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 p athologic conditions including inflammation and gastric ulceration. The lat ter is the major undesired side-effect of almost all NSAIDs. Since this eff ect 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 consid ered it interesting to modify their structure in such a way that it would l ead 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, wi th demonstrated good anti-inflammatory and antioxidant activities, showed v ery significant reduction of ulcerogenicity in the investigation of gastroi ntestinal (GI) toxicity. As indices of ulcerogenic toxicity in rats, we use d the mortality (%), the incidence of GI ulcers (%), body weight reduction (g/100 g BW) and the incidence of melena. All amide derivatives of the NSAI Ds with cysteamine were almost non-toxic in the GI tract. under our experim ental conditions, in contrast to their parent NSAIDs. These results are att ributed 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 c haracter, may lead to the development of novel, useful anti-inflammatory an d cytoprotective pharmacomolecules. with potentially important therapeutic applications. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.