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Synthesis and Tyrosinase Inhibitory Activity of (E)-5-Benzyl-7- (3-Bromobenzylidene)-3-(3-Bromophenyl)-2-Phenyl-3,3a, 4,5,6,7-Hexahydro-2H-Pyrazolo[4,3-c]Pyridine

1Department of Chemistry, University of Riau, Pekanbaru, Riau, Indonesia

2Sekolah Tinggi Ilmu Farmasi Riau, Pekanbaru, Riau, Indonesia

Received: 18 Nov 2021; Revised: 15 May 2022; Accepted: 23 May 2022; Published: 31 May 2022.
Open Access Copyright 2022 Jurnal Kimia Sains dan Aplikasi under http://creativecommons.org/licenses/by-sa/4.0.

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Abstract

The tyrosinase enzyme plays an essential role in the pigmentation of human skin, fruits, and vegetables. It has been tied with several human skin diseases and post-harvest problems. Hence, the tyrosinase enzyme becomes an excellent therapeutic target to overcome these issues. This study aimed to screen tyrosinase inhibitors by synthesizing halogen-substituted pyrazolopyridine derivatives. The pyrazolopyridine compound was obtained through two stages of synthesis. First, the intermediate compound, a derivative of 3,5-bis(arylidene)-4-piperidone, was synthesized through the Cleisen-Schmidt condensation reaction of 4-piperidone and benzaldehyde derivatives. Furthermore, the intermediate compound was reacted with phenylhydrazine through a cyclocondensation reaction to produce the titled compound with an 11% yield. The chemical structure of the target compound was identified through the interpretation of UV, FTIR, NMR, and HRMS spectra. Then an in vitro assay was conducted on the tyrosinase enzyme of the fungus Agaricus bisporus by detecting the presence of dopachrome at a wavelength of 492 nm. As a result, the in vitro assay showed that the titled compound had a weak inhibitory activity, and the IC50 value was > 500 µM. Thus, the synthesized compound is considered inactive.

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Keywords: Tyrosinase; Inhibitor tyrosinase; Pirazolo[4,3c]piridin.
Funding: Kementerian Riset Teknologi Dan Pendidikan Tinggi Republik Indonesia under contract 1385/UN.19.5.1.3/PT.01.03/2021

Article Metrics:

