Benzylidene-linked thiohydantoin derivatives as inhibitors of tyrosinase and melanogenesis: importance of the β-phenyl-α,β-unsaturated carbonyl functionality
Based on the structural characteristics of the heterocyclic scaffolds of substituted benzylidene-hydantoin, -pyrrolidinedione, and -thiazolidinedione derivatives with potent tyrosinase inhibitory activity, substituted benzylidene derivatives with a 2-thiohydantoin heterocyclic scaffold were synthesized by modified Knoevenagel condensation between benzaldehydes and 2-thiohydantoin with a view toward producing more potent, safer tyrosinase inhibitors capable of being utilized in the agricultural, food, cosmetics, and pharmaceutical industries. Of the twelve compounds synthesized, three compounds, 2c, 2d and 2i, exhibited even more potent inhibitory activities against mushroom tyrosinase than kojic acid or resveratrol, which are well-known potent tyrosinase inhibitors. The inhibitory pattern of compounds with a thiohydantoin template differed from that of compounds with a hydantoin, pyrrolidinedione, or thiazolidine scaffold, probably because of the loss of the hydrogen bonding ability of the thiocarbonyl group of thiohydantoin. Considering the high tyrosinase inhibitory activities of 5-(substituted benzylidene)thiohydantoin derivatives, the thiohydantoin template is considered a near perfect surrogate for hydantoin, pyrrolidinedione, and thiazolidinedione scaffolds. (Z)-5-(2,4-Dihydroxybenzylidene)-2-thiohydantoin (2d, IC50 = 1.07 ± 2.30 μM) had 24 times the inhibitory effect of resveratrol (IC50 = 26.63 ± 0.55 μM) and 18 times that of kojic acid (IC50 = 19.69 ± 4.90 μM) against mushroom tyrosinase and showed anti-melanogenesis through the inhibition of tyrosinase activity in B16 cells with no appreciable cytotoxicity, which suggests that 2d is a promising candidate for the development of safer and more potent fruit and food browning preventatives and skin-lightening medicines. This result and our previous data indicate that it is the “β-phenyl-α,β-unsaturated carbonyl” group that is essential for potent anti-tyrosinase activity.