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However, the currently available options still have significant side effects due to exacerbated selectivity.\n                    <jats:italic>Bis<\/jats:italic>\n                    \u2010chalcone derivatives have shown promising anti\u2010inflammatory properties with reduced side effects. In this study, a family of polyhydroxylated\n                    <jats:italic>bis<\/jats:italic>\n                    \u2010chalcones was synthesized and tested in vitro for their ability to inhibit human COX\u20102 and COX\u20101 and to assess selectivity. To further understand their mechanism of action, inhibitory kinetic analysis and in silico molecular docking calculations were performed. The results showed that\n                    <jats:italic>bis<\/jats:italic>\n                    \u2010chalcone\n                    <jats:bold>31<\/jats:bold>\n                    , with hydroxy groups at positions 3\u2032 and 4\u2032 of the B rings and three hydroxy groups at the center, was the most active. It was recognized as a mixed\u2010type inhibitor with balanced selectivity. With molecular docking, it was observed that this substitution pattern provided\n                    <jats:italic>bis<\/jats:italic>\n                    \u2010chalcone\n                    <jats:bold>31<\/jats:bold>\n                    with additional bulk that hindered its access to the active pocket of COX\u20101 over COX\u20102. Also, compound\n                    <jats:bold>31<\/jats:bold>\n                    establishes additional hydrogen bonds within the COX\u20102 pocket that\n                    <jats:italic>bis<\/jats:italic>\n                    \u2010chalcone\n                    <jats:bold>30<\/jats:bold>\n                    did not, therefore explaining the selectivity and superior potency of\n                    <jats:italic>bis<\/jats:italic>\n                    \u2010chalcone\n                    <jats:bold>31<\/jats:bold>\n                    . In conclusion,\n                    <jats:italic>bis<\/jats:italic>\n                    \u2010chalcone\n                    <jats:bold>31<\/jats:bold>\n                    with multiple hydroxy groups in its structure shows promising properties for the design of new COX\u20102 selective inhibitors.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202500784","type":"journal-article","created":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T04:19:27Z","timestamp":1777177167000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Design, Synthesis, and Evaluation of New Polyhydroxylated\n                    <i>B<\/i>\n                    <i>is<\/i>\n                    \u2010Chalcones as Potential COX\u20102 Selective Inhibitors"],"prefix":"10.1002","volume":"21","author":[{"given":"Rui","family":"Pereira","sequence":"first","affiliation":[{"name":"LAQV\u2010REQUIMTE Laboratory of Applied Chemistry Department of Chemical Sciences Faculty of Pharmacy University of Porto  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto N.","family":"Ara\u00fajo","sequence":"additional","affiliation":[{"name":"LAQV\u2010REQUIMTE Laboratory of Applied Chemistry Department of Chemical Sciences Faculty of Pharmacy University of Porto  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"LAQV\u2010REQUIMTE Laboratory of Applied Chemistry Department of Chemical Sciences Faculty of Pharmacy University of Porto  Porto Portugal"},{"name":"Institute of Agricultural and Environmental Research and Technology Faculty of Agrarian Sciences and Environment University of the Azores  Angra do Hero\u00edsmo Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismael","family":"Rufino","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy University of Lisboa  Lisboa Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuno","family":"Martinho","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy University of Lisboa  Lisboa Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita C.","family":"Guedes","sequence":"additional","affiliation":[{"name":"LAQV\u2010REQUIMTE Laboratory of Applied Chemistry Department of Chemical Sciences Faculty of Pharmacy University of Porto  Porto Portugal"},{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy University of Lisboa  Lisboa Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0938-5085","authenticated-orcid":false,"given":"Vera L. 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