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J Enzyme Inhib Med Chem. 2020 Dec;35(1):118-128. doi: 10.1080/14756366.2019.1687460.

Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatment of Alzheimer's disease.

Author information

1
Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China.
2
Jiangsu Zeyun Pharmaceutical Co., Ltd, Xibei Town Industrial Park, Wuxi, China.
3
School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China.
4
National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China.

Abstract

A series of novel quinolinone derivatives bearing dithiocarbamate moiety were designed and synthesised as multifunctional AChE inhibitors for the treatment of AD. Most of these compounds exhibited strong and clearly selective inhibition to eeAChE. Among them, compound 4c was identified as the most potent inhibitor to both eeAChE and hAChE (IC50 = 0.22 μM for eeAChE; IC50 = 0.16 μM for hAChE), and it was also the best inhibitor to AChE-induced Aβ aggregation (29.02% at 100 μM) and an efficient inhibitor to self-induced Aβ aggregation (30.67% at 25 μM). Kinetic and molecular modelling studies indicated that compound 4c was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4c had good ability to cross the BBB, showed no toxicity on SH-SY5Y neuroblastoma cells and was well tolerated in mice at doses up to 2500 mg/kg (po).

KEYWORDS:

Alzheimer’s disease; Dithiocarbamate; cholinesterase; multifunctional inhibitors; quinolinone

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