  1. Thanigaimalai Pillaiyar, Manoj Manickam, Vigneshwaran Namasivayam, Skin whitening agents: Medicinal chemistry perspective of tyrosinase inhibitors, Journal of Enzyme Inhibition and Medicinal Chemistry, 32, 1, (2017), 403-425 https://doi.org/10.1080/14756366.2016.1256882
  2. Antonio Garcia-Jimenez, Jose Antonio Teruel-Puche, Pedro Antonio Garcia-Ruiz, Jose Berna, Jose Neptuno Rodríguez-López, Jose Tudela, Francisco Garcia-Canovas, Action of 2, 2′, 4, 4′-tetrahydroxybenzophenone in the biosynthesis pathway of melanin, International Journal of Biological Macromolecules, 98, (2017), 622-629 https://doi.org/10.1016/j.ijbiomac.2017.02.032
  3. Jody P. Ebanks, R. Randall Wickett, Raymond E. Boissy, Mechanisms regulating skin pigmentation: the rise and fall of complexion coloration, International Journal of Molecular Sciences, 10, 9, (2009), 4066-4087 https://doi.org/10.3390/ijms10094066
  4. Yao Lu, Yi Xu, Meng-Ting Song, Ling-Ling Qian, Xiao-Lin Liu, Rong-Yao Gao, Rui-Min Han, Leif H. Skibsted, Jian-Ping Zhang, Promotion effects of flavonoids on browning induced by enzymatic oxidation of tyrosinase: structure–activity relationship, RSC Advances, 11, 23, (2021), 13769-13779 https://doi.org/10.1039/D1RA01369F
  5. Kyoung Mi Moon, Choon Young Kim, Jin Yeul Ma, Bonggi Lee, Xanthone-related compounds as an anti-browning and antioxidant food additive, Food Chemistry, 274, (2019), 345-350 https://doi.org/10.1016/j.foodchem.2018.08.144
  6. Kai Chen, De-Yin Zhao, Yu-Lin Chen, Xiao-Yi Wei, Yin-Ting Li, Li-Min Kong, Robert C. Hider, Tao Zhou, A novel inhibitor against mushroom tyrosinase with a double action mode and its application in controlling the browning of potato, Food and Bioprocess Technology, 10, 12, (2017), 2146-2155 https://doi.org/10.1007/s11947-017-1976-2
  7. Neelam A. Vashi, Roopal Vashi Kundu, Facial hyperpigmentation: causes and treatment, British Journal of Dermatology, 169, s3, (2013), 41-56 https://doi.org/10.1111/bjd.12536
  8. Ambati Ranga Rao, H.N. Sindhuja, Shylaja M. Dharmesh, Kadimi Udaya Sankar, Ravi Sarada, Gokare Aswathanarayana Ravishankar, Effective inhibition of skin cancer, tyrosinase, and antioxidative properties by astaxanthin and astaxanthin esters from the green alga Haematococcus pluvialis, Journal of Agricultural and Food Chemistry, 61, 16, (2013), 3842-3851 https://doi.org/10.1021/jf304609j
  9. Mariam Al-Amrani, Ahmed Al-Alawi, Insaaf Al-Marhobi, Assessment of enzymatic browning and evaluation of antibrowning methods on dates, International Journal of Food Science, 2020, 8380461, (2020), 1-9 https://doi.org/10.1155/2020/8380461
  10. M. Carcelli, D. Rogolino, J. Bartoli, N. Pala, C. Compari, N. Ronda, F. Bacciottini, M. Incerti, E. Fisicaro, Hydroxyphenyl thiosemicarbazones as inhibitors of mushroom tyrosinase and antibrowning agents, Food Chemistry, 303, 125310, (2020), 1-25 https://doi.org/10.1016/j.foodchem.2019.125310
  11. Christina L. Burnett, Wilma F. Bergfeld, Donald V. Belsito, Ronald A. Hill, Curtis D. Klaassen, Daniel C. Liebler, James G. Marks, Ronald C. Shank, Thomas J. Slaga, Paul W. Snyder, Final report of the safety assessment of kojic acid as used in cosmetics, International Journal of Toxicology, 29, 6_suppl, (2010), 244S-273S https://doi.org/10.1177/1091581810385956
  12. Christopher A. Ramsden, Patrick A. Riley, Mechanistic aspects of the tyrosinase oxidation of hydroquinone, Bioorganic & Medicinal Chemistry Letters, 24, 11, (2014), 2463-2464 https://doi.org/10.1016/j.bmcl.2014.04.009
  13. Bart Desmedt, Gamze Ates, Patricia Courselle, Jacques O. De Beer, Vera Rogiers, Benoit Hendrickx, Eric Deconinck, Kristien De Paepe, In vitro Dermal Absorption of Hydroquinone: Protocol Validation and Applicability on Illegal Skin-Whitening Cosmetics, Skin Pharmacology and Physiology, 29, 6, (2016), 300-308 https://doi.org/10.1159/000454719
  14. J.M. Gillbro, M.J. Olsson, The melanogenesis and mechanisms of skin‐lightening agents–existing and new approaches, International Journal of Cosmetic Science, 33, 3, (2011), 210-221 https://doi.org/10.1111/j.1468-2494.2010.00616.x
