Email this article Biological evaluation, docking and molecular dynamic simulation of some novel diaryl urea derivatives bearing quinoxalindione moiety
Abstract
In this study a series of diarylurea derivatives containing quinoxalindione group were biologically evaluated for their cytotoxic activities using MTT assay against MCF-7 and HepG2 cell lines. Antibacterial activities of these compounds were also evaluated by Microplate Alamar Blue Assay (MABA) against three Gram-negative (Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi), three Gram-positive (Staphylococcus aureus, Bacillus subtilis and Listeria monocitogenes) and one yeast-like fungus (Candida albicans) strain. Furthermore, molecular docking was carried out to study the binding pattern of the compounds to the active site of B-RAF kinase (PDB code: 1UWH). Molecular dynamics simulation was performed on the best ligand (16e) to investigate the ligand binding dynamics in the physiological environment. Cytotoxic evaluation revealed the most prominent cytotoxicity for 6 compounds with IC50 values of 10-18 µM against two mentioned cell lines. None of the synthesized compounds showed significant antimicrobial activity. The obtained results of the molecular docking study showed that all compounds fitted in the binding site of enzyme with binding energy range of -11.22 to -12.69 kcal/mol vs sorafenib binding energy -11.74 kcal/mol as the lead compound. Molecular dynamic simulation indicated that the binding of ligand (16e) was stable in the active site of B-RAF during the simulation.
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Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90.
Kim S-K. Handbook of anticancer drugs from marine origin. Springer International Publishing Switzerland. 2015: pp. 1-15.
Solomon VR, Hu C, Lee H. Hybrid pharmacophore design and synthesis of isatin-benzothiazole analogs for their anti-breast cancer activity. Bioorg Med Chem. 2009;17(21):7585-7592.
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.
Kim HJ, Cho HJ, Kim H, El-Gamal MI, Oh CH, Lee SH, et al. New diarylureas and diarylamides possessing acet(benz)amidophenyl scaffold: design, synthesis, and antiproliferative activity against melanoma cell line. Bioorg Med Chem Lett. 2012;22(9):3269-3273.
Zambon A, Ménard D, Suijkerbuijk BMJM, Niculescu-Duvaz I, Whittaker S, Niculescu-Duvaz D, et al. Novel hinge binder improves activity and pharmacokinetic properties of BRAF inhibitors. J Med Chem. 2010;53(15):5639-5655.
Zhao CR, Wang RQ, Li G, Xue XX, Sun CJ, Qu XJ, et al. Synthesis of indazole based diarylurea derivatives and their antiproliferative activity against tumor cell lines. Bioorg Med Chem Lett. 2013;23(7):1989-1992.
Sirohi B, Philip DS, Shrikhande SV. Regorafenib in gastrointestinal stromal tumors. Future Oncol. 2014;10(9):1581-1587.
Kim ST, Kim TW, Kim Kp, Kim TY, Han SW, Lee JY, et al. Regorafenib as salvage treatment in Korean patients with refractory metastatic colorectal cancer. Cancer Res Treat. 2015;47(4):790-795.
Wong HH, Eisen T. Tivozanib for the treatment of metastatic renal cancer. Expert Rev Anticancer Ther. 2013;13(6):649-660.
Pal SK, Bergerot PG, Figlin RA. Tivozanib: current status and future directions in the treatment of solid tumors. Expert Opin Investig Drugs. 2012;21(12):1851-1859.
Marlow M, Al-Ameedee M, Smith T, Wheeler S, Stocks MJ. Linifanib–a multi-targeted receptor tyrosine kinase inhibitor and a low molecular weight gelator. Chem Commun. 2015;51(29):6384-6387.
Toh HC, Chen PJ, Carr BI, Knox JJ, Gill S, Ansell P, et al. Phase 2 trial of linifanib (ABT‐869) in patients with unresectable or metastatic hepatocellular carcinoma. Cancer. 2013;119(2):380-387.
