Anti-tyrosinase Activity of 3’,4’,5’-Trimethoxychalcones: Experimental and Computational Studies
Article Sidebar
Keywords:
-
Anti-tyronase, Trimethoxychalcones, Molecular Docking, Molecular Dinamics
Abstract
Tyrosinase inhibitors are utilized as preservatives in the food industry and skin-lightening agents in the medical and cosmetic sectors. However, there has been little progress in clinical trials owing to challenges such as low bioavailability, significant skin irritation, and instability. Hence, the objective of this study was to evaluate the inhibitory activity of 3’,4’,5’-trimethoxychalcones through in vitro, molecular docking and molecular dynamics studies targeting tyrosinase. Five 3’,4’,5’-trimethoxychalcones (1-5) were evaluated their biological activity against tyrosinase for the first time. Compounds 4 and 5 were excellent inhibitory activity against tyrosinase with IC50 values of 1.9 and 1.7 μm compared with kojic acid and ascorbic acid. Isovanillin and catechol moieties are vital in this present study. This result was supported with molecular docking by shaping interaction in the catalytic site with histidine residues and the stability evaluation of the inhibitor-protein complexes using molecular dynamics simulation. The lipinski’s rules showed a fit with two potential inhibitors (4, 5). Therefore, 3’,4’,5’-trimethoxychalcones possessing isovanillin and catechol parts in the B ring are promising candidate for further study as tyrosinase inhibitors by evaluating their efficacy in vitro and in vivo.
References
Afzal, M., R. Mehmood, E. U. Mughal, N. Naeem, Z. Ashraf, Y. Nazir, F. M. Shalaby, A. E.-S. Abd El Hady, and A. Sadiq (2024). Elucidating Bis-Pyrimidines as New and Efficient Mushroom Tyrosinase Inhibitors: Synthesis, SAR, Kinetics and Computational Studies. RSC Advances, 14(31); 22769–22780
Akhtar, M. N., N. M. Sakeh, S. Zareen, S. Gul, K. M. Lo, Z. Ul-Haq, S. A. A. Shah, and S. Ahmad (2015). Design and Synthesis of Chalcone Derivatives as Potent Tyrosinase Inhibitors and Their Structural Activity Relationship. Journal of Molecular Structure, 1085; 97–103
Arndt, K. A. and T. B. Fitzpatrick (1965). Topical Use of Hydroquinone as a Depigmenting Agent. JAMA, 194(9); 965–967
Barrett, F. M. (1984). Wound-Healing Phenoloxidase in Larval Cuticle of Calpodes ethlius (Lepidoptera: Hesperiidae). Canadian Journal of Zoology, 62(5); 834–838
Benet, L. Z., C. M. Hosey, O. Ursu, and T. I. Oprea (2016). BDDCS, the Rule of 5 and Drugability. Advanced Drug Delivery Reviews, 101; 89–98
Boo, Y. C. (2021). Arbutin as a Skin Depigmenting Agent with Antimelanogenic and Antioxidant Properties. Antioxidants, 10(7); 1129
Breathnach, A. C., M. Nazzaro-Porro, S. Passi, and G. Zina (1989). Azelaic Acid Therapy in Disorders of Pigmentation. Clinics in Dermatology, 7(2); 106–119
Cai, P., Y. Xiong, Y. Yao, W. Chen, and X. Dong (2019). Synthesis, Screening and Biological Activity of Potent Thiosemicarbazone Compounds as a Tyrosinase Inhibitor. New Journal of Chemistry, 43(35); 14102–14111
Casadevall, A., R. J. Cordero, R. Bryan, J. Nosanchuk, and E. Dadachova (2017). Melanin, Radiation, and Energy Transduction in Fungi. Microbiology Spectrum, 5(2); 10.1128/microbiolspec.funk–0037–2016
Chen, C.-Y., L.-C. Lin, W.-F. Yang, J. Bordon, and H.-M. D. Wang (2015). An Updated Organic Classification of Tyrosinase Inhibitors on Melanin Biosynthesis. Current Organic Chemistry, 19(1); 4–18
Choi, H., I. Y. Ryu, I. Choi, S. Ullah, H. J. Jung, Y. Park, Y. Hwang, Y. Jeong, S. Hong, and P. Chun (2022). Identification of (Z)-2-Benzylidene-Dihydroimidazothiazolone Derivatives as Tyrosinase Inhibitors: Anti-Melanogenic Effects and In silico Studies. Computational and Structural Biotechnology Journal, 20; 899–912
Chumkaew, P., S. Jumrat, and Y. Pianroj (2024). New Chalcone Derivative from Persea americana and Its Anti-Tyrosinase Activity. Chemistry of Natural Compounds, 60(4); 625–628
