2. Academic Validation
  3. Multi-target-directed chromone-carboxamide hybrids: Potent AChE/MAO-B inhibitors with anti-Aβ/Tau and neuroprotective activities

Multi-target-directed chromone-carboxamide hybrids: Potent AChE/MAO-B inhibitors with anti-Aβ/Tau and neuroprotective activities

  • Eur J Med Chem. 2026 Apr 15:308:118701. doi: 10.1016/j.ejmech.2026.118701.
JiaHao Lu 1,  ChenHao Zhao 2,  YingQi Qiu 2,  Zhou Xing 2,  Li-Qun Shen 3,  Miao Zhang 4,  Hua Zhu 5
Affiliations

Affiliations

  • 1 Guangxi Key Laboratory of Zhuang and Yao Ethnic Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, 530200, China; College of Chemistry and Chemical Engineering, Guangxi Minzu University, Key Laboratory of Chemistry and Engineering of Forest Products, State Ethnic Affairs Commission, Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, Guangxi Collaborative Innovation Center for Chemistry and Engineering of Forest Products, Nanning, 530006, China.
  • 2 College of Chemistry and Chemical Engineering, Guangxi Minzu University, Key Laboratory of Chemistry and Engineering of Forest Products, State Ethnic Affairs Commission, Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, Guangxi Collaborative Innovation Center for Chemistry and Engineering of Forest Products, Nanning, 530006, China.
  • 3 College of Chemistry and Chemical Engineering, Guangxi Minzu University, Key Laboratory of Chemistry and Engineering of Forest Products, State Ethnic Affairs Commission, Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, Guangxi Collaborative Innovation Center for Chemistry and Engineering of Forest Products, Nanning, 530006, China. Electronic address: [email protected].
  • 4 Guangxi Key Laboratory of Zhuang and Yao Ethnic Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, 530200, China. Electronic address: [email protected].
  • 5 Guangxi Key Laboratory of Zhuang and Yao Ethnic Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, 530200, China. Electronic address: [email protected].
PMID: 41722429 DOI: 10.1016/j.ejmech.2026.118701
Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder involving cholinergic dysfunction, Amyloid-β (Aβ) and Tau aggregation, oxidative stress, and neuroinflammation. To address the limited efficacy of single-target therapies, a series of chromone-2-carboxamide derivatives (E1-E29) were rationally designed, synthesized, and evaluated as potential multi-target-directed ligands (MTDLs). The target compounds exhibited moderate to potent inhibitory activity against acetylcholinesterase (AChE), with several derivatives (E3, E5, E12) showing submicromolar IC50 values comparable to donepezil and pronounced selectivity over butyrylcholinesterase. Selected compounds also demonstrated preferential inhibition of monoamine oxidase-B (MAO-B), with E7 and E8 approaching the activity of selegiline. Mechanistic studies revealed that E3 and E12 acted as reversible noncompetitive AChE inhibitors. Both compounds effectively inhibited Aβ40/42 and Tau fibrillization, promoted Aβ fibril disaggregation, and suppressed intracellular amyloid accumulation, accompanied by significant antioxidant and neuroprotective effects in SH-SY5Y cells. In vivo, E12 markedly improved scopolamine-induced memory deficits in mice without observable systemic toxicity. Molecular docking and dynamics simulations supported stable binding of E3 and E12 to AChE, Aβ, and Tau targets via π-π and H-π interactions, accompanied by disruption of hydrophobic networks. Collectively, these findings identify chromone-2-carboxamide hybrids, particularly E3 and E12, as promising scaffolds for the development of multi-target anti-AD drug candidates.

Keywords

Acetylcholinesterase; Alzheimer's disease; Aβ40/42; Chromone; MAO-B; Tau.

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