Discovery of novel 2-hydroxyl-4-benzyloxybenzyl aniline derivatives as potential multifunctional agents for the treatment of Parkinson's disease

Abstract

To discover novel multifunctional agents for the treatment of Parkinson's disease, a series of 2-hydroxyl-4-benzyloxybenzyl aniline derivatives was designed, synthesized and evaluated. The biological screening indicated that representative compound 6h possessed excellent MAO-B inhibition (IC₅₀ = 0.014 μM), high antioxidant activity (ORAC = 2.14 Trolox equivalent), good metal chelating ability, appropriate BBB permeability and significant neuroprotective effect. Additionally, 6h exhibited great ability to alleviate the neuroinflammtion by suppressing the activation of NF-κB pathway in vitro. Furthermore, 6h can also ameliorate MPTP induced Parkinson's disease symptoms in mice by improving the dopamine level and repressing oxidative damage. These results indicated that compound 6h was a promising candidate for further development against PD.

Keywords: 2-hydroxyl-4-benzyloxybenzyl aniline derivatives; Anti-neuroinflammatory agents; Antioxidants; MAO-B inhibitors; Multifunctional anti-PD agents; Parkinson's disease.