Quinazoline analogues as cytotoxic agents; QSAR, docking, and in silico studies

Leila Emami , Razieh Sabet , Soghra Khabnadideh, Zeinab Faghih, Parvin Thayori


Background and purpose: Synthesis and investigation of pharmacological activity of novel compounds are time and money-consuming. However, computational techniques, docking, and in silico studies have facilitated drug discovery research to design pharmacologically effective compounds.

Experimental approach: In this study, a series of quinazoline derivatives were applied to quantitative structure-activity relationship (QSAR) analysis. A collection of chemometric methods were conducted to provide relations between structural features and cytotoxic activity of a variety of quinazoline derivatives against breast cancer cell line. An in silico-screening was accomplished and new impressive lead compounds were designed to target the epidermal growth factor receptor (EGFR)-active site based on a new structural pattern. Molecular docking was performed to delve into the interactions, free binding energy, and molecular binding mode of the compounds against the EGFR target.

Findings/Results: A comparison between different methods significantly indicated that genetic algorithm-partial least-squares were selected as the best model for quinazoline derivatives. In the current study, constitutional, functional, chemical, resource description framework, 2D autocorrelation, and charge descriptors were considered as significant parameters for the prediction of anticancer activity of quinazoline derivatives. In silico screening was employed to discover new compounds with good potential as anticancer agents and suggested to be synthesized. Also, the binding energy of docking simulation showed desired correlation with QSAR and experimental data.

Conclusion and implications: The results showed good accordance between binding energy and QSAR results. Compounds Q1-Q30 are desired to be synthesized and applied to in vitro evaluation.



Cytotoxic; Molecular docking; QSAR; Quinazoline.


Haghighijoo Z, Rezaei Z, Taheri S, Jani M, Khabnadideh S. A rapid and convenient method for synthesis of anilinoquinazoline: an improved synthesis of erlotinib derivatives. Trends Pharmacol Sci. 2015;1(3):173-178.

Rahmannejadi N, Khabnadideh S, Yavari I. Synthesis, docking, and cytotoxic activities of novel 2-aryl-4-(arylamino) quinazolines. Monatsh Chem. 2018;149(11):2085-2092.

DOI: 10.1007/s00706-018-2270-3.

Rahmannejadi N, Zomorodian K, Faghih Z, Faghih Z, Khabnadideh S, Yavari I. Preparation, docking, antimicrobial and cytotoxic activities of 2-arylquinazolinones. Br J Pharm Res. 2017;20(3):1-11.

DOI: 10.9734/JPRI/2017/38244.

Emami L, Faghih Z, Khabnadideh S, Rezaei Z, Sabet R, Harigh E, et al. 2‑(Chloromethyl)‑3‑phenylquinazolin‑4(3H)‑ones as potent anticancer agents; cytotoxicity, molecular docking and in silico studies. J Iran Chem Soc. 2021;18:1877-1889 .

DOI: 10.1007/s13738-021-02168-1.

Divar M, Zomorodian K, Bastan S, Yazdanpanah S, Khabnadideh S. Synthesis of some quinazolinone derivatives using magnetic nanoparticles-supported tungstic acid as antimicrobial agents. J Iran Chem Soc. 2018;15(7):1457-1466.

DOI: 10.1007/s13738-018-1337-8.

Faghih Z, Rahmannejadi N, Sabet R, Zomorodian K, Asad M, Khabnadideh S. Synthesis of some novel dibromo-2-arylquinazolinone derivatives as cytotoxic agents. Res Pharm Sci. 2019;14(2):115-121.

DOI: 10.4103/1735-5362.253358.

Ferreira MMC. Multivariate QSAR. In: Wang Z, editor. Encyclopedia of Physical Organic Chemistry. John Wiley & Sons; Vol. 3. 2016. pp. 1-38.

DOI: 10.1002/9781118468586.epoc3013.

Nasab RR, Mansourian M, Hassanzadeh F. Synthesis, antimicrobial evaluation and docking studies of some novel quinazolinone Schiff base derivatives. Res Pharm Sci. 2018;13(3):213-220.

DOI: 10.4103/1735-5362.228942.

Sabet R, Fassihi A, Hemmateenejad B, Saghaei L, Miri R, Gholami M. Computer-aided design of novel antibacterial 3-hydroxypyridine-4-ones: application of QSAR methods based on the MOLMAP approach. J Comput Aided Mol Des. 2012;26(3):349-361.

DOI: 10.1007/s10822-012-9561-2.

Sabet R, Fassihi A, Moeinifard B. QSAR study of PETT derivatives as potent HIV-1 reverse transcriptase inhibitors. J Mol Graph Model. 2009;28(2):146-155.

DOI: 10.1016/j.jmgm.2009.05.002.

Sadeghian-Rizi S, Sakhteman A, Hassanzadeh F. A quantitative structure-activity relationship (QSAR) study of some diaryl urea derivatives of B-RAF inhibitors. Res Pharm Sci. 2016;11(6):445-453.

DOI: 10.4103/1735-5362.194869.

