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

Document Type: Original Article

Authors

1 Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

2 Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Objective(s): Hybridization of bioactive natural and synthetic compounds is one of the most promising novel approaches for the design of hit and lead compounds with new molecular structures. In this investigation, a series of novel hybrid structures bearing quinazolinone, benzofuran and imidazolium moieties were designed and synthesized.
Materials and Methods:Novel hybrid compounds were prepared and their structures were characterized by spectral and analytical data. In order to evaluate the biological activities, the synthesized hybrid compounds were studied for in vitro antibacterial activity against three Gram positive bacteria (Staphylococcus aureu, Bacillus subtilis, Listeria monocitogenes) and three Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Salmonella entritidis) and also, Candida albicans as one yeast-like fungi strain. Cytotoxic activities of the synthesized compounds were also evaluated by the MTT assay in the human breast cancer cell line (MCF-7) and finally docking studies of cytotoxic derivatives were performed on aromatase enzyme.
Results:The results of antimicrobial activity showed that compound 14e, with two halogen atoms on quinazolinone and benzofuran was the most active against all the tested strains of microorganisms with the MIC value 16-128 µg/ml. Some of the tested compounds showed good cytotoxicity on MCF-7, and compound 14c with IC50=0.59 micromolar (μM) was found to be the most cytotoxic compound among the studied hybrid derivatives. The docking analysis showed acceptable binding interactions for these compounds.
Conclusion: Based on the obtained results, the hybrid derivatives of quinazolinone, benzofuran and imidazolium could be regarded as efficient candidates for further molecular developments of anticancer and antimicrobial agents.

Keywords


1. Muregi FW, Ishih A. Next-Generation Antimalarial Drugs: Hybrid Molecules as a New Strategy in Drug Design. Drug Dev Res 2010; 71:20-32.

2. Rane RA, Telvekar VN. Synthesis and evaluation of novel chloropyrrole molecules designed by molecular hybridization of common pharmacophores as potential antimicrobial agents. Bioorg Med Chem Lett 2010; 20:5681-5685.

3. Rizzo S, Riviere C, Piazzi L, Stefano R, Alessandra B, Gobbi S, et al. Benzofuran-based hybrid compounds for the inhibition of cholinesterase activity, amyloid aggregation, and a neurotoxicity. J Med Chem 2008; 51:2883-2886.

4. Guantai EM, Ncokazi K, Egan TJ, Gut J, Rosenthal PJ, Smith PJ, Chibale K. Design, synthesis and in vitro antimalarial evaluation of triazole-linked chalcone and dienone hybrid compounds. Bioorg Med Chem 2010; 18:8243-8256.

5. Evranos B, Altanlar N, Ertan R. Synthesis and biological activity of some new lavonylazole derivatives. Acta Pharm Sci 2007; 49:231-238.

6. Ahmed K, Pogula PK, Mohammed NA, Bobburi NS, Olepu S. Hybrid pharmacophore design and synthesis of naphthalimide– benzimidazole conjugates as potential anticancer agents. Lett Drug Des Discov 2015; 12:374-384.

7. Sashidhara KV, Rao KB, Kushwaha P, Modukuri RK, Singh P, Soni I, et al. Novel chalcone-thiazole hybrids as potentinhibitors of drug resistant staphylococcus aureus. ACS Med Chem Lett 2015; 6:809-813.

8. Yang XD, Wan WC, Deng XY, Li Y, Yang LJ, Li L, et al. Design, synthesis and cytotoxic activities of novel hybrid compounds between 2-phenylbenzofuran and imidazole. Bioorg Med Chem Lett 2012; 22:2726-2729.

9. Sharma PC, Kaur1 G, Pahwa R, Sharma A, Rajak H. Quinazolinone analogs as potential therapeutic agents. Curr Med Chem 2011; 18:4786-4812.

10. Mohammadi MA, Askari S, Rohi H, Soorki AA. Design, synthesis and antibacterial evaluation of same novel 3'-(phenylamino)-1'h-spiro[indoline-3,2'- quinazoline] -2,4'(3'h)-dione derivatives. Synth Commun 2014; 44:457-467.

11. Modh RP, Clercq ED, Pannecouque C, Chikhalia KH. Design, synthesis, antimicrobial activity and anti-HIV activity evaluationof novel hybrid quinazoline–triazine derivatives. J Enzyme Inhib Med Chem 2014; 29:100-108.

12. 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; 46:2327-2346.

13. Nevagi RJ, Dighe SN, Dighe SN. Biological and medicinal significance of benzofuran. Eur J Med Chem 2015; 97:561-581.

14. Khodarahmi GA, Asadi P, Hassanzadeh F, Khodarahmi E. Benzofuran as a promising scaffold for the synthesis of antimicrobial and antibreast cancer agents: A review. J Res Med Sci 2015; 20:1094-1104.

15.  Abdel-Wahab BF,  Awad GE,  Badria FA. Synthesis, antimicrobial, antioxidant, anti-hemolytic and cytotoxic evaluation of new imidazole-based heterocycles. Eur J Med Chem 2011; 46:1505-1511.

