Design and synthesis of multipotent 3-aminomethylindoles and 7-azaindoles with enhanced protein phosphatase 2A-activating profile and neuroprotection.

We report the synthesis and pharmacological evaluation of new 3-aminomethylindoles derivatives with neuroprotective properties designed to present multi-target activity centered on reducing the neuronal Ca overload and preventing phosphatase 2A (PP2A) inhibition, which are two important early physiophathological events observed in neurodegenerative scenarios. Chemical syntheses of proposed compounds were achieved in two straightforward reaction steps with high yields. Most of the compounds mitigated the okadaic acid-provoked inhibition of PP2A and protected SH-SY5Y cells against toxic stimuli related to Tau-hyperphosphorylation and oxidative stress, similarly to the observed in Alzheimer's disease (AD). In addition, some of them mitigated the Ca overload induced by depolarization. The derivative 1-(1-benzyl-5-chloro-1H-indol-3-yl)-N,N-dimethylmethanamine (19) outstood by its high recovery of the PP2A activity and blockade of voltage-gated Ca channels, accompanied by good neuroprotective profile. These findings make this compound eligible for further preclinical assays with the goal of positioning new innovative drugs for the treatment of AD.