2,6‐Diarylbenzo[d]oxazoles as MAO‐B inhibitors for the treatment of Parkinson's disease

Abstract Parkinson's disease (PD) is a progressive neurodegenerative disease caused by a loss of dopaminergic neurons in the substantia nigra. Monoamine oxidase‐B (MAO‐B) inhibition is a promising strategy for disease modification. Here, we synthesized a series of 2,6‐diarylbenzo[ d ]oxazoles and identified two potent and selective hMAO‐B inhibitors: 4,4′‐(benzo[ d ]oxazole‐2,6‐diyl)diphenol 4a (IC 50 = 0.182 μM) and 4‐(2‐(3‐fluorophenyl)benzo[ d ]oxazol‐6‐yl)phenol 4f (IC 50 = 0.184 μM). Molecular modeling indicated that the benzoxazole core interacts hydrophobically within the active site, contributing to their inhibitory potency. Both compounds demonstrated reversible or partially reversible inhibition of hMAO‐B and neuroprotective effects in the MPP + ‐induced neurotoxicity assay using human neuroblastoma cells. Additionally, both compounds exhibited good microsomal stability and lacked significant perturbation of hERG channel activity. While 4a showed CYP inhibition against some isozymes, 4f had minimal effects on CYP isozyme activities, suggesting a more favorable pharmacokinetic profile. Based on these findings, 4f presents a promising therapeutic candidate for the treatment of PD.