Benzylidene-6-hydroxy-3,4-dihydronaphthalenone chalconoids as potent tyrosinase inhibitors

Sara Ranjbar , Mehraneh Mohammadabadi Kamarei, Mahsima Khoshneviszadeh, Hona Hosseinpoor, Najmeh Edraki, Mehdi Khoshneviszadeh


Background and purpose: Tyrosinase enzyme has a key role in melanin biosynthesis by converting tyrosine into dopaquinone. It also participates in the enzymatic browning of vegetables by polyphenol oxidation. Therefore, tyrosinase inhibitors are useful in the fields of medicine, cosmetics, and agriculture. Many tyrosinase inhibitors having drawbacks have been reported to date; so, finding new inhibitors is a great need.

Experimental approach: A variety of 6-hydroxy-3,4-dihydronaphthalenone chalcone-like analogs (C1-C10) have been synthesized by aldol condensation of 6-hydroxy tetralone and differently substituted benzaldehydes. The compounds were evaluated for their inhibitory effect on mushroom tyrosinase by a spectrophotometric method. Moreover, the inhibition manner of the most active compound was determined by Lineweaver-Burk plots. Docking study was done using AutoDock 4.2. The drug-likeness scores and ADME features of the active derivatives were also predicted.

Results/Findings: Most of the compounds showed remarkable inhibitory activity against the tyrosinase enzyme. 6-Hydroxy-2-(3,4,5-trimethoxybenzylidene)-3,4-dihydronaphthalen-1(2H)-one (C2) was the most potent derivative amongst the series with an IC50 value of 8.8 μM which was slightly more favorable to that of the reference kojic acid (IC50 = 9.7 μM). Inhibitory kinetic studies revealed that C2 behaves as a competitive inhibitor. According to the docking results, compound C2 formed the most stable enzyme-inhibitor complex, mainly via establishing interactions with the two copper ions in the active site. In silico drug-likeness and pharmacokinetics predictions for the proposed tyrosinase inhibitors revealed that most of the compounds including C2 have proper drug-likeness scores and pharmacokinetic properties.

Conclusion and implications: Therefore, C2 could be suggested as a promising tyrosinase inhibitor that might be a good lead compound in medicine, cosmetics, and the food industry, and further drug development of this compound might be of great interest.




Keywords: Anti-tyrosinase activity; Chalcones; Drug-likeness; Kinetic studies; Molecular docking; Tyrosinase inhibitor.

Full Text:



Seo SY, Sharma VK, Sharma N. Mushroom tyrosinase: recent prospects. J Agric Food Chem. 2003;51(10):2837-2853.

DOI: 10.1021/jf020826f.

Lai X, Wichers HJ, Soler‐Lopez M, Dijkstra BW. Structure and function of human tyrosinase and tyrosinase‐related proteins. Chem Eur J. 2018;24(1):47-55.

DOI: 10.1002/chem.201704410.

Korner A, Pawelek J. Mammalian tyrosinase catalyzes three reactions in the biosynthesis of melanin. Science. 1982;217(4565):1163-1165.

DOI: 10.1126/science.6810464.

Parvez S, Kang M, Chung HS, Bae H. Naturally occurring tyrosinase inhibitors: mechanism and applications in skin health, cosmetics and agriculture industries. Phytother Res. 2007;21(9):805-816.

DOI: 10.1002/ptr.2184.

Pillaiyar T, Manickam M, Namasivayam V. Skin whitening agents: medicinal chemistry perspective of tyrosinase inhibitors. J Enzyme Inhib Med Chem. 2017;32(1):403-425.

DOI: 10.1080/14756366.2016.1256882.

Pandya AG, Guevara IL. Disorders of hyperpigmentation. Dermatol Clin. 2000;18(1):91-98.

DOI: 10.1016/s0733-8635(05)70150-9.

You A, Zhou J, Song S, Zhu G, Song H, Yi W. Structure-based modification of 3-/4-aminoacetophenones giving a profound change of activity on tyrosinase: from potent activators to highly efficient inhibitors. Eur J Med Chem. 2015;93:255-262.

DOI: 10.1016/j.ejmech.2015.02.013.

Tief K, Schmidt A, Beermann F. New evidence for presence of tyrosinase in substantia nigra, forebrain and midbrain. Brain Res Mol Brain Res. 1998;53(1-2):307-310.

