Lu_2025_Bioorg.Chem_168_109350

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 (Abeta40/42), 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 IC(50) value of 0.06 +/- 0.04 microM. Both compounds C20 and D21 showed good inhibitory effects on the aggregation of Abeta40/42 and Tau proteins, with overall IC(50) values around 1 microM. Additionally, D21 promoted the degradation of Abeta40/42 (Abeta40, IC(50) = 2.151 microM; Abeta42, IC(50) = 3.622 microM). Cellular experiments revealed that C20 and D21 could reduce intracellular and extracellular Abeta protein deposition to varying degrees, demonstrating significant protective effects in reversing Abeta40/42 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).