Jain SK, Yadav AK, Nayak P. 2D QSAR analysis on oxadiazole derivatives as anticancer agents. Int J Curr Pharm Res. 2011;3(4):27-33.

Sainy J, Sharma R. QSAR analysis of thiolactone derivatives using HQSAR, CoMFA and CoMSIA. SAR QSAR Environ Res. 2015;26(10):873-892.

DOI: 10.1080/1062936X.2015.1095238.

Todeschini R, Consonni V. Handbook of Molecular Descriptors. Weinheim: WileyVCH; 2008. pp. 516-520.

DOI: 10.1002/9783527613106.

Wan J, Zhang L, Yang G, Zhan CG. Quantitative structure-activity relationship for cyclic imide derivatives of protoporphyrinogen oxidase inhibitors: a study of quantum chemical descriptors from density functional theory. J Chem Inf Comput Sci. 2004;44(6):2099-2105.

DOI: 10.1021/ci049793p.

Hamann M, Alonso D, Martín-Aparicio E, Fuertes A, Pérez-Puerto MJ, Castro A, et al. Glycogen synthase kinase-3 (GSK-3) inhibitory activity and structure-activity relationship (SAR) studies of the manzamine alkaloids. Potential for Alzheimer’s disease. J Nat Prod. 2007;70(9):1397-1405.

DOI: 10.1021/np060092r.

Akhtar MJ, Siddiqui AA, Khan AA, Ali Z, Dewangan RP, Pasha S, et al. Design, synthesis, docking and QSAR study of substituted benzimidazole linked oxadiazole as cytotoxic agents, EGFR and erbB2 receptor inhibitors. Eur J Med Chem. 2017;126:853-869.

DOI: 10.1016/j.ejmech.2016.12.014.

Ray S, De K, Sengupta C, Roy K. QSAR study of lipid peroxidation-inhibition potential of some phenolic antioxidants. Indian J Biochem Biophys. 2008;45:198-205.

Hemmateenejad B, Emami L, Sharghi H. Multi-wavelength spectrophotometric determination of acidity constant of some newly synthesized Schiff bases and their QSPR study. Spectrochim Acta A Mol Biomol Spectrosc. 2010;75(1):340-346.

DOI: 10.1016/j.saa.2009.10.037.

Mojaddami A, Sakhteman A, Fereidoonnezhad M, Faghih Z, Najdian A, Khabnadideh S, et al. Binding mode of triazole derivatives as aromatase inhibitors based on docking, protein ligand interaction fingerprinting, and molecular dynamics simulation studies. Res Pharm Sci. 2017;12(1):21-30.

DOI: 10.4103/1735-5362.199043.

Todeschini R. Milano Chemometrics and QSAR Research Group. Available from: https://michem.unimib.it/.

Emami L, Faghih Z, Sakhteman A, Rezaei Z, Faghih Z, Salehi F, et al. Design, synthesis, molecular simulation, and biological activities of novel quinazolinone-pyrimidine hybrid derivatives as dipeptidyl peptidase-4 inhibitors and anticancer agents. New J Chem. 2020;44(45):19515-19531.

DOI: 10.1039/D0NJ03774E.

Ashok UP, Kollur SP, Arun BP, Sanjay C, Suresh KS, Anil N, et al. In vitro anticancer activity of 4(3H)-quinazolinone derived Schiff base and its Cu (II), Zn (II) and Cd (II) complexes: preparation, X-ray structural, spectral characterization and theoretical investigations. Inorganica Chim Acta. 2020;511:119846.

DOI: 10.1016/j.ica.2020.119846.

Fassihi A, Abedi D, Saghaie L, Sabet R, Fazeli H, Bostaki G, et al. Synthesis, antimicrobial evaluation and QSAR study of some 3-hydroxypyridine-4-one and 3-hydroxypyran-4-one derivatives. Eur J Med Chem. 2009;44(5):2145-2157.

DOI: 10.1016/j.ejmech.2008.10.022.

Fassihi A, Sabet R. QSAR study of p56lck protein tyrosine kinase inhibitory activity of flavonoid derivatives using MLR and GA-PLS. Int J Mol Sci. 2008;9(9):1876-1892.

DOI: 10.3390/ijms9091876.

Sabet R, Fassihi A. QSAR study of antimicrobial 3-hydroxypyridine-4-one and 3-hydroxypyran-4-one derivatives using different chemometric tools. Int J Mol Sci. 2008;9(12):2407-2423.

DOI: 10.3390/ijms9122407.

Tu Y, OuYang Y, Xu S, Zhu Y, Li G, Sun C, et al. Design, synthesis, and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors. Bioorg Med Chem. 2016;24(7):1495-1503.

DOI: 10.1016/j.bmc.2016.02.017.

OuYang Y, Zou W, Peng L, Yang Z, Tang Q, Chen M, et al. Design, synthesis, antiproliferative activity and docking studies of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline as potential EGFR inhibitors. Eur J Med Chem. 2018;154:29-43.

DOI: 10.1016/j.ejmech.2018.05.006.

