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

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.

KEYWORDS:

• Tyrosinase
• kojic acid
• molecular docking
• DPPH
• metal-binding

Acknowledgements

The authors gratefully acknowledge financial support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; project number: 402572/2018-1) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for financial support. As well as the Center for High-Performance Computing (CHPC) in Cape Town—South Africa—for computational support. Financial support by the University of Queensland.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors gratefully acknowledge financial support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; project number: 402572/2018-1) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for financial support. As well as the Center for High-Performance Computing (CHPC) in Cape Town—South Africa—for computational support. Financial support by the University of Queensland.