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Design, synthesis and evaluation of scutellarein-O-acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease.
Eur J Med Chem. 2017 Jul 28; 135:307-323.EJ

Abstract

A series of scutellarein-O-acetamidoalkylbenzylamines derivatives were designed based on a multitarget-directed ligands strategy for the treatment of Alzheimer's disease. Among these compounds, compound T-22 demonstrated excellent acetylcholinesterase inhibitory, moderate inhibitory effects on self-induced Aβ1-42 aggregation, Cu2+-induced Aβ1-42 aggregation, human AChE-induced Aβ1-40 aggregation and disassembled Cu2+-induced aggregation of the well-structured Aβ1-42 fibrils, and also acted as potential antioxidant and biometals chelator. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that T-22 interacted with both the catalytic active site and peripheral anionic site of AChE. Moreover, compound T-22 showed a good neuroprotective effect against H2O2-induced PC12 cell injury and low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test indicated T-22 significantly reversed scopolamine-induced memory deficit in mice. Taken together, the data showed that T-22 was an interesting multifunctional lead compound worthy of further study for AD.

Authors+Show Affiliations

Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China; College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061, China.Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, China. Electronic address: tanzhh616@163.com.Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. Electronic address: dengyong@scu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28458136

Citation

Sang, Zhipei, et al. "Design, Synthesis and Evaluation of scutellarein-O-acetamidoalkylbenzylamines as Potential Multifunctional Agents for the Treatment of Alzheimer's Disease." European Journal of Medicinal Chemistry, vol. 135, 2017, pp. 307-323.
Sang Z, Qiang X, Li Y, et al. Design, synthesis and evaluation of scutellarein-O-acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease. Eur J Med Chem. 2017;135:307-323.
Sang, Z., Qiang, X., Li, Y., Xu, R., Cao, Z., Song, Q., Wang, T., Zhang, X., Liu, H., Tan, Z., & Deng, Y. (2017). Design, synthesis and evaluation of scutellarein-O-acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease. European Journal of Medicinal Chemistry, 135, 307-323. https://doi.org/10.1016/j.ejmech.2017.04.054
Sang Z, et al. Design, Synthesis and Evaluation of scutellarein-O-acetamidoalkylbenzylamines as Potential Multifunctional Agents for the Treatment of Alzheimer's Disease. Eur J Med Chem. 2017 Jul 28;135:307-323. PubMed PMID: 28458136.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis and evaluation of scutellarein-O-acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease. AU - Sang,Zhipei, AU - Qiang,Xiaoming, AU - Li,Yan, AU - Xu,Rui, AU - Cao,Zhongcheng, AU - Song,Qing, AU - Wang,Ting, AU - Zhang,Xiaoyu, AU - Liu,Hongyan, AU - Tan,Zhenghuai, AU - Deng,Yong, Y1 - 2017/04/23/ PY - 2017/01/26/received PY - 2017/03/27/revised PY - 2017/04/20/accepted PY - 2017/5/2/pubmed PY - 2017/9/29/medline PY - 2017/5/2/entrez KW - Acetylcholinesterase inhibitors KW - Alzheimer's disease KW - Antioxidant agents KW - Aβ aggregation inhibitors KW - Multifunctional agents KW - Scutellarein-O-acetamidoalkylbenzylamines SP - 307 EP - 323 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 135 N2 - A series of scutellarein-O-acetamidoalkylbenzylamines derivatives were designed based on a multitarget-directed ligands strategy for the treatment of Alzheimer's disease. Among these compounds, compound T-22 demonstrated excellent acetylcholinesterase inhibitory, moderate inhibitory effects on self-induced Aβ1-42 aggregation, Cu2+-induced Aβ1-42 aggregation, human AChE-induced Aβ1-40 aggregation and disassembled Cu2+-induced aggregation of the well-structured Aβ1-42 fibrils, and also acted as potential antioxidant and biometals chelator. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that T-22 interacted with both the catalytic active site and peripheral anionic site of AChE. Moreover, compound T-22 showed a good neuroprotective effect against H2O2-induced PC12 cell injury and low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test indicated T-22 significantly reversed scopolamine-induced memory deficit in mice. Taken together, the data showed that T-22 was an interesting multifunctional lead compound worthy of further study for AD. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/28458136/Design_synthesis_and_evaluation_of_scutellarein_O_acetamidoalkylbenzylamines_as_potential_multifunctional_agents_for_the_treatment_of_Alzheimer's_disease_ DB - PRIME DP - Unbound Medicine ER -