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As the β-phenyl-α,β-unsaturated carbonyl (PUSC) structure was previously identified to play a key role in tyrosinase inhibition, 14 analogs with a PUSC structure built on a thiazol-4(5H)-one scaffold were synthesized using Knoevenagel condensation to serve as potential tyrosinase inhibitors. Through mushroom tyrosinase inhibition experiments, two analogs 9 and 11 were identified as potent tyrosinase inhibitors, with 11 exhibiting an IC 50 value of 0.4 ± 0.01 μM, which indicates its 26-fold greater potency than kojic acid. Kinetic studies using Lineweaver-Burk plots revealed that 9 and 11 are competitive and mixed-type inhibitors, respectively; these kinetic results were supported by docking simulations. According to the B16F10 cell-based experiments, 9 and 11 inhibited melanogenesis more effectively than kojic acid due to their potent cellular tyrosinase inhibitory activity. In addition, analogs 9 and 11 exhibited moderate-to-strong antioxidant capacity, scavenging ABTS + , DPPH, and ROS radicals. In particular, analog 12 with a catechol moiety exhibited very strong ROS-scavenging activity, similar to Trolox. These results suggest that analogs 9 and 11, which exhibit potent tyrosinase inhibitory activity in mushroom and mammalian cells and anti-melanogenic effects in B16F10 cells, are promising antibrowning agents for crops and skin lightening agents for hyperpigmentation-related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)