Daina, A., O. Michielin, and V. Zoete (2017). SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug-Likeness and Medicinal Chemistry Friendliness of Small Molecules. Scientific Reports, 7(1); 42717
Dallakyan, S. and A. J. Olson (2015). Small-Molecule Library Screening by Docking with PyRx. In J. E. Hempel, C. H. Williams, and C. C. Hong (Eds.), Chemical Biology: Methods and Protocols. Springer New York, pp. 243–250
Danova, A., Y. E. Maulana, E. Hermawati, and W. Chavasiri (2023a). Synthesis, Evaluation, and Molecular Docking Study of 4-Monoacyl Resorcinol Against Tyrosinase Enzyme. Indonesian Journal of Chemical Research, 11(2); 135–141
Danova, A., D. V. Nguyen, R. Toyoda, P. Mahalapbutr, T. Rungrotmongkol, P. Wonganan, and W. Chavasiri (2023b). 3’,4’,5’-Trimethoxy- and 3,4-Dimethoxychalcones Targeting A549 Cells: Synthesis, Cytotoxic Activity, and Molecular Docking. Journal of Molecular Structure, 1275; 134572
Duan, Y., C. Wu, S. Chowdhury, M. C. Lee, G. Xiong, W. Zhang, R. Yang, P. Cieplak, R. Luo, T. Lee, J. Caldwell, J. Wang, and P. Kollman (2003). A Point-Charge Force Field for Molecular Mechanics Simulations of Proteins Based on Condensed-Phase Quantum Mechanical Calculations. Journal of Computational Chemistry, 24(16); 1999–2012
Feng, Y.-x., Z.-c. Wang, J.-x. Chen, H.-r. Li, Y.-b. Wang, D.-F. Ren, and J. Lu (2021). Separation, Identification, and Molecular Docking of Tyrosinase Inhibitory Peptides from the Hydrolysates of Defatted Walnut (Juglans regia L.) Meal. Food Chemistry, 353; 129471
Friedman, M. (1996). Food Browning and Its Prevention: An Overview. Journal of Agricultural and Food Chemistry, 44(3); 631–653
G., C., G. T. Yılmaz, B. Barut, C. O. Yalcin, and N. Yayli (2023). Design, Synthesis, Biological Activity and Molecular Docking Studies of New Imine-Chalcone Derivatives. Pharmaceutical Chemistry Journal, 57(4); 550–558
Gonçalez, M., M. A. Correa, and M. Chorilli (2013). Skin Delivery of Kojic Acid-Loaded Nanotechnology-Based Drug Delivery Systems for the Treatment of Skin Aging. BioMed Research International, 2013(1); 271276
Grand View Research (2022). The Global Skin Lightening Products Market Size. https://www.grandviewresearch.com/press-release/global-skin-lightening-products-market. Accessed June 2025
Guedes, I. A., M. M. Pereira da Silva, M. Galheigo, E. Krempser, C. S. de Magalhães, H. J. Correa Barbosa, and L. E. Dardenne (2024). DockThor-VS: A Free Platform for Receptor-Ligand Virtual Screening. Journal of Molecular Biology, 436(17); 168548
Gunia-Krzyżak, A., J. Popiół, K. Słoczyńska, D. Żelaszczyk, K. Orzeł, P. Koczurkiewicz-Adamczyk, K. Wójcik-Pszczoła, P. Kasza, M. Borczuch-Kostańska, and E. Pękala (2023). In Silico and In Vitro Evaluation of a Safety Profile of a Cosmetic Ingredient: 4-Methoxychalcone (4-MC). Toxicology in Vitro, 93; 105696
Hu, Q., M. Feng, L. Lai, and J. Pei (2018). Prediction of Drug-Likeness Using Deep Autoencoder Neural Networks. Frontiers in Genetics, 9; 585
Huang, C.-H., H.-C. Sung, C.-Y. Hsiao, S. Hu, and Y.-S. Ko (2013). Transdermal Delivery of Three Vitamin C Derivatives by Er:YAG and Carbon Dioxide Laser Pretreatment. Lasers in Medical Science, 28; 807–814
Ismaya, W. T., H. J. Rozeboom, A. Weijn, J. J. Mes, F. Fusetti, H. J. Wichers, and B. W. Dijkstra (2011). Crystal Structure of Agaricus bisporus Mushroom Tyrosinase: Identity of the Tetramer Subunits and Interaction with Tropolone. Biochemistry, 50(24); 5477–5486
Jun, N., G. Hong, and K. Jun (2007). Synthesis and Evaluation of 2’,4’,6’-Trihydroxychalcones as a New Class of Tyrosinase Inhibitors. Bioorganic & Medicinal Chemistry, 15(6); 2396–2402
Khatib, S., O. Nerya, R. Musa, M. Shmuel, S. Tamir, and J. Vaya (2005). Chalcones as Potent Tyrosinase Inhibitors: The Importance of a 2,4-Substituted Resorcinol Moiety. Bioorganic & Medicinal Chemistry, 13(2); 433–441
