Exploration of Compounds with 2-Phenylbenzo[ d ]oxazole Scaffold as Potential Skin-Lightening Agents through Inhibition of Melanin Biosynthesis and Tyrosinase Activity.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, c1995-

Melanins*/biosynthesis ; Melanins*/antagonists & inhibitors ; Molecular Docking Simulation* ; Monophenol Monooxygenase*/antagonists & inhibitors ; Monophenol Monooxygenase*/metabolism ; Skin Lightening Preparations*/pharmacology ; Skin Lightening Preparations*/chemistry; Animals ; Humans ; Mice ; Agaricales/enzymology ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/chemistry ; Molecular Structure ; Oxazoles/chemistry ; Oxazoles/pharmacology ; Pyrones ; Resorcinols/chemistry ; Resorcinols/pharmacology ; Structure-Activity Relationship ; Zebrafish

Inspired by the potent tyrosinase inhibitory activity of phenolic compounds with a 2-phenylbenzo[ d ]thiazole scaffold, we explored phenolic compounds 1 - 15 with 2-phenylbenzo[ d ]oxazole, which is isosterically related to 2-phenylbenzo[ d ]thiazole, as novel tyrosinase inhibitors. Among these, compounds 3 , 8 , and 13 , featuring a resorcinol structure, exhibited significantly stronger mushroom tyrosinase inhibition than kojic acid, with compound 3 showing a nanomolar IC 50 value of 0.51 μM. These results suggest that resorcinol plays an important role in tyrosinase inhibition. Kinetic studies using Lineweaver-Burk plots demonstrated the inhibition mechanisms of compounds 3 , 8 , and 13 , while docking simulation results indicated that the resorcinol structure contributed to tyrosinase binding through hydrophobic and hydrogen bonding interactions. Additionally, these compounds effectively inhibited tyrosinase activity and melanin production in B16F10 cells and inhibited B16F10 tyrosinase activity in situ in a concentration-dependent manner. As these compounds showed no cytotoxicity to epidermal cells, melanocytes, or keratinocytes, they are appropriate for skin applications. Compounds 8 and 13 demonstrated substantially higher depigmentation effects on zebrafish larvae than kojic acid, even at 800- and 400-times lower concentrations than kojic acid, respectively. These findings suggest that 2-phenylbenzo[ d ]oxazole is a promising candidate for tyrosinase inhibition.

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Keywords: 2-phenylbenzoxazole; docking simulation; melanin; tyrosinase; zebrafish larvae

0 (Enzyme Inhibitors)
6K23F1TT52 (kojic acid)
0 (Melanins)
EC 1.14.18.1 (Monophenol Monooxygenase)
0 (Oxazoles)
0 (Pyrones)
0 (Resorcinols)
0 (Skin Lightening Preparations)

Date Created: 20240914 Date Completed: 20240914 Latest Revision: 20240924

20240924

PMC11396935

10.3390/molecules29174162

39275009