Synthesis and cytotoxic evaluation of novel quinazolinone derivatives as potential anticancer agents

Safoora Poorirani , Sedighe Sadeghian-Rizi, Ghadamali Khodarahmi, Marzieh Rahmani Khajouei, Farshid Hassanzadeh

Abstract


Nitrogen-rich heterocyclic compounds represent a unique class of chemicals with especial properties and have been modified to design novel pharmaceutically active compounds. In this study, a series of novel quinazolinone derivatives with substituted quinoxalindione were synthesized in two parts. In the first part, 6-(4-amino-3-methylphenoxy)quinoxaline-2,3(1H,4H)-dione was prepared from para-amino -m-crozol in 5 steps. In the next part, 2-alkyl-4H-benzo[d][1,3]oxazin-4-one derivatives were obtained from antranilic acid. Then reaction of 6-(4-amino-3-methylphenoxy)quinoxaline-2,3(1H,4H)-dione with 2-alkyl-4H-benzo[d][1,3]oxazin-4-one derivatives resulted in the production of final componds. The structures of synthesized compounds were confirmed by IR and 1H-NMR. Cytotoxic activity of the compounds were evaluated at 0.1, 1, 10, 50 and 100 μM concentrations against MCF-7 and HeLa cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Almost all new compounds showed cytotoxic activity in both cell lines. Among tested compounds, 11g displayed the highest cytotoxic activity against both cell lines.


Keywords


Cytotoxicity; Quinazolinone; Quinoxalindione.

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Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30.

Camarasa MJ. Heterocyclic Chemistry in Drug Discovery. Li JJ, editor. New jersey: Wiley and Sons, Hoboken; 2014: 8-16

Gomtsyan A. Heterocycles in drugs and drug discovery. Chem Heterocycl Compd (N Y). 2012;48(1):7-10.

Alaa A-M, Abou-Zeid LA, ElTahir KEH, Mohamed MA, El-Enin MAA, El-Azab AS. Design, synthesis of 2, 3-disubstitued 4 (3H)-quinazolinone derivatives as anti-inflammatory and analgesic agents: COX-1/2 inhibitory activities and molecular docking studies. Bioorg Med Chem. 2016;24(16):3818-3828.

Bouley R, Kumarasiri M, Peng Z, Otero LH, Song W, Suckow MA, et al. Discovery of antibiotic (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl) quinazolin-4 (3 H)-one. J Am Chem Soc. 2015;137(5):1738-1741.

Ryu CK, Kim YH, Im HA, Kim JY, Yoon JH, Kim A. Synthesis and antifungal activity of 6,7-bis(arylthio)-quinazoline-5,8-diones and furo[2, 3-f]quinazolin-5-ols. Bioorg Med Chem Lett. 2012;22(1):500-503.

Wang Z, Wang M, Yao X, Li Y, Tan J, Wang L, et al. Design, synthesis and antiviral activity of novel quinazolinones. Eur J Med Chem. 2012;53:275-282.

Kamal A, Reddy BS, Sridevi B, Ravikumar A, Venkateswarlu A, Sravanthi G, et al. Synthesis and biological evaluation of phaitanthrin congeners as anti-mycobacterial agents. Bioorg Med Chem Lett. 2015;25(18):3867-3872.

Bhattacharjee AK, Hartell MG, Nichols DA, Hicks RP, Stanton B, Van Hamont JE, et al. Structure-activity relationship study of antimalarial indolo [2, 1-b] quinazoline-6, 12-diones (tryptanthrins). Three dimensional pharmacophore modeling and identification of new antimalarial candidates. Eur J Med Chem. 2004;39(1):59-67.

Marzaro G, Guiotto A, Chilin A. Quinazoline derivatives as potential anticancer agents: a patent review (2007–2010). Expert Opin Ther Pat. 2012;22(3):223-252.

Ahmad I. An insight into the therapeutic potential of quinazoline derivatives as anticancer agents. MedChemComm. 2017;8(5):871-885.

Kamal A, Bharathi EV, Reddy JS, Ramaiah MJ, Dastagiri D, Reddy MK, et al. Synthesis and biological evaluation of 3,5-diaryl isoxazoline/isoxazole linked 2,3-dihydroquinazolinone hybrids as anticancer agents. Eur J Med Chem. 2011;46(2):691-703.

Zahedifard M, Faraj FL, Paydar M, Yeng Looi C, Hajrezaei M, Hasanpourghadi M, et al. Synthesis, characterization and apoptotic activity of quinazolinone Schiff base derivatives toward MCF-7 cells via intrinsic and extrinsic apoptosis pathways. Sci Rep. 2015;5:11544.

Al-Rashood ST, Aboldahab IA, Nagi MN, Abouzeid LA, Abdel-Aziz AA, Abdel-hamide SG, et al. Synthesis, dihydrofolate reductase inhibition, antitumor testing, and molecular modeling study of some new 4(3H)-quinazolinone analogs. Bioorg Med Chem. 2006;14(24):8608-8621.

Taliani S, Pugliesi I, Barresi E, Salerno S, Marchand C, Agama K, et al. Phenylpyrazolo[1,5-a]quinazolin-5(4H)-one: a suitable scaffold for the development of noncamptothecin topoisomerase I (Top1) inhibitors. J Med Chem. 2013;56(18): 7458-7462.

