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Synthesis, computational molecular docking analysis and effectiveness on tyrosinase inhibition of kojic acid derivatives.
Bioorg Chem. 2019 07; 88:102950.BC

Abstract

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.

Authors+Show Affiliations

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, İstanbul, Turkey.Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey. Electronic address: mutlud@hacettepe.edu.tr.

Pub Type(s)

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

Language

eng

PubMed ID

31075740

Citation

Karakaya, Gülşah, et al. "Synthesis, Computational Molecular Docking Analysis and Effectiveness On Tyrosinase Inhibition of Kojic Acid Derivatives." Bioorganic Chemistry, vol. 88, 2019, p. 102950.
Karakaya G, Türe A, Ercan A, et al. Synthesis, computational molecular docking analysis and effectiveness on tyrosinase inhibition of kojic acid derivatives. Bioorg Chem. 2019;88:102950.
Karakaya, G., Türe, A., Ercan, A., Öncül, S., & Aytemir, M. D. (2019). Synthesis, computational molecular docking analysis and effectiveness on tyrosinase inhibition of kojic acid derivatives. Bioorganic Chemistry, 88, 102950. https://doi.org/10.1016/j.bioorg.2019.102950
Karakaya G, et al. Synthesis, Computational Molecular Docking Analysis and Effectiveness On Tyrosinase Inhibition of Kojic Acid Derivatives. Bioorg Chem. 2019;88:102950. PubMed PMID: 31075740.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis, computational molecular docking analysis and effectiveness on tyrosinase inhibition of kojic acid derivatives. AU - Karakaya,Gülşah, AU - Türe,Aslı, AU - Ercan,Ayşe, AU - Öncül,Selin, AU - Aytemir,Mutlu Dilsiz, Y1 - 2019/04/27/ PY - 2019/01/17/received PY - 2019/04/16/revised PY - 2019/04/23/accepted PY - 2019/5/11/pubmed PY - 2019/5/11/medline PY - 2019/5/11/entrez KW - Kojic acid KW - Mannich reaction KW - Molecular docking KW - Tyrosinase inhibition SP - 102950 EP - 102950 JF - Bioorganic chemistry JO - Bioorg. Chem. VL - 88 N2 - 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. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/31075740/Synthesis_computational_molecular_docking_analysis_and_effectiveness_on_tyrosinase_inhibition_of_kojic_acid_derivatives_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0045-2068(19)30078-1 DB - PRIME DP - Unbound Medicine ER -
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