Skip to main content
SpringerLink
Log in

Design, synthesis, and biological evaluation of novel benzimidazole derivatives and their interaction with calf thymus DNA and synergistic effects with clinical drugs

  • Articles
  • Published:
Science China Chemistry Aims and scope Submit manuscript

Abstract

A series of new benzimidazole derivatives was synthesized and characterized by IR, 1H NMR, 13C NMR, MS, and HRMS spectra. All the new compounds were screened for their antimicrobial activities in vitro by a twofold serial dilution technique. The bioactive evaluation showed that 3,5-bis(trifluoromethyl)phenyl benzimidazoles were comparably or even more strongly antibacterial and antifungal than the reference drugs Chloromycin, Norfloxacin, and Fluconazole. The combination of 2,4-difluorobenzyl benzimidazole derivative 5l and its hydrochloride 7 respectively with the antibacterials Chloromycin, Norfloxacin, and the antifungal Fluconazole was more sensitive to methicillin-resistant MRSA and Fluconazole-insensitive A. flavus. In addition, the interaction of compound 5l with calf thymus DNA demonstrated that this compound could effectively intercalate into DNA to form a compound 5l-DNA complex that might block DNA replication and thereby exert good antimicrobial activity.

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

Similar content being viewed by others

References

  1. Rosato A, Piarulli M, Corbo F, Muraglia M, Carone A, Vitali ME, Vitali C. In vitro synergistic action of certain combinations of gentamicin and essential oils. Curr Med Chem, 2010, 17: 3289–3295

    Article  CAS  Google Scholar 

  2. Demchok JP, Meletiadis J, Roilides E, Walsh TJ. Comparative pharmacodynamic interaction analysis of triple combinations of caspofungin and voriconazole or ravuconazole with subinhibitory concentrations of amphotericin B against Aspergillus spp. Mycoses, 2010, 53: 239–245

    Article  CAS  Google Scholar 

  3. 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

    Article  CAS  Google Scholar 

  4. Cui SF, Wang Y, Lv JS, Damu GLV, Zhou CH. Recent advances in application of thiazole compounds. Sci Sinica Chim, 2012, 42: 1105–1131 (in Chinese)

    Article  CAS  Google Scholar 

  5. Zhang HZ, Zhou CH, Geng RX, Ji QG. Recent advances in syntheses of oxazole compounds. Chin J Org Chem, 2011, 31: 1963–1976 (in Chinese)

    CAS  Google Scholar 

  6. Zhou CH, Wang Y. Recent researches in triazole compounds as medicinal drugs. Curr Med Chem, 2012, 19: 239–280

    Article  CAS  Google Scholar 

  7. Wang Y, Zhou CH. Recent advances in the researches of triazole compounds as medicinal drugs. Sci Sinica Chim, 2011, 41: 1429–1456 (in Chinese)

    Article  Google Scholar 

  8. Zhang HZ, Damu GLV, Cai GX, Zhou CH. Current developments in the syntheses of 1,2,4-triazole compounds. Curr Org Chem, 2014, 18: 359–406

    Article  CAS  Google Scholar 

  9. Dai LL, Cui SF, Damu GLV, Zhou CH. Recent advances in the synthesis and application of tetrazoles. Chin J Org Chem, 2013, 33: 224–244 (in Chinese)

    Article  CAS  Google Scholar 

  10. Peng XM, Cai GX, Zhou CH. Recent developments in azole compounds as antibacterial and antifungal agents. Curr Top Med Chem, 2013, 13: 1963–2010

    Article  CAS  Google Scholar 

  11. Sivakumar R, Pradeepchandran R, Jayaveera KN, Kumarnallasivan P, Vijaianand PR, Venkatnarayanan R. Benzimidazole: an attractive pharmacophore in medicinal chemistry. Int J Pharma Res, 2011, 3: 19–31

    CAS  Google Scholar 

  12. Meng JP, Geng RX, Zhou CH, Gan LL. Advances in the research of benzimidazole drugs. Chin J New Drugs, 2009, 18: 1505–1514 (in Chinese)

    CAS  Google Scholar 

  13. Srikanth L, Raj VV, Raghunandan N, Venkateshwerlu L. Recent advances and potential pharmacological activities of benzimidazole derivatives. Pharma Chemica, 2011, 3: 172–193