Klinngam, W., P. Rungkamoltip, S. Thongin, J. Joothamongkhon, P. Khumkhrong, M. Khongkow, K. Namdee, S. Tepaamorndech, P. Chaikul, and M. Kanlayavattanakul (2022). Polymethoxyflavones from Kaempferia parviflora Ameliorate Skin Aging in Primary Human Dermal Fibroblasts and Ex vivo Human Skin. Biomedicine & Pharmacotherapy, 145; 112461
Kobkeatthawin, T., S. Chantrapromma, T. Suwunwong, L. Rhyman, Y. S. C. Ramasami, and Ponnadurai (2021). Synthesis, Molecular Docking and Tyrosinase Inhibitory Activity of the Decorated Methoxy Sulfonamide Chalcones: In vitro Inhibitory Effects and the Possible Binding Mode. Sains Malaysiana, 50(9); 2603–2614
Kramer, K. J. and T. L. Hopkins (1987). Tyrosine Metabolism for Insect Cuticle Tanning. Archives of Insect Biochemistry and Physiology, 6(4); 279–301
Krieger, E., T. Darden, S. B. Nabuurs, A. Finkelstein, and G. Vriend (2004). Making Optimal Use of Empirical Energy Functions: Force-Field Parameterization in Crystal Space. Proteins: Structure, Function, and Bioinformatics, 57(4); 678–683
Krieger, E. and G. Vriend (2015). New Ways to Boost Molecular Dynamics Simulations. Journal of Computational Chemistry, 36(13); 996–1007
Kumari, S., S. T. G. Thng, N. K. Verma, and H. K. Gautam (2018). Melanogenesis Inhibitors. Acta Dermato-Venereologica, 98(10); 924–931
Li, D.-F., P.-P. Hu, M.-S. Liu, X.-L. Kong, J.-C. Zhang, R. C. Hider, and T. Zhou (2013). Design and Synthesis of Hydroxypyridinone-L-Phenylalanine Conjugates as Potential Tyrosinase Inhibitors. Journal of Agricultural and Food Chemistry, 61(27); 6597–6603
Li, J., L. Feng, L. Liu, F. Wang, L. Ouyang, L. Zhang, X. Hu, and G. Wang (2021). Recent Advances in the Design and Discovery of Synthetic Tyrosinase Inhibitors. European Journal of Medicinal Chemistry, 224; 113744
Lin, J. Y. and D. E. Fisher (2007). Melanocyte Biology and Skin Pigmentation. Nature, 445(7130); 843–850
Lipinski, C. A., F. Lombardo, B. W. Dominy, and P. J. Feeney (2012). Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Advanced Drug Delivery Reviews, 64; 4–17
Liu, J., C. Chen, F. Wu, and L. Zhao (2013). Microwave-Assisted Synthesis and Tyrosinase Inhibitory Activity of Chalcone Derivatives. Chemical Biology & Drug Design, 82(1); 39–47
Loizzo, M. R., R. Tundis, and F. Menichini (2012). Natural and Synthetic Tyrosinase Inhibitors as Antibrowning Agents: An Update. Comprehensive Reviews in Food Science and Food Safety, 11(4); 378–398
McEvily, A. J. (1991). Sulfite Alternative Prevents Shrimp Melanosis. Food Technology, 45; 80–86
Najafi, Z., F. Rafiei, A. Ghafouri-Khosrowshahi, M. Mahdavi, M. Dianatpour, and A. Iraji (2023). Design, Synthesis, and Molecular Dynamics Simulation Studies of New Chalcone-Based 2-Arylidene-1,3-Indandiones as Tyrosinase Inhibitors. ChemistrySelect, 8(33); e202302192
Nerya, O., R. Musa, S. Khatib, S. Tamir, and J. Vaya (2004). Chalcones as Potent Tyrosinase Inhibitors: The Effect of Hydroxyl Positions and Numbers. Phytochemistry, 65(10); 1389–1395
Niu, C., L. Yin, L. F. Nie, J. Dou, J. Y. Zhao, G. Li, and H. A. Aisa (2016). Synthesis and Bioactivity of Novel Isoxazole Chalcone Derivatives on Tyrosinase and Melanin Synthesis in Murine B16 Cells for the Treatment of Vitiligo. Bioorganic & Medicinal Chemistry, 24(21); 5440–5448
Obaid, R. J., E. U. Mughal, N. Naeem, A. Sadiq, R. I. Alsantali, R. S. Jassas, Z. Moussa, and S. A. Ahmed (2021). Natural and Synthetic Flavonoid Derivatives as New Potential Tyrosinase Inhibitors: A Systematic Review. RSC Advances, 11(36); 22159–22198
Oetting, W. S. (2000). The Tyrosinase Gene and Oculocutaneous Albinism Type 1 (OCA1): A Model for Understanding the Molecular Biology of Melanin Formation. Pigment Cell Research, 13(5); 320–325
Parvez, S., M. Kang, H. S. Chung, and H. Bae (2007). Naturally Occurring Tyrosinase Inhibitors: Mechanism and Applications in Skin Health, Cosmetics and Agriculture Industries. Phytotherapy Research, 21(9); 805–816
Poungcho, P., R. Hairani, C. Chaotham, W. De-Eknamkul, and W. Chavasiri (2025). Methoxylated Chrysin and Quercetin as Potent Stimulators of Melanogenesis. International Journal of Molecular Sciences, 26(7); 3281