  15. Francisco Solano, Stefania Briganti, Mauro Picardo, Ghanem Ghanem, Hypopigmenting agents: an updated review on biological, chemical and clinical aspects, Pigment Cell Research, 19, 6, (2006), 550-571 https://doi.org/10.1111/j.1600-0749.2006.00334.x
  16. Hua-Li Qin, Zhen-Peng Shang, Ibrahim Jantan, Oya Unsal Tan, Muhammad Ajaz Hussain, Muhammad Sher, Syed Nasir Abbas Bukhari, Molecular docking studies and biological evaluation of chalcone based pyrazolines as tyrosinase inhibitors and potential anticancer agents, RSC Advances, 5, 57, (2015), 46330-46338 https://doi.org/10.1039/C5RA02995C
  17. Vikram Panchal, Hiren H. Variya, G.R. Patel, “Pyrazolo [3, 4-bpyridins with Pharmaceutical activity in Heterocyclic Chemistry” A review, International Journal of Applied Engineering Research, 14, 1, (2019), 43-50
  18. Enda Mora, Adel Zamri, Hilwan Y. Teruna, Neni Frimayanti, Ihsan Ikhtiarudin, Noval Herfindo, Elsa Natia Rindiana, (E)-5-Benzyl-7-(3, 4-dimethoxybenzylidene)-3-(3, 4-dimethoxyphenyl) -2-phenyl-3, 3a, 4, 5, 6, 7-hexahydro-2H-pyrazolo [4, 3c] Pyridine, Molbank, 2021, 3, (2021), 2-8 https://doi.org/10.3390/M1240
  19. Andrea Angeli, Victor Kartsev, Anthi Petrou, Boris Lichitsky, Andrey Komogortsev, Mariana Pinteala, Athina Geronikaki, Claudiu T. Supuran, Pyrazolo [4, 3-c] pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies, Pharmaceuticals, 15, 3, (2022), 316 https://doi.org/10.3390/ph15030316
  20. David Ramírez, Melissa Mejia-Gutierrez, Braulio Insuasty, Susanne Rinné, Aytug K. Kiper, Magdalena Platzk, Thomas Müller, Niels Decher, Jairo Quiroga, Pedro De-la-Torre, Wendy González, 5-(Indol-2-yl) pyrazolo [3, 4-b] pyridines as a new family of task-3 channel blockers: A pharmacophore-based regioselective synthesis, Molecules, 26, 13, (2021), 3897 https://doi.org/10.3390/molecules26133897
  21. Suresh Amaroju, Mahalakshmi Naidu Kalaga, Singireddi Srinivasarao, Agnieszka Napiórkowska, Ewa Augustynowicz-Kopeć, Sankaranarayanan Murugesan, Subhash Chander, Rangan Krishnan, Kondapalli Venkata Gowri Chandra Sekhar, Identification and development of pyrazolo[4, 3-c]pyridine carboxamides as Mycobacterium tuberculosis pantothenate synthetase inhibitors, New Journal of Chemistry, 41, 1, (2017), 347-357 https://doi.org/10.1039/C6NJ02671K
  22. Scott Eagon, Jared T. Hammill, Martina Sigal, Kevin J. Ahn, Julia E. Tryhorn, Grant Koch, Briana Belanger, Cory A. Chaplan, Lauren Loop, Anna S. Kashtanova, Synthesis and Structure–Activity Relationship of Dual-Stage Antimalarial Pyrazolo [3, 4-b] pyridines, Journal of Medicinal Chemistry, 63, 20, (2020), 11902-11919 https://doi.org/10.1021/acs.jmedchem.0c01152
  23. Neni Frimayanti, Adel Zamri, Yum Eryanti, Noval Herfindo, Veza Azteria, Docking and Molecular Dynamic Simulations Study to Search Curcumin Analogue Compounds as Potential Inhibitor Against SARS-CoV-2: A Computational Approach, Jurnal Kimia Sains dan Aplikasi, 24, 3, (2021), 85-90 https://doi.org/10.14710/jksa.24.3.85-90
  24. Rahayu Rahayu, Noval Herfindo, Nelly Oscifiani, Neni Frimayanti, Synthesis of 4-(5-(2, 3-Dimenthoxyphenyl)-3-(4-Methoxyphenyl)-4, 5-Dihydro-1H-Pyrazol-1-y1) Benzenesulfonamide as a Promosing Tyrosinase Inhibitor Candidate, Jurnal Riset Kimia, 13, 1, (2022), 49-57 https://doi.org/10.25077/jrk.v13i1.486
  25. Tyas Kuswardani, Noval Herfindo, Neni Frimayanti, Rudi Hendra, Adel Zamri, 3, 5-Bis ((E)-4-methoxybenzylidene)-1-(2-morpholinoethyl)piperidin-4-one, Molbank, 2020, 4, (2020), 1-6 https://doi.org/10.3390/M1159
  26. T. Suwunwong, T. Kobkeatthawin, K. Chanawanno, N. Saewan, P. Wisitsak, Suchada Chantrapromma, Tyrosinase inhibitory activity of pyrazole derivatives, Advanced Materials Research, 2012 https://doi.org/10.4028/www.scientific.net/AMR.506.194
  27. L Ravithej Singh, Yu-Lin Chen, Yuan-Yuan Xie, Wei Xia, Xing-Wen Gong, Robert C. Hider, Tao Zhou, Functionality study of chalcone-hydroxypyridinone hybrids as tyrosinase inhibitors and influence on anti-tyrosinase activity, Journal of Enzyme Inhibition and Medicinal Chemistry, 35, 1, (2020), 1562-1567 https://doi.org/10.1080/14756366.2020.1801669

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