Design, synthesis and evaluation of coumarin-pargyline hybrids as novel dual inhibitors of monoamine oxidases and amyloid-β aggregation for the treatment of Alzheimer's disease

被引：49

作者：

Yang, Hua-Li ^{[1
,2
,3
]}

Cai, Pei ^{[2
,3
]}

Liu, Qiao-Hong ^{[2
,3
]}

Yang, Xue-Lian ^{[2
,3
]}

Li, Fan ^{[2
,3
]}

Wang, Jin ^{[2
,3
]}

Wu, Jia-Jia ^{[2
,3
]}

Wang, Xiao-Bing ^{[2
,3
]}

Kong, Ling-Yi ^{[1
,2
,3
]}

机构：

[1] Shenyang Pharmaceut Univ, Sch Tradit Chinese Mat Med, Shenyang 110016, Liaoning, Peoples R China

[2] China Pharmaceut Univ, Jiangsu Key Lab Bioact Nat Product Res, Nanjing 210009, Jiangsu, Peoples R China

[3] China Pharmaceut Univ, State Key Lab Nat Med, Dept Nat Med Chem, Nanjing 210009, Jiangsu, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 138卷

关键词：

Alzheimer's disease; Coumarin; Pargyline; Monoamine oxidases; A beta(1-42) aggregation; MULTITARGET-DIRECTED LIGANDS; BIOLOGICAL EVALUATION; ACETYLCHOLINESTERASE INHIBITORS; METAL CHELATION; B INHIBITION; DERIVATIVES; CHOLINESTERASE; ANTIOXIDANT; TARGET; POTENT;

D O I：

10.1016/j.ejmech.2017.07.008

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of coumarin-pargyline hybrids (4a-x) have been designed, synthesized and evaluated as novel dual inhibitors of Alzheimer's disease (AD). Most of the compounds exhibited a potent ability to inhibit amyloid-beta (A(beta) aggregation and monoamine oxidases. In particular, compound 4x exhibited remarkable inhibitory activities against monoamine oxidases (IC50, 0.027 +/- 0.004 AM for MAO-B; 3.275 +/- 0.040 mu M for MAO-A) and A beta(1-42) aggregation (54.0 +/- 1.1%, 25 mu M). Moreover, compound 4x showed low toxicity according to in vitro cell toxicity test. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compound 4x would be potent to cross the blood-brain barrier. Collectively, these findings demonstrate that compound 4x was an effective and promising candidate for AD therapy. (C) 2017 Elsevier Masson SAS. All rights reserved.

引用

页码：715 / 728

页数：14

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