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

  • Eur J Med Chem. 2010 Jul;45(7):3111-5. doi: 10.1016/j.ejmech.2010.03.046.
Pei-Wen Hsieh  1 ,  Huang-Ping Yu ,  Yi-Ju Chang ,  Tsong-Long Hwang
Affiliations
  • 1. Graduate Institute of Natural Products, Chang Gung University, Tao-Yuan 333, Taiwan. [email protected]
PMID: 20417587 DOI: 10.1016/j.ejmech.2010.03.046
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.

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