DOI: 10.1016/s0169-328x(97)00301-x.

Carballo-Carbajal I, Laguna A, Romero-Giménez J, Cuadros T, Bové J, Martinez-Vicente M, et al. Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis. Nat Commun. 2019;10(1):973-991.

DOI: 10.1038/s41467-019-08858-y.

Hasegawa T. Tyrosinase-expressing neuronal cell line as in vitro model of Parkinson’s disease. Int J Mol Sci. 2010;11(3):1082-1089.

DOI: 10.3390/ijms11031082.

Zolghadri S, Bahrami A, Hassan Khan MT, Munoz-Munoz J, Garcia-Molina F, Garcia-Canovas F, et al. A comprehensive review on tyrosinase inhibitors. J Enzyme Inhib Med Chem. 2019;34(1):279-309.

DOI: 10.1080/14756366.2018.1545767.

Nerya O, Ben-Arie R, Luzzatto T, Musa R, Khativ S, Vaya J. Prevention of Agaricus bisporus postharvest browning with tyrosinase inhibitors. Postharvest Biol Technol. 2006;39(3):272-277.

DOI: 10.1016/j.postharvbio.2005.11.001.

Eghbali-Feriz S, Taleghani A, Al-Najjar H, Emami SA, Rahimi H, Asili J, et al. Anti-melanogenesis and anti-tyrosinase properties of Pistacia atlantica subsp. mutica extracts on B16F10 murine melanoma cells. Res Pharm Sci. 2018;13(6):533-545.

DOI: 10.4103/1735-5362.245965.

Saghaie L, Pourfarzam M, Fassihi A, Sartippour B. Synthesis and tyrosinase inhibitory properties of some novel derivatives of kojic acid. Res Pharm Sci. 2013;8(4):233-242.

Ranjbar S, Shahvaran PS, Edraki N, Khoshneviszadeh M, Darroudi M, Sarrafi Y, et al. 1,2,3‐Triazole‐linked 5‐benzylidene (thio) barbiturates as novel tyrosinase inhibitors and free‐radical scavengers. Arch Pharm. 2020;353(10):2000058.

DOI: 10.1002/ardp.202000058.

Karimian S, Ranjbar S, Dadfar M, Khoshneviszadeh M, Gholampour M, Sakhteman A, et al. 4H-benzochromene derivatives as novel tyrosinase inhibitors and radical scavengers: synthesis, biological evaluation, and molecular docking analysis. Mol Divers. 2020:1-11.

DOI: 10.1007/s11030-020-10123-0.

Darroudi M, Ranjbar S, Esfandiar M, Khoshneviszadeh M, Hamzehloueian M, Khoshneviszadeh M, et al. Synthesis of novel triazole incorporated thiazolone motifs having promising antityrosinase activity through green nanocatalyst CuI‐Fe3O4@ SiO2 (TMS‐EDTA). Appl Organomet Chem. 2020;34(12):e5962.

DOI: 10.1002/aoc.5962.

Chang TS. An updated review of tyrosinase inhibitors. Int J Mol Sci. 2009;10(6):2440-2475.

DOI: 10.3390/ijms10062440.

Ito N, Hirose M, Fukushima S, Tsuda H, Shirai T, Tatematsu M. Studies on antioxidants: their carcinogenic and modifying effects on chemical carcinogenesis. Food Chem Toxicol. 1986;24(10-11):1071-1082.

DOI: 10.1016/0278-6915(86)90291-7.

Rammohan A, Reddy JS, Sravya G, Rao CN, Zyryanov GV. Chalcone synthesis, properties and medicinal applications: a review. Environ Chem Lett. 2020;18:433-458.

DOI: 10.1007/s10311-019-00959-w.

Rocha S, Ribeiro D, Fernandes E, Freitas M. A systematic review on anti-diabetic properties of chalcones. Curr Med Chem. 2020;27(14):2257-2321.

DOI: 10.2174/0929867325666181001112226.

Kar Mahapatra D, Asati V, Bharti SK. An updated patent review of therapeutic applications of chalcone derivatives (2014-present). Expert Opin Ther Pat. 2019;29(5):385-406.

DOI: 10.1080/13543776.2019.1613374.

Mousavi ZSZ, Zarghi A, Alipour E. The synthesis of chalcon derivatives containing epoxide SO2Me with potential anticancerous effects. Res Pharm Sci. 2012;7(5):S613.