Radhakrishnan, S., R. Shimmon, C. Conn, and A. Baker (2015a). Design, Synthesis and Biological Evaluation of Hydroxy Substituted Amino Chalcone Compounds for Anti-tyrosinase Activity in B16 Cells. Bioorganic Chemistry, 62; 117–123
Radhakrishnan, S., R. Shimmon, C. Conn, and A. Baker (2015b). Inhibitory Kinetics of Novel 2,3-Dihydro-1H-Inden-1-One Chalcone-Like Derivatives on Mushroom Tyrosinase. Bioorganic & Medicinal Chemistry Letters, 25(23); 5495–5499
Radhakrishnan, S., R. Shimmon, C. Conn, and A. Baker (2015c). Integrated Kinetic Studies and Computational Analysis on Naphthyl Chalcones as Mushroom Tyrosinase Inhibitors. Bioorganic & Medicinal Chemistry Letters, 25(19); 4085–4091
Ranjbar, S., A. Akbari, N. Edraki, M. Khoshneviszadeh, H. Hemmatian, O. Firuzi, and M. Khoshneviszadeh (2018). 6-Methoxy-3,4-Dihydronaphthalenone Chalcone-Like Derivatives as Potent Tyrosinase Inhibitors and Radical Scavengers. Letters in Drug Design & Discovery, 15(11); 1170–1179
Sabuakham, S., N. Sutita, K. Napat, R. Thanyada, S. Atit, P. Ratchanok, and P. Mahalapbutr (2024). Anilino-1,4-Naphthoquinones as Potent Mushroom Tyrosinase Inhibitors: In vitro and In silico Studies. Journal of Enzyme Inhibition and Medicinal Chemistry, 39(1); 2357174
Sanchez-Ferrer, A., J. N. Rodriguez-Lopez, F. Garcia-Canovas, and F. Garcia-Carmona (1995). Tyrosinase: A Comprehensive Review of Its Mechanism. Biochimica et Biophysica Acta (BBA)-Protein Structure and Molecular Enzymology, 1247(1); 1–11
Seo, W. D., Y. B. Ryu, M. J. Curtis-Long, C. W. Lee, H. W. Ryu, K. C. Jang, and K. H. Park (2010). Evaluation of Anti-Pigmentary Effect of Synthetic Sulfonylamino Chalcone. European Journal of Medicinal Chemistry, 45(5); 1963–1969
Son, K. and M. Heo (2013). The Evaluation of Depigmenting Efficacy in the Skin for the Development of New Whitening Agents in Korea. International Journal of Cosmetic Science, 35(1); 9–18
Sugumaran, M. (1991). Molecular Mechanisms for Mammalian Melanogenesis: Comparison with Insect Cuticular Sclerotization. FEBS Letters, 295(1–3); 233–239
Sugumaran, M. and H. Barek (2016). Critical Analysis of the Melanogenic Pathway in Insects and Higher Animals. International Journal of Molecular Sciences, 17(10); 1753
Trott, O. and A. J. Olson (2010). AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading. Journal of Computational Chemistry, 31(2); 455–461
Tuerxuntayi, A., T. Abulikemu, and C. Niu (2022). Mechanisms of 4-Dimethylamino-4’-Methoxy Chalcone in Promoting Melanin Synthesis. Natural Product Communications, 17(3); 1934578X221086895
Widyastuti, W., E. Elmitra, D. Y. Shinta, V. Verawati, and R. Afrianti (2025). Fractionation and Formulation of Face Serum from Citrus hystrix DC. Fruit Peel Extract as Sunscreen and Skin-Lightening. Science and Technology Indonesia, 10(1); 262–272
Widyastuti, W., E. Elmitra, E. S. Wardi, and D. Agustin (2024). Plectranthus scutellarioides L. R.Br. Leaf Extract as Sunscreen, Skin Lightening, and Antiaging. Science and Technology Indonesia, 9(3); 745–755
Wu, Y., M.-H. Choi, J. Li, H. Yang, and H.-J. Shin (2016). Mushroom Cosmetics: The Present and Future. Cosmetics, 3(3); 22
Xu, Y., X. Liang, H.-M. Kim, and C.-G. Hyun (2025). In vitro and In silico Studies of Maculosin as a Melanogenesis and Tyrosinase Inhibitor. Molecules, 30(4); 860
Xue, S., Z. Li, X. Ze, X. Wu, C. He, W. Shuai, M. Marlow, J. Chen, D. Scurr, Z. Zhu, J. Xu, and S. Xu (2023). Design, Synthesis, and Biological Evaluation of Novel Hybrids Containing Dihydrochalcone as Tyrosinase Inhibitors to Treat Skin Hyperpigmentation. Journal of Medicinal Chemistry, 66(7); 5099–5117
Xue, W., X. Liu, W. Zhao, and Z. Yu (2022). Identification and Molecular Mechanism of Novel Tyrosinase Inhibitory Peptides from Collagen. Journal of Food Science, 87(6); 2744–2756
