{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T19:28:19Z","timestamp":1787772499922,"version":"build-2784847793"},"reference-count":27,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22577078"],"award-info":[{"award-number":["22577078"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22371188"],"award-info":[{"award-number":["22371188"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82470003"],"award-info":[{"award-number":["82470003"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003399","name":"Shanghai Municipal Science and Technology Commission","doi-asserted-by":"publisher","award":["25ZR1401331"],"award-info":[{"award-number":["25ZR1401331"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017950","name":"Shanghai Municipal Health Committee","doi-asserted-by":"publisher","award":["2024ZZ1010"],"award-info":[{"award-number":["2024ZZ1010"]}],"id":[{"id":"10.13039\/100017950","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,8,27]]},"abstract":"<jats:p>\n                    The SARS\u2010CoV\u20102 3C\u2010like protease (3CL\n                    <jats:sup>pro<\/jats:sup>\n                    ) is an essential enzyme for coronavirus replication and remains an attractive antiviral target due to its high sequence conservation among coronaviruses. Based on a previously identified catechol\u2010containing covalent 3CL\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitor (\n                    <jats:bold>P1\u2010E11<\/jats:bold>\n                    ), structural optimization was carried out using a linker\u2010replacement strategy to systematically modify the central linker moiety. Two series comprising 20 analogues were designed, synthesized, and evaluated for enzymatic and antiviral activities. Among them, compound\n                    <jats:bold>B2<\/jats:bold>\n                    , featuring a direct amide linkage between the catechol warhead and the 4\u2010(trifluoromethoxy)phenyl group, exhibited improved enzymatic inhibition (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.83\u2009\u00b1\u20090.06\u2009\u03bcM) and favorable covalent inhibition kinetics (\n                    <jats:italic>k<\/jats:italic>\n                    <jats:sub>inact<\/jats:sub>\n                    \/\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>i<\/jats:sub>\n                    \u2009=\u2009380.01\u2009M\n                    <jats:sup>\u22121<\/jats:sup>\n                    s\n                    <jats:sup>\u22121<\/jats:sup>\n                    ). In cell\u2010based assays (A549\u2010hACE2\u2010TMPRSS2),\n                    <jats:bold>B2<\/jats:bold>\n                    showed antiviral activity (EC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200915.03\u2009\u00b1\u20091.13\u2009\u03bcM) with acceptable cytotoxicity (CC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200979.87\u2009\u00b1\u20096.85\u2009\u03bcM). Structure\u2013activity relationship analysis revealed that sulfur\u2010containing linkers enhanced antiviral potency in certain cases but were associated with increased cytotoxicity. Collectively, this study expands the structural framework of covalent 3CL\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors and offers a rational strategy for their further optimization.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70459","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T03:12:16Z","timestamp":1787713936000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, and Structure\u2013Activity Relationship Studies of Novel 3CL\n                    <sup>pro<\/sup>\n                    Inhibitors"],"prefix":"10.1002","volume":"21","author":[{"given":"Yixuan","family":"Feng","sequence":"first","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine Innovation Research Institute of Traditional Chinese Medicine Shanghai University of Traditional 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Guangdong China"},{"name":"Guangzhou National Laboratory Guangzhou International Bio\u2010Island  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiqi","family":"Yan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine Innovation Research Institute of Traditional Chinese Medicine Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leyuan","family":"Kang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine Innovation Research Institute of Traditional Chinese Medicine Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5308-1740","authenticated-orcid":false,"given":"Wenhao","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine Innovation Research Institute of Traditional Chinese Medicine Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixin","family":"Jin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine Innovation Research Institute of Traditional Chinese Medicine Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuxiang","family":"Huang","sequence":"additional","affiliation":[{"name":"Health and Quarantine Laboratory Guangzhou Customs District Technology Center  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jincun","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease Guangzhou Institute of Respiratory Health \u2009The First Affiliated Hospital of Guangzhou Medical University  Guangzhou Guangdong China"},{"name":"Guangzhou National Laboratory Guangzhou International Bio\u2010Island  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5612-0664","authenticated-orcid":false,"given":"Ping","family":"Tian","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine Innovation Research Institute of Traditional Chinese Medicine Shanghai University of Traditional Chinese Medicine  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