Design, Synthesis and Preliminary Pharmacological Evaluation of Mutual Prodrug of Non-Steroidal Anti-Inflammatory Drugs Coupling With Natural Anti-Oxidants Via Glycine


Abstract:Non-steroidal anti-inflammatory drugs (NSAIDs); naproxen and indomethacin havebeen conjugated with different antioxidants (thymol, menthol & guaiacol) havingantiulcerogenic activity via glycine amino acid as spacer with the objective of obtainingNSAIDs-glycine- antioxidant prodrugs as gastrosparing NSAIDs devoid of ulcerogenic sideeffects and synergistically with anti-inflammatory action of glycine. Four mutual prodrugs (IIV)were synthesized using glycine as spacer and their structures were confirmed andcharacterized using elemental microanalysis (CHNO), IR, and some physiochemicalproperties.Invivo acute anti-inflammatory activity of the compounds (I & II) (naproxenderivatives) and the compounds (III & IV) (indomethacin derivatives) was evaluated in ratusing an egg-white induced edema model of inflammation in a dose equivalent to 2.5 mg/Kgof naproxen, and 2 mg/Kg of indomethacin respectively.All tested compounds produced significant reduction of paw edema with respect tothe effect of propylene glycol 50% v/v (control group). Moreover, the activity of compoundIII was significantly higher than that of indomethacin (at 2 mg/Kg), while compound IVexpressed a comparable effect to that of indomethacin in the (120–300) minute time of theexperiment, while compounds I&II was showed a comparable effect to that of naproxen at(180-300) minute time interval of the experiment. The result of this study indicates that thesemutual prodrugs of naproxen & indomethacin maintained or may enhanced their antiinflammatoryactivity.