Design and pharmacological assessment of naproxen-ibuprofen linked NSAIDs as selective COX-2 modulators in...

NSAIDs inhibit COX enzymes non-selectively, prolonged consumption of these medications frequently results in gastrointestinal (GI) damage. Although selective COX-2 inhibitors may reduce gastrointestinal issues, their therapeutic value is restricted by their cardiovascular hazards. Natural phenolic acids like ferulic and syringic acid possess anti-inflammatory and gastroprotective effects. This study explores hybrid molecules combining NSAIDs with phenolic acids to overcome these challenges.

To design, synthesize, and evaluate Naproxen and Ibuprofen acid-linked NSAID derivatives as selective COX-2 inhibitors.

Hybrid molecules were synthesized through esterification and hydrazide coupling reactions. Structural validation was followed by in-silico molecular docking and MD simulations using Schrodinger Suite and GROMACS. In-vitro COX-1/COX-2 inhibitory activities were assessed via TMPD oxidation assay. In vivo tests included rat paw oedema caused by carrageenan (anti-inflammatory), writhing caused by acetic acid (analgesic), and gastric ulcers caused by pylorus ligation (ulcerogenic).

Molecular docking showed strong binding affinity of select hybrids to COX-2 active sites, with favorable RMSD and RMSF profiles. Compounds, particularly ibuprofen-syringic and ibuprofen-ferulic acid hybrids, demonstrated Significant COX-2 selectivity, Reduced paw edema and writhing counts, and Marked decrease in ulcer index, improved pH, and reduced gastric acidity compared to control and standard NSAIDs.

NSAID-phenolic acid hybrids, especially those based on ibuprofen conjugated with syringic or ferulic acid, emerge as promising dual-action candidates combining potent anti-inflammatory and analgesic benefits with enhanced gastric safety. These findings support further development of such hybrids as next-generation COX-2 selective therapeutics.