Study on the design, synthesis and structure-activity relationships of new thiosemicarbazone compounds as tyrosinase inhibitors

摘要

Abstract 52 Structure-based thiosemicarbazone compounds bearing various substituted-lipophilic part, including substituted-benzaldehyde, substituted-phenylalkan-1-one and their biphenyl-type thiosemicarbazone analogs, were designed, synthesized and evaluated as new tyrosinase inhibitors. The results demonstrated that 22 compounds have potent inhibitory activities against tyrosinase with the IC 50 value of lower than 1.0?μM. On the basis of the obtained experimental data, the structure-activity relationships (SARs) were rationally derived. Besides, the inhibition mechanism and the inhibitory kinetics of selected compounds 3d and 6e were investigated, revealing that such type of compounds were belonged to the reversible and competitive tyrosinase inhibitors. To verify the safety of these developed thiosemicarbazone compounds, four randomly selected compounds 3d , 4e , 6a and 9a were also tested in 293T cell line for the evaluation of the cytotoxicity. Interestingly, all these compounds almost did not perform any toxicity to 293T cells even at a high concentration of 1000?μmol/L. Taken together, these results suggested that such compounds could serve as the highly efficient and more safe candidates for the treatment of tyrosinase-related disorders. Graphical abstract Display Omitted Highlights ? Higher tyrosinase inhibitory activity: the IC 50 value of 22 compounds among 52 compounds is lower than 1?μM. ? Lower toxicity: toxicity of compounds 3d , 4e , 6a and 9a is very lower. ? Clear SARs: SARs of 52 compounds were discussed in detail.