In this study, (Z)-2-(benzylamino)-5-benzylidenethiazol-4(5H)-one (BABT) derivatives were designed as tyrosinase inhibitors based on the structure of MHY2081, using a simplified approach. Of the 14 BABT derivatives synthesized, two derivatives ((Z)-2-(benzylamino)-5-(3-hydroxy-4-methoxybenzylidene)thiazol-4(5H)-one [7] and (Z)-2-(benzylamino)-5-(2,4-dihydroxybenzylidene)thiazol-4(5H)-one [8]) showed more potent mushroom tyrosinase inhibitory activities than kojic acid, regardless of the substrate used; in particular, compound 8 was 106-fold more potent than kojic acid when l-tyrosine was used as the substrate. Analysis of Lineweaver–Burk plots for 7 and 8 indicated that they were competitive inhibitors, which was confirmed via in silico docking. In experiments using B16F10 cells, 8 exerted a greater ability to inhibit melanin production than kojic acid, and it inhibited cellular tyrosinase activity in a concentration-dependent manner, indicating that the anti-melanogenic effect of 8 is attributable to its ability to inhibit tyrosinase. In addition, 8 exhibited strong antioxidant activity to scavenge 2,2-diphenyl-1-picrylhydrazyl and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radicals and peroxynitrite and inhibited the expression of melanogenesis-associated proteins (tyrosinase and microphthalmia-associated transcription factor). These results suggest that BABT derivative 8 is a promising candidate for the treatment of hyperpigmentation-related diseases, owing to its inhibition of melanogenesis-associated protein expression, direct tyrosinase inhibition, and antioxidant activity.
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 (Z)-5-(substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one analogs with high log p values for skin. These analogs were synthesized using a two-step reaction, and their stereochemistry was confirmed using the 3JC4-Hβ values of C4 measured in proton-coupled 13C mode. Analogs 2 (IC50 = 5.21 ± 0.86 µM) and 3 (IC50 = 1.03 ± 0.14 µM) more potently inhibited mushroom tyrosinase than kojic acid (IC50 = 25.26 ± 1.10 µM). Docking results showed 2 binds strongly to the active site of tyrosinase, while 3 binds strongly to an allosteric site. Kinetic studies using l-tyrosine as substrate indicated 2 and 3 competitively and non-competitively inhibit tyrosinase, respectively, which was supported by our docking results. In B16F10 cells, 3 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 3 might be due to its tyrosinase-inhibitory ability. In addition, 2 and 3 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, 3 suppressed the expressions of melanogenesis-associated proteins and genes in B16F10 cells. These results suggest (Z)-5-(substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one analogs offer a means of producing novel anti-melanogenesis agents.
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