Design, synthesis and biological evaluation of novel pyrazolinone derivatives as multifunctional ligands for the treatment of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the depletion of cholinergic neurons and the accumulation of amyloid β (Aβ) 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 IC₅₀ 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 Cu²⁺ chelating ability and effectively inhibited Cu²⁺-induced Aβ 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.

Acetylcholinesterase; Metal chelation; Multi-targeting agents; Neuroprotection; Pyrazolinone.