Emergence of a Potent AChE Inhibitor with Antioxidant and Neuroprotection Abilities

Oxidative damage and cholinergic dysfunction are common pathological features of Alzheimer's disease (AD). Maintaining the redox balance of neurons and cholinergic signaling through antioxidants and acetylcholinesterase (AChE) inhibition may provide therapeutic benefits for AD. In this regard, we discovered three AChE inhibitors with more potency than the positive control (rivastigmine; IC₅₀ = 24.5 μM). Among these active compounds, C5 (a flavonoid derivative) was the most potent AChE inhibitor with an IC₅₀ of 5.02 μM, followed by C1, C6, and C2 with IC₅₀ values of 7.94 μM, 8.13 μM, and 27.52 μM, respectively. Compound C5 also demonstrated strong neuroprotective activity, rescuing PC12 cells from H₂O₂-induced damage and scavenging various ROS models. Interestingly, C5 also prevented memory impairments in the scopolamine-induced cognitive dysfunction zebrafish model. Our findings suggest that C5 is a potential drug lead for cholinergic dysfunction-related disorders such as AD.