Emerging of a new neuroprotective isoflavonoid with potent Keap1/Nrf2/ARE pathway activation and AChE inhibition

Several neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), are characterized by disrupted redox balance and impaired cholinergic signaling. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway to restore redox equilibrium has been recognized as a potential strategy to counteract progressive neuronal degeneration; also, preserving the available levels of acetylcholine through acetylcholinesterase (AChE) inhibition, may largely alleviate cognitive malfunction in patients. In our continued efforts to discover effective neuroprotective drug leads, a library of 23 isoflavonoid derivatives and 10 deoxybenzoin intermediates was currently prepared and comprehensively evaluated for antioxidant capacity and potential neuroprotection. Among these compounds, compound 32 demonstrated the strongest activity, exhibiting robust neuroprotection against both H₂O₂- and scopolamine-induced injury in PC12 cells. Notably, it markedly upregulated vital antioxidant defense systems and efficiently inhibited the AChE (IC₅₀ = 14.79 μM), surpassing the efficacy of the reference drug rivastigmine (IC₅₀ = 24.5 μM). The mechanism studies showed its neuroprotection mainly relies on Nrf2 activation. Furthermore, compound 32 significantly ameliorated memory impairment and the neuroinflammation associated with scopolamine-initiated cognitive dysfunction in a zebrafish model. Collectively, this study identifies compound 32 as a promising dual-acting neuroprotective lead, offering potential value for advancing therapeutic strategies in AD drug development.