16. Zhang L, Peng XM, Damu GLV, Geng RX, Zhou CH. Comprehensive review in current developments of imidazole-based medicinal chemistry. Med Res Rev 2014; 34:340-437.

17. Chen W, Deng XY, Li Y, Yang LJ, Wan WC, Wang XQ, et al. Synthesis and cytotoxic activities of novel hybrid 2-phenyl-3-alkylbenzofuran and imidazole/triazole compounds. Bioorg Med Chem Lett 2013; 23:4297-4302.

18. Zahedifard M, Faraj FL, Paydar M, Looi CY, 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.

19. Ahmed MF, Hashim AA. Design, synthesis of novel quinazolin-4-one derivatives and biological evaluation against human MCF-7 breast cancer cell line. Res Chem Intermediates 2016; 42:1777-1789.

20. Brooks JD, Thompson LU. Mammalian lignans and genistein decrease the activities of aromatase and 17-hydroxysteroid dehydrogenase in MCF-7 cells. J Steroid Biochem Mol Biol 2005; 94:461-467.

21. Bheemanapalli LN, Kaur A, Arora R, Sangeeta, Akkinepally RR, Javali NM. Synthesis, evaluation of 6,8-dibromo-2-aryl-2,3-dihydroquinolin-4(1H)-ones in MCF-7 (breast cancer) cell lines and their docking studies. Med Chem Res 2012; 21:1741-1750.

22. Balouiri M,  Sadiki M,  Ibnsouda SK. Methods for in vitro evaluating antimicrobial activity: A review. J Pharma Anal 2016; 6:71-79.

23. Khodarahmi GA, Rahmani Khajouei M, Hakimelahi GH, Abedi D, Jafari E, Hassanzadeh F. Antibacterial, antifungal and cytotoxic evaluation of some new 2,3-disubstituted 4(3H)-quinazolinone derivatives. Res Pharm Sci 2012; 7:151-158.

24.  Van de Loosdrecht AA, Beelen RHJ, Ossenkoppele GJ, Broekhoven MG, Langenhuijsen MMAC. A tetrazolium-based colorimetric MTT assay to quantitate human monocyte mediated cytotoxicity against leukemic cells from cell lines and patients with acute myeloid leukemia. J Immun Methods 1994; 174:311-320.

25. Davis JM. Basic cell culture; a practical approach. United states: Oxford University; IRL press; 1994; 57-64:93-99.

26. Cho AE, Guallar V, Berne B, Friesner R. Importance of accurate charges in molecular docking: quantum mechanical/molecular mechanical (QM/MM) approach. J Comput Chem 2005; 26:915-931.

27. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, et al.  Gaussian development version, revision B.01, Gaussian. Inc., Wallingford CT: 2009.

28. Dapprich S, Komaromi I, Byun KS, Morokuma K, Frisch MJ. The calculation of energies, gradients, vibrational frequencies and electric field derivatives. J Mol Struct 1999; 462:1-21.

29. Farag DB, Farag NA, Esmat A, Abuelezz SA, Ibrahim EAS, Ella DAAE. Synthesis, 3D pharmacophore, QSAR and docking studies of novel quinazoline derivatives with nitric oxide release moiety as preferential COX-2 inhibitors. Med Chem Commun 2015; 6:283-299.

30. Ahmed B, Samad A, Hasan M. Molecular modelling studies, synthesis and antimicrobial screening of some novel sulphonamide quinazolin-4(3h)-one fused derivatives. Int J Pharm Pharm Sci 2014; 6:312-317.

31. Bozdag M, Alafeefy AM, Vullo D, Carta F, Dedeoglu N, Al-Tamimi AM, et al.  Benzenesulfonamides incorporating bulky aromatic/heterocyclic tails with potent carbonic anhydrase inhibitory activity. Bioorg Med Chem 2015; 23:7751-7764.

32. Kamble VS, Habade BM, Patil GK, Agasimundin Y. Synthesis and evaluation of 4-(1- benzofuran-2-yl)-1,3-oxazole-2-amine and its derivatives. Int J Res Pharm Chem 2012; 2:32-36.

33. Kouznetsov VV, Robles-Castellanos ML, Sojo F, Rojas-Ruiz1 FA, Arvelo F. Diverse C-6 substituted 4-methyl-2-(2-, 3- and 4-pyridinyl) quinolines: synthesis, in vitro anticancer evaluation and in silico studies. Med Chem Res 2017; 26:551-561.

34. Khodarahmi GA, Asadi P, Farrokhpour H, Hassanzadeh F, Dinari M. Design of novel potential aromatase inhibitors via hybrid pharmacophore approach: docking improvement using the QM/MM method. RSC Adv 2015; 5:58055-58064.

35. Jiang X, Liu W, Zhang W, Jiang F, Gao Z, Zhuang H, et al. Synthesis and antimicrobial evaluation of new benzofuran derivatives. Eur J Med Chem 2011; 46:3526-3530.