Benzodioxane Carboxamide Derivatives As Novel Monoamine Oxidase B Inhibitors with Antineuroinflammatory Activity.

In this study, a series of -phenyl-2,3-dihydrobenzo[][1,4]dioxine-6-carboxamide derivatives were designed, synthesized, and evaluated for their inhibitory activities against human MAO-B (MAO-B). The structure-activity relationship (SAR) was investigated and summarized. Compound (-(3,4-dichlorophenyl)-2,3-dihydrobenzo[][1,4]dioxine-6-carboxamide) showed the most potent inhibitory activity with an IC value of 0.0083 μM and the selectivity index (IC (MAO-A)/IC (MAO-B)) was >4819. Kinetics and reversibility studies confirmed that compound acted as a competitive and reversible inhibitor of MAO-B. Molecular docking studies revealed the enzyme-inhibitor interactions, and the rationale was provided. Additionally, compound could effectively inhibit the release of NO, TNF-α, and IL-1β in both LPS- and Aβ-stimulated BV2 cells and attenuate the cytotoxicity induced by Aβ. Since compound exhibited low neurotoxicity, we believe that the hit compound with dual activities of inhibiting MAO-B and antineuroinflammation could be further investigated as a novel potential lead for future studies in vivo.