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J Enzyme Inhib Med Chem. 2020 Dec;35(1):330-343. doi: 10.1080/14756366.2019.1699553.

Design, synthesis, in vitro and in vivo evaluation of benzylpiperidine-linked 1,3-dimethylbenzimidazolinones as cholinesterase inhibitors against Alzheimer's disease.

Author information

1
School of Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China.
2
Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, People's Republic of China.
3
School of pharmacy, Yantai University, Yantai, People's Republic of China.
4
Jiangsu Food and Pharmaceutical Science College, Huaian, People's Republic of China.
5
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China.

Abstract

Cholinesterase inhibitor plays an important role in the treatment of patients with Alzheimer's disease (AD). Herein, we report the medicinal chemistry efforts leading to a new series of 1,3-dimethylbenzimidazolinone derivatives. Among the synthesised compounds, 15b and 15j showed submicromolar IC50 values (15b, eeAChE IC50 = 0.39 ± 0.11 µM; 15j, eqBChE IC50 = 0.16 ± 0.04 µM) towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Kinetic and molecular modelling studies revealed that 15b and 15j act in a competitive manner. 15b and 15j showed neuroprotective effect against H2O2-induced oxidative damage on PC12 cells. This effect was further supported by their antioxidant activity determined in a DPPH assay in vitro. Morris water maze test confirmed the memory amelioration effect of the two compounds in a scopolamine-induced mouse model. Moreover, the hepatotoxicity of 15b and 15j was lower than tacrine. In summary, these data suggest 15b and 15j are promising multifunctional agents against AD.

KEYWORDS:

1,3-dimethylbenzimidazolinone derivatives; Alzheimer’s disease; cholinesterase inhibitor; molecular docking; structural modification; structure-activity relationship

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