Synthesis and Biological Evaluation of Kojic Acid Derivatives Containing 1,2,4-triazole as Potent Tyrosinase Inhibitors.

A series of 5-substituted-3-[5-hydroxy-4-pyrone-2-yl-methymercapto]-4-amino-1,2,4-triazole derivatives were synthesized by nucleophilic substitution reaction of 5-hydroxy-2-chloromethyl -4H-pyran-4-one with 5-substituted-3-mercapto-4-amino-1,2,4-triazole, and their inhibitory effects on mushroom tyrosinase were evaluated. The results indicated that most of the synthesized compounds exhibited significant inhibitory activity. Specifically, 5-(4-chlorophenyl)-3-[5-hydroxy-4-pyrone2-yl-methymercapto]-4-amino-1,2,4-triazole (6j) exhibited the most potent tyrosinase inhibitory activity with IC50 value of 4.50 +/- 0.34 mu M. The kinetic studies of the compound (6j) demonstrated that the inhibitory effects of the compound on the tyrosinase were belonging to competitive inhibitors. Meanwhile, the structure-activity relationship was also discussed.