Design and Synthesis of ()-5-(Substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one Analogues as Anti-Tyrosinase and Antioxidant Compounds: In Vitro and In Silico Insights.

Many compounds containing the β-phenyl-α,β-unsaturated carbonyl (PUSC) scaffold, including cinnamamide derivatives, have been shown to inhibit tyrosinase potently in vitro and in vivo. Structural changes to cinnamamide derivatives were produced by adding a dithionate functional group to provide eight ()-5-(substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one analogs with high log values for skin. These analogs were synthesized using a two-step reaction, and their stereochemistry was confirmed using the values of C4 measured in proton-coupled C mode. Analogs (IC = 5.21 ± 0.86 µM) and (IC = 1.03 ± 0.14 µM) more potently inhibited mushroom tyrosinase than kojic acid (IC = 25.26 ± 1.10 µM). Docking results showed binds strongly to the active site of tyrosinase, while binds strongly to an allosteric site. Kinetic studies using l-tyrosine as substrate indicated and competitively and non-competitively inhibit tyrosinase, respectively, which was supported by our docking results. In B16F10 cells, significantly and concentration-dependently reduced α-MSH plus IBMX induced increases in cellular tyrosinase activity and melanin production and the similarity between these inhibitory patterns implied that the anti-melanogenic effect of might be due to its tyrosinase-inhibitory ability. In addition, and exhibited strong antioxidant effects; for example, they reduced ROS and ONOO levels and exhibited radical scavenging activities, suggesting that these effects might underlie their anti-melanogenic effects. Furthermore, suppressed the expressions of melanogenesis-associated proteins and genes in B16F10 cells. These results suggest ()-5-(substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one analogs offer a means of producing novel anti-melanogenesis agents.