Synthesis, Cytotoxicity Evaluation and Molecular Docking Study of N-Phenylpyrazoline Derivatives

Artania Adnin Tri Suma(1), Tutik Dwi Wahyuningsih(2*), Mustofa Mustofa(3)

(1) Laboratory of Organic Chemistry, Department of Chemistry, Universitas Gadjah Mada
(2) Laboratory of Organic Chemistry, Department of Chemistry, Universitas Gadjah Mada
(3) Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Gadjah Mada,
(*) Corresponding Author


The synthesis of N-phenylpyrazolines 1-5 was performed by the cyclocondensation of phenylhydrazine and appropriate chalcones that have been synthesized from our previous work. All of the compounds were elucidated for their structure using GC-MS, FTIR, 1H, and 13C-NMR spectrometers. Their anticancer activity was evaluated against breast cancer cell line (T47D) and colorectal cancer cell line (WiDr). Compound 4 (4-(3-(4-chlorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-5-yl)-2-methoxyphenol) was found to be the most potent compound with IC50 value of 13.11 µg/mL in T47D cell line and 3.29 µg/mL in WiDr cell line. Docking study was conducted to evaluate the interaction between all compounds and EGFR receptor on cancer cells. Among the tested compounds, compound 4 is the only compound that has interaction with MET769 residue through hydrogen bonding due to the presence of hydroxyl group on its structure. Our findings suggest that the synthesized N-phenylpyrazolines in this study have a promising anticancer activity.


N-phenylpyrazoline, anticancer, cytotoxic activity, molecular docking

Full Text:

Full Text PDF


[1] Torre, L.A., Bray, F., Siegel, R.L., Ferlay, J., Lortet-Tieulent, J., and Jemal, A., 2015, Global cancer statistics 2012, CA Cancer J. Clin., 65 (2), 87–108.

[2] Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R.L., Torre, L.A., and Jemal, A., 2018, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin., 68 (6), 394–424.

[3] Patel, K., Karthikeyan, C., Solomon, V.R., Morthy, N.S.H.N., Lee, H., Sahu, K., Deora, G.S., and Trivedi, P., 2011, Synthesis of some coumarinyl chalcones and their antiproliferative activity against breast cancer cell lines, Lett. Drug Des. Discovery, 8 (4), 308–311.

[4] Lu, Z.H., Gu, X.J., Shi, K.Z., Li, X., Chen, D.D., and Chen, Li., 2017, Accessing anti-human lung tumor cell line (A549) potential of newer 3,5-disubstituted pyrazoline analogs, Arabian J. Chem., 10 (5), 624–630.

[5] Cai, X., Zhao, S., Cai, D., Zheng, J., Zhu, Z., Wei, D., Zheng, Z., Zhu, H., and Chen, Y., 2019, Synthesis and evaluation of novel D-ring substituted steroidal pyrazolines as potential anti-inflammatory agents, Steroids, 146, 70–78.

[6] Gok, S., Demet, M.M., Özdemir, A., and Turan-Zitouni, G., 2010, Evaluation of antidepressant-like effect of 2-pyrazoline derivatives, Med. Chem. Res., 19 (1), 94–101.

[7] Raghuvanshi, D.S., Verma, N., Singh, S.V., Khare, S., Pal, A., and Negi, A.S., 2019, Synthesis of thymol-based pyrazolines: An effort to perceive novel potent-antimalarials, Bioorg. Chem., 88, 102933.

[8] Altıntop, M.D., Özdemir, A., Turan-Zitouni, G., Ilgın, S., Atlı, Ö., and Kaplancıklı, Z.A., 2015, A novel series of thiazolyl–pyrazoline derivatives: Synthesis and evaluation of antifungal activity, cytotoxicity, and genotoxicity, Eur. J. Med. Chem., 92, 342–352.

[9] Rani, M., Yusuf, M., Khan, S.A., Sahota, P.P., and Pandove, G., 2015, Synthesis, studies and in-vitro antibacterial activity of N-substituted 5-(furan-2-yl)-phenyl pyrazolines, Arabian J. Chem., 8 (2), 174–180.

[10] Kumar, A., Varadaraj, B.G., and Singla, R.K., 2013, Synthesis and evaluation of antioxidant activity of novel 3,5-disubstituted-2-pyrazolines, Bull. Fac. Pharm. Cairo Univ., 51 (2), 167–173.

[11] Ahmad, A., Husain, A., Khan, S.A., Mujeeb, M., and Bhandari, A., 2016, Synthesis, antimicrobial and antitubercular activities of some novel pyrazoline derivatives, J. Saudi Chem. Soc., 20 (5), 577–584.

[12] Viveka, S., Dinesha, Shama, P., Nagaraja, G.K., Ballav, S., and Kerkar, S., 2015, Design and synthesis of some new pyrazolyl-pyrazolines as potential anti-inflammatory, analgesic and antibacterial agents, Eur. J. Med. Chem., 101, 442–451.

[13] Zhao, P.L., Wang, F., Zhang, M.Z., Liu, Z.M., Huang, W., and Yang, G.F., 2008, Synthesis, fungicidal, and insecticidal activities of β-methoxyacrylate-containing N-acetyl pyrazoline derivatives, J. Agric. Food Chem., 56 (22), 10767–10773.

[14] Pacheco, D.J., Prent, L., Trilleras, J., and Quiroga, J., 2013, Facile sonochemical synthesis of novel pyrazoline derivates at ambient conditions, Ultrason. Sonochem., 20 (4), 1033–1036.

