Hydroxy-substituted trans-cinnamoyl derivatives as multifunctional tools in the context of Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial pathology that requires multifaceted agents able to address its peculiar nature. In recent years, a plethora of proteins and biochemical pathways has been proposed as possible targets to counteract neurotoxicity. Although the complex scenario is not completely elucidated, close relationships are emerging among some of these actors. In particular, increasing evidence has shown that aggregation of amyloid beta (Aβ), glycogen synthase kinase 3β (GSK-3β) and oxidative stress are strictly interconnected and their concomitant modulation may have a positive and synergic effect in contrasting AD-related impairments. We designed compound 3 which demonstrated the ability to inhibit both GSK-3β (IC₅₀ = 24.36 ± 0.01 μM) and Aβ₄₂ self-aggregation (IC₅₀ = 9.0 ± 1.4 μM), to chelate copper (II) and to act as exceptionally strong radical scavenger (k_inh = 6.8 ± 0.5 · 10⁵ M^-1s^-1) even in phosphate buffer at pH 7.4 (k_inh = 3.2 ± 0.5 · 10⁵ M^-1s^-1). Importantly, compound 3 showed high-predicted blood-brain barrier permeability, did not exert any significant cytotoxic effects in immature cortical neurons up to 50 μM and showed neuroprotective properties at micromolar concentration against toxic insult induced by glutamate.