New Naproxen Analogs: Synthesis, Docking and Anti-Inflammatory Evaluation

Naproxen is a well-known nonsteroidal anti-inflammatory drug belonging to aryl propanoic acid family; it nonselectively inhibits major cyclo-oxygenase (COX) isoforms causing GIT irritation as a side effect. A series of Naproxen analogs with modifiable carboxylic acid functionality (2–14) have been synthesized aiming to retain anti-inflammatory activity with reduced ulcerogenic effect. Docking studies of the new compounds into cyclo-oxygenase-2 complexes with its bound inhibitor SC-558 (1CX2) were performed in order to predict the binding affinities and orientations of these compounds at the active site. Best fit Naproxen analogs, 3, 5b, 9, 10f, 14 to COX-2 active site were screened for their anti-inflammatory activity by carrageenan-induced rat paw edema test method. The target compound, 3 showed higher inhibition rate (74.71%) than the reference standard, Naproxen (71.11%), compound 10f showed comparable inhibition rate (68.94%) to Naproxen, while the other targets 5b, 9, 14 elicited moderate anti-inflammatory activities (47.98–40.27%). All the test compounds were devoid of ulcerogenicity effect compared to Naproxen. Detailed synthesis, spectroscopic, and pharmacological data are disclosed. ICM values of compounds 3 and 10f are –87.69 and –105.57 kcal/mol respectively and the number of hydrogen bonding to COX-2 prove their affinity and showed good agreement with their remarkable pharmacological data.