Nine morpholine-derived halogenated chalcone derivatives (MHC1-MHC9) were synthesized, and their inhibitory activity against monoamine oxidase (MAO) was evaluated. MHC5 showed the highest inhibitory activity against MAO-B with an IC50 value of 0.065 μM, followed by MHC7 (IC50 = 0.078 μM) and MHC6 (IC50 = 0.082 μM). The para-F substituent MHC4 was also potent (IC50 = 0.095 μM). The selectivity index values of all the compounds were high for MAO-B over MAO-A, and the values for MHC5 and MHC4 were 66.15 and 80.11, respectively. MHC5 and MHC4 were competitive MAO-B inhibitors with Ki values of 0.024 ± 0.00062 and 0.041 ± 0.0028 μM, respectively. In reversibility tests, the changes in residual activity before and after the dialysis of MHC5 and MHC4 were similar to those of safinamide, a reversible MAO-B reference inhibitor. Additionally, molecular docking and dynamic simulations predicted that the lead molecules MHC5 and MHC4 could strongly bind to the MAO-B active site with docking scores of –10.92 ± 0.08 and –10.64 ± 0.14 kcal/mol, respectively. Additionally, MHC4 and MHC5 exhibited favorable ADME features, including blood–brain barrier permeability. The experiments confirmed that MHC5 and MHC4 are reversible and potent selective inhibitors of MAO-B and are promising candidates for the treatment of neurodegenerative diseases (human health).

中文翻译：

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含吗啉环的卤代 α,β-不饱和酮作为选择性单胺氧化酶 B 抑制剂的开发

合成了九种吗啉衍生的卤代查尔酮衍生物（MHC1-MHC9），并评估了它们对单胺氧化酶（MAO）的抑制活性。MHC5 对 MAO-B 显示出最高的抑制活性，IC50 值为 0.065 μM，其次是 MHC7 (IC50 = 0.078 μM) 和 MHC6 (IC50 = 0.082 μM)。对位 F 取代基 MHC4 也很有效 (IC50 = 0.095 μM)。所有化合物的选择性指数值中，MAO-B 均高于 MAO-A，MHC5 和 MHC4 的选择性指数值分别为 66.15 和 80.11。MHC5 和 MHC4 是竞争性 MAO-B 抑制剂，Ki 值分别为 0.024 ± 0.00062 和 0.041 ± 0.0028 μM。在可逆性测试中，MHC5和MHC4透析前后残余活性的变化与可逆性MAO-B参考抑制剂沙芬酰胺相似。此外，分子对接和动态模拟预测，先导分子 MHC5 和 MHC4 可以与 MAO-B 活性位点牢固结合，对接分数分别为 –10.92 ± 0.08 和 –10.64 ± 0.14 kcal/mol。此外，MHC4 和 MHC5 表现出良好的 ADME 特征，包括血脑屏障通透性。实验证实MHC5和MHC4是MAO-B的可逆且有效的选择性抑制剂，是治疗神经退行性疾病（人类健康）的有希望的候选者。