Design, synthesis and biological evaluation of potential anti-AD hybrids with monoamine oxidase B inhibitory and iron-chelating effects

Jianan Guo; Zhisheng Mi; Xiaoying Jiang; Changjun Zhang; Zili Guo; Linzi Li; Jinping Gu; Tao Zhou; Renren Bai; Yuanyuan Xie

doi:10.1016/j.bioorg.2020.104564

Design, synthesis and biological evaluation of potential anti-AD hybrids with monoamine oxidase B inhibitory and iron-chelating effects

Bioorg Chem. 2021 Mar:108:104564. doi: 10.1016/j.bioorg.2020.104564. Epub 2020 Dec 15.

Authors

Jianan Guo¹, Zhisheng Mi², Xiaoying Jiang², Changjun Zhang², Zili Guo², Linzi Li², Jinping Gu¹, Tao Zhou³, Renren Bai⁴, Yuanyuan Xie⁵

Affiliations

¹ College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, PR China.
² Collaborative Innovation Centre of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, PR China.
³ School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, PR China.
⁴ College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, PR China. Electronic address: renrenbai@126.com.
⁵ College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, PR China; Collaborative Innovation Centre of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, PR China. Electronic address: xyycz@zjut.edu.cn.

PMID: 33353806
DOI: 10.1016/j.bioorg.2020.104564

Abstract

A series of active hybrids combining 3-hydroxypyridin-4(1H)-one and coumarin pharmacophores were designed and synthesized as potential agents for the treatment of Alzheimer's disease (AD). All the compounds exhibited excellent iron-chelating activities (pFe³⁺ = 14.8-19.2) and showed favorable monoamine oxidase B (MAO-B) inhibitory effects compared to the reference drug Pargyline (IC₅₀ = 86.9 nM). Among them, compound 11 g displayed the best MAO-B inhibitory activity with an IC₅₀ value of 99.3 nM. Molecular docking analysis showed that compound 11 g could enter the entrance cavity and substrate cavity of MAO-B. Furthermore, the compound 11 g had an excellent antioxidant effect and was capable of protecting from the amyloid-β_1-42 (Aβ_1-42) induced PC12 cell damage. In silico tools were applied for predicting the blood-brain barrier (BBB) penetration and compound 11 g was proved to overcome the brain exposure challenge. In the mice behavioral study, compound 11 g significantly ameliorated cognitive impairment induced by Scopolamine. More importantly, compound 11 g displayed favorable pharmacokinetic profiles in a rat model. In summary, compound 11 g, with both anti-MAO-B and iron-chelating ability, was proved to be a promising potential anti-AD agent for further optimization.

Keywords: 3-Hydroxypyridin-4(1H)-one; Alzheimer’s disease; Coumarin derivatives; Iron ion chelator; MAO-B inhibitors.

Publication types

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

MeSH terms

Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Animals
Dose-Response Relationship, Drug
Drug Design*
Humans
Iron Chelating Agents / chemical synthesis
Iron Chelating Agents / chemistry
Iron Chelating Agents / pharmacology*
Maze Learning / drug effects
Mice
Mice, Inbred ICR
Models, Molecular
Molecular Structure
Monoamine Oxidase / metabolism*
Monoamine Oxidase Inhibitors / chemical synthesis
Monoamine Oxidase Inhibitors / chemistry
Monoamine Oxidase Inhibitors / pharmacology*
PC12 Cells
Rats
Structure-Activity Relationship

Substances

Iron Chelating Agents
Monoamine Oxidase Inhibitors
Monoamine Oxidase