Design, synthesis and biological evaluation of hydroxypyridinone-coumarin hybrids as multimodal monoamine oxidase B inhibitors and iron chelates against Alzheimer's disease

Changjun Zhang; Ke Yang; Sihang Yu; Jing Su; Shengli Yuan; Jiaxin Han; Yan Chen; Jinping Gu; Tao Zhou; Renren Bai; Yuanyuan Xie

doi:10.1016/j.ejmech.2019.07.031

Design, synthesis and biological evaluation of hydroxypyridinone-coumarin hybrids as multimodal monoamine oxidase B inhibitors and iron chelates against Alzheimer's disease

Eur J Med Chem. 2019 Oct 15:180:367-382. doi: 10.1016/j.ejmech.2019.07.031. Epub 2019 Jul 12.

Authors

Changjun Zhang¹, Ke Yang², Sihang Yu³, Jing Su³, Shengli Yuan², Jiaxin Han², Yan Chen², Jinping Gu², Tao Zhou⁴, Renren Bai⁵, Yuanyuan Xie⁶

Affiliations

¹ Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceutical, Zhejiang University of Technology, Hangzhou, China.
² College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, China.
³ Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China.
⁴ School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China.
⁵ College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, China. Electronic address: renrenbai@zjut.edu.cn.
⁶ Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceutical, Zhejiang University of Technology, Hangzhou, China; College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, China. Electronic address: xyycz@zjut.edu.cn.

PMID: 31325784
DOI: 10.1016/j.ejmech.2019.07.031

Abstract

A series of hybrids of hydroxypyridinone and coumarin were rationally designed, synthesized and biologically evaluated for their iron ion chelating and MAO-B inhibitory activities. Most of the compounds displayed excellent iron ion chelating effects and moderate to good anti-MAO-B activities. Compound 27a exhibited the most potent activity against MAO-B, with an IC₅₀ value of 14.7 nM. Importantly, 27a showed good U251 cell protective effect and significantly ameliorated the cognitive dysfunction of scopolamine-induced AD mice. Moreover, molecular docking was performed to elucidate the probable ligand-receptor interaction, and the structure-activity relationships were also summarized.

Keywords: Alzheimer's disease; Coumarin derivatives; Hydroxypyridinones; Iron ion chelator; MAO-B inhibitor.

MeSH terms

Alzheimer Disease / chemically induced
Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Animals
Cell Line, Tumor
Cell Survival / drug effects
Coumarins / chemistry
Coumarins / pharmacology*
Dose-Response Relationship, Drug
Drug Design
Humans
Hydrogen Peroxide / antagonists & inhibitors
Hydrogen Peroxide / pharmacology
Iron Chelating Agents / chemical synthesis
Iron Chelating Agents / chemistry
Iron Chelating Agents / pharmacology*
Mice
Mice, Inbred ICR
Molecular Docking Simulation
Molecular Structure
Monoamine Oxidase / metabolism*
Monoamine Oxidase Inhibitors / chemical synthesis
Monoamine Oxidase Inhibitors / chemistry
Monoamine Oxidase Inhibitors / pharmacology*
Pyridines / chemistry
Pyridines / pharmacology*
Scopolamine
Structure-Activity Relationship

Substances

Coumarins
Iron Chelating Agents
Monoamine Oxidase Inhibitors
Pyridines
hydroxypyridines
coumarin
Hydrogen Peroxide
Scopolamine
Monoamine Oxidase