Multitarget drug design strategy against Alzheimer's disease: Homoisoflavonoid Mannich base derivatives serve as acetylcholinesterase and monoamine oxidase B dual inhibitors with multifunctional properties

被引：80

作者：

Li, Yan ^{[1
]}

Qiang, Xiaoming ^{[1
]}

Luo, Li ^{[1
]}

Yang, Xia ^{[1
]}

Xiao, Ganyuan ^{[1
]}

Zheng, Yunxiaozhu ^{[1
]}

Cao, Zhongcheng ^{[1
]}

Sang, Zhipei ^{[2
]}

Su, Fu ^{[1
]}

Deng, Yong ^{[1
]}

机构：

[1] Sichuan Univ, West China Sch Pharm, Key Lab Drug Targeting & Drug Delivery Syst, Dept Med Chem,Educ Minist, Chengdu 610041, Peoples R China

[2] Nanyang Normal Univ, Coll Chem & Pharmaceut Engn, Nanyang 473061, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2017年 / 25卷 / 02期

关键词：

Alzheimer's disease; Homoisoflavonoid; Mannich base derivatives; Acetylcholinesterase inhibitors; Monoamine oxidase B inhibitors; Multifunctional properties; TARGET-DIRECTED LIGANDS; AMYLOID-BETA; ANTIOXIDANT PROPERTIES; AGENTS; HYBRIDS; POTENT; CHOLINESTERASE; AGGREGATION; CHEMISTRY; FIBRILS;

D O I：

10.1016/j.bmc.2016.11.048

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of homoisoflavonoid Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease. It demonstrated that most of the derivatives were selective AChE and MAO-B dual inhibitors with good multifunctional properties. Among them, compound 10d displayed the comprehensive advantages, with excellent AChE and MAO-B inhibitory activities (IC50 = 2.49 +/- 0.08 nM and 1.74 +/- 0.0581 mu M, respectively), good self- and Cu2+-induced A beta(1-42) aggregation inhibitory potency, antioxidant activity, biometal chelating ability and high BBB permeability. These multifunctional properties make 10d as an excellent candidate for the development of efficient drugs against AD. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：714 / 726

页数：13

共 47 条

[1] Multi-Target-Directed Ligands and other Therapeutic Strategies in the Search of a Real Solution for Alzheimer's Disease [J].

Agis-Torres, Angel ;

Soellhuber, Monica ;

Fernandez, Maria ;

Sanchez-Montero, J. M. .

CURRENT NEUROPHARMACOLOGY, 2014, 12 (01) :2-36

[2] New Frontiers in Selective Human MAO-B Inhibitors [J].

Carradori, Simone ;

Silvestri, Romano .

JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (17) :6717-6732

[3]

Da Prada M, 1988, J Neural Transm Suppl, V26, P31

[4] Improved solvent-free Dakin oxidation protocol [J].

da Silva, Emerson Teixeira ;

Camara, Celso Amorim ;

Antunes, O. A. C. ;

Barreiro, Eliezer J. ;

Fraga, Carlos A. M. .

SYNTHETIC COMMUNICATIONS, 2008, 38 (05) :784-788

[5] Extending applicability of the oxygen radical absorbance capacity (ORAC-fluorescein) assay [J].

Dávalos, A ;

Gómez-Cordovés, C ;

Bartolomé, B .

JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 2004, 52 (01) :48-54

[6] Homoisoflavonoids: Natural Scaffolds with Potent and Selective Monoamine Oxidase-B Inhibition Properties [J].

Desideri, Nicoletta ;

Bolasco, Adriana ;

Fioravanti, Rossella ;

Monaco, Luca Proietti ;

Orallo, Francisco ;

Yanez, Matilde ;

Ortuso, Francesco ;

Acaro, Stefano .

JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (07) :2155-2164

[7] High throughput artificial membrane permeability assay for blood-brain barrier [J].

Di, L ;

Kerns, EH ;

Fan, K ;

McConnell, OJ ;

Carter, GT .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2003, 38 (03) :223-232

[8] The synthesis and evaluation of sesamol and benzodioxane derivatives as inhibitors of monoamine oxidase [J].

Engelbrecht, Idalet ;

Petzer, Jacobus P. ;

Petzer, Anel .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2015, 25 (09) :1896-1900

[9] Design, synthesis and anti-Alzheimer properties of dimethylaminomethyl-substituted curcumin derivatives [J].

Fang, Lei ;

Gou, Shaohua ;

Liu, Xuying ;

Cao, Feng ;

Cheng, Lin .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2014, 24 (01) :40-43

[10] Synthesis and antioxidant properties of substituted 3-benzylidene-7-alkoxychroman-4-ones [J].

Foroumadi, Afireza ;

Samzadeh-Kermani, Alireza ;

Emami, Saeed ;

Dehghan, Gholamreza ;

Sorkhi, Maedeh ;

Arabsorkhi, Fatemeh ;

Heidari, Mahmoud Reza ;

Abdollahi, Mohammad ;

Shafiee, Abbas .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (24) :6764-6769

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