Novel synthetic kojic acid-methimazole derivatives inhibit mushroom tyrosinase and melanogenesis

• Published in: Journal of bioscience and bioengineering Vol. 122; no. 6; pp. 666 - 672
• Main Authors: Chen, Ming-Jen, Hung, Chih-Chuan, Chen, Yan-Ru, Lai, Shih-Ting, Chan, Chin-Feng
• Format: Journal Article
• Language: English
• Published: Japan Elsevier B.V 01.12.2016
• Subjects: Agaricales - enzymology; Animals; Biphenyl Compounds - chemistry; Chick Embryo; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Kinetics; Kojic acid; Melanin; Melanins - biosynthesis; Melanoma, Experimental - pathology; Methimazole; Methimazole - chemistry; Methimazole - pharmacology; Mice; Monophenol Monooxygenase - antagonists & inhibitors; Mushroom tyrosinase; Picrates - chemistry; Pyrones - chemistry; Pyrones - pharmacology; Skin - drug effects; Skin - metabolism; Skin Neoplasms - pathology; Tumor Cells, Cultured; Methimazole; Mushroom tyrosinase; Kinetics; Kojic acid; Melanin
• ISSN: 1389-1723; 1347-4421
• DOI: 10.1016/j.jbiosc.2016.06.002

In this study, two kojic acid-methimazole (2-mercapto-1-methylimidazole, MMI, 1) derivatives, 5-hydroxy-2-{[(1-methyl-1H-imidazol-2-yl)thio]methyl}-4H-pyran-4-one (compound 4) and 5-methoxy-2-{[(1-methyl-1H-imidazol-2-yl)thio]methyl}-4H-pyran-4-one (compound 5), were synthesized to examine their inhibitory kinetics on mushroom tyrosinase. Compound 4 exhibited a potent inhibitory effect on monophenolase activity in a dose-dependent manner, with an IC50 value of 0.03 mM. On diphenolase activity, compound 4 exhibited a less inhibitory effect (IC50 = 1.29 mM) but was stronger than kojic acid (IC50 = 1.80 mM). Kinetic analysis indicated that compound 4 was both as a noncompetitive monophenolase and diphenolase inhibitor. By contrast, compound 5 exhibited no inhibitory effects on mushroom tyrosinase activity. The IC50 value of compound 4 for the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity was 4.09 mM, being much higher than the IC50 of compound 4 for inhibiting the tyrosinase activity. The results indicated that the antioxidant activity of compound 4 may be partly related to the potent inhibitory effect on mushroom tyrosinase. Compound 4 also exerted a potent inhibitory effect on intracellular melanin formation in B16/F10 murine melanoma cells, and caused no cytotoxicity. Furthermore, compound 4 induced no adverse effects on the Hen's egg test-chorioallantoic membrane (HET-CAM).