1, 4-benzodioxan-substituted Thienyl chalcone derivatives as novel reversible inhibitors of human monoamine oxidase B with anti-neuroinflammatory activity.

In this study, a series of 1, 4-benzodioxan-substituted thienyl chalcone derivatives were designed, synthesized and evaluated for their inhibitory activities against human MAO-B (hMAO-B). The structure-activity relationship was investigated and summarized. Among the 22 derivatives, compound 12 showed the most potent inhibitory activity, which exhibited an IC50 of 0.11 µM with a selectivity index greater than 333. Kinetics and reversibility studies confirmed that compound 12 acted as a competitive and reversible inhibitor of hMAO-B. Molecular docking studies revealed the enzyme-inhibitor interactions and the rationale was provided. Moreover, compound 12 could effectively inhibit the release of nitric oxide, tumor necrosis factor-alpha and interleukin-1 beta in both lipopolysaccharide and amyloid β-protein 1-42 (Aβ1-42)-stimulated BV2 cells and attenuate the cytotoxicity induced by Aβ1-42 in BV2 cells. As compound 12 exhibited low neurotoxicity, we believe the hit compound which combines the activities of MAO-B inhibiting and anti-neuroinflammation could be further investigated as a novel potential lead for future studies.