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

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 p...

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Autores principales: Fu, Jie, Bao, Fengqi, Gu, Min, Liu, Jing, Zhang, Zhipeng, Ding, Jiaoli, Xie, Sai-Sai, Ding, Jinsong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844382/
https://www.ncbi.nlm.nih.gov/pubmed/31694418
http://dx.doi.org/10.1080/14756366.2019.1687460
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author Fu, Jie
Bao, Fengqi
Gu, Min
Liu, Jing
Zhang, Zhipeng
Ding, Jiaoli
Xie, Sai-Sai
Ding, Jinsong
author_facet Fu, Jie
Bao, Fengqi
Gu, Min
Liu, Jing
Zhang, Zhipeng
Ding, Jiaoli
Xie, Sai-Sai
Ding, Jinsong
author_sort Fu, Jie
collection PubMed
description 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 (IC(50) = 0.22 μM for eeAChE; IC(50) = 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).
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spelling pubmed-68443822019-11-18 Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatment of Alzheimer’s disease Fu, Jie Bao, Fengqi Gu, Min Liu, Jing Zhang, Zhipeng Ding, Jiaoli Xie, Sai-Sai Ding, Jinsong J Enzyme Inhib Med Chem Research Paper 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 (IC(50) = 0.22 μM for eeAChE; IC(50) = 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). Taylor & Francis 2019-11-07 /pmc/articles/PMC6844382/ /pubmed/31694418 http://dx.doi.org/10.1080/14756366.2019.1687460 Text en © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Paper
Fu, Jie
Bao, Fengqi
Gu, Min
Liu, Jing
Zhang, Zhipeng
Ding, Jiaoli
Xie, Sai-Sai
Ding, Jinsong
Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatment of Alzheimer’s disease
title Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatment of Alzheimer’s disease
title_full Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatment of Alzheimer’s disease
title_fullStr Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatment of Alzheimer’s disease
title_full_unstemmed Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatment of Alzheimer’s disease
title_short Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatment of Alzheimer’s disease
title_sort design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional ache inhibitors for the treatment of alzheimer’s disease
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844382/
https://www.ncbi.nlm.nih.gov/pubmed/31694418
http://dx.doi.org/10.1080/14756366.2019.1687460
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