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Eur J Med Chem. 2016 Nov 10;123:282-297. doi: 10.1016/j.ejmech.2016.07.052. Epub 2016 Jul 25.

Rational modification of donepezil as multifunctional acetylcholinesterase inhibitors 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.
3
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: xbwang@cpu.edu.cn.

Abstract

A series of novel donepezil derivatives was designed, synthesized and evaluated as multifunctional acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD). The screening results indicated that most of the compounds exhibited potent inhibition of AChE with IC50 values in the nanomolar range. Moreover, these derivatives displayed good antioxidant, Aβ interaction, blood-brain barrier penetration (PAMPA-BBB+) and ADMET properties (in silico). Among them, 5c demonstrated excellent AChE inhibition (IC50: 85 nM for eeAChE, 73 nM for hAChE), metal chelation, and inhibitory effects on self-induced, hAChE-induced and Cu(2+)-induced Aβ1-42 aggregation (18.5%, 72.4% and 46.3%, at 20 μM). Kinetic analysis and molecular modeling studies suggested that 5c could bind simultaneously to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. More importantly, 5c exhibited significant neuroprotective potency against Aβ1-42-induced PC12 cell injury. Furthermore, the step-through passive avoidance test showed 5c significantly reversed scopolamine-induced memory deficit and no hepatotoxicity in mice. These results indicated that 5c might be a promising drug candidate for AD therapy.

KEYWORDS:

Acetylcholinesterase inhibitors; Alzheimer's disease; Donepezil derivatives; Multifunctional agents; β-amyloid aggregation

PMID:
27484514
DOI:
10.1016/j.ejmech.2016.07.052
[Indexed for MEDLINE]

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