Chromone-based monoamine oxidase B inhibitor with potential iron-chelating activity for the treatment of Alzheimer's disease. (1st January 2023)

• Record Type: Journal Article
• Authors: Zhang, Changjun; Zhang, Yujia; Lv, Yangjing; Guo, Jianan; Gao, Bianbian; Lu, Yi; Zang, Anjie; Zhu, Xi; Zhou, Tao; Xie, Yuanyuan
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 38:Number 1(2023)
• Page Start: 100
• Page End: 117
• Publication Date: 2023-01-01
• Subjects: Alzheimer's disease -- multitarget-directed ligands -- MAO-B inhibitor -- iron-chelating -- hydroxypyridinones; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2022.2134358
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: Based on the multitarget-directed ligands (MTDLs) strategy, a series of chromone-hydroxypyridinone hybrids were designed, synthesised, and evaluated as potential multimodal anti-AD ligands. Prospective iron-chelating effects and favourable monoamine oxidase B (MAO-B) inhibitory activities were observed for most of the compounds. Pharmacological assays led to the identification of compound 17d, which exhibited favourable iron-chelating potential (pFe 3+ = 18.52) and selective h MAO-B inhibitory activity (IC50 = 67.02 ± 4.3 nM, SI = 11). Docking simulation showed that 17d occupied both the substrate and the entrance cavity of MAO-B, and established several key interactions with the pocket residues. Moreover, 17d was determined to cross the blood–brain barrier (BBB), and can significantly ameliorate scopolamine-induced cognitive impairment in AD mice. Despite its undesired pharmacokinetic property, 17d remains a promising multifaceted agent that is worth further investigation. Graphical Abstract: UF0001