[15] Mubeen, M., Kini, S.G., and Pai, K.S.R., 2015, Design, synthesis, antioxidant, and anticancer activity of novel pyrazole derivatives, Der Pharma Chem., 7 (2), 215–223.

[16] Yang, W., Hu, Y., Yang, Y.S., Zhang, F., Zhang, Y.B., Wang, X.L., Tang, J.F., Zhong, W.Q., and Zhu, H.L., 2013, Design, modification and 3D QSAR studies of novel naphthalin-containing pyrazoline derivatives with/without thiourea skeleton as anticancer agents, Bioorg. Med. Chem., 21 (5), 1050–1063.

[17] Sunayana, G., Shashikant, B., and Sandeep, W., 2017, 2D, 3D, G-QSAR and docking studies of thiazolyl-pyrazoline analogues as potent (epidermal growth factor receptor-tyrosine kinase) EGFR-TK inhibitors, Lett. Drug Des. Discovery, 14 (11), 1228–1238.

[18] Ciupa, A., De Bank, P.A., Mahon, M.F., Wood, P.J., and Caggiano, L., 2013, Synthesis and antiproliferative activity of some 3-(pyrid-2-yl)-pyrazolines, Med. Chem. Commun., 4, 956–961.

[19] Bano, S., Javed, K., Ahmad, S., Rathish, I.G., Singh, S., and Alam, M.S., 2011, Synthesis and biological evaluation of some new 2-pyrazolines bearing benzene sulfonamide moiety as potential anti-inflammatory and anti-cancer agents, Eur. J. Med. Chem., 46 (12), 5763–5768.

[20] Yang, Y.S., Yang, B., Zou, Y., Li, G., and Zhu, H.L., 2016, Design, biological evaluation and 3D QSAR studies of novel dioxin-containing triaryl pyrazoline derivatives as potential B-Raf inhibitors, Bioorg. Med. Chem., 24 (13), 3052–3061.

[21] Suma, A.A.T., Wahyuningsih, T.D., and Mustofa, 2019, Efficient synthesis of chloro chalcones under ultrasound irradiation, their anticancer activities and molecular docking studies, Rasayan J. Chem., 12 (2), 502–510.

[22] Dennington, R., Keith, T., and Milliam, J., 2009, GaussView, Version 5, Semichem Inc., Shawnee Mission, KS.

[23] Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Petersson, G.A., Nakatsuji, H., Li, X., Caricato, M., Marenich, A., Bloino, J., Janesko, B.G., Gomperts, R., Mennucci, B., Hratchian, H.P., Ortiz, J.V., Izmaylov, A.F., Sonnenberg, J.L., Williams-Young, D., Ding, F., Lipparini, F., Egidi, F., Goings, J., Peng, B., Petrone, A., Henderson, T., Ranasinghe, D., Zakrzewski, V.G., Gao, J., Rega, N., Zheng, G., Liang, W., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T., Throssell, K., Montgomery, J.A., Jr., Peralta, J.E., Ogliaro, F., Bearpark, M., Heyd, J.J., Brothers, E., Kudin, K.N., Staroverov, V.N., Keith, T., Kobayashi, R., Normand, J., Raghavachari, K., Rendell, A., Burant, J.C., Iyengar, S.S., Tomasi, J., Cossi, M., Millam, J.M., Klene, M., Adamo, C., Cammi, R., Ochterski, J.W., Martin, R.L., Morokuma, K., Farkas, O., Foresman, J.B., and Fox, D.J., 2016, Gaussian 09, Revision A.02, Gaussian 09 Inc., Wallingford CT.

[24] Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S., and Olson, A.J., 2009, AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility, J. Comput. Chem., 30 (16), 2785–2791.

[25] Huey, R., Morris, G.M., Olson, A.J., and Goodsell, D.S., 2007, A semiempirical free energy force field with charge‐based desolvation, J. Comput. Chem., 28 (6), 1145–1152.

[26] Suma, A.A.T., Wahyuningsih, T.D., and Pranowo, D., 2017, Synthesis and antibacterial activities of N-phenylpyrazolines from veratraldehyde, Mater. Sci. Forum, 901, 124–132.

[27] Aghaee, F., Islamian, J.P., Baradaran, B., Mesbahi, A., Mohammadzadeh, M., and Jafarabadi, M.A., 2013, Enhancing the effects of low dose doxorubicin treatment by the radiation in T47D and SKBR3 breast cancer cells, J. Breast Cancer, 16 (2), 164–170.

[28] Gilang, Y., Hermawan, A., Fitriasari, A., and Jenie, R.I., 2012, Hesperidin increases cytotoxic effect of 5-fluorouracil on WiDr cells, IJCC, 3 (2), 404–409.

[29] Tanamatayarat, P., Limtrakul, P.N., Chunsakaow, S., and Duangrat, C., 2003, Screening of some rubiaceous plants for cytotoxic activity against cervix carcinoma (KB-3-1) cell line, Thai J. Pharm. Sci., 27, 167–172.

[30] Amin, K.M., Eissa, A.A., Abou-Seri, S.M., Awadallah, F.M., and Hassan, G.S., 2013, Synthesis and biological evaluation of novel coumarin-pyrazoline hybrids endowed with phenylsulfonyl moiety as antitumor agents, Eur. J. Med. Chem., 60, 187–198.


Article Metrics

Abstract views : 1306 | views : 1297

Copyright (c) 2019 Indonesian Journal of Chemistry

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.


Indonesian Journal of Chemistry (ISSN 1411-9420 / 2460-1578) - Chemistry Department, Universitas Gadjah Mada, Indonesia.

Analytics View The Statistics of Indones. J. Chem.