Yu, Q., L. Fan, and Z. Duan (2019). Five Individual Polyphenols as Tyrosinase Inhibitors: Inhibitory Activity, Synergistic Effect, Action Mechanism, and Molecular Docking. Food Chemistry, 297; 124910
Yuan, Y., W. Jin, Y. Nazir, C. Fercher, M. A. Blaskovich, M. A. Cooper, R. T. Barnard, and Z. M. Ziora (2020). Tyrosinase
Inhibitors as Potential Antibacterial Agents. European Journal of Medicinal Chemistry, 187; 111892
Zhuang, C., W. Zhang, C. Sheng, W. Zhang, C. Xing, and Z. Miao (2017). Chalcone: A Privileged Structure in Medicinal Chemistry. Chemical Reviews, 117(12); 7762–7810
Zolghadri, S., A. Bahrami, M. T. H. Khan, J. Muñoz-Muñoz,F. Garcia-Molina, F. Garcia-Cánovas, and A. A. Saboury
(2019). A Comprehensive Review on Tyrosinase Inhibitors.Journal of Enzyme Inhibition and Medicinal Chemistry, 34(1); 279–309
Akhtar, M. N., N. M. Sakeh, S. Zareen, S. Gul, K. M. Lo, Z. Ul-Haq, S. A. A. Shah, and S. Ahmad (2015). Design and Synthesis of Chalcone Derivatives as Potent Tyrosinase Inhibitors and Their Structural Activity Relationship. Journal of Molecular Structure, 1085; 97–103
Arndt, K. A. and T. B. Fitzpatrick (1965). Topical Use of Hydroquinone as a Depigmenting Agent. JAMA, 194(9); 965–967
Barrett, F. M. (1984). Wound-Healing Phenoloxidase in Larval Cuticle of Calpodes ethlius (Lepidoptera: Hesperiidae). Canadian Journal of Zoology, 62(5); 834–838
Benet, L. Z., C. M. Hosey, O. Ursu, and T. I. Oprea (2016). BDDCS, the Rule of 5 and Drugability. Advanced Drug Delivery Reviews, 101; 89–98
Boo, Y. C. (2021). Arbutin as a Skin Depigmenting Agent with Antimelanogenic and Antioxidant Properties. Antioxidants, 10(7); 1129
Breathnach, A. C., M. Nazzaro-Porro, S. Passi, and G. Zina (1989). Azelaic Acid Therapy in Disorders of Pigmentation. Clinics in Dermatology, 7(2); 106–119
Cai, P., Y. Xiong, Y. Yao, W. Chen, and X. Dong (2019). Synthesis, Screening and Biological Activity of Potent Thiosemicarbazone Compounds as a Tyrosinase Inhibitor. New Journal of Chemistry, 43(35); 14102–14111
Casadevall, A., R. J. Cordero, R. Bryan, J. Nosanchuk, and E. Dadachova (2017). Melanin, Radiation, and Energy Transduction in Fungi. Microbiology Spectrum, 5(2); 10.1128/microbiolspec.funk–0037–2016
Chen, C.-Y., L.-C. Lin, W.-F. Yang, J. Bordon, and H.-M. D. Wang (2015). An Updated Organic Classification of Tyrosinase Inhibitors on Melanin Biosynthesis. Current Organic Chemistry, 19(1); 4–18
Choi, H., I. Y. Ryu, I. Choi, S. Ullah, H. J. Jung, Y. Park, Y. Hwang, Y. Jeong, S. Hong, and P. Chun (2022). Identification of (Z)-2-Benzylidene-Dihydroimidazothiazolone Derivatives as Tyrosinase Inhibitors: Anti-Melanogenic Effects and In silico Studies. Computational and Structural Biotechnology Journal, 20; 899–912
Chumkaew, P., S. Jumrat, and Y. Pianroj (2024). New Chalcone Derivative from Persea americana and Its Anti-Tyrosinase Activity. Chemistry of Natural Compounds, 60(4); 625–628
Daina, A., O. Michielin, and V. Zoete (2017). SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug-Likeness and Medicinal Chemistry Friendliness of Small Molecules. Scientific Reports, 7(1); 42717
Dallakyan, S. and A. J. Olson (2015). Small-Molecule Library Screening by Docking with PyRx. In J. E. Hempel, C. H. Williams, and C. C. Hong (Eds.), Chemical Biology: Methods and Protocols. Springer New York, pp. 243–250
Danova, A., Y. E. Maulana, E. Hermawati, and W. Chavasiri (2023a). Synthesis, Evaluation, and Molecular Docking Study of 4-Monoacyl Resorcinol Against Tyrosinase Enzyme. Indonesian Journal of Chemical Research, 11(2); 135–141
Danova, A., D. V. Nguyen, R. Toyoda, P. Mahalapbutr, T. Rungrotmongkol, P. Wonganan, and W. Chavasiri (2023b). 3’,4’,5’-Trimethoxy- and 3,4-Dimethoxychalcones Targeting A549 Cells: Synthesis, Cytotoxic Activity, and Molecular Docking. Journal of Molecular Structure, 1275; 134572
Duan, Y., C. Wu, S. Chowdhury, M. C. Lee, G. Xiong, W. Zhang, R. Yang, P. Cieplak, R. Luo, T. Lee, J. Caldwell, J. Wang, and P. Kollman (2003). A Point-Charge Force Field for Molecular Mechanics Simulations of Proteins Based on Condensed-Phase Quantum Mechanical Calculations. Journal of Computational Chemistry, 24(16); 1999–2012