Matthews TP, Jones AM, Collins I. Structure-based design, discovery and development of checkpoint kinase inhibitors as potential anticancer therapies. Expert Opin Drug Discov. 2013;8(6):621-640.

Cruz-Lopez O, Conejo-García A, Nunez MC, Kimatrai M, Garcia-Rubino ME, Morales F, et al. Novel substituted quinazolines for potent EGFR tyrosine kinase inhibitors. Curr Med Chem. 2011;18(7):943-963.

Ruiz-Alcaraz AJ, Tristán-Manzano M, Guirado A, Gálvez J, Martínez-Esparza M, García-Peñarrubia P. Intracellular signaling modifications involved in the anti-inflammatory effect of 4-alkoxy-6, 9-dichloro [1, 2, 4] triazolo [4, 3-a] quinoxalines on macrophages. Eur J Pharm Sci. 2017;99:292-298.

Javidi J, Esmaeilpour M. Fe3O4@ SiO2–imid–PMAn magnetic porous nanosphere as recyclable catalyst for the green synthesis of quinoxaline derivatives at room temperature and study of their antifungal activities. Mater Res Bull. 2016;73:409-422.

Alavi S, Mosslemin MH, Mohebat R, Massah AR. Green synthesis of novel quinoxaline sulfonamides with antibacterial activity. Res Chem Intermed. 2017;43(8):4549-4559.

Barea C, Pabón A, Galiano S, Pérez-Silanes S, Gonzalez G, Deyssard C, et al. Antiplasmodial and leishmanicidal activities of 2-cyano-3-(4-phenylpiperazine-1-carboxamido) quinoxaline 1,4-dioxide derivatives. Molecules. 2012;17(8):9451-9461.

Harmenberg J, Wahren B, Bergman J, Akerfeldt S, Lundblad L. Antiherpesvirus activity and mechanism of action of indolo-(2,3-b)quinoxaline and analogs. Antimicrob Agents Chemother. 1988;32(11):1720-1724.

Ali IA, Al-Masoudi IA, Aziz NM, Al-Masoudi NA. New acyclic quinoxaline nucleosides. Synthesis and anti-hiv activity. Nucleosides Nucleotides Nucleic Acids. 2008;27(2):146-156.

Pinheiro AC, Mendonça Nogueira TC, de Souza MV. Quinoxaline nucleus: a promising scaffold in anti-cancer drug discovery. Anticancer Agents Med Chem. 2016;16(10):1339-52.

Balogh B, Carbone A, Spanò V, Montalbano A, Barraja P, Cascioferro S, et al. Investigation of isoindolo[2,1-a]quinoxaline-6-imines as topoisomerase I inhibitors with molecular modeling methods. Curr Comput Aided Drug Des. 2017;13(3):208-221.

Chowdhury N, Gangopadhyay M, Karthik S, Singh NP, Baidya M, Ghosh S. Synthesis, photochemistry, DNA cleavage/binding and cytotoxic properties of fluorescent quinoxaline and quinoline hydroperoxides. J Photochem Photobiol B. 2014;130:188-198.

González M, Cerecetto H. Quinoxaline derivatives: a patent review (2006--present). Expert Opin Ther Pat. 2012;22(11):1289-1302.

Gangjee A, Yang J, Ihnat MA, Kamat S. Antiangiogenic and antitumor agents. Design, synthesis, and evaluation of novel 2-amino-4-(3-bromoanilino)-6-benzylsubstituted pyrrolo[2, 3-d]pyrimidines as inhibitors of receptor tyrosine kinases. Bioorg Med Chem. 2003;11(23):5155-5170.

Liu Q, Sabnis Y, Zhao Z, Zhang T, Buhrlage SJ, Jones LH, et al. Developing irreversible inhibitors of the protein kinase cysteinome. Chem Biol. 2013;20(2):146-159.

Kerru N, Singh P, Koorbanally N, Raj R, Kumar V. Recent advances (2015-2016) in anticancer hybrids. Eur J Med Chem. 2017;142:179-212.

Noolvi MN, Patel HM, Bhardwaj V, Chauhan A. Synthesis and in vitro antitumor activity of substituted quinazoline and quinoxaline derivatives: search for anticancer agent. Eur J Med Chem. 2011;46(6):2327-2346.

Hosseinzadeh L, Aliabadi A, Rahnama M, Mir Mohammad Sadeghi H, Rahmani Khajouei M. Synthesis and cytotoxic evaluation of some new 3-(2-(2-phenylthiazol-4-yl) ethyl)-quinazolin-4(3H) one derivatives with potential anticancer effects. Res Pharm Sci. 2017;12(4):290-298.

Ahmed MF, Belal A. Design, synthesis, and molecular docking studies of 2‐(furan‐2‐yl)quinazolin‐4‐one derivatives as potential antiproliferative agents.

Arch Pharm (Weinheim). 2015;348(7):487-497.

Sadeghian-Rizi S, Khodarahmi G, Sakhteman A, Jahanian-Najafabadi A, Rostami M, Mirzaei M, et al. Synthesis and characterization of some novel diaryl urea derivatives bearing quinoxalindione moiety. Res. Pharm.Sci. 2018;13(1):82-92.

Gu W, Wang S, Jin X, Zhang Y, Hua D, Miao T, et al. Synthesis and evaluation of new quinoxaline derivatives of dehydroabietic acid as potential antitumor agents. Molecules. 2017;22(7):1154-1166.


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