Skip to main content
SpringerLink
Log in

Synthesis and pharmacological evaluation of polyfunctional benzimidazole-NSAID chimeric molecules combining anti-inflammatory, immunomodulatory and antioxidant activities

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Polyfunctional compounds comprise a novel class of therapeutic agents for treatment of multifactorial diseases. The present study reports a series of benzimidazole—non-steroidal anti-inflammatory drugs (NSAIDs) conjugates (1–10) as novel polyfunctional compounds synthesized in the presence of orthophosphoric acid. The compounds were evaluated for anti-inflammatory (carageenan-induced paw edema model), immunomodulatory (direct haemagglutination test and carbon clearance index models), antioxidant (in vitro and in vivo) and for ulcerogenic effects. Each of the compound has retained the anti-inflammatory activity of the corresponding parent NSAID while exhibiting significantly reduced gastric ulcers. Additionally, the compounds are found to possess potent immunostimulatory and antioxidant activities. The compound 8 was maximally potent (antibody titre value 358.4 ± 140.21, carbon clearance index 0.053 ± 0.002 and antioxidant EC50 value 0.03 ± 0.006). These compounds, exhibiting such multiple pharmacological activities, can be taken as lead for the development of potent drugs for the treatment of chronic multifactorial diseases involving inflammation, immune system modulation and oxidative stress such as cancers. The Lipinski’s parameters suggested the compounds to be bear drug like properties.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abdel-Aziz, H.A., A.M. Gamal-Eldeen, N.A. Hamdy, and I.M.I. Fakhr. 2009. Immunomodulatory and anticancer activities of some novel 2-substituted-6-bromo-3-methylthiazolo[3,2-a]benzimidazole derivatives. Archiv der Pharmazie 342: 230–237.

    Article  CAS  PubMed  Google Scholar 

  • Achar, K.C.S., K.M. Hosaman, and H.R. Seetharamareddy. 2010. In-vivo analgesic and anti-inflammatory activities of newly synthesized benzimidazole derivatives. European Journal of Medicinal Chemistry 45: 2048–2054.

    Article  CAS  PubMed  Google Scholar 

  • Aebi, H. 1974. Catalase. In Methods of enzymatic analysis, vol. 2, ed. H. Bergmeyer, 673–685. New York: Chemic Academic Press.

    Chapter  Google Scholar 

  • Bali, A., Y. Bansal, M. Sugumaran, J.S. Saggu, P. Balakumar, G. Kaur, G. Bansal, A. Sharma, and M. Singh. 2005. Design, synthesis, and evaluation of novelly substituted benzimidazole compounds as angiotensin II receptor antagonists. Bioorganic & Medicinal Chemistry Letters 15: 3962–3965.

    Article  CAS  Google Scholar 

  • Bandyopadhyay, U., D. Das, and R.K. Banerjee. 1999. Reactive oxygen species; oxidative damage and pathogenesis. Current Science 77: 658–665.

    CAS  Google Scholar 

  • Brand-Williams, W., M.E. Cuvelier, and C. Berset. 1995. Use of free radical method to evaluate antioxidant activity. LWT-Food Science and Technology 28: 25–30.

    Article  CAS  Google Scholar 

  • Buccafusco, J.J. 2009. Multifunctional receptor-directed drugs for disorders of the central nervous system. Neurotherapeutics 6: 4–13.

    Article  CAS  PubMed  Google Scholar 

  • Chu, D., and B.A. Kovacs. 1977. Anti-inflammatory activity in Oak gall extracts. Archives Internationales de Pharmacodynamie et de Thérapie 230: 166–176.

    CAS  PubMed  Google Scholar 

  • Cioli, V., S. Putzolu, V. Rossi, P.S. Barcellona, and C. Corradino. 1979. The role of direct tissue contact in the production of gastrointestinal ulcers by anti-inflammatory drugs in rat. Toxicology and Applied Pharmacology 50: 283–289.

    Article  CAS  PubMed  Google Scholar 

  • Costa, D., A. Gomes, S. Reis, J.L.F.C. Lima, and E. Fernandes. 2005. Hydrogen peroxide scavenging activity by non-steroidal anti-inflammatory drugs. Life Sciences 76: 2841–2848.

    Article  CAS  PubMed  Google Scholar 

  • Eisen, S., A.D.K. Miller, R.S. Woodward, E. Spitznagel, and T.R. Przybeck. 1990. The effect of prescribed daily dose frequency on patient medical compliance. Archives of Internal Medicine 25: 1881–1884.

    Article  Google Scholar 

  • Ellman, G.L. 1959. Tissue sulfhydryl group. Archives of Biochemistry and Biophysics 82: 70–77.

    Article  CAS  PubMed  Google Scholar 

  • Galanakis, D., A.P. Kourounakis, K.C. Tsiakitzis, C.M. Doulgkeris, E.A. Rekka, A. Gavalas, K. Kravaritou, C. Charitos, and P.N. Kourounakis. 2004. Synthesis and pharmacological evaluation of amide conjugates of NSAIDs with l-cysteine ethyl ester, combining potent anti-inflammatory and antioxidant properties with significantly reduced gastrointestinal toxicity. Bioorganic & Medicinal Chemistry Letters 14: 3639–3643.

