Design, Synthesis, and Antioxidant and Anti-Tyrosinase Activities of ()-5-Benzylidene-2-(naphthalen-1-ylamino)thiazol-4(5)-one Analogs: In Vitro and In Vivo Insights.

Fifteen compounds (-) constructed on a hybrid structure combining a β-phenyl-α,β-unsaturated carbonyl template and a 2-aminothiazol-4(5)-one scaffold were designed and synthesized as potential novel anti-tyrosinase substances. Two compounds ( and ) showed more potent inhibition against mushroom tyrosinase than kojic acid, and the inhibitory activity of (IC value: 1.60 μM) was 11 times stronger than that of kojic acid. Lineweaver-Burk plots indicated that these two compounds were competitive inhibitors that bound to the mushroom tyrosinase active site, which was supported by in silico experiments. Compound was an anti-tyrosinase and anti-melanogenic substance in B16F10 cells and was more potent than kojic acid, without cytotoxicity. Compound exhibited the most potent effect on zebrafish larval depigmentation and showed a depigmentation effect comparable to kojic acid, even at a concentration 200 times lower. Compounds and exhibited strong antioxidant capacities, scavenging 2,2-diphenyl-1-picrylhydrazyl, (2,2-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid) radicals, and reactive oxygen species. Hybrid compounds and are potential therapeutic agents for skin hyperpigmentation disorders.