In conclusion, a series of thirty-eight resorcinol-based compounds have been synthesized and evaluated to determinate their human tyrosinase inhibition activity through a set of complementary assays. Identified first via a screening assay using human melanoma MNT-1 cell lysates, compounds 10 and 23 were confirmed as potent inhibitors of hsTYR in a test involving the purified enzyme properly expressed in human HEK 293T cells, and thus associated with a native glycosylation pattern. Both compounds exhibited Ki values similar to the reference thiamidol with a partially competitive mechanism. The effect has been rationalized by molecular modeling experiments, supporting the hypothesis of binding to the copper center through the phenol at position 4' of the hemiindigoid scaffolds and suggesting a geometry consistent with the known binding mode of the natural substrate L-tyrosine. The anti-hsTYR biological activities were confirmed in whole cells, yielding a far more promising profile than the parent compound 1 for further developments. Overall, the results obtained within this study will contribute to expand the currently very small hsTYR inhibitors portfolio and to enable humandirected applications in the dermocosmetic and therapeutic fields.