Wang_2024_Bioorg.Chem_154_108052

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the depletion of cholinergic neurons and the accumulation of amyloid beta (Abeta) plaques. The complexity and multifaceted nature of AD necessitate further exploration of multi-target drugs for its treatment. In this study, a series of novel pyrazolinone-based compounds were designed, synthesized, and evaluated as acetylcholinesterase (AChE) inhibitors and antioxidants. The lead compounds ET11 and ET21 showed strong inhibitory activity against human AChE, with IC(50) values of 6.34 and 1.81 nM, respectively. In vitro DPPH and ORAC(FL) assays confirmed the compounds' strong antioxidant capabilities. ET11 exhibited excellent neuroprotective activity in the tBHP-induced SH-SY5Y cell damage model. Benefiting from the pyridopyrazolone moiety, ET11 showed significant Cu(2+) chelating ability and effectively inhibited Cu(2+)-induced Abeta aggregation. In vivo behavioral studies and histopathology analysis preliminarily confirmed the compound's cognitive improvement and neuroprotective effects. Overall, these findings suggested that compound ET11 is expected to play a synergistic role in the treatment of AD, potentially slowing disease progression.