This phenomenon suggests that all the compounds had an inhibition effect on tyrosinase. As shown in Figure 5 , while the lightest bands corresponded to 1d and 1a compounds, compound 2d showed minimal inhibitory effect compared to the other compounds.
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These results confirm our findings from inhibitory activity measured by the spectrophotometric method. Figure 5 The effect of the synthetized compounds 1a-e and 2a-e on the enzyme activity estimated by zymography using L-DOPA staining A based on 2,6-diaminochloropyrimidine and B based on 2,4,6-triaminopyrimidine. The steady-state kinetic analysis of all compounds for inhibition of enzyme activity on different concentrations of L-DOPA 0. Lines intersect on Lineweaver—Burk plots showed that all synthetic compounds were a noncompetitive inhibitor of the mushroom tyrosinase Figure 6.
Figure 6 Michaelis—Menten and Lineweaver—Burk plots of the enzyme inhibition by the compound 1d.
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The binding of 1d to tyrosinase 2Y9W was computerized by molecular docking. The results of docking were well clustered around the conformer with the best score. According to Figure 7 , the results of docking showed that hydrophobic interactions and polar—polar interaction between N3 of the ligand and carbonyl group of Lys5 play a major role in the binding of 1d to tyrosinase. Based on the results of the modeling, the dominant interaction is hydrophobic.
The important interacting residues are shown by colored lines and 1d by CPK drawing method; C a LigPlot diagram of the interaction between tyrosinase and 1d. Hydrophobic interaction plays a major role in the binding. Tyrosinase is a rate-limiting monooxygenase enzyme in the process of melanin production.
Thus, its inhibitors could be useful as insecticides in the agricultural research activities. Over recent years, there have been many studies of screening, discovery, design, and synthesis of novel tyrosinase inhibitors. Pyrimidine derivatives are active heterocyclic compounds with two nitrogen atoms in the ring and have attracted much attention in medicinal chemistry and pharmacology.
Their inhibitory activities against mushroom tyrosinase were then evaluated. Tyrosinase inhibition assay was carried out with L-DOPA as substrate and kojic acid as reference inhibitor. All synthetic compounds 1a-e and 2a-e were able to inhibit mushroom tyrosinase activity in a concentration-dependent manner, as shown in Figure 3. The data revealed that compounds with a Cl-halide group in the R position have more inhibitory activity than the compounds with an NH 2 group in the R position. The mechanisms of inhibition of mushroom tyrosinase by all synthetic compounds were further investigated by steady-state kinetic analysis.
Inhibition data were then determined using Lineweaver—Burk double reciprocal plots. These data suggest that of all synthetic compounds function as noncompetitive inhibitors of tyrosinase Table 2 , hence all synthetic compounds bound both the free enzyme molecule and enzyme-substrate complex. Liu et al 28 synthesized several compounds on the basis of thiourea containing NH group in the ring and evaluated their inhibitory potencies on mushroom tyrosinase.
For these two compounds, it was observed that adding a methyl group in the meta position on the ring could reduce the inhibitory effect of the methylthiouracil compound. By comparing the results of the present study with Liu et al it was found that the presence of a methyl group decreases the inhibitory effect of synthetic compounds 2b and 1c. Bae et al synthesized methoxy-aniline derivatives and evaluated as a tyrosinase inhibitor.
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The authors thank the Research Council of the University of Guilan for the financial support of this study. All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.
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