Feng, Y.-x., Z.-c. Wang, J.-x. Chen, H.-r. Li, Y.-b. Wang, D.-F. Ren, and J. Lu (2021). Separation, Identification, and Molecular Docking of Tyrosinase Inhibitory Peptides from the Hydrolysates of Defatted Walnut (Juglans regia L.) Meal. Food Chemistry, 353; 129471
Friedman, M. (1996). Food Browning and Its Prevention: An Overview. Journal of Agricultural and Food Chemistry, 44(3); 631–653
G., C., G. T. Yılmaz, B. Barut, C. O. Yalcin, and N. Yayli (2023). Design, Synthesis, Biological Activity and Molecular Docking Studies of New Imine-Chalcone Derivatives. Pharmaceutical Chemistry Journal, 57(4); 550–558
Gonçalez, M., M. A. Correa, and M. Chorilli (2013). Skin Delivery of Kojic Acid-Loaded Nanotechnology-Based Drug Delivery Systems for the Treatment of Skin Aging. BioMed Research International, 2013(1); 271276
Grand View Research (2022). The Global Skin Lightening Products Market Size. https://www.grandviewresearch.com/press-release/global-skin-lightening-products-market. Accessed June 2025
Guedes, I. A., M. M. Pereira da Silva, M. Galheigo, E. Krempser, C. S. de Magalhães, H. J. Correa Barbosa, and L. E. Dardenne (2024). DockThor-VS: A Free Platform for Receptor-Ligand Virtual Screening. Journal of Molecular Biology, 436(17); 168548
Gunia-Krzyżak, A., J. Popiół, K. Słoczyńska, D. Żelaszczyk, K. Orzeł, P. Koczurkiewicz-Adamczyk, K. Wójcik-Pszczoła, P. Kasza, M. Borczuch-Kostańska, and E. Pękala (2023). In Silico and In Vitro Evaluation of a Safety Profile of a Cosmetic Ingredient: 4-Methoxychalcone (4-MC). Toxicology in Vitro, 93; 105696
Hu, Q., M. Feng, L. Lai, and J. Pei (2018). Prediction of Drug-Likeness Using Deep Autoencoder Neural Networks. Frontiers in Genetics, 9; 585
Huang, C.-H., H.-C. Sung, C.-Y. Hsiao, S. Hu, and Y.-S. Ko (2013). Transdermal Delivery of Three Vitamin C Derivatives by Er:YAG and Carbon Dioxide Laser Pretreatment. Lasers in Medical Science, 28; 807–814
Ismaya, W. T., H. J. Rozeboom, A. Weijn, J. J. Mes, F. Fusetti, H. J. Wichers, and B. W. Dijkstra (2011). Crystal Structure of Agaricus bisporus Mushroom Tyrosinase: Identity of the Tetramer Subunits and Interaction with Tropolone. Biochemistry, 50(24); 5477–5486
Jun, N., G. Hong, and K. Jun (2007). Synthesis and Evaluation of 2’,4’,6’-Trihydroxychalcones as a New Class of Tyrosinase Inhibitors. Bioorganic & Medicinal Chemistry, 15(6); 2396–2402
Khatib, S., O. Nerya, R. Musa, M. Shmuel, S. Tamir, and J. Vaya (2005). Chalcones as Potent Tyrosinase Inhibitors: The Importance of a 2,4-Substituted Resorcinol Moiety. Bioorganic & Medicinal Chemistry, 13(2); 433–441
Klinngam, W., P. Rungkamoltip, S. Thongin, J. Joothamongkhon, P. Khumkhrong, M. Khongkow, K. Namdee, S. Tepaamorndech, P. Chaikul, and M. Kanlayavattanakul (2022). Polymethoxyflavones from Kaempferia parviflora Ameliorate Skin Aging in Primary Human Dermal Fibroblasts and Ex vivo Human Skin. Biomedicine & Pharmacotherapy, 145; 112461
Kobkeatthawin, T., S. Chantrapromma, T. Suwunwong, L. Rhyman, Y. S. C. Ramasami, and Ponnadurai (2021). Synthesis, Molecular Docking and Tyrosinase Inhibitory Activity of the Decorated Methoxy Sulfonamide Chalcones: In vitro Inhibitory Effects and the Possible Binding Mode. Sains Malaysiana, 50(9); 2603–2614
Kramer, K. J. and T. L. Hopkins (1987). Tyrosine Metabolism for Insect Cuticle Tanning. Archives of Insect Biochemistry and Physiology, 6(4); 279–301
Krieger, E., T. Darden, S. B. Nabuurs, A. Finkelstein, and G. Vriend (2004). Making Optimal Use of Empirical Energy Functions: Force-Field Parameterization in Crystal Space. Proteins: Structure, Function, and Bioinformatics, 57(4); 678–683
Krieger, E. and G. Vriend (2015). New Ways to Boost Molecular Dynamics Simulations. Journal of Computational Chemistry, 36(13); 996–1007
