Synthesis and anti-inflammatory effect of chalcones

The process of degranulation of mast cells and neutrophils contributes to i nflammatory disorders. Activation of microglial cells and macrophages is be lieved to be involved in inflammatory, infectious and degenerative diseases of the CNS. Combining the potent inhibition of chemical mediators released by the degranulation of mast cells or neutrophils and from the activated m icroglial cells or macrophages, would lead to a promising antiinflammatory agent for the treatment of peripheral and central inflammation. A series of chalcone derivatives have been reported to have potent anti-inflammatory a ctivity. In an effort to continually develop potent anti-inflammatory agent s, novel series of chalcones, 2'-hydroxy- and 2',5'-dihydroxychalcones were synthesized and their inhibitory effects on the activation of mast cells, neutrophils, microglial cells and macrophages were evaluated in-vitro. The chalcones were prepared by Claisen-Schmidt condensation of appropriate acet ophenones with an appropriate aromatic aldehyde. The alkoxychalcones were p repared with appropriate hydroxychalcones and alkyl iodide and the dihydrox ychalcones were prepared by hydrogenation of an appropriate chalcone with P d/C. Almost all of the hydroxychalcones exhibited potent inhibitory effects on t he release of beta-glucuronidase and lysozyme from rat neutrophils stimulat ed with formyl-Met-Leu-Phe/cytochalasin B (fMLP/CB). Of the hydroxychalcone s, compound 1 was the most potent inhibitor of the release of beta-glucuron idase (IC50=1.6 +/- 0.2 mu M) and lysozyme (IC50=1.4 +/- 0.2 mu M) from rat neutrophils stimulated with fMLP/CB. Almost all of the 2',5'-dialkoxychalc ones exhibited potent inhibitory effects on nitric oxide (NO) formation fro m murine microglial cell lines N9 stimulated with lipopolysaccharide (LPS). Of these, compound 11 showed the greatest effect (IC50=0.7 +/- 0.06 mu M). The present results demonstrated that most of the chalcone derivatives have an antiinflammatory effect. The inhibitory effects of dialkoxychalcones, 1 0-12 on inflammation are probably not due to the inhibition of mast cells a nd neutrophil degranulation, but are mediated through the suppression of NO formation from N9 cells.