Design, Synthesis, Biological Evaluation, and Docking Study of Novel 4-Anilinoquinazolines Derivatives as Anticancer Agents

Document Type : Research Article


1 Department of Chemistry, Rasht Branch, Islamic Azad University, Rasht, I.R. IRAN

2 Department of Pharmaceutical Biotechnology, School of Pharmacy, Guilan University of Medical Sciences, Rasht, I.R. IRAN


Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR) as appropriate targets for cancer therapy have recently made a noteworthy field since the introduction of vandetanib as a dual inhibitor of VEGFR and EGFR tyrosine kinases (TKIs). In this study, twelve quinazoline derivatives were designed, synthesized, and evaluated for their cytotoxicity on A431 (human carcinoma cell) as well as HU02 (Foreskin fibroblast) cell lines by MTT assay. The binding mode of the most potent compound (8a) with EGFR and VEGFR2 was studied using molecular docking. Most of the compounds showed significant inhibition on the growth of A431 cells at the concentration lower than 100 µM. The compound 8a bearing diethylamine along with 4-bromo-2-fluoroaniline exhibited the best cytotoxic activity (IC50=2.62 μM) compared to erlotinib and vandetanib as positive controls. Synthesized compounds did not indicate significant cytotoxicity against HU02 cell line. The compound 8a indicated binding energies of -6.39 and -8.24 kcal/mol as well as inhibition constants of 20.67µM and 0.9µM with EGFR and VEGFR-2, respectively, which showed the effective binding with VEGFR-2.  The higher potency of 8a may be put down to the flexibility of diethylamine and its higher lipophilicity as well as lower steric hindrance of this substituent.


[1] Antonello A., Tarozzi A., Morroni F., Cavalli A., Rosini M., Hrelia P., Bolognesi M.L., Melchiorre C., Multitarget-Directed Drug Design Strategy: A Novel Molecule Designed to Block Epidermal Growth Factor Receptor (EGFR) and to Exert Proapoptotic Effects, J. Med. Chem., 49(23):6642-6645 (2006).

[2] Ghasemi S., Sharifi S., Davaran S., Danafar H., Asgari D., Mojarrad J.S., Synthesis and Cytotoxicity Evaluation of Some Novel 1-(3-Chlorophenyl) Piperazin-2-one Derivatives Bearing Imidazole Bioisosteres, Aust. J. Chem., 66(6): 655-660 (2013).

[3] Torre L.A., Bray F., Siegel R.L., Ferlay J., Lortet-Tieulent J., Jemal A., Global Cancer Statistics, 2012, CA Cancer J. Clin., 65(2):87-108 (2015).

[4] Aliabadi A., Fereidooni R., Kiani A., Synthesis and Cytotoxicity Evaluation of N-(5-(Substituted-Benzylthio)-1, 3, 4-Thiadiazole-2-yl)-2-p-Nitrophenylacetamide Derivatives as Potential Anticancer Agents, Iran. J. Chem. Chem. Eng. (IJCCE), 38(1): 49-55 (2019).

[5] Yinhua D., Foroughi M.M., Aramesh-Boroujeni Z., Jahani S., Peydayesh M., Borhani F., Khatami M., Rohani M., Dusek M., Eigner V.,  The Synthesis, Characterization, DNA/BSA/HSA Interactions, Molecular Modeling, Antibacterial Properties, and In Vitro Cytotoxic Activities of Novel Parent and Niosome Nano-Encapsulated Ho (III) Complexes, RSC Adv., 10(39): 22891-22908 (2020).

[6] Aliabadi A., Afnanzade N.-S., Hosseinzadeh L., Mohammadi-Farani A., Shafiee M.H., Nazari H., Ahmadi F., Foroumadi A.R., N-(5-(Trifluoromethyl)-1, 3, 4-Thiadiazol-2-yl) Benzamide and Benzothioamide Derivatives Induce Apoptosis via Caspase-Dependent Pathway, Pharm. Chem. J., 53(6): 521-526 (2019).

[7] Manikala V., Synthesis, Molecular Docking and Anticancer Activity of Novel (E)-5-((1-Phenyl-1H-1, 2, 3-Triazol-4-yl) Methylene)-2-Thioxothiazolidin-4-one Analogues, Iran. J. Chem. Chem. Eng. (IJCCE),
40(6): 1793- 1799 (2021).

