{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T23:33:20Z","timestamp":1792020800929,"version":"4.4.0"},"reference-count":52,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":89,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["BioMed Research International"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    This work reports the design, synthesis, and multilevel evaluation of 20 new S\u2010alkyl derivatives of 6\u2010(5\u2010mercapto\u20104\u2010ethyl\u20104H\u20101,2,4\u2010triazol\u20103\u2010yl)pyrimidine\u20102,4(1H,3H)\u2010dione as potential selective cyclooxygenase\u20102 (COX\u20102) inhibitors with antioxidant properties. The aim was to establish structure\u2013property relationships between the S\u2010alkyl fragment, antioxidant mechanisms, and COX\u20102 inhibition and to identify lead structures for further optimization. Compounds were obtained by stepwise construction of the 1,2,4\u2010triazole fragment from orotic acid, followed by selective S\u2010alkylation of the mercaptotriazole, and their structures were confirmed by\n                    <jats:sup>1<\/jats:sup>\n                    H\/\n                    <jats:sup>13<\/jats:sup>\n                    C NMR, LC\u2010MS, and elemental analysis. Antiradical activity in vitro was assessed by the DPPH assay with determination of percent inhibition and IC\n                    <jats:sub>50<\/jats:sub>\n                    , whereas COX\u20101\/COX\u20102 inhibition was evaluated using a fluorescent enzyme assay to obtain IC\n                    <jats:sub>50<\/jats:sub>\n                    and selectivity index (SI). Density functional theory (DFT) calculations were employed to compare the thermodynamic feasibility of HAT, SET\u2013PT, and SPLET pathways, while molecular docking and molecular dynamics were used to study the affinity and stability of binding to COX\u20101 and COX\u20102. A clear increase in antiradical activity was observed in the series\n                    <jats:bold>17<\/jats:bold>\n                    \u2009&lt;\u2009ascorbic acid\u2009&lt;\u2009\n                    <jats:bold>14<\/jats:bold>\n                    \u2009&lt;\u2009\n                    <jats:bold>20<\/jats:bold>\n                    \u2009&lt;\u2009\n                    <jats:bold>13<\/jats:bold>\n                    \u2009&lt;\u2009\n                    <jats:bold>19<\/jats:bold>\n                    , reaching 72.34% DPPH inhibition for Compound\n                    <jats:bold>19<\/jats:bold>\n                    with IC\n                    <jats:sub>50<\/jats:sub>\n                    (DPPH) = 12.15 \u00b1 3.98\u2009\n                    <jats:italic>\u03bc<\/jats:italic>\n                    M, considerably surpassing ascorbic acid. Compound\n                    <jats:bold>19<\/jats:bold>\n                    also exhibited the lowest IC\n                    <jats:sub>50<\/jats:sub>\n                    (COX \u2212 2) = 24.5 \u00b1 0.9\u2009\n                    <jats:italic>\u03bc<\/jats:italic>\n                    M with SI \u2248 8.2; Compounds\n                    <jats:bold>13<\/jats:bold>\n                    and\n                    <jats:bold>20<\/jats:bold>\n                    showed moderate COX\u20102 selectivity (SI \u2248 1.2\u20131.3), whereas\n                    <jats:bold>14<\/jats:bold>\n                    and\n                    <jats:bold>17<\/jats:bold>\n                    had a COX\u20101\u2010shifted profile reminiscent of classical NSAIDs. DFT analysis indicated predominance of the SPLET mechanism for most systems, with the lowest\n                    <jats:italic>\u0394<\/jats:italic>\n                    <jats:italic>G<\/jats:italic>\n                    values for\n                    <jats:bold>19<\/jats:bold>\n                    and\n                    <jats:bold>20<\/jats:bold>\n                    , consistent with their high antioxidant activity. The combined experimental and in silico data identify Compound\n                    <jats:bold>19<\/jats:bold>\n                    as a primary lead candidate that combines potent antioxidant effects with pronounced, selective COX\u20102 inhibition and highlight\n                    <jats:bold>13<\/jats:bold>\n                    and\n                    <jats:bold>20<\/jats:bold>\n                    as promising backup structures for further preclinical studies.\n                  <\/jats:p>","DOI":"10.1155\/bmri\/4477854","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T14:46:02Z","timestamp":1774968362000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Novel 1,2,4\u2010Triazole\u2013Thiopyrimidine Hybrids as COX\u20102 Inhibitors: Synthesis, ADME Profiling, Antioxidant Activity, and Molecular 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