Kumari, S., S. T. G. Thng, N. K. Verma, and H. K. Gautam (2018). Melanogenesis Inhibitors. Acta Dermato-Venereologica, 98(10); 924–931
Li, D.-F., P.-P. Hu, M.-S. Liu, X.-L. Kong, J.-C. Zhang, R. C. Hider, and T. Zhou (2013). Design and Synthesis of Hydroxypyridinone-L-Phenylalanine Conjugates as Potential Tyrosinase Inhibitors. Journal of Agricultural and Food Chemistry, 61(27); 6597–6603
Li, J., L. Feng, L. Liu, F. Wang, L. Ouyang, L. Zhang, X. Hu, and G. Wang (2021). Recent Advances in the Design and Discovery of Synthetic Tyrosinase Inhibitors. European Journal of Medicinal Chemistry, 224; 113744
Lin, J. Y. and D. E. Fisher (2007). Melanocyte Biology and Skin Pigmentation. Nature, 445(7130); 843–850
Lipinski, C. A., F. Lombardo, B. W. Dominy, and P. J. Feeney (2012). Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Advanced Drug Delivery Reviews, 64; 4–17
Liu, J., C. Chen, F. Wu, and L. Zhao (2013). Microwave-Assisted Synthesis and Tyrosinase Inhibitory Activity of Chalcone Derivatives. Chemical Biology & Drug Design, 82(1); 39–47
Loizzo, M. R., R. Tundis, and F. Menichini (2012). Natural and Synthetic Tyrosinase Inhibitors as Antibrowning Agents: An Update. Comprehensive Reviews in Food Science and Food Safety, 11(4); 378–398
McEvily, A. J. (1991). Sulfite Alternative Prevents Shrimp Melanosis. Food Technology, 45; 80–86
Najafi, Z., F. Rafiei, A. Ghafouri-Khosrowshahi, M. Mahdavi, M. Dianatpour, and A. Iraji (2023). Design, Synthesis, and Molecular Dynamics Simulation Studies of New Chalcone-Based 2-Arylidene-1,3-Indandiones as Tyrosinase Inhibitors. ChemistrySelect, 8(33); e202302192
Nerya, O., R. Musa, S. Khatib, S. Tamir, and J. Vaya (2004). Chalcones as Potent Tyrosinase Inhibitors: The Effect of Hydroxyl Positions and Numbers. Phytochemistry, 65(10); 1389–1395
Niu, C., L. Yin, L. F. Nie, J. Dou, J. Y. Zhao, G. Li, and H. A. Aisa (2016). Synthesis and Bioactivity of Novel Isoxazole Chalcone Derivatives on Tyrosinase and Melanin Synthesis in Murine B16 Cells for the Treatment of Vitiligo. Bioorganic & Medicinal Chemistry, 24(21); 5440–5448
Obaid, R. J., E. U. Mughal, N. Naeem, A. Sadiq, R. I. Alsantali, R. S. Jassas, Z. Moussa, and S. A. Ahmed (2021). Natural and Synthetic Flavonoid Derivatives as New Potential Tyrosinase Inhibitors: A Systematic Review. RSC Advances, 11(36); 22159–22198
Oetting, W. S. (2000). The Tyrosinase Gene and Oculocutaneous Albinism Type 1 (OCA1): A Model for Understanding the Molecular Biology of Melanin Formation. Pigment Cell Research, 13(5); 320–325
Parvez, S., M. Kang, H. S. Chung, and H. Bae (2007). Naturally Occurring Tyrosinase Inhibitors: Mechanism and Applications in Skin Health, Cosmetics and Agriculture Industries. Phytotherapy Research, 21(9); 805–816
Poungcho, P., R. Hairani, C. Chaotham, W. De-Eknamkul, and W. Chavasiri (2025). Methoxylated Chrysin and Quercetin as Potent Stimulators of Melanogenesis. International Journal of Molecular Sciences, 26(7); 3281
Radhakrishnan, S., R. Shimmon, C. Conn, and A. Baker (2015a). Design, Synthesis and Biological Evaluation of Hydroxy Substituted Amino Chalcone Compounds for Anti-tyrosinase Activity in B16 Cells. Bioorganic Chemistry, 62; 117–123
Radhakrishnan, S., R. Shimmon, C. Conn, and A. Baker (2015b). Inhibitory Kinetics of Novel 2,3-Dihydro-1H-Inden-1-One Chalcone-Like Derivatives on Mushroom Tyrosinase. Bioorganic & Medicinal Chemistry Letters, 25(23); 5495–5499
Radhakrishnan, S., R. Shimmon, C. Conn, and A. Baker (2015c). Integrated Kinetic Studies and Computational Analysis on Naphthyl Chalcones as Mushroom Tyrosinase Inhibitors. Bioorganic & Medicinal Chemistry Letters, 25(19); 4085–4091
Ranjbar, S., A. Akbari, N. Edraki, M. Khoshneviszadeh, H. Hemmatian, O. Firuzi, and M. Khoshneviszadeh (2018). 6-Methoxy-3,4-Dihydronaphthalenone Chalcone-Like Derivatives as Potent Tyrosinase Inhibitors and Radical Scavengers. Letters in Drug Design & Discovery, 15(11); 1170–1179
