Natural Mimetic 4,6-dihydroxyaurone Derivatives as Tyrosinase Inhibitors: Design, Synthesis, and Biological Evaluation.

Introduction: Tyrosinase, a key enzyme in melanin biosynthesis and food browning, has become an important target for inhibitor development.

Aim: This study aimed to investigate the inhibitory potential of 4,6-dihydroxyaurone derivatives with varied ring B substituents on mushroom tyrosinase.

Method: Twenty derivatives were designed and subjected to computational studies, revealing their potential to bind to the enzyme's active site and interact with key residues and copper ions.

Result: In vitro UV-Vis spectrophotometry assays on these twenty synthesized aurones demonstrated that compound 5h, featuring a 3,4-dichlorophenyl group at ring B, exhibited the most potent inhibitory activity (IC₅₀ = 6.3 ± 0.3 μM) compared to kojic acid (IC₅₀ = 136.5 ± 11.5 μM). Further kinetic analysis and docking simulations suggested that 5h operated via a mixed inhibition mechanism with competitive and uncompetitive inhibitory constants of 21 μM and 68 μM, respectively.

Conclusion: These findings highlight the promising potential of 4,6-dihydroxyaurone derivatives as potent tyrosinase inhibitors for applications in pharmaceuticals, cosmetics, and agriculture.