Modification of diclofenac with some substitutes to increase anti-inflammatory activity and to be more selective to COX-2

Bilal J. Mohammed, Hadil J. Maayouf


In the present study, we prepared four amide derived from anti- inflammatory drug diclofenac sodium (2-[(2,6dichlorophenyl)amino] benzeneacetic acid, monosodium salt). Amides synthesized by two steps: first step preparation anhydride from sodium diclofenac by reacting two molecules of  diclofenac acid in the presence of one equivalent of dicyclohexyl carbodiimide (DCC)  and then transferred it to different amides by reacting with different amines (sulphanilamide, O-nitroaniline, 2,4 dinitroaniline, P-bromoaniline) as well as the identification and characterization of  products by     FT-IR, 1HNMR and13C NMR spectroscopy, and  C.H.N  elements data. The efficacy evaluation was assessed as analgesics using hot plate test and to test its effectiveness as inhibitors of COX enzyme and their selectivity within the body of the organism In vivo. Acute anti-inflammatory activity of the synthesized final compounds was evaluated in mice using egg-white induced edema model of inflammation in a dose equivalent to (1.5mg/Kg,3mg/kg,6mg/kg) of diclofenac. The results indicate that the compounds are effective inhibitors of cyclooxygenase, because the pain caused by the effectiveness of cyclooxygenase and the most effectiveness compound was [2-(2-(2,6-dichlorophenylamino) phenyl)-N-(4-sulfamoylphenyl)acetamide] which produced from reaction between Diclofenac  and sulphanilamide. An inflammation was introduced in the rats using carrageenan and measured PGE2 level in plasma blood. and showed a significant reduction in the level of prostaglandin. The results of this experiment showed that some prepared compounds has higher activity of inhibition than the parent medication, and give a good picture of selectivity of inhibition of COX -2 by comparing with celecoxib. Through a molecular docking studies of prepared compounds with the active site of the enzyme COX-1 and COX-2 , it was found that the compounds have affinity for the enzyme COX-2 more than their affinity to COX-1 which support selectivity As a result of this study, it was shown that converting the carboxyl group of diclofenac, which is well known as an anti-inflammatory agent to an amide group, preserves or increases inflammation activity and analgesic activity by inhibiting cyclooxygenase enzymes and compounds showing more ratio of selectivity against COX-2.


Keywords: diclofenac, cyclooxygenase, anti-inflammatory, carrageenan, analgesic, prostaglandin.

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