2. Academic Validation
  3. 3-Hydroxyquinolin-2-Ones Act as Dual Inhibitors of Ferroptosis and Monoamine Oxidase B: Reducing Alzheimer's Disease-Related Amyloid Precursor Protein and Hyperphosphorylated Tau In Vivo

3-Hydroxyquinolin-2-Ones Act as Dual Inhibitors of Ferroptosis and Monoamine Oxidase B: Reducing Alzheimer's Disease-Related Amyloid Precursor Protein and Hyperphosphorylated Tau In Vivo

  • J Med Chem. 2025 Jul 10;68(13):13661-13682. doi: 10.1021/acs.jmedchem.5c00502.
Yangjing Lv 1 2,  Xiaoxin Song 1,  Jiayan He 1,  Xiaomeng Jiang 3,  Liwen Lu 1,  Miaoliang Fan 1,  Zili Guo 4,  Changjun Zhang 1,  Yuanyuan Xie 1 5
Affiliations

Affiliations

  • 1 College of Pharmaceutical Science, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceutical, Zhejiang Key Laboratory of Green Manufacturing Technology for Chemical Drugs, Zhejiang University of Technology, Hangzhou 310014, China.
  • 2 Zhejiang Lishui Service Platform for Technological Innovations in Traditional Chinese Medicine Industry, Lishui University, Lishui 323000, China.
  • 3 Zhejiang Jianfeng Pharmaceutical Co., Ltd., Jinhua 321000, China.
  • 4 Interdisciplinary Research Academy (IRA), Zhejiang Shuren University, Hangzhou 310015, China.
  • 5 State Key Laboratory of Green Chemical Synthesis and Conversion, Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, Hangzhou 310014, China.
PMID: 40542726 DOI: 10.1021/acs.jmedchem.5c00502
Abstract

The challenges in the current treatment landscape for Alzheimer's disease (AD) underscore the urgent need for novel therapeutic strategies targeting multiple pathological pathways. Recent studies have implicated iron in ROS-dependent neuronal injury through Ferroptosis. Additionally, overexpression of Monoamine Oxidase B (MAO-B) induces oxidative stress and decreases cognitive function. In this study, we presented the novel dual inhibitors of Ferroptosis and MAO-B for AD management, aiming to address both the symptomatic and neurodegenerative aspects of this disease. Compound 21d emerged as a promising candidate, exhibiting potent and selective MAO-B inhibitory activity (IC50 = 87.47 nM, SI > 229), as well as excellent antiferroptosis activity through modulation of the iron metabolic pathway and GSH-GPX4 axis in vitro. Importantly, 21d normalized cognitive and memory impairments in a 3×Tg (APP/Tau/Ps1) AD mouse model and reduced levels of AD-related proteins, including amyloid precursor protein and phosphorylated Tau Protein, in the brains of AD mice.

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