| Summary: | Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons at level of <i>substantia nigra pars compacta</i>. To date, there is no cure for this pathology, except for some drugs able to alleviate the symptoms of PD. In this paper we report the synthesis and biological evaluation of novel sulfur- and selenyl-<span style="font-variant: small-caps;">l</span>-Dopa (LD) derivatives (<b>SP1−6</b>) obtained through the amide junction between the amino group of LD and carboxylic moiety of sulfur- and selenyl-organic compounds, which are commercially available. Biological activity was evaluated on human undifferentiated and retinoic acid/phorbol myristyl acetate (RA/PMA)-differentiated SY-SH5Y neuroblastoma cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Antioxidant activity against oxidative stress was measured using nitroblue tetrazolium (NBT) and 2’,7’-dichlorodihydrofluorescein diacetate (H<sub>2</sub>DCFDA) assays. Finally, physico-chemical characterization and plasma stability studies of <b>SP1−6</b> were also performed. Biological data revealed that <b>SP6</b> has a significant protective action against the neurotoxic action of 6-hydroxydopamine (6-OHDA) and H<sub>2</sub>O<sub>2</sub> in a RA/PMA-differentiated SY-SH5Y neuroblastoma cell line that proved to be an effective antioxidant and protective compound. <b>SP6</b>, endowed with a lipophilic nature, low molecular weight, and plasma stability, can easily cross biological membranes via passive diffusion such as through the blood−brain barrier. <b>SP6</b> has great potential for developing novel pharmacological approach for neurodegenerative diseases, such as PD. Further studies will help define its exact antioxidant mechanism and determine whether the neuroprotective action is mediated or modulated by glutathione peroxidase (GPx).
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