Akhtar MN, Sakeh NM, Zareen S, Gul S, Lo KM, Ul-Haq Z, et al. Design and synthesis of chalcone derivatives as potent tyrosinase inhibitors and their structural activity relationship. J Mol Struct. 2015;1085:97-103.

DOI: 10.1016/j.molstruc.2014.12.073.

Kostopoulou I, Detsi A. Recent developments on tyrosinase inhibitors based on the chalcone and aurone scaffolds. Curr Enzym Inhib. 2018;14:3-17.

DOI: 10.2174/1573408013666170208102614.

Khatib S, Nerya O, Musa R, Shmuel M, Tamir S, Vaya J. Chalcones as potent tyrosinase inhibitors: the importance of a 2,4-substituted resorcinol moiety. Bioorg Med Chem. 2005;13(2):433-441.

DOI: 10.1016/j.bmc.2004.10.010.

Ranjbar S, Akbari A, Edraki N, Khoshneviszadeh M, Hemmatian H, Firuzi O, et al. 6-Methoxy-3,4-dihydronaphthalenone chalcone-like derivatives as potent tyrosinase inhibitors and radical scavengers. Lett Drug Des Discov. 2018;15(11):1170-1179.

DOI: 10.2174/1570180815666180219155027.

Ghafari S, Ranjbar S, Larijani B, Amini M, Biglar M, Mahdavi M, et al. Novel morpholine containing cinnamoyl amides as potent tyrosinase inhibitors. Int J Biol Macromol. 2019;135:978-985.

DOI: 10.1016/j.ijbiomac.2019.05.201.

Dehghani Z, Khoshneviszadeh M, Khoshneviszadeh M, Ranjbar S. Veratric acid derivatives containing benzylidene-hydrazine moieties as promising tyrosinase inhibitors and free radical scavengers. Bioorg Med Chem. 2019;27(12):2644-2651.

DOI: 10.1016/j.bmc.2019.04.016.

Tehrani MB, Emani P, Rezaei Z, Khoshneviszadeh M, Ebrahimi M, Edraki N, et al. Phthalimide-1,2,3-triazole hybrid compounds as tyrosinase inhibitors; synthesis, biological evaluation and molecular docking analysis. J Mol Struct. 2019;1176:86-93.

DOI: 10.1016/j.molstruc.2018.08.033.

Yee SW, Jarno L, Gomaa MS, Elford C, Ooi LL, Coogan MP, et al. Novel tetralone-derived retinoic acid metabolism blocking agents: synthesis and in vitro evaluation with liver microsomal and MCF-7 CYP26A1 cell assays. J Med Chem. 2005;48(23):7123-7131.

DOI: 10.1021/jm0501681.

Mahdavi M, Ashtari A, Khoshneviszadeh M, Ranjbar S, Dehghani A, Akbarzadeh T, et al. Synthesis of new benzimidazole‐1,2,3‐triazole hybrids as tyrosinase inhibitors. Chem Biodivers. 2018;15(7):e1800120.

DOI: 10.1002/cbdv.201800120.

Yee SW, Simons C. Synthesis and CYP24 inhibitory activity of 2-substituted-3,4-dihydro-2H-naphthalen-1-one (tetralone) derivatives. Bioorg Med Chem Lett. 2004;14(22):5651-5654.

DOI: 10.1016/j.bmcl.2004.08.040.

Asadi P, Khodarahmi G, Farrokhpour H, Hassanzadeh F, Saghaei L. Quantum mechanical/molecular mechanical and docking study of the novel analogues based on hybridization of common pharmacophores as potential anti-breast cancer agents. Res Pharm Sci. 2017;12(3):233-240.

DOI: 10.4103/1735-5362.207204.

Khodarahmi G, Asadi P, Farrokhpour H, Hassanzadeh F, Dinari M. Design of novel potential aromatase inhibitors via hybrid pharmacophore approach: docking improvement using the QM/MM method. RSC Adv. 2015;5:58055-58064.

DOI: 10.1039/C5RA10097F.

Zhang X, Hu X, Hou A, Wang H. Inhibitory effect of 2,4,2′,4′-tetrahydroxy-3-(3-methyl-2-butenyl)-chalcone on tyrosinase activity and melanin biosynthesis. Biol Pharm Bull. 2009;32(1):86-90.

DOI: 10.1248/bpb.32.86.


  • There are currently no refbacks.

Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.