[8] Li S., Guo C., Sun X., Li Y., Zhao H., Zhan D., Lan M., Tang Y., Synthesis and Biological Evaluation of Quinazoline and Quinoline Bearing 2, 2, 6, 6-Tetramethylpiperidine-N-Oxyl as Potential Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors and EPR Bio-Probe Agents, Eur. J. Med. Chem., 49: 271-278 (2012).

[9] Wee P., Wang Z., Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways, Cancers, 9(5): 52-97 (2017).

[10] Li R.-D., Zhang X., Li Q.-Y., Ge Z.-M., Li R.-T., Novel EGFR Inhibitors Prepared by Combination of Dithiocarbamic Acid Esters and 4-Anilinoquinazolines, Bioorg. Med. Chem., 21(12): 3637-3640 (2011).

[11] Sarfraz M., Rashid U., Sultana N., Tariq M.I., Synthesis, X-Rays Analysis, Docking Study and Cholinesterase Inhibition Activity of 2, 3-Dihydroquinazolin-4 (1H)-One Derivatives, Iran. J. Chem. Chem. Eng. (IJCCE), 38(6): 213-227 (2019).

[12] Sun M., Jia J., Sun H., Wang F., Design and Synthesis of a Novel Class EGFR/HER2 Dual Inhibitors Containing Tricyclic Oxazine Fused Quinazolines Scaffold, Bioorg. Med. Chem., 30(9):1-6 (2020).

[13] Garofalo A., Goossens L., Lemoine A., Ravez S., Six P., Howsam M., Farce A., Depreux P., [4-(6, 7-Disubstituted Quinazolin-4-ylamino) Phenyl] Carbamic Acid Esters: A Novel Series of Dual EGFR/VEGFR-2 Tyrosine Kinase Inhibitors, MedChemComm, 2(1): 65-72 (2011).

[14] Sini P., Wyder L., Schnell C., O'Reilly T., Littlewood A., Brandt R., Hynes N.E., Wood J., The Antitumor and Antiangiogenic Activity of Vascular Endothelial Growth Factor Receptor Inhibition is Potentiated by ErbB1 Blockade, Clin. Cancer Res., 11(12): 4521-4532 (2005).

[15] Garofalo A., Goossens L., Six P., Lemoine A., Ravez S., Farce A., Depreux P., Impact of Aryloxy-Linked Quinazolines: A Novel Series of Selective VEGFR-2 Receptor Tyrosine Kinase Inhibitors, Bioorg. Med. Chem., 21(7): 2106-2112 (2011).

[16] Xu P., Chu J., Li Y., Wang Y., He Y., Qi C., Chang J., Novel Promising 4-Anilinoquinazoline-Based Derivatives as Multi-Target RTKs Inhibitors: Design, Molecular Docking, Synthesis, and Antitumor Activities In Vitro and Vivo, Bioorg. Med. Chem., 27(20): 1-8 (2019).

[17] Ismail R.S.M., Abou-Seri S.M., Eldehna W.M., Ismail N.S.M., Elgazwi S.M., Ghabbour H.A., Ahmed M.S., Halaweish F.T., Abou El Ella D.A., Novel Series of 6-(2-Substitutedacetamido)-4-Anilinoquinazolines as EGFR-ERK Signal Transduction Inhibitors in MCF-7 Breast Cancer Cells, Eur. J. Med. Chem., 155:782-796 (2018).

[18] Wei H., Duan Y., Gou W., Cui J., Ning H., Li D., Qin Y., Liu Q., Li Y., Design, Synthesis and Biological Evaluation of Novel 4-Anilinoquinazoline Derivatives as Hypoxia-Selective EGFR and VEGFR-2 Dual Inhibitors, Eur. J. Med. Chem., 181(1):1-12 (2019).

[19] Hennequin L.F., Stokes E.S., Thomas A.P., Johnstone C., Plé P.A., Ogilvie D.J., Dukes M., Wedge S.R., Kendrew J., Curwen J.O., Novel 4-Anilinoquinazolines with C-7 Basic Side Chains: Design and Structure-Activity Relationship of a Series of Potent, Orally Active, VEGF Receptor Tyrosine Kinase Inhibitors, J. Med. Chem., 45(6):1300-1312 (2002).

[20] Hennequin L.F., Thomas A.P., Johnstone C.,  Stokes E.S., Plé P.A., Lohmann J.-J.M., Ogilvie D.J., Dukes M., Wedge S.R., Curwen J.O., Kendrew J., van der Brempt Ch.L., Design and Structure−Activity Relationship of a New Class of Potent VEGF Receptor Tyrosine Kinase Inhibitors, J. Med. Chem., 42(26):5369-5389 (1999).

