Experimental and theoretical approaches for the development of 4H-Chromene derivatives as inhibitors of tyrosinase

Abstract

ABSTRACT 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.