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This study aimed to evaluate the in\u00a0vitro antiviral activity of various natural alkaloids against coronaviruses, clarify molecular effects via bioassays and docking, and explore structure\u2013activity relationships. Tested compounds included a wide variety of isoquinoline and Amaryllidaceae\u2010type alkaloids.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methodology<\/jats:title>\n                    <jats:p>Antiviral activity was assessed using HCoV\u2010229E and pseudotyped lentivirus assays for different strains of severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102). Cytotoxicity was evaluated with the WST\u20101 assay. AutoDock was used for molecular docking, online tools assessed drug\u2010likeness, and ChemGPS\u2010NP analyzed physicochemical properties correlated to antiviral clinical drugs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Several bis\u2010benzylisoquinoline alkaloids, especially from\n                      <jats:styled-content style=\"fixed-case\">\n                        <jats:italic>Berberis vulgaris<\/jats:italic>\n                      <\/jats:styled-content>\n                      L., and specific Amaryllidaceae alkaloids showed protective activity against HCoV\u2010229E (EC\n                      <jats:sub>50<\/jats:sub>\n                      \u2009=\u20094.1\u20138.1\u2009\u03bcM). Active compounds were further tested against SARS\u2010CoV\u20102 variants. Aromoline (Compound\n                      <jats:bold>16<\/jats:bold>\n                      ) exhibited strong antiviral activity, inhibiting D614G, Delta, and Omicron variants in pseudovirus assays with IC\n                      <jats:sub>50<\/jats:sub>\n                      values of 0.47\u20130.66\u2009\u03bcM. Other bis\u2010benzylisoquinoline analogues showed moderate activity (IC\n                      <jats:sub>50<\/jats:sub>\n                      \u2009=\u20091.24\u20132.86\u2009\u03bcM). Docking studies revealed aromoline's favorable interaction at the SARS\u2010CoV\u20102 spike\/ACE2 interface, forming hydrogen bonds with Gln493 and Ser494 (binding energy \u22125.34\u2009kcal\/mol). ChemGPS\u2010NP analysis highlighted a distinct cluster of active bis\u2010benzylisoquinolines (Compounds\n                      <jats:bold>16<\/jats:bold>\n                      \u2013\n                      <jats:bold>19<\/jats:bold>\n                      ) in chemical space.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study highlights the antiviral potential of bis\u2010benzylisoquinoline and Amaryllidaceae alkaloids, particularly aromoline. The findings support their relevance as scaffolds for developing novel anticoronavirus agents and advance the understanding of their structure\u2013activity relationships.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/irv.70166","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T04:25:44Z","timestamp":1759724744000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Anticoronavirus Isoquinoline Alkaloids: Unraveling the Secrets of Their Structure\u2013Activity Relationship"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4690-5107","authenticated-orcid":false,"given":"Marcela","family":"Safratova","sequence":"first","affiliation":[{"name":"Department of Pharmacognosy and Pharmaceutical Botany Faculty of Pharmacy, Charles University  Hradec Kralove Czech 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