Advertisement

Medicinal Chemistry Research

, Volume 23, Issue 1, pp 76–86 | Cite as

Synthesis, molecular docking of novel 1,8-naphthyridine derivatives and their cytotoxic activity against HepG2 cell lines

  • Ahmad F. EweasEmail author
  • Nagy M. Khalifa
  • Nisreen S. Ismail
  • Mohamed A. Al-Omar
  • Abdel Mohsen M. Soliman
Original Research

Abstract

A series of novel 2,7-dimethyl-1,8-naphthyridine derivatives substituted with Mannich bases 2ad, N-β-glycosides 6ae, 7ae, Schiff’s bases 8ac, pyrazolone 9, and S-alkylated derivatives 10ac have been synthesized in good yields starting from 4-hydroxy-2,7-dimethyl-1,8-naphthyridine 1 through multi-step synthesis. The newly synthesized title compounds were evaluated for their HepG2 cell growth inhibition, the results revealed that all the tested compounds process inhibitory effects on the growth of HepG2 liver cancer cells. Compound 8b showed the highest inhibition activity against HepG2 cell line (IC50 equals 3.2 μg/mL) among all tested compounds. The results were compared to 5-Fluorouracil (5-FU) and doxorubicin as reference drugs, (IC50 5 and 3.56 μg/mL). Furthermore, molecular docking of compounds 3b, 6a, and 8b into the binding site of topoisomerase II was carried out. The results of the binding energy scores of these compounds were compared to the docking score of Vosaroxin, a known 1,8-naphthyridine derivative which is in clinical trials as potential anticancer drug. Compound 8b docking result revealed that it is the only tested compound that intercalate with DNA segment of the topoisomerase II, similar to Vosaroxin which was used as reference drug for docking comparison.

Graphical Abstract

Keywords

2,7-Dimethyl-1,8-naphthyridine derivatives Sugar hydrazones Cytotoxic activity HepG2 cell line Molecular docking 

