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Tyrosinase (TYR) is a key enzyme that catalyzes the synthesis of melanin in plants, microorganisms and mammalian cells. Kojic acid (KA) is a well-known TYR inhibitor widely used as a popular cosmetic skin-lightening ingredient. However, KA is reported to have poor inhibitory activity against pigmentation within intact melanocytes or in clinical assays. In this study, a series of dihydropyrano[3,2-b] chromenedione (DHPC) (1a, 2a, 3a, 4a, 5a, 6a and 7a) and 1,8-dioxooctahydroxanthene (DOHX) (1b, 2b, 3b and 4b) derivatives were evaluated using a DPPH radical-scavenging assay. These results showed that 7a exhibited the most potent radical-scavenging activity. Compound 7a was characterised by X-ray crystallographic studies. Molecular docking was carried out to shed light on the mode of action and types of interaction between the compounds and the target. A metal-binding study suggested that these synthetic heterocyclic compounds may behave as competitive inhibitors for the L-DOPA binding site of the TYR. Finally, molecular modeling provided important insight into the mechanism of binding interactions with the TYR copper active site.

Inhibition of mushroom tyrosinase was observed with synthetic dihydropyrano[3,2-b]chromenediones. Among them, DHPC04 displayed the most potent tyrosinase inhibitory activity with a Ki value of 4μM, comparable to the reference standard inhibitor kojic acid. A kinetic study suggested that these synthetic heterocyclic compounds behave as competitive inhibitors for the L-DOPA binding site of the enzyme. Furthermore, molecular modeling provided important insight into the mechanism of binding interactions with the tyrosinase copper active site.