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Medicinal Chemistry

Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Promising Anticancer Activity of Pyrazole Compounds against Glioblastoma Multiforme: Their Synthesis, In vitro, and Molecular Docking Studies

Author(s): Kemal Alp Nalcı, Cihat Mete, Zeynep Demir, İshak Bildirici and Adnan Cetin*

Volume 21, Issue 6, 2025

Published on: 17 January, 2025

Page: [536 - 545] Pages: 10

DOI: 10.2174/0115734064337582241103172720

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Abstract

Background: Glioblastoma Multiforme (GBM), a highly aggressive and prevalent brain cancer with a higher incidence in males, has limited treatment success due to drug resistance, inadequate targeting and penetration of cancer cells, and an incomplete understanding of its molecular pathways. GBM is a highly aggressive brain cancer with limited treatment options. This study investigates the anticancer potential of synthesized pyrazole compounds against GBM cells.

Methods: A series of pyrazole derivatives were synthesized and tested for their efficacy against GBM using MTT assays. Molecular docking studies were conducted to explore the binding interactions of these compounds with GBM receptors.

Results: Compounds 3 and 5 demonstrated significant anticancer activity, reducing cell viability more effectively than the control group. MTT assay results confirmed their potency. Molecular docking studies revealed strong binding interactions with GBM receptors, highlighting their potential as anticancer agents.

Conclusion: The study evaluated the anticancer activity of synthesized compounds on human GBM cells, with compounds 3 and 5 showing the most promising results. Pyrazole 3 significantly reduced cell viability at high concentrations, while both pyrazoles 3 and 5 required higher doses to achieve substantial effects, as indicated by their IC50 values. Molecular docking studies confirmed strong binding interactions with the GBM receptor, and the pharmacokinetic properties suggest their potential as anticancer agents. These results highlight compounds 3 and 5 as candidates for further investigation.

Keywords: Anticancer, brain diseases, heterocyclic, pharmacologic activity, pyrazole, spectroscopy.

