Skip to content
2000
Volume 21, Issue 8
  • ISSN: 1573-4064
  • E-ISSN: 1875-6638

Abstract

Introduction

Tyrosinase, a key enzyme in melanin biosynthesis and food browning, has become an important target for inhibitor development. This study aimed to investigate the inhibitory potential of 4,6-dihydroxyaurone derivatives with varied ring B substituents on mushroom tyrosinase.

Methods

A set of 4,6-dihydroxyaurone derivatives, each with varied substituent patterns on ring B, were designed and subjected to computational studies to predict their binding affinity, binding modes with tyrosinase, and drug-likeness properties. These aurone derivatives were subsequently synthesized and evaluated for their tyrosinase inhibitory activity. Enzyme kinetics studies were conducted to determine the mode of tyrosinase inhibition.

Results

Computational studies of the twenty designed aurone derivatives indicated their strong binding within the active site and exhibited favorable drug-likeness properties. UV-Vis spectrophotometric assays of the synthesized compounds revealed that compound , featuring a 3,4-dichlorophenyl substituent on ring B, showed the most potent tyrosinase inhibitory activity (IC = 6.3 ± 0.3 µM) compared to kojic acid (IC = 136.5 ± 11.5 µM). Kinetic studies and molecular docking simulations indicated that compound inhibits tyrosinase through a mixed-type inhibition mechanism, with competitive and uncompetitive inhibition constants of 21 µM and 68 µM, respectively.

Conclusion

These findings highlight the promising potential of 4,6-dihydroxyaurone derivatives as potent tyrosinase inhibitors for applications in pharmaceuticals, cosmetics, and agriculture.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/mc/10.2174/0115734064371213250508115259
2025-05-15
2025-11-14

