Discovery of Resorcinol-Based Polycyclic Structures as Tyrosinase Inhibitors for Treatment of Parkinson’s Disease

Abstract

Tyrosinase is involved in the synthesis of neuromelanin in the substantia nigra, which is closely correlated with the pathogenesis of Parkinson's disease. Herein, we identified <b>S05014</b> (l-Tyr, IC₅₀ = 6.25 ± 1.43 nM; l-Dopa, IC₅₀ = 0.64 ± 0.40 μM) as a highly effective tyrosinase inhibitor. It could inhibit the tyrosinase function from different origins and decrease the expression of tyrosinase. <b>S05014</b> presented good medication safety and inhibited melanogenesis in a dose-dependent manner. Moreover, as a resorcinol derivative, <b>S05014</b> could scavenge the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical and significantly reduce the overproduction of LPS-induced reactive oxidative species (ROS), indicating its antioxidative profile. <b>S05014</b> exhibited an excellent neuroprotective effect against methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) impairment <i>in vitro</i> and could remarkably alleviate movement abnormalities and exploratory activities <i>in vivo</i>. Altogether, <b>S05014</b> is considered as a promising inhibitor for tyrosinase, melanogenesis, and oxidative stress and has great potential to be utilized in anti-Parkinsonian syndrome. From this point of view, tyrosinase inhibition has been further confirmed to be a novel strategy to improve locomotor capacity and treat Parkinson's disease.