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

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 (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.

Graphical Abstract

Keywords:

• Alzheimer’s disease
• multitarget-directed ligands
• MAO-B inhibitor
• iron-chelating
• hydroxypyridinones

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This project was supported by the Zhejiang Key R&D Program [No. 2021C03085]; National Natural Science Foundation of China, NSFC [Grant No. 21978273]; China Postdoctoral Science Foundation, CPSF [No. 2021M702897]; Research and Application Service Platform Project of API Manufacturing Environmental Protection and Safety Technology in China [2020–0107–3–1]. This project is also supported by the National Key R&D Program [No. 2021YFC2100800].