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Graphical Abstract

Graphical abstract illustrating key findings of the study

[1]
Grochans, S.; Cybulska, A.M.; Simińska, D.; Korbecki, J.; Kojder, K.; Chlubek, D.; Baranowska-Bosiacka, I. Epidemiology of glioblastoma multiforme–literature review. Cancers (Basel), 2022, 14(10), 2412.
[http://dx.doi.org/10.3390/cancers14102412] [PMID: 35626018]
[2]
Rosińska, S.; Gavard, J. Tumor vessels fuel the fire in glioblastoma. Int. J. Mol. Sci., 2021, 22(12), 6514.
[http://dx.doi.org/10.3390/ijms22126514] [PMID: 34204510]
[3]
De Felice, M.; De Marinis, P.; Martin, G.; Bruscella, S.; De Bellis, A.; Poliero, L.; Turitto, G. Dramatic response to regorafenib in early glioblastoma progression: case report and review of the literature. Eur. Rev. Med. Pharmacol. Sci., 2022, 26(14), 5008-5013.
[PMID: 35916797]
[4]
Minniti, G.; Muni, R.; Lanzetta, G.; Marchetti, P.; Enrici, R.M. Chemotherapy for glioblastoma: current treatment and future perspectives for cytotoxic and targeted agents. Anticancer Res., 2009, 29(12), 5171-5184.
[PMID: 20044633]
[5]
Cruz, J.V.R.; Batista, C.; Afonso, B.H.; Alexandre-Moreira, M.S.; Dubois, L.G.; Pontes, B.; Moura Neto, V.; Mendes, F.A. Obstacles to glioblastoma treatment two decades after temozolomide. Cancers (Basel), 2022, 14(13), 3203.
[http://dx.doi.org/10.3390/cancers14133203] [PMID: 35804976]
[6]
Fabro, F.; Lamfers, M.L.M.; Leenstra, S. Advancements, challenges, and future directions in tackling glioblastoma resistance to small kinase inhibitors. Cancers (Basel), 2022, 14(3), 600.
[http://dx.doi.org/10.3390/cancers14030600] [PMID: 35158868]
[7]
Lasorella, A.; Sanson, M.; Iavarone, A. FGFR-TACC gene fusions in human glioma. Neuro-oncol., 2016, 19(4), now240.
[http://dx.doi.org/10.1093/neuonc/now240] [PMID: 27852792]
[8]
Cai, Q.; Fan, H.; Li, X.; Giannotta, M.; Bachoo, R.; Qin, Z. Optical modulation of the blood-brain barrier for glioblastoma treatment. Bio Protoc., 2024, 14(1337), e4920.
[http://dx.doi.org/10.21769/BioProtoc.4920] [PMID: 38268976]
[9]
Baren, M.H.; Ibrahim, S.A.; Al-Rooqi, M.M.; Ahmed, S.A.; El-Gamil, M.M.; Hekal, H.A. A new class of anticancer activity with computational studies for a novel bioactive aminophosphonates based on pyrazole moiety. Sci. Rep., 2023, 13(1), 14680.
[http://dx.doi.org/10.1038/s41598-023-40265-8] [PMID: 37673913]
[10]
Kandhasamy, K.; Surajambika, R.R.; Velayudham, P.K. Pyrazolo - pyrimidines as targeted anticancer scaffolds - a comprehensive review. Med. Chem., 2024, 20(3), 293-310.
[http://dx.doi.org/10.2174/0115734064251256231018104623] [PMID: 37885114]
[11]
Havrylyuk, D.; Roman, O.; Lesyk, R. Synthetic approaches, structure activity relationship and biological applications for pharmacologically attractive pyrazole/pyrazoline–thiazolidine-based hybrids. Eur. J. Med. Chem., 2016, 113, 145-166.
[http://dx.doi.org/10.1016/j.ejmech.2016.02.030] [PMID: 26922234]
[12]
Cetin, A. Pyrazole carboxylic acid and derivatives: synthesis and biological applications. Mini Rev. Org. Chem., 2021, 18(1), 93-109.
[http://dx.doi.org/10.2174/1570193X17999200507094857]
[13]
Youssef, A.M.; Neeland, E.G.; Villanueva, E.B.; White, M.S.; El-Ashmawy, I.M.; Patrick, B.; Klegeris, A.; Abd-El-Aziz, A.S. Synthesis and biological evaluation of novel pyrazole compounds. Bioorg. Med. Chem., 2010, 18(15), 5685-5696.
[http://dx.doi.org/10.1016/j.bmc.2010.06.018] [PMID: 20609589]
[14]
Zhang, X.X.; Jin, H.; Deng, Y.J.; Gao, X.H.; Li, Y.; Zhao, Y.T.; Tao, K.; Hou, T-P. Synthesis and biological evaluation of novel pyrazole carboxamide with diarylamine-modified scaffold as potent antifungal agents. Chin. Chem. Lett., 2017, 28(8), 1731-1736.
[http://dx.doi.org/10.1016/j.cclet.2017.04.021]
[15]
Song, H.; Liu, Y.; Xiong, L.; Li, Y.; Yang, N.; Wang, Q. Design, synthesis, and insecticidal evaluation of new pyrazole derivatives containing imine, oxime ether, oxime ester, and dihydroisoxazoline groups based on the inhibitor binding pocket of respiratory complex I. J. Agric. Food Chem., 2013, 61(37), 8730-8736.
