Design, In Silico, and Experimental Evaluation of Novel Naproxen–Azetidinone Hybrids as Selective COX-2 Inhibitors
Year: 2025
Type: article
Abstract: 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 N4c (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 N4c, 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 N4d, N4e, and N4f 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.
Source: Molecules
Institutions: Mustansiriyah University, University of Kerbala
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,258
OpenAlex ID: W4416101555