Tyrosinase inhibition by hemiindigoid-based compounds with a copper-interacting hydroxamic acid head

Tyrosinase inhibition is a key strategy to reduce melanogenesis in vivo , making the enzyme an attractive target for cosmetic and dermatological applications. Despite the large number of reported compounds, many inhibitors show limited efficacy against the human enzyme, such as kojic acid, or instead act as alternative substrates or pseudo-substrates, such as hydroquinone. Given the controversial activity of polyphenolic scaffolds on tyrosinase, we designed a new series of hemiindigoid derivatives by replacing the classical resorcinol moiety with functional groups known for their copper-binding potential, including amines, halogens, non-oxidizable phenols and hydroxamic acids. Among the 43 compounds evaluated, para - and meta -hydroxamic acid derivatives afforded the best results, demonstrating nanomolar inhibition of both mushroom tyrosinase and human tyrosinase from cell lysates. Structural and kinetic studies provided insight into their inhibition mechanism and binding geometry, while whole cell assays confirmed their ability to suppress melanogenesis in the micromolar range. • Forty-three hemiindigoids were synthesized as new tyrosinase inhibitors • Tests against mushroom and human tyrosinases yielded nanomolar-range values • The proposed binding mode is relevant and matches previous structural observations • Therapeutic index in cell-based assays were low but suitable for dermatology