[21] Zhang H.-Q., Gong F.-H., Li C.-G., Zhang C., Wang Y.-J., Xu Y.-G., Sun L.P., Design and Discovery of 4-Anilinoquinazoline-Acylamino Derivatives as EGFR and VEGFR-2 Dual TK Inhibitors, Eur. J. Med. Chem., 109:371-379 (2016).

 [22] Eweas A.F., Maghrabi I.A., Namarneh A.I., Advances in Molecular Modeling and Docking as a Tool for Modern Drug Discovery, Der Pharma Chem., 6(6):211-228 (2014).

[23] Zhao M., Wang L., Zheng L., Zhang M., Qiu C., Zhang Y., Du D., Niu B., 2D-QSAR and 3D-QSAR Analyses for EGFR Inhibitors, Biomed Res. Int., 2017 (2017).

[24] Zhao F., Lin Z., Wang F., Zhao W., Dong X., Four-Membered Heterocycles-Containing 4-Anilino-Quinazoline Derivatives as Epidermal Growth Factor Receptor (EGFR) Kinase Inhibitors, Bioorg. Med. Chem., 23(19):5385-5388 (2013).

[25] Heydari Alizadeh B., Vosooghi M., Khoobi M., Javidnia A., Panah F., Safavi M., Adrestani S., Shafiee A., Synthesis and Cytotoxic Activity of Novel 9-[Hydroxy (Substituted Phenyl) Methyl]-2, 2-Dimethyl-2, 3, 8, 9-Tetrahydro-4H, 10H-Pyrano
[2, 3-f] Chromene-4, 10-Diones
, Iran. J. Chem. Chem. Eng. (IJCCE), 29(4):189-196 (2010).

[26] Holladay M.W., Campbell B.T., Rowbottom M.W., Chao Q., Sprankle K.G., Lai A.G., Abraham S., Setti E., Faraoni R., Tran L., Armstrong R.C., Gunawardane R.N., Gardner M.F., Cramer M.D., Gitnick D., Ator M.A., Dorsey B.D., Ruggeri B.R., James J., 4-Quinazolinyloxy- diaryl Ureas as Novel BRAFV600E Inhibitors, Bioorg. Med. Chem., 21(18): 5342-5346 (2011).

[27] Mozaffari S., Ghasemi S., Baher H., Khademi H., Amini M., Sakhteman A., Foroumadi A., Ebrahimabadi A.H., Sharifzadeh M., Synthesis and Evaluation of some Novel methylene-bridged Aryl Semicarbazones as Potential Anticonvulsant Agents, Medicinal Chemistry Research, 21(11): 3797-3808 (2012).

[28] Zhang N., Wu B., Powell D., Wissner A., Floyd M.B., Kovacs E.D., Toral-Barza L., Kohler C., Synthesis and Structure–Activity Relationships of 3-cyano-4-(phenoxyanilino) Quinolines as MEK (MAPKK) Inhibitors, Bioorg. Med. Chem., 10(24): 2825-2828 (2000).

[29] Ghasemi S., Sharifi S., Mojarrad J.S., Design, Synthesis and Biological Evaluation of Novel Piperazinone Derivatives as Cytotoxic Agents, Adv. Pharm. Bull., 10(3):423-429 (2020).

[30] Zhang Y., Gao H., Liu R., Liu J., Chen L., Li X., Zhao L., Wang W., Li B., Quinazoline-1-deoxynojirimycin Hybrids as High Active Dual Inhibitors of EGFR and α-glucosidase, Bioorg. Med. Chem., 27(18): 4309-4313 (2017).

[31] Garofalo A., Farce A., Ravez S.v., Lemoine A.l., Six P., Chavatte P., Goossens L., Depreux P., Synthesis and Structure-Activity relationships of (aryloxy) quinazoline Ureas as Novel, Potent, and Selective Vascular Endothelial Growth Factor Receptor-2 Inhibitors, J. Med. Chem., 55(3):1189-1204 (2012).

[32] Barker A.J., inventor; Zeneca Limited (London, GB2), Assignee. Quinazoline Derivatives Useful for Treatment of Neoplastic Disease,  US Patent, 5457105 (1995).

[33] Thomas A.P., Johnstone C., Hennequin L.F.A., inventors; Zeneca Limited (London, GB), Assignee. 4-anilinoquinazoline Derivatives, US Patent 6291455 (2001).

