{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T21:38:23Z","timestamp":1774993103793,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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\u2013azetidinone 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\u2019s rule and predicted favorable gastrointestinal absorption. Molecular docking revealed high COX-2 binding affinities (\u221211.93 to \u22129.72 kcal\/mol), while MM\/GBSA analysis identified compound N4c (\u0394G = \u221262.27 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\u2013LUMO gap (\u0394E = 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\u2013naproxen hybrids as promising selective COX-2 inhibitors with enhanced pharmacokinetic and electronic properties.<\/jats:p>","DOI":"10.3390\/molecules30224358","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T08:57:41Z","timestamp":1762851461000},"page":"4358","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Design, In Silico, and Experimental Evaluation of Novel Naproxen\u2013Azetidinone Hybrids as Selective COX-2 Inhibitors"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2353-6444","authenticated-orcid":false,"given":"Ayad Kareem","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy, Mustansiriyah University, Baghdad 10052, Iraq"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9518-8904","authenticated-orcid":false,"given":"Noor Riyadh","family":"Mahmood","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy, Mustansiriyah University, Baghdad 10052, Iraq"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9992-5653","authenticated-orcid":false,"given":"Mohammed Abdulaali","family":"Sahib","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy, University of Kerbala, Karbala 56001, Iraq"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.4103\/jad.jad_129_23","article-title":"Inflammation: Complexity and Significance of Cellular and Molecular Responses","volume":"13","year":"2024","journal-title":"J. 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