Design, synthesis, and biological evaluation of highly potent and selective hMAO-B inhibitors featuring a tetrahydrobenzo[f][1,4]oxazepine core.

The advancement of human monoamine oxidase B (hMAO-B) inhibitors for the management of Parkinson's disease (PD) has seen notable progress, however, the clinical application of existing hMAO-B inhibitors is hindered by their limited efficacy and associated adverse effects. This article presents highly potent and selective hMAO-B inhibitors characterized by either a 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine core or a 2,3,4,5-tetrahydro-1H-benzo[c]azepine core. These compounds were designed through the cyclization of the amine group with the phenyl ring of safinamide, a second-generation hMAO-B inhibitor that has received approval for PD treatment. Among the synthesized compounds, ZM24 and ZM26, which possess the 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane core structure, exhibited a significant increase in both efficacy and isoform selectivity relative to safinamide. Subsequent biological assessments revealed that these two compounds act as reversible hMAO-B inhibitors, demonstrate substantial neuroprotective properties, and significantly improve motor dysfunction in MPTP-induced mouse models of PD, thereby reinforcing their potential therapeutic applications in the treatment of PD.