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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Taylor & Francis Group
2020-01-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | http://dx.doi.org/10.1080/14756366.2019.1687460 |
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doaj-78887ec9017f43a28cdbf77e167622112021-07-15T13:10:31ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742020-01-0135111812810.1080/14756366.2019.16874601687460Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatment of Alzheimer’s diseaseJie Fu0Fengqi Bao1Min Gu2Jing Liu3Zhipeng Zhang4Jiaoli Ding5Sai-Sai Xie6Jinsong Ding7Xiangya School of Pharmaceutical Sciences, Central South UniversityJiangsu Zeyun Pharmaceutical Co., Ltd, Xibei Town Industrial ParkJiangsu Zeyun Pharmaceutical Co., Ltd, Xibei Town Industrial ParkSchool of Pharmacy, Jiangxi University of Traditional Chinese MedicineNational Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese MedicineNational Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese MedicineNational Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese MedicineXiangya School of Pharmaceutical Sciences, Central South UniversityA 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).http://dx.doi.org/10.1080/14756366.2019.1687460dithiocarbamatequinolinonecholinesterasealzheimer’s diseasemultifunctional inhibitors |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Jie Fu Fengqi Bao Min Gu Jing Liu Zhipeng Zhang Jiaoli Ding Sai-Sai Xie Jinsong Ding |
| spellingShingle |
Jie Fu Fengqi Bao Min Gu Jing Liu Zhipeng Zhang Jiaoli Ding Sai-Sai Xie Jinsong Ding Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatment of Alzheimer’s disease Journal of Enzyme Inhibition and Medicinal Chemistry dithiocarbamate quinolinone cholinesterase alzheimer’s disease multifunctional inhibitors |
| author_facet |
Jie Fu Fengqi Bao Min Gu Jing Liu Zhipeng Zhang Jiaoli Ding Sai-Sai Xie Jinsong Ding |
| author_sort |
Jie Fu |
| title |
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_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_sort |
design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional ache inhibitors for the treatment of alzheimer’s disease |
| publisher |
Taylor & Francis Group |
| series |
Journal of Enzyme Inhibition and Medicinal Chemistry |
| issn |
1475-6366 1475-6374 |
| publishDate |
2020-01-01 |
| 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 (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). |
| topic |
dithiocarbamate quinolinone cholinesterase alzheimer’s disease multifunctional inhibitors |
| url |
http://dx.doi.org/10.1080/14756366.2019.1687460 |
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