{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T01:10:58Z","timestamp":1790212258831,"version":"4.1.0"},"reference-count":38,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T00:00:00Z","timestamp":1625011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010607","name":"Universit\u00e0 degli Studi di Perugia","doi-asserted-by":"publisher","award":["Fondo per la ricerca di base 2019"],"award-info":[{"award-number":["Fondo per la ricerca di base 2019"]}],"id":[{"id":"10.13039\/501100010607","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fundaci\u00f3n hna ; Miguel Servet Program from Instituto de Salud Carlos III","award":["CPII13\/00017"],"award-info":[{"award-number":["CPII13\/00017"]}]},{"name":"Fondo de Investigaciones Sanitarias from Instituto de Salud Carlos III, and European Union (ERDF\/ESF, \u2018Investing in your future\u2019)","award":["PI18\/00349"],"award-info":[{"award-number":["PI18\/00349"]}]},{"name":"Spanish Ministry of Economy and Competitiveness","award":["BFU2016-78232-P and SAF2017-83265-R"],"award-info":[{"award-number":["BFU2016-78232-P and SAF2017-83265-R"]}]},{"name":"Spanish Ministry of Science, Innovation and Universities (FPI Predoctoral Research Contract)","award":["BES-2017-080739"],"award-info":[{"award-number":["BES-2017-080739"]}]},{"DOI":"10.13039\/501100003339","name":"Spanish National Research Council","doi-asserted-by":"publisher","award":["202020E079"],"award-info":[{"award-number":["202020E079"]}],"id":[{"id":"10.13039\/501100003339","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Diputaci\u00f3n General de Arag\u00f3n Predoctoral Research Contract 2019","award":["(Predoctoral Research Contract 2019) - (Protein Targets and Bioactive Compounds Group\u2019 E45_20R) - (Digestive Pathology Group\u2019 B25_20R)"],"award-info":[{"award-number":["(Predoctoral Research Contract 2019) - (Protein Targets and Bioactive Compounds Group\u2019 E45_20R) - (Digestive Pathology Group\u2019 B25_20R)"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior - Brasil (CAPES)","award":["Finance Code 001"],"award-info":[{"award-number":["Finance Code 001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The development of new antiviral drugs against SARS-CoV-2 is a valuable long-term strategy to protect the global population from the COVID-19 pandemic complementary to the vaccination. Considering this, the viral main protease (Mpro) is among the most promising molecular targets in light of its importance during the viral replication cycle. The natural flavonoid quercetin 1 has been recently reported to be a potent Mpro inhibitor in vitro, and we explored the effect produced by the introduction of organoselenium functionalities in this scaffold. In particular, we report here a new synthetic method to prepare previously inaccessible C-8 seleno-quercetin derivatives. By screening a small library of flavonols and flavone derivatives, we observed that some compounds inhibit the protease activity in vitro. For the first time, we demonstrate that quercetin (1) and 8-(p-tolylselenyl)quercetin (2d) block SARS-CoV-2 replication in infected cells at non-toxic concentrations, with an IC50 of 192 \u03bcM and 8 \u03bcM, respectively. Based on docking experiments driven by experimental evidence, we propose a non-covalent mechanism for Mpro inhibition in which a hydrogen bond between the selenium atom and Gln189 residue in the catalytic pocket could explain the higher Mpro activity of 2d and, as a result, its better antiviral profile.<\/jats:p>","DOI":"10.3390\/ijms22137048","type":"journal-article","created":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T10:03:19Z","timestamp":1625047399000},"page":"7048","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Seleno-Functionalization of Quercetin Improves the Non-Covalent Inhibition of Mpro and Its Antiviral Activity in Cells against SARS-CoV-2"],"prefix":"10.3390","volume":"22","author":[{"given":"Francesca","family":"Mangiavacchi","sequence":"first","affiliation":[{"name":"Group of Catalysis, Synthesis and Organic Green Chemistry, Department of Pharmaceutical Sciences, University of Perugia Via del Liceo 1, 06100 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9006-1568","authenticated-orcid":false,"given":"Pawel","family":"Botwina","sequence":"additional","affiliation":[{"name":"Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland"},{"name":"Microbiology Department, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Menichetti","sequence":"additional","affiliation":[{"name":"Group of Catalysis, Synthesis and Organic Green Chemistry, Department of Pharmaceutical Sciences, University of Perugia Via del Liceo 1, 06100 Perugia, Italy"},{"name":"School of Science and Technology, Chemistry Division, University of Camerino, Via S. Agostino, 62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0622-4561","authenticated-orcid":false,"given":"Luana","family":"Bagnoli","sequence":"additional","affiliation":[{"name":"Group of Catalysis, Synthesis and Organic Green Chemistry, Department of Pharmaceutical Sciences, University of Perugia Via del Liceo 1, 06100 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ornelio","family":"Rosati","sequence":"additional","affiliation":[{"name":"Group of Catalysis, Synthesis and Organic Green Chemistry, Department of Pharmaceutical Sciences, University of Perugia Via del Liceo 1, 06100 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0747-5060","authenticated-orcid":false,"given":"Francesca","family":"Marini","sequence":"additional","affiliation":[{"name":"Group of Catalysis, Synthesis and Organic Green Chemistry, Department of Pharmaceutical Sciences, University of Perugia Via del Liceo 1, 06100 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9rgio F.","family":"Fonseca","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de S\u00edntese Org\u00e2nica Limpa\u2014LASOL, CCQFA, Universidade Federal de Pelotas\u2014UFPel, P.O. 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Box 354, 96010-900 Pelotas, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1499-4950","authenticated-orcid":false,"given":"Agnieszka","family":"Dabrowska","sequence":"additional","affiliation":[{"name":"Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland"},{"name":"Microbiology Department, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8404-2176","authenticated-orcid":false,"given":"Anna","family":"Kula-Pacurar","sequence":"additional","affiliation":[{"name":"Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Ortega-Alarcon","sequence":"additional","affiliation":[{"name":"Institute for Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain"},{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Jimenez-Alesanco","sequence":"additional","affiliation":[{"name":"Institute for Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain"},{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7223-1719","authenticated-orcid":false,"given":"Laura","family":"Ceballos-Laita","sequence":"additional","affiliation":[{"name":"Institute for Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Arag\u00f3n (IIS Aragon), 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Vega","sequence":"additional","affiliation":[{"name":"Institute for Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1110-764X","authenticated-orcid":false,"given":"Bruno","family":"Rizzuti","sequence":"additional","affiliation":[{"name":"Institute for Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain"},{"name":"CNR-NANOTEC, SS Rende (CS), Licryl-UOS Cosenza and CEMIF.Cal, Department of Physics, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Abian","sequence":"additional","affiliation":[{"name":"Institute for Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain"},{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Arag\u00f3n (IIS Aragon), 50009 Zaragoza, Spain"},{"name":"Instituto Aragon\u00e9s de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en el \u00c1rea Tem\u00e1tica de Enfermedades Hep\u00e1ticas Digestivas (CIBERehd), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7920-3289","authenticated-orcid":false,"given":"Eder J.","family":"Lenard\u00e3o","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de S\u00edntese Org\u00e2nica Limpa\u2014LASOL, CCQFA, Universidade Federal de Pelotas\u2014UFPel, P.O. 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