{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T12:22:28Z","timestamp":1789906948242,"version":"4.0.1"},"reference-count":41,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012541","name":"Hercules Foundation","doi-asserted-by":"publisher","award":["ZW13\u221202"],"award-info":[{"award-number":["ZW13\u221202"]}],"id":[{"id":"10.13039\/501100012541","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":[[2026,4,14]]},"abstract":"<jats:p>\n                    The Severe Acute Respiratory Syndrome Coronavirus\u20102 (SARS\u2010CoV\u20102) pandemic has highlighted the fragility of our therapeutic arsenal against human coronaviruses and the urgent need to develop new antivirals. They should exhibit broad\u2010spectrum activity to address future pandemics and target alternative viral proteins to mitigate resistance. We have previously identified a hit compound based on a 2\u2010phenylquinoline scaffold that is able to hinder SARS\u2010CoV\u20102 replication through nonstructural protein 13 (nsp13) helicase inhibition. Here we reported a SAR study that led to identify new analogs such as 2\u2010(4\u2010butoxyphenyl)\u20104\u2010[2\u2010(6,7\u2010dimethoxy\u20103,4\u2010dihydroisoquinolin\u20102(1H)\u2010yl)ethoxy]\u22125,7\u2010dimethoxyquinoline (\n                    <jats:bold>14<\/jats:bold>\n                    ) and 4\u2010[2\u2010(6,7\u2010dimethoxy\u20103,4\u2010dihydroisoquinolin\u20102(1H)\u2010yl)ethoxy]\u20102\u2010(4\u2010isopropoxyphenyl)\u22125,7\u2010dimethoxyquinoline (\n                    <jats:bold>15<\/jats:bold>\n                    ), which exhibited a good antiviral profile (EC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20098.06 and 9.11\u2009\u00b5M) coupled with a low micromolar inhibition of nsp13 helicase. Time\u2010of\u2010addition assays and binding analyses confirmed helicase as their primary target, while kinetic studies revealed ATP\u2010competitive inhibition. The butoxy derivative\n                    <jats:bold>14<\/jats:bold>\n                    also inhibited HCoV\u2010229E and HCoV\u2010OC43 replication, indicating broad\u2010spectrum potential. The safety of the compounds was validated in bronchial epithelium cells BEAS\u20102B cells and H9c2 cardiac cells, where they did not affect cell viability or reactive oxygen species (ROS) production. Finally, preliminary ADME studies on\n                    <jats:bold>15<\/jats:bold>\n                    showed a positive profile in terms of membrane permeability and metabolic stability in plasma and human liver microsomes. This SAR study, along with mechanistic exploration, paves the way for further optimization of 2\u2010phenylquinoline\u2010based compounds.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202501063","type":"journal-article","created":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T02:25:28Z","timestamp":1775874328000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["2\u2010Phenylquinolines Exhibit Anti\u2010Severe Acute Respiratory Syndrome Coronavirus\u20102 Activity Through the Nonstructural Protein 13 Helicase Inhibition"],"prefix":"10.1002","volume":"21","author":[{"given":"Giada","family":"Cernicchi","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Giulia","family":"Nizi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Emmolo","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari, Cittadella Universitaria di Monserrato  Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leentje","family":"Persoons","sequence":"additional","affiliation":[{"name":"KU Leuven Department of Microbiology, Immunology and Transplantation Rega Institute for Medical Research, Molecular Genetics and Therapeutics in Virology and Oncology Research Group  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"Laporte","sequence":"additional","affiliation":[{"name":"KU Leuven Department of Microbiology, Immunology and Transplantation Rega Institute for Medical Research, Virology, Antiviral Drug &amp; Vaccine Research Group  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Jochmans","sequence":"additional","affiliation":[{"name":"KU Leuven Department of Microbiology, Immunology and Transplantation Rega Institute for Medical Research, Virology, Antiviral Drug &amp; Vaccine Research Group  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Romeo","sequence":"additional","affiliation":[{"name":"Department of Health Sciences University of \u201cMagna Gr\u00e6cia\u201d of Catanzaro  Catanzaro Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Pepe","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Salerno  Fisciano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciro","family":"Milite","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Salerno  Fisciano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Campiglia","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Salerno  Fisciano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacopo","family":"Spezzini","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Pisa  Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alma","family":"Martelli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Pisa  Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Brogi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Pisa  Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Esposito","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari, Cittadella Universitaria di Monserrato  Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Felicetti","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Massari","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Manfroni","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Sabatini","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Sbardella","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Salerno  Fisciano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Alcaro","sequence":"additional","affiliation":[{"name":"Department of Health Sciences University of \u201cMagna Gr\u00e6cia\u201d of Catanzaro  Catanzaro Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Neyts","sequence":"additional","affiliation":[{"name":"KU Leuven Department of Microbiology, Immunology and Transplantation Rega Institute for Medical Research, Virology, Antiviral Drug &amp; 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