Reduction of gastrointestinal toxicity of NSAIDs via molecular modifications leading to antioxidant anti-inflammatory drugs

Reactive oxygen species and free radical reactions are related to several pathologic conditions including inflammation and gastric ulceration. The latter is the major undesired side-effect of almost all NSAIDs. Since this effect of NSAIDs is greatly influenced not only by the type of cyclooxygenase which is inhibited but also by the acidic nature of the molecule, we considered it interesting to modify their structure in such a way that it would lead to an antioxidant, neutral molecule or a molecule with greatly reduced acidic character. Thus, we synthesized amide derivatives of four well-known NSAIDs. i.e. diclofenac acid, tolfenamic acid, ibuprofen and indomethacin, with cysteamine, a well-known antioxidant. The synthesized derivatives, with demonstrated good anti-inflammatory and antioxidant activities, showed very significant reduction of ulcerogenicity in the investigation of gastrointestinal (GI) toxicity. As indices of ulcerogenic toxicity in rats, we used the mortality (%), the incidence of GI ulcers (%), body weight reduction (g/100 g BW) and the incidence of melena. All amide derivatives of the NSAIDs with cysteamine were almost non-toxic in the GI tract. under our experimental conditions, in contrast to their parent NSAIDs. These results are attributed to the acquired antioxidant activity as well as to the reduction of acidic character compared with the parent compounds. Therefore, it call be concluded that the combination of these two properties, anti-inflammatory and antioxidant activity, with a simultaneous drastic reduction of acidic character, may lead to the development of novel, useful anti-inflammatory and cytoprotective pharmacomolecules. with potentially important therapeutic applications. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.