Thioureas, thiosemicarbazones, hydroxamic acids and related compounds as copper-chelating tyrosinase inhibitors

Tyrosinases are copper-containing enzymes involved in melanin biosynthesis and represent key targets for treating hyperpigmentation disorders. This review focuses on tyrosinase inhibitors bearing carboxylate- and thiocarboxylate-based moieties, with particular emphasis on their metal-chelating properties and interaction with the dicopper active site. We provide a comparative analysis of major scaffold families, including thioureas, thiosemicarbazones, and hydroxamic acids, highlighting structure-activity relationships and key determinants of binding affinity. Beyond simple copper coordination, kinetic studies reveal complex inhibition mechanisms, often involving mixed or noncompetitive behaviors, which are critically discussed in light of recent structural insights. Particular attention is given to limitations associated with the use of non-human tyrosinases and to strategies aimed at improving relevance to human systems. By integrating available biochemical, kinetic, and structural data, this work identifies current limitations and outlines strategies for the rational design of next-generation inhibitors with improved translational relevance.