Multifunctional coumarin derivatives: monoamine oxidase B (MAO-B) inhibition, anti-β-amyloid (Aβ) aggregation and metal chelation properties against Alzheimer's disease

Ming Huang; Sai-Sai Xie; Neng Jiang; Jin-Shuai Lan; Ling-Yi Kong; Xiao-Bing Wang

doi:10.1016/j.bmcl.2014.12.034

Multifunctional coumarin derivatives: monoamine oxidase B (MAO-B) inhibition, anti-β-amyloid (Aβ) aggregation and metal chelation properties against Alzheimer's disease

Bioorg Med Chem Lett. 2015 Feb 1;25(3):508-13. doi: 10.1016/j.bmcl.2014.12.034. Epub 2014 Dec 19.

Authors

Ming Huang¹, Sai-Sai Xie¹, Neng Jiang¹, Jin-Shuai Lan¹, Ling-Yi Kong², Xiao-Bing Wang³

Affiliations

¹ State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
² State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China. Electronic address: cpu_lykong@126.com.
³ State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China. Electronic address: xbwang@cpu.edu.cn.

PMID: 25542589
DOI: 10.1016/j.bmcl.2014.12.034

Abstract

A series of coumarin derivatives were designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer's disease (AD). In vitro studies showed that most of these compounds exhibited significant potency to inhibit hMAO-B selectively and self-induced Aβ1-42 aggregation. In particular, compound 13 presented the greatest potential to inhibit hMAO-B (IC50=0.081μM, SI >1234) and good inhibition of Aβ1-42 aggregation (52.9% at 20μM). Moreover, compound 13 could function as a metal-chelator, penetrate the blood-brain barrier (BBB) and show low cell toxicity in rat pheochromocytoma (PC12) and SH-SY5Y cells. Taken together, these results suggested that compound 13 might be a promising multifunctional agent for AD treatment.

Keywords: Alzheimer’s disease; Coumarin derivatives; MAO; Metal chelator; β-Amyloid aggregation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / drug therapy
Alzheimer Disease / metabolism
Alzheimer Disease / pathology
Amyloid beta-Peptides / chemistry
Amyloid beta-Peptides / metabolism*
Animals
Binding Sites
Blood-Brain Barrier / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Chelating Agents / chemistry*
Chelating Agents / therapeutic use
Chelating Agents / toxicity
Coumarins / chemistry*
Coumarins / therapeutic use
Coumarins / toxicity
Drug Design
Humans
Metals / chemistry
Molecular Docking Simulation
Monoamine Oxidase / chemistry*
Monoamine Oxidase / metabolism
Monoamine Oxidase Inhibitors / chemistry*
Monoamine Oxidase Inhibitors / therapeutic use
Monoamine Oxidase Inhibitors / toxicity
PC12 Cells
Protein Structure, Tertiary
Rats

Substances

Amyloid beta-Peptides
Chelating Agents
Coumarins
Metals
Monoamine Oxidase Inhibitors
Monoamine Oxidase