Multi-target-directed drug design strategy: From a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer's disease

被引：246

作者：

Bolognesi, Maria Laura ^{[1
]}

Cavalli, Andrea ^{[1
]}

Valgimigli, Luca ^{[1
]}

Bartolini, Manuela ^{[1
]}

Rosini, Michela ^{[1
]}

Andrisano, Vincenza ^{[1
]}

Recanatini, Maurizio ^{[1
]}

Melchiorre, Carlo ^{[1
]}

机构：

[1] Univ Bologna, A Mangini Alma Mater Studiorum, Dept Organ Chem, Dept Pharmaceut Sci, I-40126 Bologna, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 26期

关键词：

D O I：

10.1021/jm701225u

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A design strategy to convert a dual-binding site AChE inhibitor into triple functional compounds with promising in vitro profile against multifactorial syndromes, such as Alzheimer's disease, is proposed. The lead compound bis(7)-tacrine (2) was properly modified to confer to the new molecules the ability of chelating metals, involved in the neurodegenerative process. The multifunctional compounds show activity against human AChE, are able to inhibit the AChE-induced amyloid-beta aggregation, and chelate metals, such as iron and copper.

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页码：6446 / 6449

页数：4

相关论文

共 34 条

[1] BIS(SULFO-N-SUCCINIMIDYL) DOXYL-2-SPIRO-5'-AZELATE - SYNTHESIS, CHARACTERIZATION, AND REACTION WITH THE ANION-EXCHANGE CHANNEL IN INTACT HUMAN-ERYTHROCYTES [J].

ANJANEYULU, PSR ;

BETH, AH ;

COBB, CE ;

JULIAO, SF ;

SWEETMAN, BJ ;

STAROS, JV .

BIOCHEMISTRY, 1989, 28 (16) :6583-6590

[2] β-amyloid aggregation induced by human acetylcholinesterase:: inhibition studies [J].

Bartolini, M ;

Bertucci, C ;

Cavrini, V ;

Andrisano, V .

BIOCHEMICAL PHARMACOLOGY, 2003, 65 (03) :407-416

[3]

Baum L, 2004, J ALZHEIMERS DIS, V6, P367

[4]

Bolognesi Maria Laura, 2003, Farmaco (Lausanne), V58, P917, DOI 10.1016/S0014-827X(03)00150-2

[5] ACIAP, Autonomous hierarchical agglomerative Cluster Analysis based protocol to partition conformational datasets [J].

Bottegoni, Giovanni ;

Rocchia, Walter ;

Recanatini, Maurizio ;

Cavalli, Andrea .

BIOINFORMATICS, 2006, 22 (14) :E58-E65

[6] Further studies on the interaction of the 5-hydroxytryptamine3 (5-HT3) receptor with arylpiperazine ligands.: Development of a new 5-HT3 receptor ligand showing potent acetylcholinesterase inhibitory properties [J].

Cappelli, A ;

Gallelli, A ;

Manini, M ;

Anzini, M ;

Mennuni, L ;

Makovec, F ;

Menziani, MC ;

Alcaro, S ;

Ortuso, F ;

Vomero, S .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (10) :3564-3575

[7] Heterodimeric tacrine-based acetylcholinesterase inhibitors: Investigating ligand-peripheral site interactions [J].

Carlier, PR ;

Chow, ESH ;

Han, YF ;

Liu, J ;

El Yazal, J ;

Pang, YP .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (20) :4225-4231

[8] Targeting beta-amyloid pathogenesis through acetylcholinesterase inhibitors [J].

Castro, Ana ;

Martinez, Ana .

CURRENT PHARMACEUTICAL DESIGN, 2006, 12 (33) :4377-4387

[9] A small molecule targeting the multifactorial nature of Alzheimer's disease [J].

Cavalli, Andrea ;

Bolognesi, Maria Laura ;

Capsoni, Simona ;

Andrisano, Vincenza ;

Bartolini, Manuela ;

Margotti, Elisa ;

Cattaneo, Antonino ;

Recanatini, Maurizio ;

Melchiorre, Carlo .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2007, 46 (20) :3689-3692

[10] MODELS FOR PYRIDINE-NUCLEOTIDE COENZYMES - SYNTHESIS AND PROPERTIES OF BRIDGED DINICOTINAMIDE DERIVATIVES [J].

DITTMER, DC ;

BLIDNER, BB .

JOURNAL OF ORGANIC CHEMISTRY, 1973, 38 (16) :2873-2882

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