Ebselen analogues with dual human neutrophil elastase (HNE) inhibitory and antiradical activity

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 due to the N-CO group, target of Ser195-OH, at position 2 of the scaffold, while antiradical activity to 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 M) and antiradical effects and antiradical activity (IC50 = 0.05-0.7 M). 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.