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<p>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 (<i>h</i>MAO-B). The structure-activity relationship was investigated and summarized. Among the 22 derivatives, compound <b>12</b> showed the most potent inhibitory activity, which exhibited an IC<sub>50</sub> of 0.11 µM with a selectivity index greater than 333. Kinetics and reversibility studies confirmed that compound <b>12</b> acted as a competitive and reversible inhibitor of <i>h</i>MAO-B. Molecular docking studies revealed the enzyme-inhibitor interactions and the rationale was provided. Moreover, compound <b>12</b> 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 (Aβ<sub>1-42</sub>)-stimulated BV2 cells and attenuate the cytotoxicity induced by Aβ<sub>1-42</sub> in BV2 cells. As compound <b>12</b> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月13日

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  • Demeng Sun,
  • Mengxue Mu,
  • Yanmei Jiang,
  • Bo Wang,
  • Zuo Kong,
  • Jingbo Tan,
  • Yun Hu

摘要

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.