Design, synthesis, and evaluation of carboxylic acid-substituted celecoxib isosteres as potential anti-inflammatory agents

Abstract

A library comprising twenty-four isosteric derivatives of celecoxib substituted with carboxylic acid (labeled as 5a-5x), was synthesized and characterized through ¹H NMR, ¹³C NMR, HRMS, and elemental analysis. Molecular docking studies revealed that all compounds successfully docked into the binding pocket of COX-2, and the introduction of carboxyl group enhances the interaction between the derivatives and COX-2. The compounds were further evaluated for cell toxicity, and in vitro anti-inflammatory activity. Notably, compound 5l exhibited significant inhibition of both COX-2 and NO release in vitro in comparison to the standard compound, displaying the highest selectivity towards the COX-2 enzyme (SI = 295.9) in comparison to celecoxib (SI = 261.3). 5l also exhibited the most potent anti-inflammatory activity and safety (ulcer index = 5.2) in vivo comparable to celecoxib at the same concentration. Through the molecular modeling and dynamics analysis, it was observed that compound 5l effectively stabilized within the active binding site of COX-2 through strong hydrogen bond interactions, and through the ADMET studies investigated the physiochemical properties and drug-likeliness behavior of compound 5l. In conclusion, compound 5l demonstrated to be a potential selective COX-2 anti-inflammatory candidate with reduced gastrointestinal risks.