Synthesis, cytotoxicity assay, and molecular docking study of hydroxychalcone derivatives as potential tyrosinase inhibitors

doi:10.5246/jcps.2021.08.051

中国药学(英文版) ›› 2021, Vol. 30 ›› Issue (8): 634-644.DOI: 10.5246/jcps.2021.08.051

Synthesis, cytotoxicity assay, and molecular docking study of hydroxychalcone derivatives as potential tyrosinase inhibitors

Aris Stiawan¹, Eti Nurwening Sholikhah², Yehezkiel Steven Kurniawan¹^,³, Yoga Priastomo¹, Jumina¹^,^*()

1. Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
2. Department of Pharmacology and Therapy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
3. Ma Chung Research Center for Photosynthetic Pigments, Universitas Ma Chung, Villa Puncak Tidar N-01, Malang 65151, Indonesia

收稿日期:2020-12-06 修回日期:2021-03-18 接受日期:2021-04-13 出版日期:2021-08-29 发布日期:2021-08-29
通讯作者: Jumina
作者简介:
+ Tel.: +62-274-545188, E-mail: jumina@ugm.ac.id

Synthesis, cytotoxicity assay, and molecular docking study of hydroxychalcone derivatives as potential tyrosinase inhibitors

Aris Stiawan¹, Eti Nurwening Sholikhah², Yehezkiel Steven Kurniawan¹^,³, Yoga Priastomo¹, Jumina¹^,^*()

1 Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
2 Department of Pharmacology and Therapy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
3 Ma Chung Research Center for Photosynthetic Pigments, Universitas Ma Chung, Villa Puncak Tidar N-01, Malang 65151, Indonesia

Received:2020-12-06 Revised:2021-03-18 Accepted:2021-04-13 Online:2021-08-29 Published:2021-08-29
Contact: Jumina

摘要/Abstract

摘要：

In this work, we studied the synthesis, cytotoxicity assay, and molecular docking of hydroxychalcone derivatives as tyrosinase inhibitors. Synthesis of chalcone derivatives was carried out through a Claisen-Schmidt condensation reaction between acetophenone and benzaldehyde derivatives under alkaline conditions for 48 h. The synthesized products were characterized by using Fourier transform infrared (FTIR), gas chromatography-mass spectrometry (GC-MS), proton and carbon nuclear magnetic resonance (¹H and ¹³C NMR) spectrometer. The in vitro inhibitory activity was evaluated against tyrosinase enzyme by employing L-3,4-dihydroxyphenylalanine (L-DOPA) as the substrate. We successfully synthesized 4-hydroxychalcone (HC) and 4-hydroxy-3-methoxychalcone (HMC) with a yield of 60% and 76%, respectively. While the tyrosinase inhibitory test of HC and HMC gave the IC₅₀ value of 64.35 and 21.56 μg/mL, respectively, demonstrating that their inhibitory activities against tyrosinase enzyme were better compared with kojic acid and hydroquinone as the positive controls. We also found that HC gave 2025 μg/mL as the IC₅₀ value against Vero cells, confirming that it was not toxic to the normal cell line. The molecular docking study gave the root-mean-square deviation value of less than 2 ?. Furthermore, the binding energies of hydroxychalcone derivatives were found as –30.13 and –31.38 kJ/mol, showing that those compounds could be potentially used as the alternative tyrosinase inhibitors in medical application.

关键词: Hydroxychalcone, Cytotoxicity, In vitro, Molecular docking, Tyrosinase inhibitors

Abstract:

Key words: Hydroxychalcone, Cytotoxicity, In vitro, Molecular docking, Tyrosinase inhibitors

Supporting:

Figure S1. Inhibition of tyrosinase enzyme by 4-hydroxychalcone, 4-hydroxy-3-methoxychalcone and hydroquinone compounds.

Aris Stiawan, Eti Nurwening Sholikhah, Yehezkiel Steven Kurniawan, Yoga Priastomo, Jumina. Synthesis, cytotoxicity assay, and molecular docking study of hydroxychalcone derivatives as potential tyrosinase inhibitors[J]. 中国药学(英文版), 2021, 30(8): 634-644.

