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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 (<i>Z</i>)-5-(substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one analogs with high log <i>p</i> values for skin. These analogs were synthesized using a two-step reaction, and their stereochemistry was confirmed using the ³<i>J</i>_C4-Hβ values of C4 measured in proton-coupled ¹³C mode. Analogs <b>2</b> (IC₅₀ = 5.21 ± 0.86 µM) and <b>3</b> (IC₅₀ = 1.03 ± 0.14 µM) more potently inhibited mushroom tyrosinase than kojic acid (IC₅₀ = 25.26 ± 1.10 µM). Docking results showed <b>2</b> binds strongly to the active site of tyrosinase, while <b>3</b> binds strongly to an allosteric site. Kinetic studies using <span style="font-variant: small-caps;">l</span>-tyrosine as substrate indicated <b>2</b> and <b>3</b> competitively and non-competitively inhibit tyrosinase, respectively, which was supported by our docking results. In B16F10 cells, <b>3</b> 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 <b>3</b> might be due to its tyrosinase-inhibitory ability. In addition, <b>2</b> and <b>3</b> 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, <b>3</b> suppressed the expressions of melanogenesis-associated proteins and genes in B16F10 cells. These results suggest (<i>Z</i>)-5-(substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one analogs offer a means of producing novel anti-melanogenesis agents.