Anti-tyrosinase flavone derivatives and their anti-melanogenic activities: Importance of the β-phenyl-α,β-unsaturated carbonyl scaffold

[Display omitted] •Flavone derivatives with an intrinsic β-phenyl-α,unsaturated carbonyl (PUSC) scaffold were synthesized as potential anti-tyrosinase compounds.•In B16F10 murine cells, 1a and 1e inhibited melanin production more strongly than kojic acid, and this anti-melanogenesis effect was attributable to the inhibition of cellular tyrosinase.•These flavones also exhibited strong antioxidant activities (scavenging intracellular ROS and ABTS and DPPH radicals) and inhibited melanogenesis-related gene expression.•Flavone derivatives may be promising melanogenesis inhibitors via (i) their direct tyrosinase inhibition, (ii) antioxidant capacity, and (iii) the inhibition of melanogenesis-related gene expression.•Flavones are excellent natural potential anti-melanogenic compounds as they have a PUSC scaffold in their internal molecular structure that plays an important role in anti-tyrosinase effect. Flavone derivatives were designed and synthesized based on the hypothesis that flavones containing the β-phenyl-α,β-unsaturated carbonyl (PUSC) scaffold have potential anti-tyrosinase activity. Flavones 1a and 1e inhibited mushroom tyrosinase more potently than kojic acid, and 1e inhibited monophenolase and diphenolase 61- and 28-fold more than kojic acid, respectively. Kinetic studies on mushroom tyrosinase indicated that 1a and 1e competitively inhibit monophenolase and diphenolase, and docking results supported these results. In an in vitro assay using B16F10 murine cells, 1a and 1e inhibited melanin production more potently than kojic acid, and this was attributed to the inhibition of tyrosinase. Furthermore, 1a and 1e strongly scavenged DPPH and ABTS radicals and ROS, which suggested that their antioxidant properties were at least partly responsible for their anti-melanogenic effects. Moreover, flavone 1a also inhibited the gene expressions of the melanogenesis-related genes tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2. Our findings that flavone derivatives (i) directly inhibit tyrosinase, (ii) act as antioxidants, and (iii) inhibit the expressions of melanogenesis-related genes suggest their potential use as natural melanogenesis inhibitors. Furthermore, the study confirms that the PUSC scaffold confers anti-tyrosinase activity.