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Synthesis, computational molecular docking analysis and effectiveness on tyrosinase inhibition of kojic acid derivatives. 2019

Gülşah Karakaya, and Aslı Türe, and Ayşe Ercan, and Selin Öncül, and Mutlu Dilsiz Aytemir
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.

Tyrosinase inhibitors have become increasingly important as whitening agents and for the treatment of pigmentary disorders. In this study, the synthesis of kojic acid derivatives having 2-substituted-3-hydroxy-6-hyroxymethyl/chloromethyl/methyl/morpholinomethylpiperidinyl- methyl/pyrrolidinylmethyl-4H-pyran-4-one structure (compounds 1-30) with inhibitory effects on tyrosinase enzyme were described. One-pot Mannich reaction was carried out by using kojic acid/chlorokojic acid/allomaltol and substituted benzylpiperazine derivatives in presence of formaline. Subsequently, cyclic amine (morpholine, piperidine and pyrrolidine) derivatives of the 6th-position of chlorokojic acid were obtained with nucleophilic substitutions in basic medium. The structures of new compounds were identified by FT-IR, 1H- and 13C NMR, ESI-MS and elemental analysis data. The potential mushroom tyrosinase inhibitory activity of the compounds were evaluated by the spectrophotometric method using l-DOPA as a substrate and kojic acid as the control agent. The potential inhibitory activity was also investigated in silico using molecular docking simulation method. Tyrosinase inhibitory action was significantly more efficacious for several compounds (IC50: 86.2-362.1 µM) than kojic acid (IC50: 418.2). Compound 3 bearing 3,4-dichlorobenzyl piperazine moiety was proven to have the highest inhibitory activity. The results of docking studies showed that according to the predicted conformation of compound 3 in the enzyme binding site, hydroxymethyl group provides a metal complex with copper ions and enzyme. Thus, this interaction explain the high inhibitory activities of the compounds 1, 3 and 4 possessing hydroxymethyl substituent supporting the mushroom assay results with docking studies. In accordance with the results, it is suggested that Mannich bases of kojic acid bearing substituted benzyl piperazine groups (compounds 1, 3, 4, 11, 13, 14, 23, 24, 28, and 29) could be promising antityrosinase agents. Additionally, considering the relationship between tyrosinase inhibitory activity results and molecular docking, a new tyrosinase inhibition mechanism can be proposed.

UI MeSH Term Description Entries
D011753 Pyrones Keto-pyrans.
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D000363 Agaricales An extensive order of basidiomycetous fungi whose fruiting bodies are commonly called mushrooms. Agaricaceae,Mushrooms,Agaricale,Mushroom
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D014442 Monophenol Monooxygenase An enzyme of the oxidoreductase class that catalyzes the reaction between L-tyrosine, L-dopa, and oxygen to yield L-dopa, dopaquinone, and water. It is a copper protein that acts also on catechols, catalyzing some of the same reactions as CATECHOL OXIDASE. EC 1.14.18.1. Dopa Oxidase,Phenoloxidase,Tyrosinase,Cresolase,Phenol Oxidase,Phenoloxidase A,Phenoloxidase B,Monooxygenase, Monophenol,Oxidase, Dopa,Oxidase, Phenol
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D062105 Molecular Docking Simulation A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein. Molecular Docking,Molecular Docking Simulations,Molecular Docking Analysis,Analysis, Molecular Docking,Docking Analysis, Molecular,Docking Simulation, Molecular,Docking, Molecular,Molecular Docking Analyses,Molecular Dockings,Simulation, Molecular Docking

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