Noorulla S, Sreenivasulu N, Khan A, Sayeed A. Antibacterial activity of novel substituted quinoxaline heterocycles. Pharmanest. 2011;2(2-3):229-238.
Gupta G, Verma P. Antimicrobial activity of quinoxaline derivatives. Chem Inform. 2015;46(4):876-884.
Batra S, Tusi Z, Madapa S. Medicinal chemistry of ureido derivatives as anti-infectives. antiinfect agents. Med Chem. 2006;5(2):135-160.
Doğruer DS, Urlu Ş, Önkol T, Özçelik B, Şahin MF. Synthesis of some pyridazine derivatives carrying urea, thiourea, and sulfonamide moieties and their antimicrobial activity. Turk J Chem. 2010;34(1):57-65.
Madapa S, Tusi Z, Sridhar D, Kumar A, Siddiqi MI, Srivastava K, et al. Search for new pharmacophores for antimalarial activity. Part I: synthesis and antimalarial activity of new 2-methyl-6-ureido-4-quinolinamides. Bioorg Med Chem. 2009;17(1):203-221.
Sadeghian-Rizi S, Khodarahmi G, Amirhossein 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. Ahead print.
Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65(1-2):55-63.
Freshney R. Ian . Culture of animal cells: a manual of basic technique. John Wiley and Sons, Inc. Hoboken, New Jersey. Published simultaneously in Canada. 1994: pp. 205-216.
Schwalbe R, Steele-Moore L, Goodwin A.C. Antimicrobial susceptibility testing protocols. New York CRC. 2007: pp. 75-79.
To WK, Fothergill AW, Rinaldi MG. Comparative evaluation of macrodilution and alamar colorimetric microdilution broth methods for antifungal susceptibility testing of yeast isolates. J Clin Microbiol. 1995;33(10):2660-2664.
Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116(6):855-867.
Sanner MF. Python: a programming language for software integration and development. J Mol Graph Model. 1999;17(1):57-61.
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.
Levinson NM, Kuchment O, Shen K, Young MA, Koldobskiy M, et al. A Src-like inactive conformation in the abl tyrosine kinase domain. PLoS Biol. 2006;4(5):e144.
Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, et al. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015;1:19-25.
Oostenbrink C, Villa A, Mark AE, Van Gunsteren WF. A biomolecular force field based on the free enthalpy of hydration and solvation: the GROMOS force‐field parameter sets 53A5 and 53A6. J. Comput. Chem. 2004;25(13):1656-1676.
SchuÈttelkopf AW, Van Aalten DM. PRODRG: a tool for high-throughput crystallography of protein–ligand complexes. Acta Crystallogr D Biol Crystallogr. 2004;60(8):1355-1363.
Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph Model. 1996;14(1):33-38.
Corona P, Carta A, Loriga M, Vitale G, Paglietti G. Synthesis and in vitro antitumor activity of new quinoxaline derivatives. Eur J Med Chem. 2009;44(4):1579-1591.
Grande F, Aiello F, Grazia OD, Brizzi A, Garofalo A, Neamati N. Synthesis and antitumor activities of a series of novel quinoxalinhydrazides. Bioorg Med Chem. 2007;15(1):288-294.
Tanimori S, Nishimura T, Kirihata M. Synthesis of novel quinoxaline derivatives and its cytotoxic activities. Bioorg Med Chem Lett. 2009;19(15):4119-4121.
Zarranz B, Jaso A, Aldana I, Monge A. Synthesis and anticancer activity evaluation of new 2-alkylcarbonyl and 2-benzoyl-3-trifluoromethyl-quinoxaline 1,4-di-N-oxide derivatives. Bioorg Med Chem. 2004;12(13):3711-3721.
Kumari R, Kumar R, Lynn A. g_mmpbsa—A GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model. 2014;54(7):1951-1962.
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