  • From This Site

    /content/journals/mc/10.2174/0115734064371213250508115259
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. ItoS. WakamatsuK. Chemistry of Melanins.In: The Pigmentary System: Physiology and Pathophysiology.Wiley2006282310
     [Google Scholar]
  2. RileyP.A. Melanogenesis and melanoma.Pigment Cell Res.200316554855210.1034/j.1600‑0749.2003.00069.x12950735
     [Google Scholar]
  3. SlominskiA. TobinD.J. ShibaharaS. WortsmanJ. Melanin pigmentation in mammalian skin and its hormonal regulation.Physiol. Rev.20048441155122810.1152/physrev.00044.200315383650
     [Google Scholar]
  4. RaoA.R. SindhujaH.N. DharmeshS.M. SankarK.U. SaradaR. RavishankarG.A. Effective inhibition of skin cancer, tyrosinase, and antioxidative properties by astaxanthin and astaxanthin esters from the green alga Haematococcus pluvialis.J. Agric. Food Chem.201361163842385110.1021/jf304609j23473626
     [Google Scholar]
  5. MulawaM.E. NiczyporukM. Skin pigmentation changes, causes and methods of their elimination.Pol. J. Appl. Sci.2024922834
     [Google Scholar]
  6. Casanola-MartinG. Le-Thi-ThuH. Marrero-PonceY. Castillo-GaritJ. TorrensF. RescignoA. AbadC. KhanM. Tyrosinase enzyme: 1. An overview on a pharmacological target.Curr. Top. Med. Chem.201414121494150110.2174/156802661466614052312142724853560
     [Google Scholar]
  7. SeoS.Y. SharmaV.K. SharmaN. Mushroom tyrosinase: Recent prospects.J. Agric. Food Chem.200351102837285310.1021/jf020826f12720364
     [Google Scholar]
  8. SchallreuterK.U. KothariS. ChavanB. SpencerJ.D. Regulation of melanogenesis – controversies and new concepts.Exp. Dermatol.200817539540410.1111/j.1600‑0625.2007.00675.x18177348
     [Google Scholar]
  9. ChangT.S. An updated review of tyrosinase inhibitors.Int. J. Mol. Sci.20091062440247510.3390/ijms1006244019582213
     [Google Scholar]
  10. PengZ. WangG. ZengQ.H. LiY. LiuH. WangJ.J. ZhaoY. A systematic review of synthetic tyrosinase inhibitors and their structure-activity relationship.Crit. Rev. Food Sci. Nutr.202262154053409410.1080/10408398.2021.187172433459057
     [Google Scholar]
  11. ZacharyC.M. WangJ.V. SaediN. Kojic acid for melasma: Popular ingredient in skincare products.Skinmed2006185271273
     [Google Scholar]
  12. GuptaA.K. GoverM.D. NouriK. TaylorS. The treatment of melasma: A review of clinical trials.J. Am. Acad. Dermatol.20065561048106510.1016/j.jaad.2006.02.00917097400
     [Google Scholar]
  13. O’DonoghueJ.L. Hydroquinone and its analogues in dermatology: A risk‐benefit viewpoint.J. Cosmet. Dermatol.20065319620310.1111/j.1473‑2165.2006.00253.x17177740
     [Google Scholar]
  14. NewmanD.J. CraggG.M. Natural products as sources of new drugs over the last 25 years.J. Nat. Prod.200770346147710.1021/np068054v17309302
     [Google Scholar]
  15. BeutlerJ.A. Natural products as a foundation for drug discovery.Curr Protoc Pharmacol20094619.11.19.11.21.10.1002/0471141755.ph0911s46
     [Google Scholar]
  16. ToplissJ.G. ClarkA.M. ErnstE. HuffordC.D. JohnstonG.A.R. RimoldiJ.M. WeimannB.J. Natural and synthetic substances related to human health (IUPAC Technical Report).Pure Appl. Chem.200274101957198510.1351/pac200274101957
     [Google Scholar]
  17. ShubinD.A. KuznetsovD.N. KobrakovK.I. StarosotnikovA.M. MerkulovaN.L. Synthesis of aurone derivatives on the basis of 2,4,6-trihydroxytoluene.Chem. Heterocycl. Compd.201955121174117810.1007/s10593‑019‑02597‑0
     [Google Scholar]
  18. NakayamaT. Biochemistry and regulation of aurone biosynthesis.Biosci. Biotechnol. Biochem.202286555757310.1093/bbb/zbac03435259212
     [Google Scholar]
  19. PopovaA.V. BondarenkoS.P. FrasinyukM.S. Aurones: Synthesis and properties.Chem. Heterocycl. Compd.2019554-528529910.1007/s10593‑019‑02457‑x
     [Google Scholar]
