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

European journal of medicinal chemistry (2010-04-27)
Pei-Wen Hsieh, Huang-Ping Yu, Yi-Ju Chang, Tsong-Long Hwang
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Phenylmethanesulfonyl fluoride solution, ~0.1 M in ethanol (T)
Sigma-Aldrich
Phenylmethanesulfonyl fluoride, ≥98.5% (GC)