series of compounds obtained by fusing the acetylcholinesterase (AChE) inhibitor donepezil and the antioxidant melatonin were designed as multi-target-directed ligands for the treatment of Alzheimer’s disease (AD). In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (eqBuChE and hBuChE), and β-amyloid (Aβ) aggregation, and to act as potential antioxidants and biometal chelators. Especially, boldFont">4u displayed a good inhibition of AChE (IC₅₀ value of 193 nM for eeAChE and 273 nM for hAChE), strong inhibition of BuChE (IC₅₀ value of 73 nM for eqBuChE and 56 nM for hBuChE), moderate inhibition of Aβ aggregation (56.3% at 20 μM) and good antioxidant activity (3.28 trolox equivalent by ORAC assay). Molecular modeling studies in combination with kinetic analysis revealed that boldFont">4u was a mixed-type inhibitor, binding simultaneously to catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, boldFont">4u could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood–brain barrier (BBB). Taken together, these results strongly indicated the hybridization approach is an efficient strategy to identify novel scaffolds with desired bioactivities, and further optimization of boldFont">4u may be helpful to develop more potent lead compound for AD treatment.