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Bioorg Med Chem. 2016 Apr 1;24(7):1528-39. doi: 10.1016/j.bmc.2016.02.023. Epub 2016 Feb 20.

Design, synthesis and biological evaluation of novel donepezil-coumarin hybrids as multi-target agents for the treatment of Alzheimer's disease.

Author information

1
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
2
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China. Electronic address: cpu_lykong@126.com.

Abstract

Combining N-benzylpiperidine moiety of donepezil and coumarin into in a single molecule, novel hybrids with ChE and MAO-B inhibitory activity were designed and synthesized. The biological screening results indicated that most of compounds displayed potent inhibitory activity for AChE and BuChE, and clearly selective inhibition to MAO-B. Of these compounds, 5m was the most potent inhibitor for eeAChE and eqBuChE (0.87 μM and 0.93 μM, respectively), and it was also a good and balanced inhibitor to hChEs and hMAO-B (1.37 μM for hAChE; 1.98 μM for hBuChE; 2.62 μM for hMAO-B). Molecular modeling and kinetic studies revealed that 5m was a mixed-type inhibitor, which bond simultaneously to CAS, PAS and mid-gorge site of AChE, and it was also a competitive inhibitor, which occupied the active site of MAO-B. In addition, 5m showed good ability to cross the BBB and had no toxicity on SH-SY5Y neuroblastoma cells. Collectively, all these results suggested that 5m might be a promising multi-target lead candidate worthy of further pursuit.

KEYWORDS:

Alzheimer’s disease; Cholinesterase; Coumarin; Docking; Donepezil; Monoamine oxidase

PMID:
26917219
DOI:
10.1016/j.bmc.2016.02.023
[Indexed for MEDLINE]

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