{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T23:31:56Z","timestamp":1789687916686,"version":"4.0.1"},"reference-count":29,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T00:00:00Z","timestamp":1767139200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T00:00:00Z","timestamp":1767139200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemBioChem"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    Nonsteroidal anti\u2010inflammatory drugs are among the most prescribed worldwide to treat pain, fever, and inflammation. However, they can cause severe adverse effects such as gastric, duodenal, hepatic, and renal injuries. Thus, the search for effective and new drugs is of high priority. Herein, the synthesis of a new series 4\u2010((5\u2010substituted\u20103\u2010(trifluoromethyl)\u20101\n                    <jats:italic>H<\/jats:italic>\n                    \u2010pyrazol\u20101\u2010yl)methyl)\u20106\u2010(trifluoromethyl) pyrimidin\u20102\u2010substituted (pyrazole\u2013pyrimidines) obtained through the cyclocondensation reaction of pyrazole\u2013enaminones with amidines under mild conditions is reported. The chemical structures are confirmed by\n                    <jats:sup>1<\/jats:sup>\n                    H and\n                    <jats:sup>13<\/jats:sup>\n                    C NMR, mass spectrometry, and single\u2010crystal X\u2010ray analysis for compounds\n                    <jats:bold>4c<\/jats:bold>\n                    and\n                    <jats:bold>4g<\/jats:bold>\n                    . Molecular docking studies are conducted to identify selective cyclooxygenase\u20102 (COX\u20102) inhibitors, revealing that compounds\n                    <jats:bold>4d<\/jats:bold>\n                    ,\n                    <jats:bold>4j<\/jats:bold>\n                    , and\n                    <jats:bold>4k<\/jats:bold>\n                    display higher binding affinity. ADMET predictions (absorption, distribution, metabolism, excretion, and toxicity) corroborate to the docking results, suggesting favorable pharmacokinetic and toxicological properties. The in\u2009vivo antinociceptive activity is investigated in mice using the capsaicin\u2010induced nociception model. Oral administration of compounds\n                    <jats:bold>4d<\/jats:bold>\n                    ,\n                    <jats:bold>4e<\/jats:bold>\n                    ,\n                    <jats:bold>4f<\/jats:bold>\n                    ,\n                    <jats:bold>4j<\/jats:bold>\n                    , and\n                    <jats:bold>4k<\/jats:bold>\n                    significantly reduces nociceptive responses, achieving effects comparable or superior to celecoxib, without altering locomotor activity. Altogether, the findings demonstrate that pyrazole\u2013pyrimidine derivatives, especially\n                    <jats:bold>4d<\/jats:bold>\n                    and\n                    <jats:bold>4k<\/jats:bold>\n                    , are promising candidates for the development of selective COX\u20102 analgesics, combining antinociceptive efficacy with a favorable toxicological profile.\n                  <\/jats:p>","DOI":"10.1002\/cbic.202500688","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T11:31:03Z","timestamp":1767180663000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Design, Synthesis, Molecular Docking, Structure Activity Relationship, and In Vivo Evaluation of Pyrazole\u2013Pyrimidines for Discovering New Nonsteroidal Anti\u2010Inflammatory Drugs"],"prefix":"10.1002","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1430-2766","authenticated-orcid":false,"given":"Paulo A.","family":"Moraes","sequence":"first","affiliation":[{"name":"N\u00facleo de Qu\u00edmica de Heterociclos (NUQUIMHE) Departamento de Qu\u00edmica Universidade Federal de Santa Maria  Santa Maria RS 97105\u2013900 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genilson S.","family":"Pereira","sequence":"additional","affiliation":[{"name":"N\u00facleo de Qu\u00edmica de Heterociclos (NUQUIMHE) Departamento de Qu\u00edmica Universidade Federal de Santa Maria  Santa Maria RS 97105\u2013900 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9656-2099","authenticated-orcid":false,"given":"M\u00e1rio A.","family":"Marangoni","sequence":"additional","affiliation":[{"name":"N\u00facleo de Qu\u00edmica de Heterociclos (NUQUIMHE) Departamento de Qu\u00edmica Universidade Federal de Santa Maria  Santa Maria RS 97105\u2013900 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o Pedro V.","family":"Lopes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Neurobiologia da Dor Centro de Ci\u00eancias Naturais e Exatas Universidade Federal de Santa Maria  Santa Maria RS 97105\u2013900 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Favarin","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Neurobiologia da Dor Centro de Ci\u00eancias Naturais e Exatas Universidade Federal de Santa Maria  Santa Maria RS 97105\u2013900 Brazil"},{"name":"Programa de P\u00f3s\u2010Gradua\u00e7\u00e3o em Ci\u00eancias Biol\u00f3gicas: Bioqu\u00edmica Toxicol\u00f3gica Universidade Federal de Santa Maria  Santa Maria RS 97105\u2013900 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriano F.","family":"Camargo","sequence":"additional","affiliation":[{"name":"N\u00facleo de Qu\u00edmica de Heterociclos (NUQUIMHE) Departamento de Qu\u00edmica Universidade Federal de Santa Maria  Santa Maria RS 97105\u2013900 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9133-6102","authenticated-orcid":false,"given":"Pablo A.","family":"Nogara","sequence":"additional","affiliation":[{"name":"Ci\u00eancia e Tecnologia Sul\u2010rio\u2010grandense (IFSul) Instituto Federal de Educa\u00e7\u00e3o  Avenue Leonel de Moura Brizola, 2501 Bag\u00e9 RS 96418\u2013400 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2745-2061","authenticated-orcid":false,"given":"Helio G.","family":"Bonacorso","sequence":"additional","affiliation":[{"name":"N\u00facleo de Qu\u00edmica de Heterociclos (NUQUIMHE) Departamento de Qu\u00edmica Universidade Federal de Santa Maria  Santa Maria RS 97105\u2013900 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2379-220X","authenticated-orcid":false,"given":"Marcos A. 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