Synthesis and Evaluation of Benzophenone Oximes Derivatized with Sydnone as Inhibitors of Secretory Phospholipase A_2 with Anti-inflammatory Activity

概要

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A series of benzophenone oximes appended with sydnone (3a-h) bearing different substituents on aroyl moiety were synthesized to evaluate in vivo and in vitro for their inhibitory activity against purified phospholipase A_2 (PLA_2) enzymes from snake venom and human inflammatory pleural and ascites fluid. In vivo and in vitro inhibition studies were carried out against PLA_2 with respect to the modification of the pharmacophore (substituent) to analyze the specificity for PLA_2. The substituent at the aroyl ring was responsible for enhancing the inhibition towards PLA_2 enzymes. Most of the newly synthesized compounds inhibit the purified PLA_2 enzyme, and the inhibition was more in hydrophobic and aromatic substituents and less when no such substituents were present. The inhibitory effect of the compounds appeared to be due to the direct interaction of compounds with the enzyme. Inhibition is substrate dependent, and the inhibition competes with the substrate for the same binding site of the enzyme. The most active interacting compound 3h from in vitro inhibition of PLA_2 activity showed similar potency in the in vivo neutralization of PLA_2 induced mouse paw edema and hemolytic activity. Thus, the in vitro inhibition correlated well with the in vivo inhibition and hence the reported derivatives are therapeutically important anti-inflammatory drugs.
2009-01-01