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Kinetic and in silico studies of novel hydroxy-based thymol analogues as inhibitors of mushroom tyrosinase.
Eur J Med Chem. 2015 Jun 15; 98:203-11.EJ

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+Show Affiliations

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.Department of Biology, College of Natural Sciences, Kongju National University, Gongju 314-701, Republic of Korea.Department of Biology, College of Natural Sciences, Kongju National University, Gongju 314-701, Republic of Korea. Electronic address: dnalove@kongju.ac.kr.Department of Chemistry, Chungnam National University Daejeon, 305-764, Republic of Korea.Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, H-12, Kashmir Highway, Islamabad, 44000, Pakistan.Department of Chemistry, Chungnam National University Daejeon, 305-764, Republic of Korea.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26025140

Citation

Ashraf, Zaman, et al. "Kinetic and in Silico Studies of Novel Hydroxy-based Thymol Analogues as Inhibitors of Mushroom Tyrosinase." European Journal of Medicinal Chemistry, vol. 98, 2015, pp. 203-11.
Ashraf Z, Rafiq M, Seo SY, et al. Kinetic and in silico studies of novel hydroxy-based thymol analogues as inhibitors of mushroom tyrosinase. Eur J Med Chem. 2015;98:203-11.
Ashraf, Z., Rafiq, M., Seo, S. Y., Kwon, K. S., Babar, M. M., & Zaidi, N. U. (2015). Kinetic and in silico studies of novel hydroxy-based thymol analogues as inhibitors of mushroom tyrosinase. European Journal of Medicinal Chemistry, 98, 203-11. https://doi.org/10.1016/j.ejmech.2015.05.031
Ashraf Z, et al. Kinetic and in Silico Studies of Novel Hydroxy-based Thymol Analogues as Inhibitors of Mushroom Tyrosinase. Eur J Med Chem. 2015 Jun 15;98:203-11. PubMed PMID: 26025140.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Kinetic and in silico studies of novel hydroxy-based thymol analogues as inhibitors of mushroom tyrosinase. AU - Ashraf,Zaman, AU - Rafiq,Muhammad, AU - Seo,Sung-Yum, AU - Kwon,Kang Sung, AU - Babar,Mustafeez Mujtaba, AU - Zaidi,Najam-us-Sahar Sadaf, Y1 - 2015/05/21/ PY - 2015/03/19/received PY - 2015/04/30/revised PY - 2015/05/20/accepted PY - 2015/5/31/entrez PY - 2015/5/31/pubmed PY - 2016/4/14/medline KW - Antioxidant activity KW - Kinetic mechanism KW - Molecular docking KW - Mushroom tyrosinase inhibitors KW - Synthesis KW - Thymol analogues SP - 203 EP - 11 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 98 N2 - 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. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/26025140/Kinetic_and_in_silico_studies_of_novel_hydroxy_based_thymol_analogues_as_inhibitors_of_mushroom_tyrosinase_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(15)30058-1 DB - PRIME DP - Unbound Medicine ER -