Design, In Silico, and Experimental Evaluation of Novel Naproxen–Azetidinone Hybrids as Selective COX-2 Inhibitors

The therapeutic use of non-steroidal anti-inflammatory drugs (NSAIDs) is limited by gastrointestinal and renal adverse effects caused by non-selective COX-1 and COX-2 inhibition. To address this issue, a new series of naproxen-azetidinone hybrids was rationally designed and synthesized to enhance COX-2 selectivity and reduce off-target toxicity. The synthesis involved esterification, hydrazide formation, Schiff base condensation, and intramolecular cyclization with chloroacetyl chloride. Structural characterization was achieved through FT-IR, ¹H NMR, and ¹³C NMR analyses. In silico ADMET profiling confirmed compliance with Lipinski's rule and predicted favorable gastrointestinal absorption. Molecular docking revealed high COX-2 binding affinities (-11.93 to -9.72 kcal/mol), while MM/GBSA analysis identified compound <b>N4_c</b> (ΔG = -62.27 kcal/mol) as the most stable complex, surpassing meloxicam and naproxen. DFT (B3LYP/6-31G(d,p)) frontier molecular orbital analysis indicated a narrow HOMO-LUMO gap (ΔE = 2.97 eV) for <b>N4_c</b>, suggesting high electronic reactivity and strong enzyme interaction. Molecular dynamics simulations confirmed complex stability. In vivo anti-inflammatory testing using an egg-white-induced rat paw edema model showed that <b>N4_d</b>, <b>N4_e</b>, and <b>N4_f</b> achieved higher inhibition (19.22%, 16.98%, and 16.98%) than naproxen (4.3%). These results highlight 2-azetidinone-naproxen hybrids as promising selective COX-2 inhibitors with enhanced pharmacokinetic and electronic properties.