图/表 11

Figure 1. Synthetic scheme of chalcone derivatives.

Table 1. Tyrosinase enzyme inhibition activity by HC.

Table 2. Tyrosinase enzyme inhibition activity by HMC.

Table 3. Tyrosinase enzyme inhibition activity by hydroquinone.

Table 4. The IC50 value of HC, HMC and hydroquinone against tyrosinase enzyme.

Table 5. The IC50 value of HC and HMC against Vero cell lines.

Figure 2. 2D visualization of conformation of kojic acid compound in protein tyrosinase.

Figure 3. Visualization of 2D conformation of hydroquinone in protein tyrosinase.

Figure 4. 2D Visualization conformation of HC in protein tyrosinase.

Figure 5. 2D Visualization conformation of HMC in protein tyrosinase.

Table 6. The bonding distance between compounds and important amino acid residues of 3NQ1 protein.

参考文献 22

[1]	Ezzedine, K.; Guinot, C.; Mauger, E.; Pistone, T.; Rafii, N.; Receveur, M.C.; Galan, P.; Hercberg, S.; Malvy, D. Expatriates in high-UV index and tropical countries: Sun exposure and protection behavior in 9, 416 French adults. J. Travel. Med. 2007, 14, 85–91.
[2]	Wang, Y.; Branicky, R.; Noë, A.; Hekimi, S. Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling. J. Cell Biol. 2018, 217, 1915–1928.
[3]	Niu, C.; Aisa, H.A. Upregulation of melanogenesis and tyrosinase activity: potential agents for vitiligo. Molecules. 2017, 22, 1303.
[4]	Saeedi, M.; Eslamifar, M.; Khezri, K. Kojic acid applications in cosmetic and pharmaceutical preparations. Biomed. Pharmacother. 2019, 110, 582–593.
[5]	Desmedt, B.; Ates, G.; Courselle, P.; de Beer, J.O.; Rogiers, V.; Hendrickx, B.; Deconinck, E.; de Paepe, K. In vitro dermal absorption of hydroquinone: protocol validation and applicability on illegal skin-whitening cosmetics. Ski. Pharmacol. Physiol. 2017, 29, 300–308.
[6]	Promden, W.; Viriyabancha, W.; Monthakantirat, O.; Umehara, K.; Noguchi, H.; De-Eknamkul, W. Correlation between the potency of flavonoids on mushroom tyrosinase inhibitory activity and melanin synthesis in melanocytes. Molecules. 2018, 23, 1403.
[7]	Higgs, J.; Wasowski, C.; Marcos, A.; Jukič, M.; Paván, C.H.; Gobec, S.; de Tezanos Pinto, F.; Colettis, N.; Marder, M. Chalcone derivatives: synthesis, in vitro and in vivo evaluation of their anti-anxiety, anti-depression and analgesic effects. Heliyon. 2019, 5, e01376.
[8]	Sabina, X.J.; Karthikeyan, J.; Velmurugan, G.; Tamizh, M.M.; Shetty, A.N. Design and in vitro biological evaluation of substituted chalcones synthesized from nitrogen mustards as potent microtubule targeted anticancer agents. New J. Chem. 2017, 41, 4096–4109.
[9]	Venkatesh, T.; Bodke, Y.D. Synthesis, antimicrobial and antioxidant activity of chalcone derivatives containing thiobarbitone nucleus. Med. Chem. 2016, 6, 440–448.
[10]	Syahri, J.; Yuanita, E.; Nurohmah, B.A.; Armunanto, R.; Purwono, B. Chalcone analogue as potent anti-malarial compounds against Plasmodium falciparum: Synthesis, biological evaluation, and docking simulation study. Asian Pac. J. Trop. Biomed. 2017, 7, 675–679.
