Human neutrophil elastase (HNE) plays an essential role in host defense against bacteria but is also involved in several respiratory diseases. Recent reports suggest that compounds exhibiting a combination of HNE inhibitory activity with antiradical properties may be therapeutically beneficial for the treatment of respiratory diseases involving inflammation and oxidative stress. We report here the synthesis and biological evaluation of novel ebselen analogues exhibiting HNE inhibitory and antiradical activities. HNE inhibition was evaluated in an enzymatic system using human HNE, whereas antiradical activity was evaluated in a cell-based assay system using phorbol 12-myristate 13-acetate (PMA)-stimulated murine bone marrow leukocytes as the source of reactive oxygen species (ROS). HNE inhibition was due to the N–CO group targeting Ser195-OH at position 2 of the scaffold, while antiradical activity was due to the presence of the selenium atom. The most active compounds 4d, 4f, and 4j exhibited a good balance between anti-HNE (IC₅₀ = 0.9–1.4 μM) and antiradical activity (IC₅₀ = 0.05–0.7 μM). Additionally, the solid-state structure of 4d was determined and compared to that of the similar compound N-propionyl-1,2-benzisoselenazol-3(2H)-one.

中文翻译：

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依布硒啉类似物具有双重人中性粒细胞弹性蛋白酶 (HNE) 抑制和抗自由基活性

人中性粒细胞弹性蛋白酶（HNE）在宿主防御细菌方面发挥着重要作用，但也与多种呼吸道疾病有关。最近的报告表明，表现出 HNE 抑制活性与抗自由基特性相结合的化合物可能对治疗涉及炎症和氧化应激的呼吸系统疾病有益。我们在此报告了具有 HNE 抑制和抗自由基活性的新型依布硒啉类似物的合成和生物学评价。使用人 HNE 在酶系统中评估 HNE 抑制作用，而使用佛波醇 12-肉豆蔻酸酯 13-乙酸酯 (PMA) 刺激的小鼠骨髓白细胞作为活性氧 (ROS) 来源，在基于细胞的测定系统中评估抗自由基活性）。HNE 抑制是由于 N-CO 基团靶向支架 2 位的 Ser195-OH，而抗自由基活性是由于硒原子的存在。最活跃的化合物4d、4f和4j在抗 HNE (IC ₅₀ = 0.9–1.4 μM) 和抗自由基活性 (IC ₅₀ = 0.05–0.7 μM) 之间表现出良好的平衡。此外，还确定了4d的固态结构，并与类似化合物N-丙酰基-1,2-苯并异硒唑-3(2 H )-酮的固态结构进行了比较。