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

Abstract

In this study, a series of N-phenyl-2,3dihydrobenzo[b][1,4]dioxine-6-carboxamide derivatives were designed, synthesized, and evaluated for their inhibitory activities against human MAO-B (hMAO-B). The structure−activity relationship (SAR) was investigated and summarized. Compoundshowed the most potent inhibitory activity with an IC 50 value of 0.0083 μM and the selectivity index (IC 50 (hMAO-A)/IC 50 (hMAO-B)) was >4819. Kinetics and reversibility studies confirmed that compound 1l acted as a competitive and reversible inhibitor of hMAO-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.