6-Benzyloxyphthalides as selective and reversible monoamine oxidase B inhibitors with antioxidant and anti-neuroinflammatory activities for Parkinson's disease treatment.

[Display omitted] • Novel 6-benzyloxyphthalides were synthesized. • Most compounds showed selective, competitive and reversible MAO-B inhibitory and antioxidant activities. • 8f and 14a were the outstanding representative with good in vitro multifunctional and drug-like properties. • 8f and 14a could alleviate the progress of PD in MPTP-induced mouse acute and subacute model. A series of 6-benzyloxyphthalides were designed and synthesized as potent monoamine oxidase B inhibitors with antioxidant and anti-neuroinflammatory activities. The representative compounds 8f and 14a exhibited excellent selective MAO-B inhibition activity (IC 50 = 1.33 nM, SI = 865; IC 50 = 0.02 nM, SI = 40250, respectively) and moderate antioxidant activity (0.34 and 0.36 Trolox equivalent, respectively). Further studies showed that they were competitive and quasi-reversible MAO-B inhibitors. In cellular experiments, they could significantly decrease the production of NO and TNF- α in LPS-stimulated BV-2 cells to perform their in vitro anti-neuroinflammatory activities. Moreover, BBB permeability study and the predicted physicochemical properties indicated they were suitable for the CNS. Finally, in in vivo acute and subacute MPTP-induced mice model of PD, 8f and 14a could significantly improve most behavioral disorders, restore the DA content and decrease the MDA content in the mice striatum, exhibiting better anti-PD effects than clinically used safinamide. Hence, compounds 8f and 14a are identified in our studies as prospective prototype in the research of innovative multifunctional drugs for Parkinson's disease treatment. [ABSTRACT FROM AUTHOR]