Synthesis and evaluation of benzoxazinone derivatives on activity of human neutrophil elastase and on hemorrhagic shock-induced lung injury in rats

A new series of benzoxazinone analogs were designed, synthesized, and assayed to determine their effects on superoxide anion generation and neutrophil elastase (NE) release in formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-activated human neutrophils. Of these, compounds 6–10 showed a potent dual inhibitory effect on NE release and superoxide anion generation. In contrast, compounds 11–15 exhibited highly selective and potent inhibitory activities on NE release. These results indicate that the inhibitory activity on NE release in FMLP-activated human neutrophils depended on the position of chloro-substituent in the A ring. On the other hand, 13 significantly attenuated the increase in myeloperoxidase (MPO) activity and edema in the lung of rats after trauma-hemorrhagic shock. Therefore, these compounds could be developed as new NE inhibitors.

Series new 5-/ or 7-chloro benzoxazinone analogs were synthesized. These compounds showed directly inhibited elastase activity.Figure optionsDownload as PowerPoint slide