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

In this study, a series of N -phenyl-2,3-dihydrobenzo[ b ][1,4]dioxine-6-carboxamide derivatives were designed, synthesized, and evaluated for their inhibitory activities against human MAO-B ( h MAO-B). The structure–activity relationship (SAR) was investigated and summarized. Compound 1l ( N -(3,4-dichlorophenyl)-2,3-dihydrobenzo[ b ][1,4]dioxine-6-carboxamide) showed the most potent inhibitory activity with an IC 50 value of 0.0083 μM and the selectivity index (IC 50 ( h MAO-A)/IC 50 ( h MAO-B)) was >4819. Kinetics and reversibility studies confirmed that compound 1l acted as a competitive and reversible inhibitor of h MAO-B. Molecular docking studies revealed the enzyme–inhibitor interactions, and the rationale was provided. Additionally, compound 1l could effectively inhibit the release of NO, TNF-α, and IL-1β in both LPS- and Aβ 1–42 -stimulated BV2 cells and attenuate the cytotoxicity induced by Aβ 1–42 . Since compound 1l 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.