Medicinal Chemistry Research

, Volume 22, Issue 10, pp 4663–4676 | Cite as

Synthesis, structure, anticancer, and antioxidant activity of para-xylyl linked bis-benzimidazolium salts and respective dinuclear Ag(I) N-heterocyclic carbene complexes (Part-II)

  • Rosenani A. Haque
  • Muhammad Adnan Iqbal
  • Patrick Asekunowo
  • A. M. S. Abdul Majid
  • Mohamed B. Khadeer Ahamed
  • Muhammad Ihtisham Umar
  • Sawsan S. Al-Rawi
  • Fouad Saleih R. Al-Suede
Original Research


The article describes synthesis, characterization (NMR, FT-IR, microanalysis, X-ray crystallography), in vitro anticancer, and antioxidant activity of para-xylyl linked bis-benzimidazolium salts and respective dinuclear Ag–NHC complexes. All the compounds were tested for their cytotoxicity against human colorectal cancer cells (HCT 116) and DPPH antioxidant evaluation. According to cell viability measurements using MTT assay, all the tested compounds showed dose-dependent cytotoxic activity against HCT 116 cells. The tested compounds demonstrated significant activity with IC50 values range 0.29–3.30 μM for HCT 116 and % age inhibition 6.37–21.00 for DPPH antioxidant study. 5-Fluorouracil was used as standard drug (IC50 19.2 μM for HCT 116) whereas for DPPH analysis, Gallic acid was used as positive control (% age inhibition 77.68). All the compounds showed potential anticancer activity against human colorectal cancer whereas antioxidant activity was not significant. We found that as the size of N-alkyl substitution on benzimidazolium salt increases its cytotoxicity against cancer decreases whereas a reverse occurs in case of respective complexes.


Benzimidazole Benzimidazolium salts N-Heterocyclic carbenes (NHCs) Ag–NHC complexes Human colon cancer (HCT 116) Antioxidant 



RAH thanks Universiti Sains Malaysia (USM) for the Research University (RU) Grants (1001/PKIMIA/811157) and (1001/PKIMIA/823082). MAI is grateful to (IPS) USM for financial support [fellowship: USM.IPS/JWT/1/19 (JLD 6): P-KD0030/11(R)] and funds [P-KM0018/10(R)-308/AIPS/415401] for a research attachment (Aug. 2011–Nov. 2011) to University of Western Australia (UWA), Perth, Australia.