    CAS  Google Scholar 

  14. Zhang SL, Damu GLV, Zhang L, Geng RX, Zhou CH. Synthesis and biological evaluation of novel benzimidazole derivatives and their binding behavior with bovine serum albumin. Eur J Med Chem, 2012, 55: 164–175

    Article  CAS  Google Scholar 

  15. Fang B, Zhou CH, Rao XC. Synthesis and biological activities of novel amine-derived bis-azoles as potential antibacterial and antifungal agents. Eur J Med Chem, 2010, 45: 4388–4398

    Article  CAS  Google Scholar 

  16. Zhang HZ, Damu GLV, Cai GX, Zhou CH. Design, synthesis and antimicrobial evaluation of novel benzimidazole type of Fluconazole analogues and their synergistic effects with Chloromycin, Norfloxacin and Fluconazole. Eur J Med Chem, 2013, 64: 329–344

    Article  CAS  Google Scholar 

  17. Narasimhan B, Sharma D, Kumar P. Benzimidazole: a medicinally important heterocyclic moiety. Med Chem Res, 2012, 21: 269–283

    Article  CAS  Google Scholar 

  18. Zhang DT, Wang ZH, Xu WR, Sun FG, Tang LD, Wang JW. Design, synthesis and antibacterial activity of novel actinonin derivatives containing benzimidazole heterocycles. Eur J Med Chem, 2009, 44: 2202–2210

    Article  CAS  Google Scholar 

  19. Özkay Y, Tunali Y, Karaca H, Işıkdağ İ. Antimicrobial activity of a new combination system of benzimidazole and various azoles. Arch Pharm, 2011, 11: 264–271

    Article  Google Scholar 

  20. Jubie S, Rajeshkumar R, Yellareddy B, Siddhartha G, Sandeep M, Surendrareddy K, Dushyanth HS, Elango K. Microwave assisted synthesis of some novel benzimidazole substituted fluoroquinolones and their antimicrobial evaluation. J Pharm Sci Res, 2010, 2: 69–76

    CAS  Google Scholar 

  21. Zhang SL, Chang JJ, Damu GLV, Fang B, Zhou XD, Geng RX, Zhou CH. Novel berberine triazoles: synthesis, antimicrobial evaluation and competitive interactions with metal ions to human serum albumin. Bioorg Med Chem Lett, 2013, 23: 1008–1012

    Article  CAS  Google Scholar 

  22. Zhang SL, Chang JJ, Damu GLV, Geng RX, Zhou CH. Berberine azoles as antimicrobial agents: synthesis, biological evaluation and their interactions with human serum albumin. Med Chem Comm, 2013, 4: 839–846

    Article  CAS  Google Scholar 

  23. Zhang L, Chang JJ, Zhang SL, Damu GLV, Geng RX, Zhou CH. Synthesis and bioactive evaluation of novel hybrids of metronidazole and berberine as new type of antimicrobial agents and their transportation behavior by human serum albumin. Bioorg Med Chem, 2013, 21: 4158–4169

    Article  CAS  Google Scholar 

  24. Wang XL, Wan K, Zhou CH. Synthesis of novel sulfanilamide-derived 1,2,3-triazoles and their evaluation for antibacterial and antifungal activities. Eur J Med Chem, 2010, 45: 4631–4639

    Article  CAS  Google Scholar 

  25. Yin BT, Yan CC, Peng XM, Zhang SL, Rasheed S, Geng RX, Zhou CH. Synthesis and biological evaluation of α-triazolyl chalcones as a new type of potential antimicrobial agents and their interaction with calf thymus DNA and human serum albumin. Eur J Med Chem, 2014, 71: 148–159

    Article  CAS  Google Scholar 

  26. Lv JS, Peng XM, Kishore B, Zhou CH. 1,2,3-Triazole-derived naphthalimides as a novel type of potential antimicrobial agents: synthesis, antimicrobial activity, interaction with calf thymus DNA and human serum albumin. Bioorg Med Chem Lett, 2014, 24: 308–313

    Article  CAS  Google Scholar 

  27. Zhang YY, Zhou CH. Synthesis and activities of naphthalimide azoles as a new type of antibacterial and antifungal agents. Bioorg Med Chem Lett, 2011, 21: 4349–4352