    Article  CAS  Google Scholar 

  • Gilman, S.C., R.P. Carlson, J. Chang, and A.J. Lewis. 1985. The anti-inflammatory activity of the immunomodulator Wy-18,251 (3-(p-chlorophenyl)thiazolo[3,2-a]benzimidazole-2-acetic acid). Agents Action 17: 53–59.

    Article  CAS  Google Scholar 

  • Hassan, A., E. Martin, and P. Puig-Parellada. 1998. Role of antioxidants in gastric mucosal damage induced by indomethacin in rats. Methods and Findings in Experimental and Clinical Pharmacology 20: 849–854.

    Article  CAS  PubMed  Google Scholar 

  • Hoh, C., M.J. Dankoff, A. Colacone, and M. Afilalo. 2001. Polypharmacy, adverse drug-related events, and potential adverse drug interactions in elderly patients presenting to an emergency department. Annals of Emergency Medicine 38: 666–671.

    Article  Google Scholar 

  • Hussain, M., A. Javeed, M. Ashraf, N. Al-Zaubai, A. Stewart, and M.M. Mukhtar. 2012. Non-steroidal anti-inflammatory drugs, tumour immunity and immunotherapy. Pharmacological Research 66: 7–18.

    Article  CAS  PubMed  Google Scholar 

  • Jarrahpour, A., J. Fathi, M. Mimouni, T.B. Hadda, J. Sheikh, Z.H. Chohan, and A.P. Petra. 2011. Osiris and molinspiration (POM) together as a successful support in drug design: antibacterial activity and biopharmaceutical characterization of some azo schiff bases. Medicinal Chemistry Research 19: 1–7.

    Google Scholar 

  • Jarrahpour, A., M. Motamedifar, M. Zarei, M.H. Youssoufi, M. Mimouni, Z.H. Chohan, T.B. Hadda, and A.P. Petra. 2010. Osiris and molinspiration together as a guide in drug design: predictions and correlation structure/antibacterial activity relationships of new N-sulfonyl monocyclic β-lactams (part II). Phosphorus, Sulfur, and Silicon and the Related Elements 185: 491–497.

    Article  CAS  Google Scholar 

  • Jayathirtha, M.G., and S.H. Mishra. 2004. Preliminary immunomodulatory activities of methanol extracts of Eclipta alba and Centella asiatica. Phytomedicine 11: 361–365.

    Article  CAS  PubMed  Google Scholar 

  • Jimenez, M.J., and M.J. Alcaraz. 1988. Flavonoids as anti-inflammatory agents. Fitoterapia 59: 25–38.

    Google Scholar 

  • Kamada, H., H. Itoh, H. Shibata, T. Koshio, A. Hayashi, and F. Nakagami. 1997. Inhibitory mechanism of mizoribine on the antibody production of mouse B cells stimulated with lipopolysaccharide. Japanese Journal of Pharmacology 74: 323–330.

    Article  CAS  PubMed  Google Scholar 

  • Karoli, T., S.K. Mamidyala, J. Zuegg, S.R. Fry, E.H.L. Tee, T.A. Bradford, P.K. Madala, J.X. Huang, S. Ramu, M.S. Butler, and M.A. Cooper. 2012. Structure aided design of chimeric antibiotics. Bioorganic & Medicinal Chemistry Letters 22: 2428–2433.

    Article  CAS  Google Scholar 

  • Kazura, J.W., W. Negendank, D. Guerry, and A.D. Schreiber. 1979. Human monocyte-lymphocyte interaction and its enhancement by levamisole. Clinical and Experimental Immunology 35: 258–268.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Keith, C.T., A.A. Borisy, and B.R. Stockwell. 2005. Multicomponent therapeutics for networked systems. Nature Reviews Drug Discovery 4: 71–78.

    Article  CAS  PubMed  Google Scholar 

  • Lipinski CA, Lombardo F, Dominy BW, Feeney P. 2001. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 46: 3–26. Calculation of molecular properties and bioactivity score was done by software available at website http://www.molinspiration.com. Accessed 20 Feb 2013.

  • Locatelli, M., R. Gindro, F. Travaglia, J.D. Coïsson, M. Rinaldi, and M. Arlorio. 2009. Study of the DPPH-scavenging activity: development of a free software for the correct interpretation of data. Food Chemistry 114: 889–897.

    Article  CAS  Google Scholar 

  • Luck, H.I., and R.S. Nussenzweig. 1969. Plasmodium chabaudi and Plasmodium vinckei: phagocytic activity of mouse reticuloendothelial system. Experimental Parasitology 25: 319–323.

    Article  Google Scholar 

  • Medina-Franco, J.L., M.A. Giulianotti, G.S. Welmaker, and R.A. Houghten. 2013. Shifting from the single to the multitarget paradigm in drug discovery. Drug Discovery Today 18: 495–501. doi:10.1016/j.drudis.2013.01.008.

