Exploration of the novel phthalimide-hydroxypyridinone derivatives as multifunctional drug candidates against Alzheimer's disease

Xi Zhu; Yangjing Lv; Miaoliang Fan; Jianan Guo; Yujia Zhang; Bianbian Gao; Changjun Zhang; Yuanyuan Xie

doi:10.1016/j.bioorg.2023.106817

Exploration of the novel phthalimide-hydroxypyridinone derivatives as multifunctional drug candidates against Alzheimer's disease

Bioorg Chem. 2023 Dec:141:106817. doi: 10.1016/j.bioorg.2023.106817. Epub 2023 Sep 9.

Authors

Xi Zhu¹, Yangjing Lv¹, Miaoliang Fan¹, Jianan Guo¹, Yujia Zhang¹, Bianbian Gao¹, Changjun Zhang², Yuanyuan Xie³

Affiliations

¹ College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, PR China.
² College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, PR China. Electronic address: zhangchangjun@zjut.edu.cn.
³ College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, PR China; Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, PR China; Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, Key Laboratory of Pharmaceutical Engineering of Zhejiang Province, Hangzhou, PR China. Electronic address: xyycz@zjut.edu.cn.

PMID: 37690318
DOI: 10.1016/j.bioorg.2023.106817

Abstract

A novel series of phthalimide-hydroxypyridinone derivatives were rationally designed and evaluated as potential anti-Alzheimer's disease (AD) agents. Bioactivity tests showed that all compounds displayed great iron ions-chelating activity (pFe³⁺ = 17.07-19.52), in addition to potent inhibition of human monoamine oxidase B (hMAO-B). Compound 11n emerged as the most effective anti-AD lead compound with a pFe³⁺ value of 18.51, along with selective hMAO-B inhibitory activity (IC₅₀ = 0.79 ± 0.05 μM, SI > 25.3). The results of cytotoxicity assays demonstrated that 11n showed extremely weak toxicity in PC12 cell line at 50 μM. Additionally, compound 11n displayed a cytoprotective effect against H₂O₂-induced oxidative damage. Moreover, compound 11n exhibited ideal blood-brain barrier (BBB) permeability in the parallel artificial membrane permeation assay (PAMPA), and significantly improved scopolamine-induced cognitive and memory impairment in mice behavioral experiments. In conclusion, these favorable experimental results suggested compound 11n deserved further investigation as an anti-AD lead compound.

Keywords: Alzheimer's disease; HMAO-B inhibitor; Hydroxypyridinone; Iron ions chelator; Multifunctional agent.

Publication types

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

MeSH terms

Acetylcholinesterase / metabolism
Alzheimer Disease* / drug therapy
Alzheimer Disease* / metabolism
Amyloid beta-Peptides
Animals
Cholinesterase Inhibitors / pharmacology
Cholinesterase Inhibitors / therapeutic use
Drug Design
Humans
Hydrogen Peroxide
Mice
Monoamine Oxidase / metabolism
Monoamine Oxidase Inhibitors / pharmacology
Monoamine Oxidase Inhibitors / therapeutic use
Phthalimides / pharmacology
Structure-Activity Relationship

Substances

Monoamine Oxidase Inhibitors
Hydrogen Peroxide
Cholinesterase Inhibitors
Monoamine Oxidase
Phthalimides
Amyloid beta-Peptides
Acetylcholinesterase