In our study,a new series of Schiffs base derivatives:(Z)-4-amino-5-(2-(3-fluorobenzylidene)hydrazinyl)-4H-1,2,4-triazole-3-thiol(Y1),(Z)-3-((2-(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)hydrazono)methyl)phenol(Y2),(Z)-2-((2-(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)hydrazono)methyl)phenol(Y3)and 3-((Z)-(2-(4-(((E)-3-hydroxybenzylidene)amino)-5-mercapto-4H-1,2,4-triazol-3-yl)hydrazono)methyl)phenol(Y4)have been synthesized by 4-Amino-3-hydrazino-5-mercapto-1,2,4-triazole and benzaldehyde.The structures were characterized by LC-MS and 1H NMR.The inhibition effects on tyrosinase of these compounds were evaluated and compounds Y1,Y2 and Y3 had shown good inhibitory potential.Their IC50 value on the enzyme was determined to be 12.5,7.0 and 1.5 μM,respectively,and the inhibition mechanisms were determined to be reversible and mixed types.The combinations of these compounds with the enzyme active site were analyzed using fluorescence quenching,copper interacting,and molecular simulation assays.These results proved that 2-substituted on the benzene ring was superior to 3-substituted,and that hydroxyl substituted was better than fluorine substituted,which were in contrast to antioxidant assay.In addition,two benzene rings connecting to the triazole ring would produce larger steric hindrance,and affect the bonding between tyrosinase and inhibitors to decrease the inhibitory effects.The data would facilitate changes in developing and designing of antityrosinase agents of fresh-keeping and whitening cosmetics.