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Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer’s Disease

A series of novel ligustrazine derivatives 8a–r were designed, synthesized, and evaluated as multi-targeted inhibitors for anti-Alzheimer’s disease (AD) drug discovery. The results showed that most of them exhibited a potent ability to inhibit both ChEs, with a high selectivity towards AChE. In part...

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Autores principales: Wu, Wenhao, Liang, Xintong, Xie, Guoquan, Chen, Langdi, Liu, Weixiong, Luo, Guolin, Zhang, Peiquan, Yu, Lihong, Zheng, Xuehua, Ji, Hong, Zhang, Chao, Yi, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222487/
https://www.ncbi.nlm.nih.gov/pubmed/30301153
http://dx.doi.org/10.3390/molecules23102540
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author Wu, Wenhao
Liang, Xintong
Xie, Guoquan
Chen, Langdi
Liu, Weixiong
Luo, Guolin
Zhang, Peiquan
Yu, Lihong
Zheng, Xuehua
Ji, Hong
Zhang, Chao
Yi, Wei
author_facet Wu, Wenhao
Liang, Xintong
Xie, Guoquan
Chen, Langdi
Liu, Weixiong
Luo, Guolin
Zhang, Peiquan
Yu, Lihong
Zheng, Xuehua
Ji, Hong
Zhang, Chao
Yi, Wei
author_sort Wu, Wenhao
collection PubMed
description A series of novel ligustrazine derivatives 8a–r were designed, synthesized, and evaluated as multi-targeted inhibitors for anti-Alzheimer’s disease (AD) drug discovery. The results showed that most of them exhibited a potent ability to inhibit both ChEs, with a high selectivity towards AChE. In particular, compounds 8q and 8r had the greatest inhibitory abilities for AChE, with IC(50) values of 1.39 and 0.25 nM, respectively, and the highest selectivity towards AChE (for 8q, IC(50) BuChE/IC(50) AChE = 2.91 × 10(6); for 8r, IC(50) BuChE/IC(50) AChE = 1.32 × 10(7)). Of note, 8q and 8r also presented potent inhibitory activities against Aβ aggregation, with IC(50) values of 17.36 µM and 49.14 µM, respectively. Further cellular experiments demonstrated that the potent compounds 8q and 8r had no obvious cytotoxicity in either HepG2 cells or SH-SY5Y cells, even at a high concentration of 500 μM. Besides, a combined Lineweaver-Burk plot and molecular docking study revealed that these compounds might act as mixed-type inhibitors to exhibit such effects via selectively targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChEs. Taken together, these results suggested that further development of these compounds should be of great interest.
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spelling pubmed-62224872018-11-13 Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer’s Disease Wu, Wenhao Liang, Xintong Xie, Guoquan Chen, Langdi Liu, Weixiong Luo, Guolin Zhang, Peiquan Yu, Lihong Zheng, Xuehua Ji, Hong Zhang, Chao Yi, Wei Molecules Article A series of novel ligustrazine derivatives 8a–r were designed, synthesized, and evaluated as multi-targeted inhibitors for anti-Alzheimer’s disease (AD) drug discovery. The results showed that most of them exhibited a potent ability to inhibit both ChEs, with a high selectivity towards AChE. In particular, compounds 8q and 8r had the greatest inhibitory abilities for AChE, with IC(50) values of 1.39 and 0.25 nM, respectively, and the highest selectivity towards AChE (for 8q, IC(50) BuChE/IC(50) AChE = 2.91 × 10(6); for 8r, IC(50) BuChE/IC(50) AChE = 1.32 × 10(7)). Of note, 8q and 8r also presented potent inhibitory activities against Aβ aggregation, with IC(50) values of 17.36 µM and 49.14 µM, respectively. Further cellular experiments demonstrated that the potent compounds 8q and 8r had no obvious cytotoxicity in either HepG2 cells or SH-SY5Y cells, even at a high concentration of 500 μM. Besides, a combined Lineweaver-Burk plot and molecular docking study revealed that these compounds might act as mixed-type inhibitors to exhibit such effects via selectively targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChEs. Taken together, these results suggested that further development of these compounds should be of great interest. MDPI 2018-10-05 /pmc/articles/PMC6222487/ /pubmed/30301153 http://dx.doi.org/10.3390/molecules23102540 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wu, Wenhao
Liang, Xintong
Xie, Guoquan
Chen, Langdi
Liu, Weixiong
Luo, Guolin
Zhang, Peiquan
Yu, Lihong
Zheng, Xuehua
Ji, Hong
Zhang, Chao
Yi, Wei
Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer’s Disease
title Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer’s Disease
title_full Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer’s Disease
title_fullStr Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer’s Disease
title_full_unstemmed Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer’s Disease
title_short Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer’s Disease
title_sort synthesis and evaluation of novel ligustrazine derivatives as multi-targeted inhibitors for the treatment of alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222487/
https://www.ncbi.nlm.nih.gov/pubmed/30301153
http://dx.doi.org/10.3390/molecules23102540
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