Design, synthesis, biological evaluation, and comparative Cox1 and Cox2 docking of p-substituted benzylidenamino phenyl esters of ibuprofenic and mefenamic acids

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently associated with gastric mucosal and renal adverse reactions, related to inhibition of cyclooxygenase1 (Cox1) in tissues where prostaglandins exert physiological effects. This led us to develop a set of ibuprofenic acid and mefenamic acid esters, namely: 4-((4-substituted benzylidene)amino)phenyl 2-(4-isobutylphenyl)propanoate and 4-((4-substituted benzylidene)amino)phenyl 2-((2,4-dimethylphenyl)amino)benzoate analogs, which were synthesized by condensation of the corresponding acids with Schiff’s bases [4-(4-substituted benzylideneamino)phenols] involving dicyclohexyl carbodiimmide (DCC) as mild dehydrating agent. The main objective is to reduce the GIT toxicity associated with acute and chronic NSAIDs use. Anti-inflammatory, analgesic as well as ulcerogenic activities of the prepared esters were evaluated in vivo and compared with that of ibuprofen as reference standard in all screenings, involving the carrageenan induced paw oedema model and hot plate method. Most of the synthesized esters showed remarkable analgesic and anti-inflammatory activities. Interestingly, all of the compounds were found to be non-ulcerogenic under the tested conditions. This evidence have suggested that modification of the carboxyl function of representative NSAIDs results in retained or enhanced anti-inflammatory and analgesic activities with reduced ulcerogenic potential. Additionally, a comparative AutoDock study into Cox 1 and Cox2 has been done involving both of rigid and flexible docking for potential selectivity of our compounds within different Cox enzymes and to find out the binding orientation of these novel esters into their binding site. Some of the newly prepared aforementioned compounds showed considerable more Cox2 over Cox1 binding affinities by flexible docking better than rigid one.

The ibuprofenic acid and mefenamic acid esters coupled with [4-(4-substituted benzylidene amino)phenols] Schiff’s bases revealed remarkable analgesic anti-inflammatory activities with surprising non-ulcerogenic effects. A correleation between their biological activities and AutoDock binding free energies was obtained by comparative docking into Cox1 and Cox2.Figure optionsDownload as PowerPoint slide