Development of novel caffeic acid derivatives as multifunctional agents for the treatment of AD

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder for which the multi-target-directed ligand (MTDL) strategy offers a promising therapeutic approach. In this study, a caffeic acid-dopamine hybrid was designed and evaluated for its multifunctional activities. Subsequently, two derivatives incorporating a carbamate fragment were synthesized. Among these, compound 3 demonstrated excellent antioxidant activity, significant inhibition of self-induced Aβ_1–42 aggregation, anti-inflammatory properties, and neuroprotective effects, though it exhibited weak cholinesterase inhibition and limited blood-brain barrier (BBB) permeability. In contrast, the derivative TM-2 showed potent butyrylcholinesterase inhibition (IC₅₀ = 0.36 μM), potential antioxidant activity, and significant inhibition of self-induced Aβ_1–42 aggregation (48.9%). TM-2 also reduced NO and IL-6 levels, provided significant anti-inflammatory effects, and exhibited neuroprotective effects against Glu-/Aβ_25–35-induced injury in PC12 cells. Importantly, TM-2 demonstrated BBB permeability in vitro and significantly improved memory impairment in a scopolamine-induced mouse model. These findings suggest that TM-2 is a promising multifunctional agent for the treatment of AD.