Sabuakham, S., N. Sutita, K. Napat, R. Thanyada, S. Atit, P. Ratchanok, and P. Mahalapbutr (2024). Anilino-1,4-Naphthoquinones as Potent Mushroom Tyrosinase Inhibitors: In vitro and In silico Studies. Journal of Enzyme Inhibition and Medicinal Chemistry, 39(1); 2357174
Sanchez-Ferrer, A., J. N. Rodriguez-Lopez, F. Garcia-Canovas, and F. Garcia-Carmona (1995). Tyrosinase: A Comprehensive Review of Its Mechanism. Biochimica et Biophysica Acta (BBA)-Protein Structure and Molecular Enzymology, 1247(1); 1–11
Seo, W. D., Y. B. Ryu, M. J. Curtis-Long, C. W. Lee, H. W. Ryu, K. C. Jang, and K. H. Park (2010). Evaluation of Anti-Pigmentary Effect of Synthetic Sulfonylamino Chalcone. European Journal of Medicinal Chemistry, 45(5); 1963–1969
Son, K. and M. Heo (2013). The Evaluation of Depigmenting Efficacy in the Skin for the Development of New Whitening Agents in Korea. International Journal of Cosmetic Science, 35(1); 9–18
Sugumaran, M. (1991). Molecular Mechanisms for Mammalian Melanogenesis: Comparison with Insect Cuticular Sclerotization. FEBS Letters, 295(1–3); 233–239
Sugumaran, M. and H. Barek (2016). Critical Analysis of the Melanogenic Pathway in Insects and Higher Animals. International Journal of Molecular Sciences, 17(10); 1753
Trott, O. and A. J. Olson (2010). AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading. Journal of Computational Chemistry, 31(2); 455–461
Tuerxuntayi, A., T. Abulikemu, and C. Niu (2022). Mechanisms of 4-Dimethylamino-4’-Methoxy Chalcone in Promoting Melanin Synthesis. Natural Product Communications, 17(3); 1934578X221086895
Widyastuti, W., E. Elmitra, D. Y. Shinta, V. Verawati, and R. Afrianti (2025). Fractionation and Formulation of Face Serum from Citrus hystrix DC. Fruit Peel Extract as Sunscreen and Skin-Lightening. Science and Technology Indonesia, 10(1); 262–272
Widyastuti, W., E. Elmitra, E. S. Wardi, and D. Agustin (2024). Plectranthus scutellarioides L. R.Br. Leaf Extract as Sunscreen, Skin Lightening, and Antiaging. Science and Technology Indonesia, 9(3); 745–755
Wu, Y., M.-H. Choi, J. Li, H. Yang, and H.-J. Shin (2016). Mushroom Cosmetics: The Present and Future. Cosmetics, 3(3); 22
Xu, Y., X. Liang, H.-M. Kim, and C.-G. Hyun (2025). In vitro and In silico Studies of Maculosin as a Melanogenesis and Tyrosinase Inhibitor. Molecules, 30(4); 860
Xue, S., Z. Li, X. Ze, X. Wu, C. He, W. Shuai, M. Marlow, J. Chen, D. Scurr, Z. Zhu, J. Xu, and S. Xu (2023). Design, Synthesis, and Biological Evaluation of Novel Hybrids Containing Dihydrochalcone as Tyrosinase Inhibitors to Treat Skin Hyperpigmentation. Journal of Medicinal Chemistry, 66(7); 5099–5117
Xue, W., X. Liu, W. Zhao, and Z. Yu (2022). Identification and Molecular Mechanism of Novel Tyrosinase Inhibitory Peptides from Collagen. Journal of Food Science, 87(6); 2744–2756
Yu, Q., L. Fan, and Z. Duan (2019). Five Individual Polyphenols as Tyrosinase Inhibitors: Inhibitory Activity, Synergistic Effect, Action Mechanism, and Molecular Docking. Food Chemistry, 297; 124910
Yuan, Y., W. Jin, Y. Nazir, C. Fercher, M. A. Blaskovich, M. A. Cooper, R. T. Barnard, and Z. M. Ziora (2020). Tyrosinase
Inhibitors as Potential Antibacterial Agents. European Journal of Medicinal Chemistry, 187; 111892
Zhuang, C., W. Zhang, C. Sheng, W. Zhang, C. Xing, and Z. Miao (2017). Chalcone: A Privileged Structure in Medicinal Chemistry. Chemical Reviews, 117(12); 7762–7810
Zolghadri, S., A. Bahrami, M. T. H. Khan, J. Muñoz-Muñoz,F. Garcia-Molina, F. Garcia-Cánovas, and A. A. Saboury
(2019). A Comprehensive Review on Tyrosinase Inhibitors.Journal of Enzyme Inhibition and Medicinal Chemistry, 34(1); 279–309
Authors
Danova, A., Hermawati, E., Chavasiri, W., Mujahidin, D., Musthapa, I., & Kurniadewi, F. (2025). Anti-tyrosinase Activity of 3’,4’,5’-Trimethoxychalcones: Experimental and Computational Studies. Science and Technology Indonesia, 10(4), 982–989. https://doi.org/10.26554/sti.2025.10.4.982-989
This work is licensed under a Creative Commons Attribution 4.0 International License.