Design, synthesis, and multi-target evaluation of Chromone-based derivatives as promising anti-Alzheimer's disease agents

  • Bioorg Chem. 2026 Jan:168:109350. doi: 10.1016/j.bioorg.2025.109350.
Jia Hao Lu  1 ,  Chen Hao Zhao  2 ,  Ying Qi Qiu  2 ,  Li Qun Shen  3 ,  Miao Zhang  4 ,  Hua Zhu  5
Affiliations
  • 1. Guangxi Key Laboratory of Zhuang and Yao Ethnic Medicine, Guangxi University of Chinese Medicine, 530200 Nanning, Guangxi, 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, 530200 Nanning, Guangxi, China. Electronic address: [email protected].
  • 5. Guangxi Key Laboratory of Zhuang and Yao Ethnic Medicine, Guangxi University of Chinese Medicine, 530200 Nanning, Guangxi, China. Electronic address: [email protected].
PMID: 41389606 DOI: 10.1016/j.bioorg.2025.109350
Abstract

A series of novel chromone derivatives were designed and synthesized, primarily composed of enamine/hydrazine/hydrazide-based chromone derivatives. Their potential for multi-target (acetylcholinesterase (AChE), monoamine oxidase-B (MAO-B), amyloid-beta-40/42 (Aβ40/42), Tau) therapy against Alzheimer's disease was systematically evaluated. In vitro studies demonstrated that compound C20 exhibited potent and selective AChE inhibitory activity with no significant effect on butyrylcholinesterase (BChE), and showed strong MAO-B inhibition with an IC50 value of 0.06 ± 0.04 μM. Both compounds C20 and D21 showed good inhibitory effects on the aggregation of Aβ40/42 and Tau proteins, with overall IC50 values around 1 μM. Additionally, D21 promoted the degradation of Aβ40/42 (Aβ40, IC50 = 2.151 μM; Aβ42, IC50 = 3.622 μM). Cellular experiments revealed that C20 and D21 could reduce intracellular and extracellular Aβ protein deposition to varying degrees, demonstrating significant protective effects in reversing Aβ40/42 oligomer-induced neurotoxicity while also decreasing intracellular Reactive Oxygen Species (ROS) production. These findings highlight the promising potential of compounds C20 and D21 as multi-target therapeutic agents for Alzheimer's disease (AD).

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