[http://dx.doi.org/10.1021/jf402719z] [PMID: 23972278]
[16]
Ma, Y.; Sun, G.; Chen, D.; Peng, X.; Chen, Y.L.; Su, Y.; Ji, Y.; Liang, J.; Wang, X.; Chen, L.; Ding, J.; Xiong, B.; Ai, J.; Geng, M.; Shen, J. Design and optimization of a series of 1-sulfonylpyrazolo[4,3-b]pyridines as selective c-Met inhibitors. J. Med. Chem., 2015, 58(5), 2513-2529.
[http://dx.doi.org/10.1021/jm502018y] [PMID: 25668160]
[17]
Huynh, T.; Chen, Z.; Pang, S.; Geng, J.; Bandiera, T.; Bindi, S.; Vianello, P.; Roletto, F.; Thieffine, S.; Galvani, A.; Vaccaro, W.; Poss, M.A.; Trainor, G.L.; Lorenzi, M.V.; Gottardis, M.; Jayaraman, L.; Purandare, A.V. Optimization of pyrazole inhibitors of coactivator associated arginine methyltransferase 1 (CARM1). Bioorg. Med. Chem. Lett., 2009, 19(11), 2924-2927.
[http://dx.doi.org/10.1016/j.bmcl.2009.04.075] [PMID: 19419866]
[18]
Dore, A.; Asproni, B.; Scampuddu, A.; Pinna, G.A.; Christoffersen, C.T.; Langgård, M.; Kehler, J. Synthesis and SAR study of novel tricyclic pyrazoles as potent phosphodiesterase 10A inhibitors. Eur. J. Med. Chem., 2014, 84, 181-193.
[http://dx.doi.org/10.1016/j.ejmech.2014.07.020] [PMID: 25016376]
[19]
Saman, S.; Srivastava, N.; Yasir, M.; Chauhan, I. A comprehensive review on current treatments and challenges involved in the treatment of ovarian cancer. Curr. Cancer Drug Targets, 2024, 24(2), 142-166.
[http://dx.doi.org/10.2174/1568009623666230811093139] [PMID: 37642226]
[20]
Decuypère, E.; Plougastel, L.; Audisio, D.; Taran, F. Sydnone–alkyne cycloaddition: applications in synthesis and bioconjugation. Chem. Commun. (Camb.), 2017, 53(84), 11515-11527.
[http://dx.doi.org/10.1039/C7CC06405E] [PMID: 28959814]
[21]
Bildirici, İ.; Şener, A.; Atalan, E.; Battal, A.; Genç, H. Synthesis and antibacterial activity of 4-benzoyl-1-(4-carboxy-phenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid and derivatives. Med. Chem. Res., 2009, 18(5), 327-340.
[http://dx.doi.org/10.1007/s00044-008-9130-3]
[22]
Balça-Silva, J.; Matias, D.; Do Carmo, A.; Dubois, L.G.; Gonçalves, A.C.; Girão, H.; Silva Canedo, N.H.; Correia, A.H.; De Souza, J.M.; Sarmento-Ribeiro, A.B.; Lopes, M.C.; Moura-Neto, V. Glioblastoma entities express subtle differences in molecular composition and response to treatment. Oncol. Rep., 2017, 38(3), 1341-1352.
[http://dx.doi.org/10.3892/or.2017.5799] [PMID: 28714013]
[23]
Das, S.; Mondal, S.; Patel, T.; Himaja, A.; Adhikari, N.; Banerjee, S.; Baidya, S.K.; De, A.K.; Gayen, S.; Ghosh, B.; Jha, T. Derivatives of D(−) glutamine-based MMP-2 inhibitors as an effective remedy for the management of chronic myeloid leukemia-Part-I: Synthesis, biological screening and in silico binding interaction analysis. Eur. J. Med. Chem., 2024, 274, 116563.
[http://dx.doi.org/10.1016/j.ejmech.2024.116563] [PMID: 38843586]
[24]
Cetin, A.; Kurt, H. Synthesis, antibacterial activity and molecular docking studies of new pyrazole derivatives. Lett. Drug Des. Discov., 2020, 17(6), 745-756.
[http://dx.doi.org/10.2174/1570180816666190905155510]
[25]
Türkan, F.; Cetin, A.; Rozbicki, P.; Oğuz, E.; Wolińska, E.; Branowska, D. Pharmacological assessment of disulfide–triazine hybrids: synthesis, enzyme inhibition, and molecular docking study. Med. Chem. Res., 2024, 33(7), 1205-1217.
[http://dx.doi.org/10.1007/s00044-024-03251-x]
[26]
Ananta, J.S.; Paulmurugan, R.; Massoud, T.F. Temozolomide-loaded PLGA nanoparticles to treat glioblastoma cells: a biophysical and cell culture evaluation. Neurol. Res., 2016, 38(1), 51-59.
[http://dx.doi.org/10.1080/01616412.2015.1133025] [PMID: 26905383]
[27]
Ramchandani, S.; Naz, I.; Dhudha, N.; Garg, M. An overview of the potential anticancer properties of cardamonin. Explor. Target. Antitumor Ther., 2020, 1(6), 413-426.
[28]