    Article  PubMed Central  PubMed  Google Scholar 

  • Morphy, R., and Z. Rankovic. 2005. Designed multiple ligands. An emerging drug discovery paradigm. Journal of Medicinal Chemistry 48: 6523–6543.

    Article  CAS  PubMed  Google Scholar 

  • Muregi, F.W., and A. Ishih. 2010. Next-generation antimalarial drugs: hybrid molecules as a new strategy in drug design. Drug Development Research 71: 20–32.

    CAS  PubMed Central  PubMed  Google Scholar 

  • OECD Test Guideline 425. 2001. Guidelines for testing of chemicals. Guidelines 425, acute oral toxicity—up-and-down procedure. www.oecd.org. Accessed 10 Oct 2012.

  • Ohkawa, H., N. Ohishi, and K. Yagi. 1979. Assay of lipid peroxidation in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry 95: 351–358.

    Article  CAS  PubMed  Google Scholar 

  • Ohshika, Y., N. Umesaki, and T. Sugawa. 1988. Immunomodulating capacity of the monocyte macrophage system in patients with uterine cervical cancer. Nippon Sanka Fujinka Gakkai Zasshi 40: 601–608.

    CAS  PubMed  Google Scholar 

  • Puri, A., R. Saxena, K.C. Saxena, and J.S. Tandon. 1994. Immunostimulant activity of Nyctanthes arbor-tristis L. Journal of Ethnopharmacology 42: 31–37.

    Article  CAS  PubMed  Google Scholar 

  • Reddy, A., and S.S. Zhang. 2013. Polypharmacology: drug discovery for the future. Expert Review of Clinical Pharmacology 6: 41–47.

    Article  CAS  PubMed  Google Scholar 

  • Repetto, M.G., and S.F. Llesuy. 2002. Antioxidant properties of natural compounds used in popular medicine for gastric ulcers. Brazilian Journal of Medical and Biological Research 35: 523–534.

    Article  CAS  PubMed  Google Scholar 

  • Samotrueva, M.A., S.A. Khivrina, and A.B. Matveev. 2005. Some aspects of immunomodulatory effects of new benzimidazole derivatives. Bulletin of Experimental Biology and Medicine 139: 75–76.

    Article  CAS  PubMed  Google Scholar 

  • Schuster, M., A. Nechansky, and R. Kircheis. 2006. Cancer immunotherapy. Biotechnology Journal 1: 138–147.

    Article  CAS  PubMed  Google Scholar 

  • Sondhi, S.M., S. Rajvanshi, M. Johar, N. Bharti, A. Azam, and A.K. Singh. 2002. Anti-inflammatory, analgesic and antiamoebic activity evaluation of pyrimido[1,6-a]benzimidazole derivatives synthesized by the reaction of ketoisothiocyanates with mono and diamines. European Journal of Medicinal Chemistry 37: 835–843.

    Article  CAS  PubMed  Google Scholar 

  • Spain, R.I., M.H. Cameron, and D. Bourdette. 2009. Recent developments in multiple sclerosis therapeutics. BMC Medicine 7: 74.

    Article  PubMed Central  PubMed  Google Scholar 

  • Volin, M.V., and A.E. Koch. 2011. Interleukin-18: a mediator of inflammation and angiogenesis in rheumatoid arthritis. Journal of Interferon and Cytokine Research 31: 745–751.

    Article  CAS  PubMed  Google Scholar 

  • Wang, L., Y. Song, X. Zhang, and Y. Liu. 2006. An exploratory theoretical elucidation on the peroxyl-radical-scavenging mechanism and structure–activity relationship of nonsteroidal anti-inflammatory drugs. Bioorganic & Medicinal Chemistry Letters 16: 3241–3244.

    Article  CAS  Google Scholar 

  • Winter, C.A., E.A. Risley, and G.W. Nuss. 1962. Carrageenan-induced edema in hind paw of the rat as an assay for anti-inflammatory drugs. Proceedings of the Society for Experimental Biology and Medicine 111: 544–547.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are thankful to Crystal Pharmaceuticals (Ambala, India), FDC India Ltd (Mumbai, India), Ranbaxy Research Laboratories (Gurgaon, India) and Dr. Reddy’s Research Laboratory (Hyderabad, India) for providing the NSAIDS and other drugs as generous gift samples.

Author information

Authors and Affiliations

  1. Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, India

    Yogita Bansal & Om Silakari

Authors
  1. Yogita Bansal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Om Silakari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Om Silakari.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bansal, Y., Silakari, O. Synthesis and pharmacological evaluation of polyfunctional benzimidazole-NSAID chimeric molecules combining anti-inflammatory, immunomodulatory and antioxidant activities. Arch. Pharm. Res. 37, 1426–1436 (2014). https://doi.org/10.1007/s12272-013-0282-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-013-0282-4

Keywords

Search

Navigation