N-Propargylamine-hydroxypyridinone hybrids as multitarget agents for the treatment of Alzheimer's disease

Jianan Guo; Yujia Zhang; Changjun Zhang; Chuansheng Yao; Jingqi Zhang; Xiaoying Jiang; Zhichao Zhong; Jiamin Ge; Tao Zhou; Renren Bai; Yuanyuan Xie

doi:10.1016/j.bioorg.2021.105013

N-Propargylamine-hydroxypyridinone hybrids as multitarget agents for the treatment of Alzheimer's disease

Bioorg Chem. 2021 Aug:113:105013. doi: 10.1016/j.bioorg.2021.105013. Epub 2021 May 25.

Authors

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 College of Material Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou, PR China.
⁴ School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, PR China.
⁵ 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.
⁶ 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: 34062405
DOI: 10.1016/j.bioorg.2021.105013

Abstract

AD is a progressive brain disorder. Because of the lack of remarkable single-target drugs against neurodegenerative disorders, the multitarget-directed ligand strategy has received attention as a promising therapeutic approach. Herein, we rationally designed twenty-nine hybrids of N-propargylamine-hydroxypyridinone. The designed hybrids possessed excellent iron-chelating activity (pFe³⁺ = 17.09-22.02) and potent monoamine oxidase B inhibitory effects. Various biological evaluations of the optimal compound 6b were performed step by step, including inhibition screening of monoamine oxidase (hMAO-B IC₅₀ = 0.083 ± 0.001 µM, hMAO-A IC₅₀ = 6.11 ± 0.08 µM; SI = 73.5), prediction of blood-brain barrier permeability and mouse behavioral research. All of these favorable results proved that the N-propargylamine-hydroxypyridinone scaffold is a promising structure for the discovery of multitargeted ligands for AD therapy.

Keywords: Alzheimer’s disease; Hydroxypyridinone; Iron-chelating; Monoamine oxidase B; Multitarget-directed ligands; N-Propargylamine.

Publication types

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

MeSH terms

Alzheimer Disease / drug therapy
Animals
Blood-Brain Barrier / drug effects
Blood-Brain Barrier / metabolism
Disease Models, Animal
Drug Design
Drug Stability
Humans
Hydrogen-Ion Concentration
Inhibitory Concentration 50
Iron Chelating Agents / chemical synthesis
Iron Chelating Agents / chemistry
Iron Chelating Agents / pharmacology
Iron Chelating Agents / therapeutic use
Maze Learning / drug effects
Mice
Mice, Inbred ICR
Monoamine Oxidase / chemistry
Monoamine Oxidase / metabolism
Monoamine Oxidase Inhibitors / chemical synthesis
Monoamine Oxidase Inhibitors / chemistry*
Monoamine Oxidase Inhibitors / pharmacology
Monoamine Oxidase Inhibitors / therapeutic use
Pargyline / analogs & derivatives*
Pargyline / chemistry
Propylamines / chemistry*
Pyridines / chemistry*
Structure-Activity Relationship

Substances

Iron Chelating Agents
Monoamine Oxidase Inhibitors
Propylamines
Pyridines
hydroxypyridines
propargylamine
Pargyline
Monoamine Oxidase