Some novel hybrid quinazoline-based heterocycles as potent cytotoxic agents

Mahla Malekzadeh , Shadi Dadkhah, Ghadam Ali Khodarahmi, Parvin Asadi, Farshid Hassanzadeh, Mahboubeh Rostami

Abstract


Background and purpose: In this study, some new cytotoxic hybrid structures were synthesized by combining pyrazolinone and imidazolinone rings with quinazoline pharmacophores.

Experimental approach: The benzoxazinone, pyrazolo-quinazoline fused ring, and imidazolinone anchored quinazoline derivatives were synthesized by simple ring-opening, ring expansion, and ring closure strategies from oxazolones. The molecular docking studies of the final derivatives were accomplished on the epidermal growth factor receptor enzyme. The cytotoxic effect of the final compounds on the MCF-7 cell line was evaluated by MTT assay.

Findings/Results: The docking results confirmed the optimized electrostatic, H-bonding, and hydrophobic interactions of structures with the key residues of the active site (DGbin < -9Kcal/mol). The derivatives have been obtained in good yield and purity, and their structures were confirmed by different methods (FT-IR, 1H-NMR, 13C-NMR, and CHNS analysis). The IC50s of all final derivatives against the MCF-7 cell line were lower than 10 μM, and between all, the IXa from pyrazolo-quinazolinone class (IC50: 6.43 µM) with chlorine substitute was the most potent. Furthermore, all derivatives showed negligible cytotoxicity on HUVEC normal cell line which would be a great achievement for a novel cytotoxic agent.

Conclusion and implications: Based on the obtained results, pyrazolo[1,5-c] quinazolin-2-one series were more cytotoxic than imidazolinone methyl quinazoline-4(3H)-ones against MCF-7 cells. Chlorine substitute in the para position of the aromatic ring improved the cytotoxicity effect in both classes.  It could be related to the polarizability of a chlorine atom and making better intermolecular interactions. Further pre-clinical evaluations are required for the promising synthesized cytotoxic compounds.


Keywords


Keywords: Anticancer activity; Molecular docking; Oxazolone; Pyrazoline; Quinizolinone.

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References


Xu P, Yu B, Li FL, Cai XF, Ma CQ. Microbial degradation of sulfur, nitrogen and oxygen heterocycles. Trends Microbiol. 2006;14(9):398-405.

DOI: 10.1016/j.tim.2006.07.002.

Khan MF, Alam MM, Verma G, Akhtar W, Akhter M, Shaquiquzzaman M. The therapeutic voyage of pyrazole and its analogs: a review. Eur J Med Chem. 2016;120:170-201.

DOI: 10.1016/j.ejmech.2016.04.077.

Alagarsamy V, Chitra K, Saravanan G, Solomon VR, Sulthana MT, Narendhar B. An overview of quinazolines: pharmacological significance and recent developments. Eur J Med Chem. 2018;151:628-685.

DOI: 10.1016/j.ejmech.2018.03.076.

Guerrini G, Vergelli C, Cantini N, Giavannoni MP, Daniele S, Mascia MP, et al. Synthesis of new GABAA receptor modulator with pyrazolo [1,5-a] quinazoline (PQ) scaffold. Int J Mol Sci. 2019;20(6):1438-1458.

DOI: 10.3390/ijms20061438.

Hussein MA. Synthesis, anti-inflammatory, and structure antioxidant activity relationship of novel 4-quinazoline. Med Chem Res. 2013;22(10):4641-4653.

DOI: 10.1007/s00044-013-0468-9.

Kumar D, Kaur G, Negi A, Kumar S, Singh S, Kumar R. Synthesis and xanthine oxidase inhibitory activity of 5,6-dihydropyrazolo/pyrazolo[1,5-c] quinazoline derivatives. Bioorg Chem. 2014;57:57-64.

DOI: 10.1016/j.bioorg.2014.08.007.

