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Design, synthesis and evaluation of genistein-O-alkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease.
Eur J Med Chem. 2014 Apr 09; 76:314-31.EJ

Abstract

A series of genistein derivatives with carbon spacer-linked alkylbenzylamines were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good acetylcholinesterase (AChE) inhibitory activity, with moderate-to-good anti-oxidative activity. Specifically, compounds 10b, 19d and 25d exhibited significant inhibition of β-amyloid (Aβ) aggregation and exhibited metal chelating properties. In particular, 25d inhibited: self-induced Aβ₁₋₄₂ aggregation, Cu(2+)-induced Aβ₁₋₄₂ aggregation, and human AChE-induced Aβ₁₋₄₀ aggregation by 35%, 77.8%, and 36.2%, respectively. Moreover, both kinetic analysis of AChE inhibition and the molecular modeling study suggested that 25d binds simultaneously to catalytic active site and peripheral anionic site of AChE. More importantly, compound 25d disassembled the well-structured Aβ fibrils generated by Cu(2+)-induced Aβ aggregation by 72.1%. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. These results suggest that 25d may be a promising multifunctional agent for AD treatment.

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.Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, 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

24589487

Citation

Qiang, Xiaoming, et al. "Design, Synthesis and Evaluation of genistein-O-alkylbenzylamines as Potential Multifunctional Agents for the Treatment of Alzheimer's Disease." European Journal of Medicinal Chemistry, vol. 76, 2014, pp. 314-31.
Qiang X, Sang Z, Yuan W, et al. Design, synthesis and evaluation of genistein-O-alkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease. Eur J Med Chem. 2014;76:314-31.
Qiang, X., Sang, Z., Yuan, W., Li, Y., Liu, Q., Bai, P., Shi, Y., Ang, W., Tan, Z., & Deng, Y. (2014). Design, synthesis and evaluation of genistein-O-alkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease. European Journal of Medicinal Chemistry, 76, 314-31. https://doi.org/10.1016/j.ejmech.2014.02.045
Qiang X, et al. Design, Synthesis and Evaluation of genistein-O-alkylbenzylamines as Potential Multifunctional Agents for the Treatment of Alzheimer's Disease. Eur J Med Chem. 2014 Apr 9;76:314-31. PubMed PMID: 24589487.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis and evaluation of genistein-O-alkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease. AU - Qiang,Xiaoming, AU - Sang,Zhipei, AU - Yuan,Wen, AU - Li,Yan, AU - Liu,Qiang, AU - Bai,Ping, AU - Shi,Yikun, AU - Ang,Wei, AU - Tan,Zhenghuai, AU - Deng,Yong, Y1 - 2014/02/17/ PY - 2013/11/26/received PY - 2014/02/09/revised PY - 2014/02/16/accepted PY - 2014/3/5/entrez PY - 2014/3/5/pubmed PY - 2014/12/15/medline KW - Acetylcholinesterase inhibitors KW - Alzheimer's disease KW - Aβ aggregation inhibitors KW - Genistein-O-alkylbenzylamines KW - Metal-chelating KW - Multifunctional agents SP - 314 EP - 31 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 76 N2 - A series of genistein derivatives with carbon spacer-linked alkylbenzylamines were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good acetylcholinesterase (AChE) inhibitory activity, with moderate-to-good anti-oxidative activity. Specifically, compounds 10b, 19d and 25d exhibited significant inhibition of β-amyloid (Aβ) aggregation and exhibited metal chelating properties. In particular, 25d inhibited: self-induced Aβ₁₋₄₂ aggregation, Cu(2+)-induced Aβ₁₋₄₂ aggregation, and human AChE-induced Aβ₁₋₄₀ aggregation by 35%, 77.8%, and 36.2%, respectively. Moreover, both kinetic analysis of AChE inhibition and the molecular modeling study suggested that 25d binds simultaneously to catalytic active site and peripheral anionic site of AChE. More importantly, compound 25d disassembled the well-structured Aβ fibrils generated by Cu(2+)-induced Aβ aggregation by 72.1%. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. These results suggest that 25d may be a promising multifunctional agent for AD treatment. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/24589487/Design_synthesis_and_evaluation_of_genistein_O_alkylbenzylamines_as_potential_multifunctional_agents_for_the_treatment_of_Alzheimer's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(14)00165-2 DB - PRIME DP - Unbound Medicine ER -