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A rational design strategy was employed to synthesize compounds that inhibit inflammation\u2010related carbonic anhydrase isoforms (II, IX, and XII) alongside achieving selective inhibition of cyclooxygenase\u20102 (COX\u20102). Remarkably, the sulfonamide derivatives\n                    <jats:bold>6f, 8d,<\/jats:bold>\n                    and\n                    <jats:bold>10e<\/jats:bold>\n                    displayed high activity as carbonic anhydrase inhibitors against isoforms II, IX and XII in addition to their potent and selective COX\u20102 inhibition effect (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200957\u201387\u2009nM; SI\u2009=\u2009175\u2013100). Among them, the multitargeted inhibitor\n                    <jats:bold>10e<\/jats:bold>\n                    (COX\u20102, IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200957\u2009nM; CA II,\n                    <jats:italic>\n                      K\n                      <jats:sub>i<\/jats:sub>\n                    <\/jats:italic>\n                    \u2009=\u200949.9\u2009nM; CA IX,\n                    <jats:italic>\n                      K\n                      <jats:sub>i<\/jats:sub>\n                    <\/jats:italic>\n                    \u2009=\u200967.5\u2009nM; CA XII,\n                    <jats:italic>\n                      K\n                      <jats:sub>i<\/jats:sub>\n                    <\/jats:italic>\n                    \u2009=\u200954.6\u2009nM) was further evaluated in vivo and demonstrated strong dual anti\u2010inflammatory and analgesic properties, with a rapid onset of action within the first hour and sustained efficacy over 5\u2009h. Toxicological studies revealed that compound\n                    <jats:bold>10e<\/jats:bold>\n                    possessed a favorable safety profile, showing no significant adverse effects on liver, kidney, or cardiac functions and minimal ulcerogenic potential. Molecular docking studies further supported these findings by confirming key binding interactions with CA II, IX, XII, and COX\u20102 active sites.\n                  <\/jats:p>","DOI":"10.1002\/ddr.70214","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T10:36:54Z","timestamp":1767004614000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Multitargeted Anti\u2010Inflammatory Agents: Novel Pyrazole and Pyrazolo[1,5\u2010\n                    <i>a<\/i>\n                    ]Pyrimidine Carbonic Anhydrase and COX\u20102 Inhibitors With Optimal In Vivo Efficacy and Low Toxicity"],"prefix":"10.1002","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1855-6918","authenticated-orcid":false,"given":"Mariam M.","family":"Fakhry","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Egyptian Russian University Badr City, Cairo Egypt"},{"name":"Laboratoire de G\u00e9nie Chimique Universit\u00e9 de Toulouse, Toulouse INP, CNRS, LGC Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed A.","family":"Said","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Egyptian Russian University Badr City, Cairo Egypt"},{"name":"Department of pharmaceutical chemistry, College of Pharmacy University of Kut Waist Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ammara","sequence":"additional","affiliation":[{"name":"Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences University of Florence, Polo Scientifico Firenze Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jalloul","family":"Bouajila","sequence":"additional","affiliation":[{"name":"Laboratoire de G\u00e9nie Chimique Universit\u00e9 de Toulouse, Toulouse INP, CNRS, LGC Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences University of Florence, Polo Scientifico Firenze Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hatem A.","family":"Abdel\u2010Aziz","sequence":"additional","affiliation":[{"name":"Department of Applied Organic Chemistry Department National Research Center Dokki Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahar M.","family":"Abou\u2010Seri","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Cairo University, Kasr El\u2010Aini Street Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,29]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2021.104827"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2019.01.031"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.112662"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arabjc.2022.104015"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2017.08.014"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2021.105122"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2019.1697250"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.14202\/vetworld.2018.627-635"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2022.2114079"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00044-011-9895-7"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.2460\/ajvr.2005.66.966"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11515-011-1123-9"},{"key":"e_1_2_9_14_1","first-page":"631","article-title":"The Potential Protective Effect of Vildagliptin on Paw Edema: An Experimental Study","author":"Alkabbani M. 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