Zhao H, Hu X, Cao K, Zhang Y, Zhao K, Tang C, et al. Synthesis and SAR of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as potent and selective CDK4/6 inhibitors. Eur J Med Chem. 2018;157:935-945.

DOI: 10.1016/j.ejmech.2018.08.043.

Mohareb RM, Abdo NYM, Wardakhan WW. Synthesis and evaluation of pyrazolo[5,1-b]quinazoline-2-carboxylate, and its thiazole derivatives as potential antiproliferative agents and Pim-1 kinase inhibitors. Med Chem Res. 2017;26:2520-2537.

DOI: 10.1007/s00044-017-1951-5.

El-Naggar M, Hasan AS, Awad HM, Mady MF. Design, synthesis and antitumor evaluation of novel pyrazolopyrimidines and pyrazoloquinazolines. Molecules. 2018;23(6):1249-1268.

DOI: 10.3390/molecules23061249.

Haghighijoo Z, Rezaei Z, Jaberipoor M, Taheri S, Jani M, Khabnadideh S. Structure based design and anti-breast cancer evaluation of some novel 4-anilinoquinazoline derivatives as potential epidermal growth factor receptor inhibitors. Res Pharm Sci. 2018;13(4):360-367.

DOI: 10.4103/1735-5362.235163.

RezaeeNasab R, Mansourian M, Hassanzadeh F, Shahlaei M. Exploring the interaction between epidermal growth factor receptor tyrosine kinase and some of the synthesized inhibitors using combination of in silico and in vitro cytotoxicity methods. Res Pharm Sci. 2018;13(6):509-522.

DOI: 10.4103/1735-5362.245963.

Borsook H, Dubnoff J. The biological synthesis of hippuric acid in vitro. J Biol Chem. 1940;132(1):307-324.

DOI: 10.1016/s0021-9258(18)73418-2.

Rostami M, Khosropour AR, Mirkhani V, Mohammadpoor-Baltork I, Moghadam M, Tangestaninejad S. [C6(MIm)2]2W10O32.2H2O: a novel and powerful catalyst for the synthesis of 4-arylidene-2-phenyl-5(4)-oxazolones under ultrasonic condition. C R Chimie. 2011;14(10):869-877.

DOI: 10.1016/j.crci.2011.02.003.

Haneen DSA, Gouhar RS, Hashem HE, Youssef ASA. Synthesis and reactions of 4H-3,1-benzoxazin-4-one derivative bearing pyrazolyl moiety as antimicrobial and antioxidant agents. Synth Commun. 2019;49(21):2840-2855.

DOI: 10.1080/00397911.2019.1646288.

Hemdan MM, Youssef AS, El-Mariah FA, Hashem HE. Synthesis and antimicrobial assessments of some quinazolines and their annulated systems. J Chem Res. 2017;41(2):106-111.

DOI: 10.3184/174751917X14858862342269.

Alagarsamy V, Murugananthan G, Venkateshperumal R. Synthesis, analgesic, anti-inflammatory and antibacterial activities of some novel 2-methyl-3-substituted quinazolin-4-(3H)-ones. Biol Pharm Bull. 2003;26(12): 1711-1714.

DOI: 10.1248/bpb.26.1711.

Morris GM, Huey R, Olson AJ. Using autodock for ligand‐receptor docking. Curr Protoc Bioinformatics. 2008;8(14):Unit 8.14,1-40.

DOI: 10.1002/0471250953.bi0814s24.

Visualizer D. Accelrys Discovery Studio Visualizer 3.0. Available from: https://accelrys-discovery-studio-visualizer.software.informer.com/3.0/.

El-Hachem N, Haibe-Kains B, Khalil A, Kobeissy FH, Nemer G. AutoDock and AutoDockTools for Protein-Ligand Docking: Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) as a Case Study. In: Neuroproteomics. Springer; 2017. pp: 391-403.

DOI: 10.1007/978-1-4939-6952-4_20.