[11]	Gomes, M.N.; Braga, R.C.; Grzelak, E.M.; Neves, B.J.; Muratov, E.; Ma, R.; Klein, L.L.; Cho, S.; Oliveira, G.R.; Franzblau, S.G.; Andrade, C.H. QSAR-driven design, synthesis and discovery of potent chalcone derivatives with antitubercular activity. Eur. J. Med. Chem. 2017, 137, 126–138.
[12]	Sahu, N.K.; Balbhadra, S.S.; Choudhary, J.; Kohli, D.V. Exploring pharmacological significance of chalcone scaffold: a review. Curr. Med. Chem. 2012, 19, 209–225.
[13]	Akhtar, M.N.; Sakeh, N.M.; Zareen, S.; Gul, S.; Lo, K.M.; Ul-Haq, Z.; Shah, S.A.A.; Ahmad, S. Design and synthesis of chalcone derivatives as potent tyrosinase inhibitors and their structural activity relationship. J. Mol. Struct. 2015, 1085, 97–103.
[14]	Nerya, O.; Musa, R.; Khatib, S.; Tamir, S.; Vaya, J. Chalcones as potent tyrosinase inhibitors: the effect of hydroxyl positions and numbers. Phytochemistry. 2004, 65, 1389–1395.
[15]	Hsu, K.D.; Chan, Y.H.; Chen, H.J.; Lin, S.P.; Cheng, K.C. Tyrosinase-based TLC Autography for anti-melanogenic drug screening. Sci. Rep. 2018, 8, 401.
[16]	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, 433–441.
[17]	Bhanja Dey, T.; Chakraborty, S.; Jain, K.K.; Sharma, A.; Kuhad, R.C. Antioxidant phenolics and their microbial production by submerged and solid state fermentation process: a review. Trends Food Sci. Technol. 2016, 53, 60–74.
[18]	Garcia-Jimenez, A.; Teruel-Puche, J.A.; Garcia-Ruiz, P.A.; Saura-Sanmartin, A.; Berna, J.; Garcia-Canovas, F.; Rodriguez-Lopez, J.N. Structural and kinetic considerations on the catalysis of deoxyarbutin by tyrosinase. PLoS One. 2017, 12, e0187845.
[19]	Mohan, V.R.; Doss, A.; Tresina, P.S. Ethnomedical Plants with Therapeutic Properties, Oakville. Apple Academic Press Inc. 2019, 196–202.
[20]	Duval, R.E.; Clarot, I.; Dumarcay-Charbonnier, F.; Fontanay, S.; Marsura, A. Interest of designed cyclodextrin-tools in gene delivery. Ann. Pharm. Françaises. 2012, 70, 360–369.
[21]	Boukes, G.J.; Koekemoer, T.C.; van de Venter, M.; Govender, S. Cytotoxicity of thirteen South African macrofungal species against five cancer cell lines. S. Afr. N. J. Bot. 2017, 113, 62–67.
[22]	Nithitanakool, S.; Pithayanukul, P.; Bavovada, R.; Saparpakorn, P. Molecular docking studies and anti-tyrosinase activity of Thai mango seed kernel extract. Molecules. 2009, 14, 257–265.

Synthesis, cytotoxicity assay, and molecular docking study of hydroxychalcone derivatives as potential tyrosinase inhibitors

Synthesis, cytotoxicity assay, and molecular docking study of hydroxychalcone derivatives as potential tyrosinase inhibitors

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 11

参考文献 22

相关文章 3

编辑推荐

Metrics

本文评价

[1]	Eric Wei Chiang Chan, Ying Ki Ng, Hung Tuck Chan, Siu Kuin Wong. An overview of flavonoids from Sophora flavescens (kushen) with some emphasis on the anticancer properties of kurarinone and sophoraflavanone G[J]. 中国药学(英文版), 2023, 32(8): 603-615.
[2]	Eric Wei Chiang Chan, Siu Kuin Wong, Hung Tuck Chan. Genipin and geniposide from Gardenia jasminoides: An overview of their anti-cancer and other pharmacological properties[J]. 中国药学(英文版), 2022, 31(1): 1-12.
[3]	LI Sha, HOU Xin-pu^*. Alginate-Chitosan Microcapsules for Renal Arterial Embolization[J]. , 2003, 12(3): 170-171.