Supplementary material

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Supplementary material 1 (TIFF 158 kb)
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  1. Babizhayev M, Courbebaisse Y, Nicolay J-F, Semiletov Y (1998) Design and biological activity of imidazole-containing peptidomimetics with a broad-spectrum antioxidant activity. Lett Pept Sci 5(2–3):163–169Google Scholar
  2. Baker MV, Brown DH, Haque RA, Skelton BW, White AH (2004) Dinuclear N-heterocyclic carbene complexes of silver(i), derived from imidazolium-linked cyclophanes. Dalton Trans 21:3756–3764PubMedCrossRefGoogle Scholar
  3. Baker MV, Brown DH, Haque RA, Skelton BW, White AH (2009) Silver(I) and mercury(II) complexes of meta- and para-xylyl linked bis(imidazol-2-ylidenes). J Incl Phenom Macrocycl Chem 65(1):97–109CrossRefGoogle Scholar
  4. Bansal Y, Silakari O (2012) The therapeutic journey of benzimidazoles: a review. Bioorg Med Chem 20(21):6208–6236PubMedCrossRefGoogle Scholar
  5. Bildstein B, Malaun M, Kopacka H, Wurst K, Mitterböck M, Ongania K-H, Opromolla G, Zanello P (1999) N, N′-Diferrocenyl-N-heterocyclic carbenes and their derivatives. Organometallics 18(21):4325–4336CrossRefGoogle Scholar
  6. Cole ER, Crank G, Salam-Sheikh A (1974) Antioxidant properties of benzimidazoles. J Agric Food Chem 22(5):918PubMedCrossRefGoogle Scholar
  7. Graham C (2005) The role of silver in wound healing. Br J Nutr 14(19):S22Google Scholar
  8. Haque RA, Iqbal MA (2012a) Synthesis and characterization of ortho-xylyl linked bis-benzimidazolium salts. Asian J Chem 24(6):2625–2628Google Scholar
  9. Haque RA, Iqbal MA (2012b) Synthesis and characterization of ortho-xylyl linked bis-benzimidazolium salts (Part-II). Asian J Chem 25(4):3049–3054Google Scholar
  10. Haque RA, Iqbal MA, Hemamalini M, Fun H-K (2011) 3,3′-[1,2-Phenylenebis(methylene)]bis(1-heptylbenzimidazolium) dibromide monohydrate. Acta Crystallogr E 67(7):o1814–o1815CrossRefGoogle Scholar
  11. Haque RA, Ghdhayeb MZ, Budagumpi S, Salman AW, Khadeer Ahamed MB, Majid AMSA (2012a) Non-symmetrically substituted N-heterocyclic carbene–Ag(I) complexes of benzimidazol-2-ylidenes: synthesis, crystal structures, anticancer activity and transmetallation studies. Inorg Chim Acta 392:61–72CrossRefGoogle Scholar
  12. Haque RA, Iqbal MA, Ahmad SA, Chia TS, Fun H-K (2012b) 3,3′-[1,4-Phenylenebis(methylene)]bis(1-propylbenzimidazolium) dichloride dihydrate. Acta Crystallogr E 68(3):o845–o846CrossRefGoogle Scholar
  13. Haque RA, Iqbal MA, Budagumpi S, Hemamalini M, Fun H-K (2012c) 3,3′-[1,2-Phenylenebis(methylene)]bis(1-ethylbenzimidazolium) dibromide. Acta Crystallogr E 68(3):o573CrossRefGoogle Scholar
  14. Haque RA, Iqbal MA, Fun H-K, Arshad S (2012d) 3,3′-[1,2-Phenylenebis(methylene)]bis(1-octylbenzimidazolium) dibromide monohydrate. Acta Crystallogr E 68(4):o924–o925CrossRefGoogle Scholar
  15. Haque RA, Iqbal MA, Khadeer MB, Majeed AA, Abdul Hameed ZA (2012e) Design, synthesis and structural studies of meta-xylyl linked bis-benzimidazolium salts: potential anticancer agents against ‘human colon cancer’. Chem Cent J 6(1):68PubMedCrossRefGoogle Scholar
  16. Haque RA, Iqbal MA, Rosli MM, Fun H-K (2012f) 3,3′-[1,2-Phenylenebis(methylene)]bis(1-ethyl-1H-benzimidazol-1-ium) bis(hexaflourophosphate). Acta Crystallogr E 68(6):o1635CrossRefGoogle Scholar
  17. Hranjec M, Starčević K, Pavelić SK, Lučin P, Pavelić K, Karminski Zamola G (2011) Synthesis, spectroscopic characterization and antiproliferative evaluation in vitro of novel Schiff bases related to benzimidazoles. Eur J Med Chem 46(6):2274–2279PubMedCrossRefGoogle Scholar
  18. Iqbal MA, Haque RA, Ahamed MBK, Abdul MAMS, Al-Rawi S (2013) Synthesis and anticancer activity of para-xylyl linked bis-benzimidazolium salts and respective Ag(I) N-heterocyclic carbene complexes. Med Chem Res. doi: 10.1007/s00044-00012-00240-00046 Google Scholar
  19. Kascatan-Nebioglu A, Panzner MJ, Tessier CA, Cannon CL, Youngs WJ (2007) N-Heterocyclic carbene-silver complexes: a new class of antibiotics. Coord Chem Rev 251(5–6):884–895CrossRefGoogle Scholar
  20. Kim KS, Lee S, Lee YS, Jung SH, Park Y, Shin KH, Kim B-K (2003) Anti-oxidant activities of the extracts from the herbs of Artemisia apiacea. J Ethnopharmacol 85(1):69–72PubMedCrossRefGoogle Scholar
  21. Narasimhan B, Sharma D, Kumar P (2012) Benzimidazole: a medicinally important heterocyclic moiety. Med Chem Res 21(3):269–283CrossRefGoogle Scholar
  22. Starikova OV, Dolgushin GV, Larina LI, Ushakov PE, Komarova TN, Lopyrev TN (2003) Synthesis of 1,3-dialkylimidazolium and 1,3-dialkylbenzimidazolium salts. Russ J Org Chem 39(10):1467–1470CrossRefGoogle Scholar
  23. Weitz J, Koch M, Debus J, Höhler T, Galle PR, Büchler MW (2005) Colorectal cancer. The Lancet 365(9454):153–165CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Rosenani A. Haque
    • 1
  • Muhammad Adnan Iqbal
    • 1
  • Patrick Asekunowo
    • 1
  • A. M. S. Abdul Majid
    • 2
  • Mohamed B. Khadeer Ahamed
    • 2
  • Muhammad Ihtisham Umar
    • 3
  • Sawsan S. Al-Rawi
    • 2
  • Fouad Saleih R. Al-Suede
    • 2
  1. 1.The School of Chemical Sciences, Universiti Sains MalaysiaPenangMalaysia
  2. 2.EMAN Research and Testing LaboratoryThe School of Pharmaceutical Sciences, Universiti Sains MalaysiaPenangMalaysia
  3. 3.The School of Pharmaceutical Sciences, Universiti Sains MalaysiaPenangMalaysia

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