Novel Anti-Melanogenic Compounds, ( Z )-5-(Substituted Benzylidene)-4-thioxothiazolidin-2-one Derivatives: In Vitro and In Silico Insights

To confirm that the β-phenyl-α,β-unsaturated thiocarbonyl (PUSTC) scaffold, similar to the β-phenyl-α,β-unsaturated carbonyl (PUSC) scaffold, acts as a core inhibitory structure for tyrosinase, twelve ( )-5-(substituted benzylidene)-4-thioxothiazolidin-2-one (( )-BTTZ) derivatives were designed and synthesized. Seven of the twelve derivatives showed stronger inhibitory activity than kojic acid against mushroom tyrosinase. Compound (IC = 0.47 ± 0.97 µM) exerted a 141-fold higher inhibitory potency than kojic acid. Kinetic studies' results confirmed that compounds and are competitive tyrosinase inhibitors, which was supported by high binding affinities with the active site of tyrosinase by docking simulation. Docking results using a human tyrosinase homology model indicated that and might potently inhibit human tyrosinase. In vitro assays of and were conducted using B16F10 melanoma cells. Compounds and significantly and concentration-dependently inhibited intracellular melanin contents, and the anti-melanogenic effects of at 10 µM and at 25 µM were considerably greater than the inhibitory effect of kojic acid at 25 µM. Compounds and similarly inhibited cellular tyrosinase activity and melanin contents, indicating that the anti-melanogenic effects of both were due to tyrosinase inhibition. A strong binding affinity with the active site of tyrosinase and potent inhibitions of mushroom tyrosinase, cellular tyrosinase activity, and melanin generation in B16F10 cells indicates the PUSTC scaffold offers an attractive platform for the development of novel tyrosinase inhibitors.