2',4'-dihydroxyaurones, were always associated with an inhibitor behavior, regardless of the TYR source. This observation was consistent with the known beneficial effect of resorcinol moiety in the frame of TYR inhibition, as witnessed by the number of reported inhibitors containing this chemical group. Indeed, if some resorcinols were previously found to undergo a slow oxidation process in the presence of TYR and additives, they act as true inhibitors in physiological conditions. Some of them are actually used for treating human hyperpigmentation disorders, such as 4-n-butylresorcinol (i.e. rucinol, marketed as Iklen ® , Figure ). The resorcinol-based thiamidol (Figure ) seems especially very promising, regarding both in vitro (Ki = 0.25 µM against hsTYR), and clinical contexts (facial hyperpigmentation improvement in 96% of treated women with melasma after 12 weeks of treatment). Altogether, the introduction of a resorcinol moiety on an aurone scaffold, or on a related hemiindigoid core, could combine an efficient copper-chelating resorcinol head with a hsTYR-tailored hemiindigoid backbone, able to interact with the second coordination sphere of the enzyme. Thus, we report herein a series of thirty-eight molecules designed starting from compound 1 and including a 2',4'-resorcinol moiety, or close analogues, at the B-ring. The best derivatives, identified through a preliminary screening using hsTYR-containing human melanoma MNT-1 cell lysates, were evaluated both on the isolated enzyme expressed in a mammalian-cell system, thus insuring the expression of a mammalian glycosylation profile, and against melanogenesis in a human whole-cell system. Potential cytotoxicity issues were finally examined, and a binding geometry was proposed through molecular modelling, using a recent homology model of hsTYR.