References

  1. Aggarwal N, Kumar R, Dureja P, Khurana JM (2011) Synthesis antimicrobial evaluation and QSAR analysis of novel nalidixic acid based 124-triazole derivatives. Eur J Med Chem 45(2):572–580Google Scholar
  2. Burden DA, Oshereroff N (1998) Mechanism of action of eukaryotic topoisomerase II and drugs targeted to the enzyme. Biochim Biophys Acta 1400:139–154CrossRefPubMedGoogle Scholar
  3. Cioffi G, Piaz FD, Vassallo A, Venturella F, Caprariis PD, Simone FD, Tommasi ND (2008) Antiproliferative oleanane saponins from Meryta denhamii. J Nat Prod 71:1000–1004CrossRefPubMedGoogle Scholar
  4. George TG, Johnsamuel J, Delfín DA, Yakovich A, Mukherjee M, Phelps MA, Dalton JT, Sackett DL, Kaiser M, Brun R, Werbovetz KA (2006) Antikinetoplastid antimitotic activity and metabolic stability of dinitroaniline sulfonamides and benzamides. Bioorg Med Chem 14(16):5699–5710CrossRefPubMedGoogle Scholar
  5. Hu WP, Yu HS, Chen YR, Tsai YM, Chen YK, Liao CC, Chang LS, Wang JJ (2008) Synthesis and biological evaluation of thiobenzanilides as anticancer agents. Bioorg Med Chem 16:5295–5302CrossRefPubMedGoogle Scholar
  6. Hussain S, Slevin M, Ahmed N, West D, Choudhary MI, Naz H, Gaffney J (2009) Stilbene glycosides are natural product inhibitors of FGF-2-induced angiogenesis. BMC Cell Biol 10:30–31PubMedCentralCrossRefPubMedGoogle Scholar
  7. Iqbal N, Iqbal J, Imran M (2009) Synthesis, characterization and antibacterial screening of some metal complexes of a Schiff Base derived from Benzaldehyde. J Sci Res 19(1):15–19Google Scholar
  8. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics. CA Cancer J Clin 58:71–76CrossRefPubMedGoogle Scholar
  9. Jiang ZH, Wen XY, Tanaka T, Wu SY, Liu ZQ, Iwata H, Hirose Y, Wu SG, Kouno I (2008) Cytotoxic hydrolyzable tannins from Balanophora japonica. J Nat Prod 71:719–723CrossRefPubMedGoogle Scholar
  10. Jones RA, Krische MJ (2009) Asymmetric total synthesis of the iridoid beta-glucoside (+)-geniposide via phosphine organocatalysis. Org Lett 8:1849–1851CrossRefGoogle Scholar
  11. Kamel MM, Ali HI, Anwar MM, Mohamed NA, Soliman AM (2010) Synthesis antitumor activity and molecular docking study of novel sulfonamide-Schiff’s bases thiazolidinones benzothiazinones and their C-nucleoside derivatives. Eur J Med Chem 45(2):572–580CrossRefPubMedGoogle Scholar
  12. Kemnitzer W, Jiang S, Wang Y, Kasibhatla S, Crogan GC, Bubenik M, Labrecque D, Denis R, Lamothe S, Attardo G, Gourdeau H, Tseng B, Drewe J, Cai SX (2008) Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based HTS assay. Part 5: modifications of the 2- and 3-positions. Bioorg Med Chem Lett 18:603CrossRefPubMedGoogle Scholar
  13. Kommana P, Chung SW, Donaldson WA (2008) Synthetic studies directed toward amphidinol Elucidation of the relative configuration of the C1–C10 fragment. Tetrahedron Lett 49:6209–6211CrossRefGoogle Scholar
  14. Kren V, Martínková L (2001) Glycosides in medicine: “the role of glycosidic residue in biological activity”. Med Chem 8:1313–1328Google Scholar
  15. Kren V, Rezanka T (2008) Sweet antibiotics—the role of glycosidic residues in antibiotic and antitumor activity and their randomization. FEMS Microbiol Rev 32:858–889CrossRefPubMedGoogle Scholar
  16. Kumar S, Niranjan MS, Chaluvaraju KC, Jamakhandi CM, Kadadevar D (2010) Synthesis and antimicrobial study of some Schiff bases of sulfonamides. J Curr Pharm Res 1:39–42Google Scholar
  17. Lee ER, Kang YJ, Choi HY, Kang GH, Kim JH, Kim BW, Han YS, Nah SY, Paik HD, Park YS, Cho SG (2007) Induction of apoptotic cell death by synthetic naringenin derivatives in human lung epithelial carcinoma A549 cells. Biol Pharm Bull 30:2394–2398CrossRefPubMedGoogle Scholar
  18. Ma J, Zhao PJ, Shen YM (2007) New amide N-glycosides of ansamitocins identified from Actinosynnema pretiosum. Arch Pharm Res 30:670–673CrossRefPubMedGoogle Scholar
  19. Manikpuri AD (2010) Synthesis and antimicrobial studies on therapeutically significant Schiff bases of Salicaldehyde and sulfonamides. Res J Pharm Biol Chem Sci 1(2):21–27Google Scholar
  20. Maskey RP, Grun WI, Fiebig HH, Laatsch H (2002) Akashins A, B, and C: novel chlorinated indigoglycosides from Streptomyces sp. GW 48/1497. Angew Chem Int Ed 41:597CrossRefGoogle Scholar
  21. Norris P (2008) Pyranose N-glycosyl amines: emerging targets with diverse biological potential. Curr Top Med Chem 8:101–113CrossRefPubMedGoogle Scholar
