Structure-based design, synthesis, and evaluation of structurally rigid donepezil analogues as dual AChE and BACE-1 inhibitors

被引：18

作者：

Gabr, Moustafa T. ^{[1
,2
]}

Abdel-Raziq, Mohammed S. ^{[3
,4
]}

机构：

[1] Mansoura Univ, Fac Pharm, Dept Med Chem, Mansoura 35516, Egypt

[2] Univ Iowa, Dept Chem, Iowa City, IA 52242 USA

[3] Mansoura Univ, Fac Pharm, Mansoura 35516, Egypt

[4] Univ Queensland, Sch Chem & Mol Biosci, St Lucia, Qld 4072, Australia

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 17期

关键词：

Multi-target-directed ligands; Acetylcholinesterase; beta-Secretase; Donepezil; Hybridization; BIOLOGICAL EVALUATION; ALZHEIMERS-DISEASE; BETA-SECRETASE; DERIVATIVES; DISCOVERY; POTENT; AGENTS;

D O I：

10.1016/j.bmcl.2018.07.019

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new series of structurally rigid donepezil analogues was designed, synthesized and evaluated as potential multi-target-directed ligands (MTDLs) against neurodegenerative diseases. The investigated compounds 10-13 displayed dual AChE and BACE-1 inhibitory activities in comparison to donepezil, the FDA-approved drug. The hybrid compound 13 bearing 2-aminoquinoline scaffold exhibited potent AChE inhibition (IC50 value of 14.7 nM) and BACE-1 inhibition (IC50 value of 13.1 nM). Molecular modeling studies were employed to reveal potential dual binding mode of 13 to AChE and BACE-1. The effect of the investigated compounds on the viability of SH-SY5Y neuroblastoma cells and their ability to cross the blood-brain barrier (BBB) in PAMPA-BBB assay were further studied.

引用

页码：2910 / 2913

页数：4

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