  20. HaudecoeurR. BoumendjelA. Recent advances in the medicinal chemistry of aurones.Curr. Med. Chem.201219182861287510.2174/09298671280067208522519399
     [Google Scholar]
  21. ZwergelC GaaschtF ValenteS DiederichM BagrelD KirschG Interesting natural and synthetic compounds with emerging biological potential.Nat. Product Commun2012731934578X1200700322.10.1177/1934578X1200700322
     [Google Scholar]
  22. DemirayakS. YurttasL. Gundogdu-KaraburunN. KaraburunA.C. KayagilI. Synthesis and anti-cancer activity evaluation of new aurone derivatives.J. Enzyme Inhib. Med. Chem.201530581682510.3109/14756366.2014.97656825716125
     [Google Scholar]
  23. HaudecoeurR. CarottiM. GouronA. MarescaM. BuitragoE. HardréR. BergantinoE. JametH. BelleC. RéglierM. BubaccoL. BoumendjelA. 2-Hydroxypyridine- N -oxide-embedded aurones as potent human tyrosinase inhibitors.ACS Med. Chem. Lett.201781556010.1021/acsmedchemlett.6b0036928105275
     [Google Scholar]
  24. AlshayeN.A. MughalE.U. ElkaeedE.B. AshrafZ. KehiliS. NazirY. NaeemN. Abdul MajeedN. SadiqA. Synthesis and biological evaluation of substituted aurone derivatives as potential tyrosinase inhibitors: In vitro, kinetic, QSAR, docking and drug-likeness studies.J. Biomol. Struct. Dyn.202341178307832210.1080/07391102.2022.213229636255179
     [Google Scholar]
  25. KostopoulouI. DetsiA. Recent developments on tyrosinase inhibitors based on the chalcone and aurone scaffolds.Curr. Enzym. Inhib.201814131710.2174/1573408013666170208102614
     [Google Scholar]
  26. OkombiS. RivalD. BonnetS. MariotteA.M. PerrierE. BoumendjelA. Discovery of benzylidenebenzofuran-3(2H)-one (aurones) as inhibitors of tyrosinase derived from human melanocytes.J. Med. Chem.200649132933310.1021/jm050715i16392817
     [Google Scholar]
  27. RoulierB. RushI. LazinskiL.M. PérèsB. OlleikH. RoyalG. FishmanA. MarescaM. HaudecoeurR. Resorcinol-based hemiindigoid derivatives as human tyrosinase inhibitors and melanogenesis suppressors in human melanoma cells.Eur. J. Med. Chem.202324611497210.1016/j.ejmech.2022.11497236462443
     [Google Scholar]
  28. VoT.C.V. DaoQ.M. VoH.M. TranH.P. HuynhN.H.P. Microwave-assisted synthesis of 4,6-dihydroxyaurone derivatives.VJST2023652182210.31276/VJST.65(2).18‑22
     [Google Scholar]
  29. IsmayaW.T. RozeboomH.J. WeijnA. MesJ.J. FusettiF. WichersH.J. DijkstraB.W. Crystal structure of Agaricus bisporus mushroom tyrosinase: Identity of the tetramer subunits and interaction with tropolone.Biochemistry201150245477548610.1021/bi200395t21598903
     [Google Scholar]
  30. MorrisG.M. HueyR. LindstromW. SannerM.F. BelewR.K. GoodsellD.S. OlsonA.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility.J. Comput. Chem.200930162785279110.1002/jcc.2125619399780
     [Google Scholar]
  31. O’BoyleN.M. BanckM. JamesC.A. MorleyC. VandermeerschT. HutchisonG.R. Open Babel: An open chemical toolbox.J. Cheminform.2011313310.1186/1758‑2946‑3‑3321982300
     [Google Scholar]
  32. McNuttA.T. FrancoeurP. AggarwalR. MasudaT. MeliR. RagozaM. SunseriJ. KoesD.R. GNINA 1.0: Molecular docking with deep learning.J. Cheminform.20211314310.1186/s13321‑021‑00522‑234108002
     [Google Scholar]
  33. FrancoeurP.G. MasudaT. SunseriJ. JiaA. IovanisciR.B. SnyderI. KoesD.R. Three-dimensional convolutional neural networks and a cross-docked data set for structure-based drug design.J. Chem. Inf. Model.20206094200421510.1021/acs.jcim.0c0041132865404
     [Google Scholar]
  34. DainaA. MichielinO. ZoeteV. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules.Sci. Rep.2017714271710.1038/srep4271728256516
     [Google Scholar]
  35. BeneyC. MariotteA-M. BoumandjelA. An efficient synthesis of 4, 6-dimethoxyaurones. Heterocycles-Sendai Inst. Heterocycl.Chem2001555967972
     [Google Scholar]
  36. WinderA.J. HarrisH. New assays for the tyrosine hydroxylase and dopa oxidase activities of tyrosinase.Eur. J. Biochem.1991198231732610.1111/j.1432‑1033.1991.tb16018.x1674912
