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

Abstract

Introduction: Tyrosinase, a key enzyme in melanin biosynthesis and food browning, has become an important target for inhibitor development. This study aimed to investigate the inhibitory potential of 4,6-dihydroxyaurone derivatives with varied ring B substituents on mushroom tyrosinase.

Methods: A set of 4,6-dihydroxyaurone derivatives, each with varied substituent patterns on ring B, were designed and subjected to computational studies to predict their binding affinity, binding modes with tyrosinase, and drug-likeness properties. These aurone derivatives were subsequently synthesized and evaluated in vitro for their tyrosinase inhibitory activity. Enzyme kinetics studies were conducted to determine the mode of tyrosinase inhibition.

Results: Computational studies of the twenty designed aurone derivatives indicated their strong binding within the active site and exhibited favorable drug-likeness properties. In vitro UV-Vis spectrophotometric assays of the synthesized compounds revealed that compound 5h, featuring a 3,4-dichlorophenyl substituent on ring B, showed the most potent tyrosinase inhibitory activity (IC₅₀ = 6.3 ± 0.3 μM) compared to kojic acid (IC₅₀ = 136.5 ± 11.5 μM). Kinetic studies and molecular docking simulations indicated that compound 5h inhibits tyrosinase through a mixedtype inhibition mechanism, with competitive and uncompetitive inhibition 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.

Keywords: ADME.; Tyrosinase; aurone; inhibition; melanogenesis; molecular docking.