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Pterostilbene-O-acetamidoalkylbenzylamines derivatives as novel dual inhibitors of cholinesterase with anti-β-amyloid aggregation and antioxidant properties for the treatment of Alzheimer's disease.
Bioorg Med Chem Lett. 2016 Apr 15; 26(8):2035-9.BM

Abstract

A series of pterostilbene-O-acetamidoalkylbenzylamines were designed, synthesized and evaluated as dual inhibitors of AChE and BuChE. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and inhibitory effects on self-induced Aβ1-42 aggregation and HuAChE-induced Aβ1-40 aggregation were also tested. The results showed that most of these compounds could effectively inhibit AChE and BuChE. Particularly, compound 21d exhibited the best AChE inhibitory activity (IC50=0.06 μM) and good inhibition of BuChE (IC50=28.04 μM). Both the inhibition kinetic analysis and molecular modeling study revealed that these compounds showed mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. In addition to cholinesterase inhibitory activities, these compounds showed different levels of antioxidant activity. However, the inhibitory activities against self-induced and HuAChE-induced Aβ aggregation of these new derivatives were unsatisfied. Taking into account the results of the biological evaluation, further modifications will be designed in order to increase the potency on the different targets. The results displayed in this Letter can be a new starting point for further development of multifunctional agents for Alzheimer's disease.

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.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
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26947607

Citation

Li, Yuxing, et al. "Pterostilbene-O-acetamidoalkylbenzylamines Derivatives as Novel Dual Inhibitors of Cholinesterase With Anti-β-amyloid Aggregation and Antioxidant Properties for the Treatment of Alzheimer's Disease." Bioorganic & Medicinal Chemistry Letters, vol. 26, no. 8, 2016, pp. 2035-9.
Li Y, Qiang X, Li Y, et al. Pterostilbene-O-acetamidoalkylbenzylamines derivatives as novel dual inhibitors of cholinesterase with anti-β-amyloid aggregation and antioxidant properties for the treatment of Alzheimer's disease. Bioorg Med Chem Lett. 2016;26(8):2035-9.
Li, Y., Qiang, X., Li, Y., Yang, X., Luo, L., Xiao, G., Cao, Z., Tan, Z., & Deng, Y. (2016). Pterostilbene-O-acetamidoalkylbenzylamines derivatives as novel dual inhibitors of cholinesterase with anti-β-amyloid aggregation and antioxidant properties for the treatment of Alzheimer's disease. Bioorganic & Medicinal Chemistry Letters, 26(8), 2035-9. https://doi.org/10.1016/j.bmcl.2016.02.079
Li Y, et al. Pterostilbene-O-acetamidoalkylbenzylamines Derivatives as Novel Dual Inhibitors of Cholinesterase With Anti-β-amyloid Aggregation and Antioxidant Properties for the Treatment of Alzheimer's Disease. Bioorg Med Chem Lett. 2016 Apr 15;26(8):2035-9. PubMed PMID: 26947607.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pterostilbene-O-acetamidoalkylbenzylamines derivatives as novel dual inhibitors of cholinesterase with anti-β-amyloid aggregation and antioxidant properties for the treatment of Alzheimer's disease. AU - Li,Yuxing, AU - Qiang,Xiaoming, AU - Li,Yan, AU - Yang,Xia, AU - Luo,Li, AU - Xiao,Ganyuan, AU - Cao,Zhongcheng, AU - Tan,Zhenghuai, AU - Deng,Yong, Y1 - 2016/02/27/ PY - 2015/12/21/received PY - 2016/02/17/revised PY - 2016/02/26/accepted PY - 2016/3/8/entrez PY - 2016/3/8/pubmed PY - 2016/12/15/medline KW - Alzheimer’s disease KW - Antioxidant KW - Aβ aggregation inhibitors KW - Dual cholinesterase inhibitors KW - Pterostilbene-O-acetamidoalkylbenzylamines SP - 2035 EP - 9 JF - Bioorganic & medicinal chemistry letters JO - Bioorg Med Chem Lett VL - 26 IS - 8 N2 - A series of pterostilbene-O-acetamidoalkylbenzylamines were designed, synthesized and evaluated as dual inhibitors of AChE and BuChE. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and inhibitory effects on self-induced Aβ1-42 aggregation and HuAChE-induced Aβ1-40 aggregation were also tested. The results showed that most of these compounds could effectively inhibit AChE and BuChE. Particularly, compound 21d exhibited the best AChE inhibitory activity (IC50=0.06 μM) and good inhibition of BuChE (IC50=28.04 μM). Both the inhibition kinetic analysis and molecular modeling study revealed that these compounds showed mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. In addition to cholinesterase inhibitory activities, these compounds showed different levels of antioxidant activity. However, the inhibitory activities against self-induced and HuAChE-induced Aβ aggregation of these new derivatives were unsatisfied. Taking into account the results of the biological evaluation, further modifications will be designed in order to increase the potency on the different targets. The results displayed in this Letter can be a new starting point for further development of multifunctional agents for Alzheimer's disease. SN - 1464-3405 UR - https://www.unboundmedicine.com/medline/citation/26947607/Pterostilbene_O_acetamidoalkylbenzylamines_derivatives_as_novel_dual_inhibitors_of_cholinesterase_with_anti_β_amyloid_aggregation_and_antioxidant_properties_for_the_treatment_of_Alzheimer's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0960-894X(16)30204-9 DB - PRIME DP - Unbound Medicine ER -