Asadi P, Khodarahmi G, Jahanian-Najafabadi A, Saghaie L, Hassanzadeh F. Synthesis, characterization, molecular docking studies and biological evaluation of some novel hybrids based on quinazolinone, benzofuran and imidazolium moieties as potential cytotoxic and antimicrobial agents. Iran J Basic Med Sci. 2017;20(9):975-989.

DOI: 10.22038/IJBMS.2017.9260.

Sharma N, Banerjee J, Shrestha N, Chaudhury D. A review on oxazolone, it’s method of synthesis and biological activity. European J Biomed Pharm Sci. 2015;2(3):964-987.

Puterová Z, Sterk H, Krutošíková A. Reaction of substituted furan-2-carboxaldehydes and furo[b]pyrrole type aldehydes with hippuric acid. Molecules. 2004;9(1):11-21.

DOI: 10.3390/90100011.

Hekal MH, Abu El-Azm FS. New potential antitumor quinazolinones derived from dynamic 2-undecyl benzoxazinone: synthesis and cytotoxic evaluation. Synth Commun. 2018;48(18):2391-2402.

DOI: 10.1080/00397911.2018.1490433.

Fortin S, Bérubé G. Advances in the development of hybrid anticancer drugs. Expert Opin Drug Discov. 2013;8(8):1029-1047.

DOI: 10.1517/17460441.2013.798296.

Asadi P, Khodarahmi G, Jahanian‐Najafabadi A, Saghaie L, Hassanzadeh F. Biologically active heterocyclic hybrids based on quinazolinone, benzofuran and imidazolium moieties: synthesis, characterization, cytotoxic and antibacterial evaluation. Chem Biodivers. 2017;14(4):e1600411.

DOI: 10.1002/cbdv.201600411.

Ansari AJ, Joshi G, Yadav UP, Maurya AK, Agnihotri VK, Kalra S, et al. Exploration of Pd-catalysed four-component tandem reaction for one-pot assembly of pyrazolo [1,5-c] quinazolines as potential EGFR inhibitors. Bioorg Chem. 2019;93:103314,1-12.

DOI: 10.1016/j.bioorg.2019.103314.

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.

Kumar D, Mariappan G, Husain A, Monga J, Kumar S. Design, synthesis and cytotoxic evaluation of novel imidazolone fused quinazolinone derivatives. Arab J Chem. 2017;10(3):344-350.

DOI: 10.1016/j.arabjc.2014.07.001.

Abandansari HS, Abuali M, Nabid MR, Niknejad H. Enhance chemotherapy efficacy and minimize anticancer drug side effects by using reversibly pH-and redox-responsive cross-linked unimolecular micelles. Polymer. 2017;116:16-26.

DOI: 10.1016/j.polymer.2017.03.062.

Verbeek BS, Adriaansen-Slot SS, Vroom TM, Beckers T, Rijksen G. Overexpression of EGFR and c-erbB2 causes enhanced cell migration in human breast cancer cells and NIH3T3 fibroblasts. FEBS Lett. 1998;425(1):145-150.

DOI: 10.1016/s0014-5793(98)00224-5.

Thirumurugan K, Lakshmanan S, Govindaraj D, Prabu DSD, Ramalakshmi N, Antony SA. Design, and anti-inflammatory activity of pyrimidine scaffold benzamide derivatives as epidermal growth factor receptor tyrosine kinase inhibitors. J Mol Struct. 2018;1171:541-550.

DOI: 10.1016/j.molstruc.2018.06.003.

Zhu ML, Wang CY, Xu CM, Bi WP, Zhou XY. Evaluation of 6-chloro-N-[3,4-disubstituted-1,3-thiazol-2(3H)-ylidene]-1,3-benzothiazol-2-amine using drug design concept for their targeted activity against colon cancer cell lines HCT-116, HCT15, and HT29. Med Sci Monit. 2017;23:1146-1155.

DOI: 10.12659/msm.899646.


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