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The chemical identity of the desired structure is confirmed by nuclear magnetic resonance and single crystal X\u2010ray diffraction analyses. All novel derivatives are tested as potential USP\u20107 inhibitors and compounds <jats:bold>1a\u2013d<\/jats:bold> block enzyme activity in a dose\u2010dependent manner and with lower IC<jats:sub>50<\/jats:sub> values compared to the lead compound <jats:bold>STIRUR\u201041<\/jats:bold>. Notably, <jats:bold>1d<\/jats:bold>, bearing a <jats:italic>meta<\/jats:italic>\u2010trifluoromethylphenyl group linked to the carbamate moiety, proved to be the most active candidate. Conversely, compounds belonging to series <jats:bold>2<\/jats:bold>, which possess greater steric hindrance, exhibit no activity. The most effective compounds of series <jats:bold>1<\/jats:bold> are noncytotoxic across a panel of tumor and normal cell lines at 10\u2009\u03bcM concentration. For the most active compound <jats:bold>1d,<\/jats:bold> a parallel artificial membrane permeability assay is also performed, as well as docking and molecular dynamics simulations.<\/jats:p>","DOI":"10.1002\/cmdc.202500185","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T21:50:47Z","timestamp":1750801847000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting Ubiquitin\u2010Specific Protease 7 with Novel 5\u2010Amino\u2010Pyrazole Inhibitors: Design, Synthesis, and Biological Evaluation"],"prefix":"10.1002","volume":"20","author":[{"given":"Matteo","family":"Lusardi","sequence":"first","affiliation":[{"name":"Department of Pharmacy Universit\u00e0 degli Studi di Genova  viale Benedetto XV, 3 16132 Genova Italy"},{"name":"Molecular Modeling and Drug Discovery Laboratory Istituto Italiano di Tecnologia  Via Morego, 30 16163 Genova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elva","family":"Morretta","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Naples \u201cFederico II\u201d  Via Domenico Montesano, 49 80131 Napoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Spallarossa","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Universit\u00e0 degli Studi di Genova  viale Benedetto XV, 3 16132 Genova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Chiara Monti","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Naples \u201cFederico II\u201d  Via Domenico Montesano, 49 80131 Napoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camillo","family":"Rosano","sequence":"additional","affiliation":[{"name":"Proteomics and Mass Spectrometry Laboratory IRCCS Ospedale Policlinico San Martino  L.go. 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