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In this work, the possible synergic effect generated by a combination of known inhibitors is studied. For this, derivatives containing kojic acid (KA) and 2\u2010hydroxypyridine\u2010<jats:italic>N<\/jats:italic>\u2010oxide (HOPNO) combined with a thiosemicarbazone (TSC) moiety were synthetized. Their inhibition activities were evaluated on purified tyrosinases from different sources (mushroom, bacterial, and human) as well as on melanin production by lysates from the human melanoma MNT\u20101 cell line. Results showed significant enhancement of the inhibitory effects compared with the parent compounds, in particular for HOPNO\u2010TSC. To elucidate the interaction mode with the dicopper(II) active site, binding studies with a tyrosinase bio\u2010inspired model of the dicopper(II) center were investigated. The structure of the isolated adduct between one ditopic inhibitor (KA\u2010TSC) and the model complex reveals that the binding to a dicopper center can occur with both chelating sites. Computational studies on model complexes and docking studies on enzymes led to the identification of KA and HOPNO moieties as interacting groups with the dicopper active site.<\/jats:p>","DOI":"10.1002\/chem.202004695","type":"journal-article","created":{"date-parts":[[2020,12,7]],"date-time":"2020-12-07T10:32:04Z","timestamp":1607337124000},"page":"4384-4393","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Ditopic Chelators of Dicopper Centers for Enhanced Tyrosinases Inhibition"],"prefix":"10.1002","volume":"27","author":[{"given":"Elina","family":"Buitrago","sequence":"first","affiliation":[{"name":"CNRS DCM Universit\u00e9 Grenoble Alpes  38000 Grenoble France"},{"name":"CNRS DPM Universit\u00e9 Grenoble Alpes  38000 Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clarisse","family":"Faure","sequence":"additional","affiliation":[{"name":"CNRS DCM Universit\u00e9 Grenoble Alpes  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