期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 98, 期 -, 页码 203-211出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.05.031
关键词
Thymol analogues; Synthesis; Antioxidant activity; Mushroom tyrosinase inhibitors; Kinetic mechanism; Molecular docking
资金
- Business for Cooperative R D [C0036335]
- Korea Small and Medium Business Administration
- National Research Foundation of Korea [22A20130000039] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
The present studies reports the synthesis of hydoxylated thymol analogues (4a-e) and (6a-c) as mushroom tyrosinase inhibitors. The title compounds were obtained in good yield and characterized by FTIR, H-1 NMR, C-13 NMR, Mass spectral data and X-ray crystallography in case of compound (6a). The inhibitory effects on mushroom tyrosinase and DPPH were evaluated and it was observed that 2-[5-methyl-2-(propan-2-yl)phenoxy]-2-oxoethyl (2E)-3-(4-hydroxyphenyl)prop-2-enoate (6b) showed tyrosinase inhibitory activity (IC50 15.20 mu M) comparable to kojic acid (IC50 16.69 mu M) while 2-[5-methyl-2-(propan-2-yl)phenoxy]-2-oxoethyl 3,4-dihydroxybenzoate (4d) exhibited higher antioxidant potential (IC50 11.30 mu M) than standard ascorbic acid (IC50 24.20 mu M). The docking studies of synthesized thymol analogues was also performed against tyrosinase protein (PDBID 2ZMX) to compare the binding affinities with IC50 values. The predicted binding affinities are in good agreement with the IC50 values as compound (6b) showed highest binding affinity -7.1 kcal/mol. The kinetic mechanism analyzed by Line-weaver-Burk plots exhibited that compound (4d) and (6b) inhibit the enzyme by two different pathways displayed mixed-type inhibition. The inhibition constants Ki calculated from Dixon plots for compounds (4d) and (6b) are 34 mu M and 25 mu M respectively. It was also found from kinetic analysis that derivative (6b) formed reversible enzyme inhibitor complex. It is propose on the basis of our investigation that title compound (6b) may serve as lead structure for the design of more potent tyrosinase inhibitors. (C) 2015 Published by Elsevier Masson SAS.
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