[34] Kondori T., Shahraki O., Akbarzadeh-T N., Aramesh-Boroujeni Z., Two Novel Bipyridine-Based Cobalt (II) Complexes: Synthesis, Characterization, Molecular Docking, DNA-Binding and Biological Evaluation, J. Biomol. Struct. Dyn.:1-15 (2020).

[35] Aramesh-Boroujeni Z., Aramesh N., Jahani S., Khorasani-Motlagh M., Kerman K., Noroozifar M., Experimental and Computational Interaction Studies of Terbium (III) and Lanthanide (III) Complexes Containing 2, 2′-Bipyridine with Bovine Serum Albumin and their In Vitro Anticancer and Antimicrobial Activities, J. Biomol. Struct. Dyn.:1-12 (2020).

[36] Aramesh-Boroujeni Z., Jahani S., Khorasani-Motlagh M., Kerman K., Noroozifar M., Parent and Nano-Encapsulated Ytterbium (III) Complex toward Binding with Biological Macromolecules, In Vitro Cytotoxicity, Cleavage and Antimicrobial Activity Studies, RSC Adv., 10(39): 23002-23015 (2020).

[37] Hamidi M., Ghasemi S., Bavafa Bighdilou B., Eghbali Koohi D., Evaluation of Antioxidant, Antibacterial and Cytotoxic Activity of Methanol Extract from Leaves and Fruits of Iranian Squirting Cucumber (Ecballium Elaterium (L.) A. Rich), Res. J. Pharmacogn. (RJP), 7(1): 23-29 (2020).

[38] Yousefbeyk F., Tabaside J., Ostad S., Salehi Sourmaghi M., Amin G., Investigation of Chemical Composition and Cytotoxic Activity of Aerial Parts of Ziziphora Clinopodioides Lam, Res. J. Pharmacogn. (RJP), 3(2):47-51 (2016).

[39] Zuo K., Qian J., Gong J., Zhang J., Li H., Zhou G., Synthesis, Characterization, Molecular Docking and Cytotoxicity Studies of Bagasse Xylem Ferulate-Acrylamide/Methyl Methacrylate Composite, Iran. J. Chem. Chem. Eng. (IJCCE), 38(3):107-116 (2019).

[40] Ghasemi S., Davaran S., Sharifi S., Comparison of Cytotoxic Activity of L778123 as a Farnesyltranferase Inhibitor and Doxorubicin Against A549 and HT-29 Cell Lines, Adv. Pharm. Bull., 3(1): 73 (2013).

[41] Robichaux J.P., Elamin Y.Y., Tan Z., Carter B.W., Zhang S., Liu S., Li Sh., Chen T., Pottete A., Estrada-Bernal A., Le A.T., Truini A., Nilsson M.B., Sun H., Roarty E., Goldberg S.B., Brahmer J.R., Altan M., Lu Ch., Papadimitrakopoulou V., Politi K., Doebele R.C., Wong K.K., Heymach J.V., Mechanisms and Clinical Activity of an EGFR and HER2 Exon 20–Selective Kinase Inhibitor in Non–Small Cell Lung Cancer, Nat. Med., 24(5): 638-646 (2018).

[42] Meng F., Molecular Dynamics Simulation of VEGFR2 with Sorafenib and Other Urea-Substituted Aryloxy Compounds, J. Theor. Chem., 2013:739574 (2013).

[43] Aramesh-Boroujeni Z., Bordbar A.-K., Khorasani-Motlagh M., Fani N., Sattarinezhad E., Noroozifar M., Computational and Experimental Study on the Interaction of Three Novel Rare Earth Complexes Containing 2, 9-Dimethyl-1, 10-Phenanthroline with Human Serum Albumin, J. Iran. Chem. Soc., 15(7): 1581-1591 (2018).

[44] Aramesh-Boroujeni Z., Jahani S., Khorasani-Motlagh M., Kerman K., Noroozifar M., Evaluation of Parent and Nano-Encapsulated Terbium (III) Complex toward its Photoluminescence Properties, FS-DNA, BSA Binding Affinity, and Biological Applications, J. Trace Elem. Med. Biol., 126564 (2020).

[45] Ibezim A.E., Onoabedje E.A., Akpomie K.G., Docking and Biological Screening of Bezo [A] Phenothiazinones as Novel Inhibitors of Bacterial Peptidogloycan Transpeptidase, Iran. J. Chem. Chem. Eng. (IJCCE), 38(6):243-250 (2019).


Main Subjects