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).
