Li_2025_Bioorg.Med.Chem_133_118499

The multifaceted nature of Alzheimer's disease (AD) spurred growing interest in developing multi-target-directed ligands (MTDLs) for its prevention and treatment. Coumarin and quinoline scaffolds, recognized for their broad spectrum of AD-related biological activities including amyloid-beta (Abeta) aggregation regulation, cholinesterase (ChE) inhibition, beta-secretase 1 (BACE1) inhibition and neuroprotection, were identified as potential building blocks. Here in this study, 24 novel coumarin-quinoline hybrid compounds were rationally designed and synthesized. Inhibition studies targeting Abeta, ChE and BACE1 identified compound B8 as a promising lead compound. B8 exhibited effective binding to Abeta, and significantly attenuated Abeta-induced SH-SY5Y cell death by lowering oxidative stress and decreasing cellular apoptosis. Crucially, B8 demonstrated excellent blood-brain barrier (BBB) permeability, and intragastric administration of B8 to 7-month-old APP/PS1 transgenic mice resulted in improved cognitive function. This improvement was supported by the protection of hippocampal and cortical neurons from necrosis, attenuation of oxidative stress and inflammation in these brain regions, as well as a reduction in Abeta deposition. These findings highlight the potential of coumarin-quinoline hybrids as a novel class of AD therapeutics, with B8 emerging as a promising lead candidate warranting further investigation.