  22. Panneerselvam P, Rather BA, Reddy DS, Kumar NR (2009) Synthesis and anti-microbial screening of some Schiff bases of 3-amino-6,8-dibromo-2-phenylquinazolin-4(3H)-ones. Eur J Med Chem 44(5):2328–2333CrossRefPubMedGoogle Scholar
  23. Piochon M, Legault J, Gauthier C, Pichette A (2009) Synthesis and cytotoxicity evaluation of natural alpha-bisabolol beta-D-fucopyranoside and analogues. Phytochemistry 70:228–236CrossRefPubMedGoogle Scholar
  24. Shao H, Wang Z, Lacroix E, Wu SH, Jennings HJ, Zou W (2002) Novel zinc (II)-mediated epimerization of 2′-carbonylalkyl-alpha-C-glycopyranosides to their beta-anomers. J Am Chem Soc 124:2130–2131CrossRefPubMedGoogle Scholar
  25. Siddiqui N, Pandeya SN, Khan SA, James S, Rana A, Mahfuz A (2007) Synthesis and anticonvulsant activity of sulfonamide derivatives-hydrophobic domain. Bioorg Med Chem Lett 17:255–259CrossRefPubMedGoogle Scholar
  26. Singh UK, Pandeya SN, Jindal S, Pandey M, Srivastava BK, Singh A (2010a) Synthesis and antimicrobial activity of Schiff’s and Mannich bases of 1H-indole-2,3-dione derivatives. Der Pharma Chemica 2(2):392–399Google Scholar
  27. Singh UK, Pandeya SN, Singh A, Srivastava BK, Pandey M (2010b) Synthesis and antimicrobial activity of Schiff’s and N-Mannich bases of isatin and its derivatives with 4-amino-N-carbamimidoyl benzene sulfonamide. Int J Pharm Sci Drug Res 2(2):151–154Google Scholar
  28. Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer 82:1107–1112CrossRefGoogle Scholar
  29. Srivastava SK, Jaggi M, Singh AT, Madaan A, Rani N, Vishnoi M, Agarwal SK, Mukherjee R, Burman AC (2007) Anticancer and anti-inflammatory activities of 1,8-naphthyridine-3-carboxamide derivatives. Bioorg Med Chem Lett 17(23):6660–6664CrossRefPubMedGoogle Scholar
  30. Su DM, Qu J, Hu YC, Yu SS, Tang WZ, Liu YB, Ma SG, Yu DQ (2008) A new glycoside from the leaves of Neoalsomitra integrifoliola Chin. Chem Lett 19:845Google Scholar
  31. Tomita K, Tsuzuki Y, Shibamori K, Tashima M, Kajikawa F, Sato Y, Kashimoto S, Chiba K, Hino K (2002) Synthesis and structure-activity relationships of novel 7-substituted 14-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents. Part 1. J Med Chem 45:5564–5575CrossRefPubMedGoogle Scholar
  32. Tsuzuki Y, Tomita K, Shibamori K, Sato Y, Kashimoto S, Chiba K (2004a) Synthesis and structure-activity relationships of novel 7-substituted 14-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents. Part 2. J Med Chem 47:2097–2109CrossRefPubMedGoogle Scholar
  33. Tsuzuki Y, Tomita K, Shibamori K, Sato Y, Kashimoto S, Chiba K (2004b) Synthesis and structure–activity relationships of 3-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines as novel antitumor agents. Bioorg Med Chem Lett 14(12):3189–3319CrossRefPubMedGoogle Scholar
  34. Vazzana I, Terranova E, Mattioli F, Sparatore F (2004) Aromatic Schiff bases and 2,3-disubstituted 13-thiazolidin-4-one derivatives as anti-inflammatory agents. ARKIVOC 5:364–374Google Scholar
  35. Wu ZB, Zhao YY, Yang XW, Liang H (2009) Flavonoids from Bauhinia glauca subsp. pernervosa. Chem Pharm Bull 57:628–631CrossRefPubMedGoogle Scholar
  36. Zarghi A, Zebardast T, Hakimion F, Shirazi FH, Rao PNP, Knaus EE (2006) Synthesis and biological evaluation of 1,3-diphenylprop-2-en-1-ones possessing a methanesulfon amido or an azido pharmacophore as cyclooxygenase-1/-2 inhibitors. Bioorg Med Chem 14(20):7044–7050CrossRefPubMedGoogle Scholar
  37. Zhong W, Moya C, Jacobs RS, Little RD (2008) Synthesis and an evaluation of the bioactivity of the C-glycoside of pseudopterosin A methyl ether. J Org Chem 73:7011–7016CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Ahmad F. Eweas
    • 1
    • 2
    Email author
  • Nagy M. Khalifa
    • 1
    • 3
  • Nisreen S. Ismail
    • 1
  • Mohamed A. Al-Omar
    • 3
    • 4
  • Abdel Mohsen M. Soliman
    • 1
  1. 1.Department of Medicinal ChemistryNational Research CentreCairoEgypt
  2. 2.Pharmaceutical Chemistry Department, College of PharmacyTaif UniversityTaifSaudi Arabia
  3. 3.Drug Exploration & Development Chair (DEDC), College of Pharmacy, King Saud UniversityRiyadhSaudi Arabia
  4. 4.Pharmaceutical Chemistry DepartmentCollege of Pharmacy, King Saud UniversityRiyadhSaudi Arabia

Personalised recommendations