Design and synthesis of 6-benzyloxybenzo[c]thiophen-1(3H)-ones as selective monoamine oxidase-B inhibitors with antioxidant and anti-neuroinflammatory activities against Parkinson's disease.

Based on previous work, a series of 6-benzyloxybenzo[c]thiophen-1(3H)-one derivatives endowed with H2S-releasing properties were designed and synthesized. These compounds were tailored to act as selective MAO-B inhibitors with concurrent antioxidant, anti-neuroinflammatory, and neuroprotective activities, along with a favorable drug-like profile. Among them, compound 12d exhibited the most balanced pharmacological profile, functioning as a highly potent, reversible, and competitive MAO-B inhibitor (IC50 = 0.35 nM, SI = 6342.8) with moderate free-radical scavenging ability (0.59 Trolox equivalent). In vitro cellular models further confirmed its pronounced neuroprotective and anti-inflammatory efficacies. Pharmacokinetic profiling revealed that 12d possesses a suitable half-life and central nervous system penetrability, along with markedly improved water solubility. Importantly, in vivo studies demonstrated that oral administration of 12d alleviated motor deficits in a subacute MPTP-induced PD mouse model, accompanied by restored dopamine and H2S levels, reduced malondialdehyde content, and significantly preserved tyrosine hydroxylase (TH)-positive neurons in the brain. Collectively, these findings validate 12d as an innovative, multi-target candidate with considerable potential for the treatment of Parkinson's disease.