title: Synthesis, kinetic mechanism and docking studies of vanillin derivatives as inhibitors of mushroom tyrosinase.
abstract: The purpose of the present study was to discover the extent of contribution to antityrosinase activity by adding hydroxy substituted benzoic acid, cinnamic acid and piperazine residues to vanillin. The study showed the transformation of vanillin into esters as shown in (4a-4d), (6a-6b), and (8a-8b). In addition, the relationship between structures of these esters and their mushroom tyrosinase inhibitory activity was explored. The kinetics of inhibition on mushroom tyrosinase by these esters was also investigated. It was found that hydroxyl substituted benzoic acid derivatives were weak inhibitors; however hydroxy or chloro substituted cinnamic acid and piperazine substituted derivatives were able to induce significant tyrosinase inhibition. The mushroom tyrosinase (PDBID 2ZWE) was docked with synthesized vanillin derivatives and their calculated binding energies were compared with experimental IC50 values which provided positive correlation. The most potent derivative 2-(4-formyl-2-methoxyphenoxy)-2-oxoethyl (2E)-3-(4-hydroxyphenyl)prop-2-enoate (6a) possesses hydroxy substituted cinnamic acid scaffold having IC50 value 16.13 μM with binding energy of -7.2 kcal/mol. The tyrosinase inhibitory activity of (6a) is comparable with standard kojic acid. Kinetic analysis indicated that compound 6a was mixed-type tyrosinase inhibitor with inhibition constant values Ki (13 μM) and Ki' (53 μM) and formed reversible enzyme inhibitor complex. The active vanillin analog (6a) was devoid of toxic effects as shown in cytotoxic studies.
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: 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: Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, H-12, Kashmir Highway, Islamabad 44000, Pakistan.
authors.forename: Najam-us-Sahar Sadaf
authors.initials: NU
authors.lastname: Zaidi
mesh_terms: D000363:Agaricales / Q000201:enzymology*; D001547:Benzaldehydes / Q000138:chemical synthesis* / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry*
chemical_list: D001547:Benzaldehydes; D004791:Enzyme Inhibitors; C100058:vanillin
keywords: In silico docking; Kinetic mechanism; Mushroom tyrosinase inhibitors; Synthesis; Vanillin derivatives