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To address this point, we previously designed a class of 4\u2010(4\u2010fluorobenzyl)piperazin\u20101\u2010yl\u2010based compounds, which proved to be more active inhibitors against tyrosinase from mushroom <jats:italic>Agaricus bisporus<\/jats:italic> than the positive control kojic acid. Herein, we report the synthesis of further series of 4\u2010(4\u2010fluorobenzyl)piperazin\u20101\u2010yl analogues bearing a (hetero)aromatic fragment as key feature to improve protein affinity. The newly synthesized compounds were assayed <jats:italic>in\u2005vitro<\/jats:italic> and proved to be potent inhibitors in the low\u2010micromolar range. The active 2\u2010thienyl and 2\u2010furyl derivatives were selected for further modification to allow their binding mode to be analyzed by docking studies and to give satisfactory safety profiles.<\/jats:p>","DOI":"10.1002\/cmdc.202000125","type":"journal-article","created":{"date-parts":[[2020,7,21]],"date-time":"2020-07-21T16:10:53Z","timestamp":1595347853000},"page":"1757-1764","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["4\u2010Fluorobenzylpiperazine\u2010Containing Derivatives as Efficient Inhibitors of Mushroom Tyrosinase"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6092-5011","authenticated-orcid":false,"given":"Serena","family":"Vittorio","sequence":"first","affiliation":[{"name":"Department of Chemical Biological Pharmaceutical and Environmental Sciences University of Messina  Viale Palatucci 13 98168 Messina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Ielo","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry University of Vienna  Althanstrasse 14 1090 Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Mirabile","sequence":"additional","affiliation":[{"name":"Department of Chemical Biological Pharmaceutical and Environmental Sciences University of Messina  Viale Palatucci 13 98168 Messina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0002-2253","authenticated-orcid":false,"given":"Rosaria","family":"Gitto","sequence":"additional","affiliation":[{"name":"Department of Chemical Biological Pharmaceutical and Environmental Sciences University of Messina  Viale Palatucci 13 98168 Messina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Fais","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari  09042 Monserrato Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Floris","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari  09042 Monserrato Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Rapisarda","sequence":"additional","affiliation":[{"name":"Department of Chemical Biological Pharmaceutical and Environmental Sciences University of Messina  Viale Palatucci 13 98168 Messina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Paola","family":"German\u00f2","sequence":"additional","affiliation":[{"name":"Department of Chemical Biological Pharmaceutical and Environmental Sciences University of Messina  Viale Palatucci 13 98168 Messina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0614-5713","authenticated-orcid":false,"given":"Laura","family":"De Luca","sequence":"additional","affiliation":[{"name":"Department of Chemical Biological Pharmaceutical and Environmental Sciences University of Messina  Viale Palatucci 13 98168 Messina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,8,20]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.2340\/00015555-3002"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2019.103419"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751-1097.2007.00226.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b00967"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08858-y"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2020.126952"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2019.07.017"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodchem.2019.125506"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.111892"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2019.1661401"},{"key":"e_1_2_7_11_1","author":"Vittorio S.","year":"2019","journal-title":"Mol. 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