Bibak, B.; Shakeri, F.; Keshavarzi, Z.; Mollazadeh, H.; Javid, H.; Jalili-Nik, M.; Sathyapalan, T.; Afshari, A.R.; Sahebkar, A. Anticancer mechanisms of Berberine: a good choice for glioblastoma multiforme therapy. Curr. Med. Chem., 2022, 29(26), 4507-4528.
[http://dx.doi.org/10.2174/0929867329666220224112811] [PMID: 35209812]
[29]
Wu, W.; Klockow, J.L.; Zhang, M.; Lafortune, F.; Chang, E.; Jin, L.; Wu, Y.; Daldrup-Link, H.E. Glioblastoma multiforme (GBM): An overview of current therapies and mechanisms of resistance. Pharmacol. Res., 2021, 171, 105780.
[http://dx.doi.org/10.1016/j.phrs.2021.105780] [PMID: 34302977]
[30]
Patil, R.; Das, S.; Stanley, A.; Yadav, L.; Sudhakar, A.; Varma, A.K. Optimized hydrophobic interactions and hydrogen bonding at the target-ligand interface leads the pathways of drug-designing. PLoS One, 2010, 5(8), e12029.
[http://dx.doi.org/10.1371/journal.pone.0012029] [PMID: 20808434]
[31]
Hosseini Nasab, N.; Azimian, F.; Shim, R.S.; Eom, Y.S.; Shah, F.H.; Kim, S.J. Synthesis, anticancer evaluation, and molecular docking studies of thiazolyl-pyrazoline derivatives. Bioorg. Med. Chem. Lett., 2023, 80, 129105.
[http://dx.doi.org/10.1016/j.bmcl.2022.129105] [PMID: 36513215]
[32]
Sadri, A. Is target-based drug discovery efficient? Discovery and “off-target” mechanisms of all drugs. J. Med. Chem., 2023, 66(18), 12651-12677.
[http://dx.doi.org/10.1021/acs.jmedchem.2c01737] [PMID: 37672650]
[33]
Almohaimeed, H.M.; Almars, A.I.; Al Abdulmonem, W.; Alghsham, R.S.; Aljohani, A.S.M.; Alharbi, Y.M.; Badahdah, F.A.; Alkhudhairy, B.S.M.; Soliman, M.H. Molecular dynamics exploration of Lupenone: therapeutic implications for glioblastoma multiforme and Alzheimer’s amyloid beta pathogenesis. Metab. Brain Dis., 2023, 39(1), 77-88.
[http://dx.doi.org/10.1007/s11011-023-01319-y] [PMID: 38129732]
[34]
Li, Y.L.; Yan, L.J.; Chen, H.X.; Ruan, B.K.; Dao, P.; Du, Z.Y.; Dong, C.Z.; Meunier, B. Design, synthesis and evaluation of novel pyrimidinylaminothiophene derivatives as FGFR1 inhibitors against human glioblastoma multiforme. Eur. J. Med. Chem., 2023, 260, 115764.
[http://dx.doi.org/10.1016/j.ejmech.2023.115764] [PMID: 37651879]
[35]
Tsuji, S.; Kudo, U.; Hatakeyama, R.; Shoda, K.; Nakamura, S.; Shimazawa, M. Linagliptin decreased the tumor progression on glioblastoma model. Biochem. Biophys. Res. Commun., 2024, 711, 149897.
[http://dx.doi.org/10.1016/j.bbrc.2024.149897] [PMID: 38608433]
[36]
Volkamer, A.; Kuhn, D.; Rippmann, F.; Rarey, M. DoGSiteScorer: a web server for automatic binding site prediction, analysis and druggability assessment. Bioinformatics, 2012, 28(15), 2074-2075.
[http://dx.doi.org/10.1093/bioinformatics/bts310] [PMID: 22628523]
[37]
Amin, S.; Adhikari, N.; Agrawal, R.; Jha, T.; Gayen, S.R.; Jha, T.; Gayen, S. Possible binding mode analysis of Pyrazolo-triazole hybrids as potential anticancer agents through validated molecular docking and 3D-QSAR modeling approaches. Lett. Drug Des. Discov., 2017, 14(5), 515-527.
[http://dx.doi.org/10.2174/1570180813666160916153017]
[38]
Cetin, A.; Donmez, A.; Dalar, A.; Bildirici, I. Amino acid and dicyclohexylurea linked pyrazole analogues: Synthesis, in silico and in vitro studies. ChemistrySelect, 2023, 8(6), e202204926.
[http://dx.doi.org/10.1002/slct.202204926]
[39]
Seyma, S.Z.; Bildirici, N.; Cetin, A.; Bildirici, I. GABA-AT inhibitors: Design, synthesis, pharmacological characterization, molecular docking and ADMET studies. ChemistrySelect, 2023, 8(35), e202302683.
[http://dx.doi.org/10.1002/slct.202302683]
[40]
Rozbicki, P.; Oğuz, E.; Wolińska, E.; Türkan, F.; Cetin, A.; Branowska, D. Synthesis and examination of 1,2,4‐triazine‐sulfonamide hybrids as potential inhibitory drugs: Inhibition effects on AChE and GST enzymes in silico and in vitro conditions. Arch. Pharm. (Weinheim), 2024, 357(9), 2400182.
[http://dx.doi.org/10.1002/ardp.202400182] [PMID: 38771105]

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