Design, synthesis, molecular modeling, and biological evaluation of novel kojic acid derivatives containing bioactive heterocycle moiety as inhibitors of tyrosinase and antibrowning agents.

Abstract Tyrosinase plays an important role in melanin biosynthesis and enzymatic browning of fresh-cut fruit and vegetables. To discover potent tyrosinase inhibitors and antibrowning agents, a series of novel kojic acid derivatives containing bioactive heterocycle moiety (4a-4l) were designed and synthesized. Thereinto, 4d displayed the most potent tyrosinase inhibitory activity with IC50 of 3.23 ± 0.26 μM and behaved as a competitive inhibitor with a Ki of 1.96 μM, compared to kojic acid (IC50 = 32.23 ± 2.01 μM). Besides, copper-chelating assay, fluorescence spectrum quenching experiment, ANS-binding fluorescence quenching analysis, and molecular modeling studies indicated that 4d may inhibit tyrosinase activity by chelating with copper ions in the active site of tyrosinase. Furthermore, 4d exhibited low cytotoxic activity and significant antibrowning effects. This study suggests that these compounds may serve as lead molecules for developing novel tyrosinase inhibitors and antibrowning agents.