Abbas SE, Barsoum FF, Georgey HH, Mohammed ER. Synthesis and antitumor activity of certain 2,3,6-trisubstituted quinazolin-4 (3H)-one derivatives. Bull Fac Pharm Cairo Univ. 2013;51(2):273-282.

DOI: 10.1016/j.bfopcu.2013.08.003.

Abdel-Fattah HA, El-Etrawy AS, Gabr NRM. Synthesis and biological evaluation of some new 1,3,4-oxa, thiadiazole and 1,2,4-triazole derivatives attached to benzimidazole. Int J Pharm Chem. 2014;04(03):112-118.


El-Azab AS, Al-Omar MA, Alaa AM, Abdel-Aziz NI, Magda AA, Aleisa AM, et al. Design, synthesis and biological evaluation of novel quinazoline derivatives as potential antitumor agents: molecular docking study. Eur J Med Chem. 2010;45(9):4188-4198.

DOI: 10.1016/j.ejmech.2010.06.013.

Ghorab MM, Alsaid MS. Novel 4-aminoquinazoline derivatives as new leads for anticancer drug discovery. Acta Pharm. 2015;65(3):299-309.

DOI: 10.1515/acph-2015-0021.

Madhavi S, Sreenivasulu R, Yazala JP, Raju RR. Synthesis of chalcone incorporated quinazoline derivatives as anticancer agents. Saudi Pharm J. 2017;25(2):275-279.

DOI: 10.1016/j.jsps.2016.06.005.

Koljonen J, Nordling TE, Alander JT. A review of genetic algorithms in near infrared spectroscopy and chemometrics: past and future. J Near Infrared Spec. 2008;16(3):189-197.

DOI: 10.1255/jnirs.778.

Sabet R, Fassihi A, Saghaie L. Octanol-water partition coefficients determination and QSPR study of some 3-hydroxy pyridine-4-one derivatives. J Pharm Res Int. 2018;22(4):1-15.

DOI: 10.9734/JPRI/2018/41142.

Salentin S, Schreiber S, Haupt VJ, Adasme MF, Schroeder M. PLIP: fully automated protein-ligand interaction profiler. Nucleic Acids Res. 2015;43(Web Server issue):W443-W447.

DOI: 10.1093/nar/gkv315.

Fereidoonnezhad M, Faghih Z, Mojaddami A, Rezaei Z, Sakhteman A. A comparative QSAR analysis, molecular docking and PLIF studies of some N-arylphenyl-2,2-dichloroacetamide analogues as anticancer agents. Iran J Pharm Res. 2017;16(3):981-998.

PMID: 29535790.

Emami L, Sabet R, Sakhteman A, Zade MK. Quantitative structure-activity relationship and molecular docking studies of imidazolopyrimidine amides as potent dipeptidyl peptidase-4 (DPP4) inhibitors. J Pharm Res Int. 2019;27(6):1-15.

DOI: 10.9734/jpri/2019/v27i630186.

Sabet R, Khabnadideh S, Fathi D, Emami L. QSAR and docking study of isatin analogues as cytotoxic agents. J Pharm Res Int. 2019;27(5):1-22.

DOI: 10.9734/jpri/2019/v27i530184.

Morris GM, Huey R, Olson AJ. Using autodock for ligand‐receptor docking. Curr Protoc Bioinformatics. 2008;8:Unit 8.14.

DOI: 10.1002/0471250953.bi0814s24.

Zarenezhad E, Esmaielzadeh S, Behrouz S, Emami L. Copper Schiff base complex as a new immobilized heterogeneous catalyst: experimental, theoretical, biological and docking study. J Iran Chem Soc. 2021;18:283-295.

DOI: 10.1007/s13738-020-02024-8.

Ferreira LG, Dos Santos RN, Oliva G, Andricopulo AD. Molecular docking and structure-based drug design strategies. Molecules. 2015;20(7):13384-13421.

DOI: 10.3390/molecules200713384.

Lo YC, Rensi SE, Torng W, Altman RB. Machine learning in chemoinformatics and drug discovery. Drug Discov Today. 2018;23(8):1538-1546.

DOI: 10.1016/j.drudis.2018.05.010.

van de Waterbeemd H, Timmerman H, Mannhold R, Krogsgaard-Larsen P. Chemometric Methods in Molecular Design. John Wiley & Sons; 2008. pp. 1-379.

DOI: 10.1002/9783527615452.

Mahani NM, Zarandi AM, Horzadeh A. QSAR studies of novel iminochromene derivatives as carbonyl reductase 1 (CBR1) inhibitors. Marmara Pharm J. 2018;22(2):227-236.

DOI: 10.12991/mpj.2018.60.

Qian Y, Wang Y, Sa R, Yan H, Pan X, Yang Y, et al. Metabolic fingerprinting of Angelica sinensis during growth using UPLC-TOFMS and chemometrics data analysis. Chem Cent J. 2013;7(1):42-51.

DOI: 10.1186/1752-153X-7-42.

Pasha FA, Muddassar M, Srivastava AK, Cho SJ. In silico QSAR studies of anilinoquinolines as EGFR inhibitors. J Mol Model. 2010;16(2):263-277.

DOI: 10.1007/s00894-009-0534-x.


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