title: Kinetic and in silico studies of novel hydroxy-based thymol analogues as inhibitors of mushroom tyrosinase.
abstract: 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, (1)H NMR, (13)C 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 μM) comparable to kojic acid (IC50 16.69 μM) while 2-[5-methyl-2-(propan-2-yl)phenoxy]-2-oxoethyl 3,4-dihydroxybenzoate (4d) exhibited higher antioxidant potential (IC50 11.30 μM) than standard ascorbic acid (IC50 24.20 μM). 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 Lineweaver-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 μM and 25 μM 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.
authors.affiliation: Department of Biology, College of Natural Sciences, Kongju National University, Gongju 314-701, Republic of Korea; Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan.
authors.forename: Zaman
authors.initials: Z
authors.lastname: Ashraf
authors.affiliation: Department of Biology, College of Natural Sciences, Kongju National University, Gongju 314-701, Republic of Korea.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Rafiq
authors.affiliation: Department of Biology, College of Natural Sciences, Kongju National University, Gongju 314-701, Republic of Korea. Electronic address: dnalove@kongju.ac.kr.
authors.forename: Sung-Yum
authors.initials: SY
authors.lastname: Seo
authors.affiliation: Department of Chemistry, Chungnam National University Daejeon, 305-764, Republic of Korea.
authors.forename: Kang Sung
authors.initials: KS
authors.lastname: Kwon
authors.affiliation: Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, H-12, Kashmir Highway, Islamabad, 44000, Pakistan.
authors.forename: Mustafeez Mujtaba
authors.initials: MM
authors.lastname: Babar
authors.affiliation: Department of Chemistry, Chungnam National University Daejeon, 305-764, Republic of Korea.
authors.forename: Najam-us-Sahar Sadaf
authors.initials: NU
authors.lastname: Zaidi
mesh_terms: D000363:Agaricales / Q000201:enzymology*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006900:Hydroxylation; D007700:Kinetics; D062105:Molecular Docking Simulation; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors*; D013943:Thymol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D013943:Thymol; D014442:Monophenol Monooxygenase
keywords: Antioxidant activity; Kinetic mechanism; Molecular docking; Mushroom tyrosinase inhibitors; Synthesis; Thymol analogues