Synthesis and pharmacological evaluation of novel derivatives of anti-inflammatory drugs with increased antioxidant and anti-inflammatory activities

The role of reactive oxygen species in inflammatory processes has been well documented, while several antioxidan compounds have been shown to exhibit anti-inflammatory activity. We designed novel compounds as potential agents that combine enhanced antioxidant and anti-inflammatory activities. Deriva tives of indomethacin, diclofenac, tolfenamic acid, and ibuprofen, four wid ely used nonsteroidal anti-inflammatory drugs, with cysteamine, a polar ant ioxidant molecule, were synthesized. The compounds were evaluated for their effect on free radical processes (protection against rat hepatic microsoma l lipid-peroxidation and interaction with the stable free radical 1,1-diphe nyl-2-picrylhydrazyl), as well as on carrageenan-induced inflammation (mous e paw edema inhibition). Furthermore, ulcerogenicity tests in rats were per formed in order to evaluate the gastrointestinal irritation of the novel in domentacin derivative. It was found that all compounds were very potent ant ioxidants in vitro; they could inhibit lipid peroxidation very significantl y, having IC50 values ranging from 55 to 510 mu M, while they could also in teract similar to 90% with DPPH at equimolar concentrations. We attribute t hese activities to their sulfhydryl group, as well as to their increased li pophilicity compared to cysteamine. Furthermore, the derivatives demonstrat ed significant antiinflammatory activity, comparable to that of the parent molecules, while they showed significantly reduced ulcerogenic potency. Our results indicate that the combined pharmacological properties of these new derivatives may prove useful for the design and development of novel cytop rotective/anti-inflammatory molecules with potentially important therapeuti c applications. (C) 1999 Wiley-Liss, Inc.