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The methodology involved substituting the conventional acidic pharmacophore in NSAIDs with a neutral aldehyde to enhance gastrointestinal safety. The derivatives were synthesized with high yields (90%\u201399%) through an optimized Suzuki\u2013Miyaura cross\u2010coupling procedure. In silico ADMET analysis demonstrated excellent drug\u2010like characteristics and oral bioavailability throughout the series. Docking studies revealed strong binding affinities to COX\u20102, particularly for compound\n                    <jats:bold>1<\/jats:bold>\n                    <jats:bold>g<\/jats:bold>\n                    (MolDock score: \u2212136.79\u00a0kcal\/mol), with critical interactions at Tyr385 and Trp387 residues. To assess metabolic stability, the acidic metabolites (\n                    <jats:bold>2a\u2013l<\/jats:bold>\n                    ) were modeled, maintaining or improving enzymatic affinity. Molecular dynamics simulations (100\u00a0ns) confirmed the structural stability of these complexes. In vivo evaluation utilizing the carrageenan\u2010induced rat paw edema model supported the computational findings, with lead compound\n                    <jats:bold>1<\/jats:bold>\n                    <jats:bold>g<\/jats:bold>\n                    achieving complete edema reduction at 4 h, surpassing diclofenac. These results suggest that biarylcarbaldehyde frameworks serve as promising nonacidic alternatives for anti\u2010inflammatory therapy with an improved safety profile.\n                  <\/jats:p>","DOI":"10.1002\/cbdv.202502322","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T06:13:09Z","timestamp":1781849589000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Non\u2010acidic Biarylcarbaldehydes as Potent COX\u20102 Inhibitors: Design, Microwave Synthesis, and Multidisciplinary Validation With Improved Gastrointestinal Safety"],"prefix":"10.1002","volume":"23","author":[{"given":"Katia","family":"Mohand Saidi","sequence":"first","affiliation":[{"name":"Department of Chemistry Faculty of Exact Sciences and Informatics University of Mohamed Seddik Ben Yahia \u2010 Jijel  Jijel Algeria"},{"name":"Laboratory of Phytochemistry and Pharmacology Pharmaceutical Chemistry team University of Mohamed Seddik Ben Yahia \u2010 Jijel  Jijel Algeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bassam","family":"A. Najri","sequence":"additional","affiliation":[{"name":"Department of Chemistry Faculty of Sciences Eskisehir Osmangazi University  Eskisehir Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Zakaria","family":"Stiti","sequence":"additional","affiliation":[{"name":"Department of Chemistry Faculty of Exact Sciences and Informatics University of Mohamed Seddik Ben Yahia \u2010 Jijel  Jijel Algeria"},{"name":"Laboratory of Phytochemistry and Pharmacology Pharmaceutical Chemistry team University of Mohamed Seddik Ben Yahia \u2010 Jijel  Jijel Algeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelmadjid","family":"Guendouzi","sequence":"additional","affiliation":[{"name":"Higher Normal School (ENS)  Constantine Algeria"},{"name":"Pharmaceutical Sciences Research Center (CRSP)  Constantine Algeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamel","family":"Harrouche","sequence":"additional","affiliation":[{"name":"Department of Chemistry Faculty of Exact Sciences and Informatics University of Mohamed Seddik Ben Yahia \u2010 Jijel  Jijel Algeria"},{"name":"Laboratory of Phytochemistry and Pharmacology Pharmaceutical Chemistry team University of Mohamed Seddik Ben Yahia \u2010 Jijel  Jijel Algeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arif","family":"Kivrak","sequence":"additional","affiliation":[{"name":"Department of Chemistry Faculty of Sciences Eskisehir Osmangazi University  Eskisehir Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7343-0242","authenticated-orcid":false,"given":"Smail","family":"Khelili","sequence":"additional","affiliation":[{"name":"Department of Chemistry Faculty of Exact Sciences and Informatics University of Mohamed Seddik Ben Yahia \u2010 Jijel  Jijel Algeria"},{"name":"Laboratory of Phytochemistry and Pharmacology Pharmaceutical Chemistry team University of Mohamed Seddik Ben Yahia \u2010 Jijel  Jijel Algeria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"e_1_2_10_2_1","first-page":"197","volume-title":"Pathophysiology: Biological and Behavioral Perspectives"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07201"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1276"},{"key":"e_1_2_10_5_1","volume-title":"Studies of Cyclooxygenase\u20101 (COX\u20101) and Cyclooxygenase\u20102 (COX\u20102) Inhibitors With Analgesic, Anti\u2010inflammatory and Anti\u2010platelet Activities","author":"Rasheed H.","year":"2003"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.102.041244"},{"key":"e_1_2_10_7_1","first-page":"323","article-title":"Inhibition of Prostaglandin Synthesis as a Mechanism of Action for Aspirin\u2010Like Drugs","volume":"231","author":"Van J.","year":"1971","journal-title":"Nature New Biology"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2006.08.032"},{"key":"e_1_2_10_9_1","volume-title":"Foye's Principles of Medicinal Chemistry","author":"Foye W. 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