Journal of Enzyme Inhibition and Medicinal Chemistry (Dec 2023)

Chromone-based monoamine oxidase B inhibitor with potential iron-chelating activity for the treatment of Alzheimer’s disease

  • Changjun Zhang,
  • Yujia Zhang,
  • Yangjing Lv,
  • Jianan Guo,
  • Bianbian Gao,
  • Yi Lu,
  • Anjie Zang,
  • Xi Zhu,
  • Tao Zhou,
  • Yuanyuan Xie

DOI
https://doi.org/10.1080/14756366.2022.2134358
Journal volume & issue
Vol. 38, no. 1
pp. 100 – 117

Abstract

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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 (pFe3+ = 18.52) and selective hMAO-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.

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