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The main protease (M<jats:sup>pro<\/jats:sup>) of SARS\u2010CoV\u20102 was immediately identified as a crucial enzyme for viral replication and has been validated as a drug target. Here, we present the design and synthesis of peptidomimetic M<jats:sup>pro<\/jats:sup> covalent inhibitors characterized by quinoline\u2010based P<jats:sub>3<\/jats:sub> moieties. Structure\u2013activity relationships (SARs) were also investigated at P<jats:sub>1<\/jats:sub> and P<jats:sub>2<\/jats:sub>, as well as for different warheads. The binding modes of the designed inhibitors were assessed using X\u2010ray crystallographic and molecular docking studies. The identified M<jats:sup>pro<\/jats:sup> inhibitors were tested for their antiviral activities in cell\u2010based assays, and the results were encouraging. The SAR studies presented here can contribute to the future design of improved inhibitors by addressing some of the current or prospective issues regarding M<jats:sup>pro<\/jats:sup> inhibitors currently used in therapy.<\/jats:p>","DOI":"10.1002\/ardp.202400812","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T11:59:36Z","timestamp":1738065576000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthesis and biological investigation of peptidomimetic SARS\u2010CoV\u20102 main protease inhibitors bearing quinoline\u2010based heterocycles at P<sub>3<\/sub>"],"prefix":"10.1002","volume":"358","author":[{"given":"Sara","family":"Rossi","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy University of Siena Siena 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