     [Google Scholar]
  37. Rodríguez-LópezJ.N. TudelaJ. VarónR. García-CarmonaF. García-CánovasF. Analysis of a kinetic model for melanin biosynthesis pathway.J. Biol. Chem.199226763801381010.1016/S0021‑9258(19)50597‑X1740428
     [Google Scholar]
  38. NohH. LeeSJ. JoHJ. ChoiH.W. HongS. KongKH. Histidine residues at the copper-binding site in human tyrosinase are essential for its catalytic activities.J. Enzyme Inhib. Med. Chem.202035172673210.1080/14756366.2020.174069132180482
     [Google Scholar]
  39. GouL. LüZ.R. ParkD. OhS.H. ShiL. ParkS.J. BhakJ. ParkY.D. RenZ.L. ZouF. The effect of histidine residue modification on tyrosinase activity and conformation: Inhibition kinetics and computational prediction.J. Biomol. Struct. Dyn.200826339540110.1080/07391102.2008.1050725418808205
     [Google Scholar]
  40. AguileraF. McDougallC. DegnanB.M. Origin, evolution and classification of type-3 copper proteins: Lineage-specific gene expansions and losses across the Metazoa.BMC Evol. Biol.20131319610.1186/1471‑2148‑13‑9623634722
     [Google Scholar]
  41. BeaumetM. LazinskiL.M. MarescaM. HaudecoeurR. Tyrosinase inhibition and antimelanogenic effects of resorcinol‐containing compounds.ChemMedChem20241923e20240031410.1002/cmdc.20240031439105380
     [Google Scholar]
  42. Thi VoC.V. Thanh NguyenT. Ngoc DangT. Quoc DaoM. Thao VoV. Thi TranO. Thanh VuL. TranT.D. Design, synthesis, biological evaluation and molecular docking of alkoxyaurones as potent pancreatic lipase inhibitors.Bioorg. Med. Chem. Lett.20249812957410.1016/j.bmcl.2023.12957438052378
     [Google Scholar]
  43. SmithB.C. Spectroscopy(31), Fundamentals of FTIR and Infrared Spectral Interpretation.LondonCRC Press20162834
     [Google Scholar]
  44. ElhadiA.A. OsmanH. IqbalM.A. RajeswariS.K. AhamedM.B.K. Abdul MajidA.M.S. RosliM.M. RazakI.A. MajidA.S.A. Synthesis and structural elucidation of two new series of aurone derivatives as potent inhibitors against the proliferation of human cancer cells.Med. Chem. Res.20152493504351510.1007/s00044‑015‑1400‑2
     [Google Scholar]
  45. DeriB. KanteevM. GoldfederM. LecinaD. GuallarV. AdirN. FishmanA. The unravelling of the complex pattern of tyrosinase inhibition.Sci. Rep.2016613499310.1038/srep3499327725765
     [Google Scholar]
  46. SaghaieL. PourfarzamM. FassihiA. SartippourB. Synthesis and tyrosinase inhibitory properties of some novel derivatives of kojic acid.Res. Pharm. Sci.201384233242[PMID: 24082892
     [Google Scholar]
  47. DuboisC. HaudecoeurR. OrioM. BelleC. BochotC. BoumendjelA. HardréR. JametH. RéglierM. Versatile effects of aurone structure on mushroom tyrosinase activity.ChemBioChem201213455956510.1002/cbic.20110071622307818
     [Google Scholar]
  48. HassaniS. HaghbeenK. FazliM. Non-specific binding sites help to explain mixed inhibition in mushroom tyrosinase activities.Eur. J. Med. Chem.201612213814810.1016/j.ejmech.2016.06.01327344491
     [Google Scholar]
  49. MasuriS. EraB. PintusF. CadoniE. CabidduM.G. FaisA. PivettaT. Hydroxylated coumarin-based thiosemicarbazones as dual antityrosinase and antioxidant agents.Int. J. Mol. Sci.2023242167810.3390/ijms2402167836675192
     [Google Scholar]
/content/journals/mc/10.2174/0115734064371213250508115259
Loading
Natural Mimetic 4,6-Dihydroxyaurone Derivatives as Tyrosinase Inhibitors: Design, Synthesis, and Biological Evaluation
Med. Chem. 21, 880 (2025); https://doi.org/10.2174/0115734064371213250508115259
/content/journals/mc/10.2174/0115734064371213250508115259
/content/journals/mc/10.2174/0115734064371213250508115259
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): ADME; aurone; inhibition; melanogenesis; molecular docking; Tyrosinase

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test