{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T08:06:16Z","timestamp":1789027576140,"version":"build-2803163510"},"reference-count":86,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Cyclooxygenase (COX) plays a crucial role in the inflammatory response, making selective COX\u20102 inhibition a significant strategy for developing safer anti\u2010inflammatory medications. Accordingly, developing new pharmacotherapies is a critical objective in anti\u2010inflammatory drug discovery. In this study, a new pyrazole\u2010linked pyridine derivatives\n                    <jats:bold>2\u20107<\/jats:bold>\n                    were synthesized through the reaction of the 4\u2010(pyridin\u20101\u2010yl)benzohydrazide derivative\n                    <jats:bold>1<\/jats:bold>\n                    with substituted\u2010ketenes, activated olefinic dimers, and\n                    <jats:italic>\u03b1,\u03b2<\/jats:italic>\n                    \u2010unsaturated carbonyl compounds. The synthesized derivatives were characterized and subsequently assessed in vitro for their inhibitory effects on COX\u20102. The results of the COX\u20102 inhibition assay revealed a broad range of activity, with IC\n                    <jats:sub>50<\/jats:sub>\n                    values ranging from 0.70\u2009\u00b1\u20090.02 to 63.49\u2009\u00b1\u20092.32\u2009\u00b5M. Among the derivatives,\n                    <jats:bold>3<\/jats:bold>\n                    and\n                    <jats:bold>7b<\/jats:bold>\n                    demonstrated the most significant inhibitory effects, with IC\n                    <jats:sub>50<\/jats:sub>\n                    values of 1.11\u2009\u00b1\u20090.04 and 0.70\u2009\u00b1\u20090.02\u2009\u00b5M, respectively, compared to celecoxib (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.87\u2009\u00b1\u20090.03\u2009\u00b5M). Furthermore, these promising derivatives exhibited COX\u20101 inhibitory activity, with IC\n                    <jats:sub>50<\/jats:sub>\n                    values of 16.08\u2009\u00b1\u20090.54\u2009\u00b5M (SI\n                    <jats:sub>cox\u20102<\/jats:sub>\n                    \u2009=\u200914.48) and 2.77\u2009\u00b1\u20090.09\u2009\u00b5M (SI\n                    <jats:sub>cox\u20102<\/jats:sub>\n                    \u2009=\u20093.95), respectively, compared to indomethacin (0.199\u2009\u00b1\u20090.01\u2009\u00b5M) and celecoxib (21.62\u2009\u00b1\u20090.73\u2009\u00b5M). Given the extensive COX activity of\n                    <jats:bold>7b<\/jats:bold>\n                    , further investigations were conducted, as it demonstrated immunomodulatory potential through the suppression of IL\u20106 (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u2009167.65\u2009\u00b1\u20096.65\u2009pg\/mL) and TNF\u2010\u03b1 (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u2009816.59\u2009\u00b1\u200928.01\u2009pg\/mL) compared to celecoxib's IC\n                    <jats:sub>50<\/jats:sub>\n                    (129.50\u2009\u00b1\u20094.44\u2009pg\/mL) and (399.7\u2009\u00b1\u200913.7\u2009pg\/mL), respectively. Additionally, pyrazole\u2010linked pyridine derivative\n                    <jats:bold>7b<\/jats:bold>\n                    significantly reduced PGE2 levels to 539.49\u2009\u00b1\u200917.87\u2009pg\/mL and NO production to 4.230\u2009\u00b1\u20090.159\u2009nM, compared to celecoxib 256.79\u2009\u00b1\u20098.50\u2009pg\/mL for PGE2 and 3.997\u2009\u00b1\u20090\u2009nM for NO, respectively, suggesting that compound\n                    <jats:bold>7b<\/jats:bold>\n                    can attenuate both cytokine and eicosanoid signaling, exhibit extensive anti\u2010inflammatory activity, and may serve as a potential multi\u2010target therapeutic agent. The molecular docking simulation revealed that compound\n                    <jats:bold>7b<\/jats:bold>\n                    exhibited a significant binding affinity through various interactions. Finally, the DFT calculation indicated that\n                    <jats:bold>7b<\/jats:bold>\n                    has a low energy band gap, which suggests lower hardness and higher softness that implies a greater ability to redistribute electron density during binding, favoring the formation of stable polar interactions with protein residues. Overall, these findings demonstrate that compound\n                    <jats:bold>7b<\/jats:bold>\n                    is a promising multi\u2010target anti\u2010inflammatory lead drug with strong COX\u20102 inhibition and immunomodulatory properties. Moreover, further studies will concentrate on in vivo anti\u2010inflammatory evaluation and pharmacokinetic profiling.\n                  <\/jats:p>","DOI":"10.1002\/ddr.70362","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:49:01Z","timestamp":1786978141000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of New Pyrazole\u2010Linked Pyridine Derivatives as Multi\u2010Target Anti\u2010Inflammatory Agents With Immunomodulatory Potential"],"prefix":"10.1002","volume":"87","author":[{"given":"Mohamed A.","family":"Salem","sequence":"first","affiliation":[{"name":"Health Specialties, Basic Sciences and Their Applications Unit, Applied College, Muhayl Asir, King Khalid University Abha Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reham R.","family":"Raslan","sequence":"additional","affiliation":[{"name":"Department of Chemistry Faculty 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