1, 2, 4-Oxadiazole Incorporated Ketoprofen Analogues in Search of Safer Non-steroidal Anti-inflammatory Agents: Design, Syntheses, Biological Evaluation and Molecular Docking Studies

Background: Improving the gastrointestinal safety profile of Non-Steroidal Anti- Inflammatory Drugs (NSAIDs) is an important goal. An important strategy to develop NSAIDs with minimal Gastrointestinal (GI) toxicity is to target the COX-2 isoform with a selective inhibitor. Methods: In this study we selected ketoprofen as a lead NSAID for development into safer agents. 1, 2, 4-Oxadiazole moiety was employed to mask the free acid group of the ketoprofen to get six different derivatives hypothesized to have minimal GI irritation. In Vivo anti-inflammatory and analgesic activities of these six synthesized derivatives were tested and compared to equivalent dose of the parent drug. Results: Three compounds showed superior anti-inflammatory activity (76.29%, 80.45% &79.06% inhibition) compared to the parent drug (72.71% inhibition), in a carrageenan induced paw edema model (peak at 4h). One compound, 3d also showed moderate analgesic activity (51.14%), in comparison to ketoprofen (63.97%) in an acetic acid induced writhing model. In addition, the tested compounds were found to possess much less degree of ulcerogenic potential (almost half) compared to the parent NSAID, ketoprofen. Their unique selectivity toward the COX-2 enzyme was investigated using molecular modeling techniques. Conclusion: Results of compound 3d which showed highest anti-inflammatory and analgesic activities with much reduced ulcerogenic potential, are highly encouraging and may serve as new COX-2 selective lead and merits further investigation. Keywords: Ketoprofen, 1, 2, 4-oxadiazole, NSAIDs, anti-inflammatory, ulcerogenic, analgesic activities.