    Article  CAS  Google Scholar 

  28. Wang QP, Zhang JQ, Damu GLV, Wan K, Zhang HZ, Zhou CH. Synthesis and biological activities of thio-triazole derivatives as new potential antibacterial and antifungal agents. Sci China Chem, 2012, 55: 2134–2153

    Article  CAS  Google Scholar 

  29. Luo Y, Lu YH, Gan LL, Zhou CH, Wu J, Geng RX, Zhang YY. Synthesis, antibacterial and antifungal activities of novel 1,2,4-triazolium derivatives. Arch Pharm, 2009, 342: 386–393

    Article  CAS  Google Scholar 

  30. Peng XM, Damu GLV, Zhou CH. Current developments of coumarin compounds in medicinal chemistry. Curr Pharm Des, 2013, 19: 3884–3930

    Article  CAS  Google Scholar 

  31. Shi Y, Zhou CH. Synthesis and evaluation of a class of new coumarin triazole derivatives as potential antimicrobial agents. Bioorg Med Chem Lett, 2011, 21: 956–960

    Article  CAS  Google Scholar 

  32. Shi Y, Zhou CH, Zhou XD, Geng RX, Ji QG. Synthesis and antimicrobial evaluation of coumarin-based benzotriazoles and their synergistic effects with chloromycin and fluconazole. Acta Pharm Sin, 2011, 46: 798–810 (in Chinese)

    CAS  Google Scholar 

  33. Zhang FF, Zhou CH, Yan JP. New progress of researches in carbazole compounds. Chin J Org Chem, 2010, 30: 783–796 (in Chinese)

    CAS  Google Scholar 

  34. Zhang FF, Gan LL, Zhou CH. Synthesis, antibacterial and antifungal activities of some carbazole derivatives. Bioorg Med Chem Lett, 2010, 20: 1881–1884

    Article  CAS  Google Scholar 

  35. Li XL, Hu YJ, Wang H, Yu BQ, Yue HL. Molecular spectroscopy evidence of berberine binding to DNA: comparative binding and thermodynamic profile of intercalation. Biomacromolecules, 2012, 13: 873–880

    Article  CAS  Google Scholar 

  36. Cui SF, Ren Y, Zhang SL, Peng XM, Damu GLV, Geng RX, Zhou CH. Synthesis and biological evaluation of a class of quinolone triazoles as potential antimicrobial agents and their interactions with calf thymus DNA. Bioorg Med Chem Lett, 2013, 23: 3267–3272

    Article  CAS  Google Scholar 

  37. Ramla MM, Omar MA, Tokuda H, Ei-Diwani HI. Synthesis and inhibitory activity of new benzimidazole derivatives against Burkitt’s lymphoma promotion. Bioorg Med Chem, 2007, 15: 6489–6496

    Article  CAS  Google Scholar 

  38. Achar KCS, Hosamani KM, Seetharamareddy HR. In-vivo analgesic and anti-inflammatory activities of newly synthesized benzimidazole derivatives. Eur J Med Chem, 2010, 45: 2043–2054

    Article  Google Scholar 

  39. Zhang YY, Mi JL, Zhou CH. Zhou XD. Synthesis of novel fluconazoliums and their evaluation for antibacterial and antifungal activities. Eur J Med Chem, 2011, 46: 4391–4402

    Article  CAS  Google Scholar 

  40. Wang Y, Damu GLV, Lv JS, Geng RX, Yang DC, Zhou CH. Design, synthesis and evaluation of clinafloxacin triazole hybrids as a new type of antibacterial and antifungal agents. Bioorg Med Chem Lett, 2012, 22: 5363–5366

    Article  CAS  Google Scholar 

  41. Hunziker D, Wyss PC, Angehrn P, Mueller A, Marty HP, Halm R, Kellenberger L, Bitsch V, Biringer G, Arnold W, Stämpfli A, Schmitt-Hoffmannb A, Cousot D. Novel ketolide antibiotics with a fused five-membered lactone ring-synthesis, physicochemical and antimicrobial properties. Bioorg Med Chem, 2004, 12: 3503–3519

    Article  CAS  Google Scholar 

  42. Damu GLV, Wang QP, Zhang HZ, Zhang YY, Lv JS, Zhou CH. A series of naphthalimide triazoles: design, synthesis and bioactive evaluation as potential antimicrobial agents. Sci China Chem, 2013, 56: 952–969

    Article  CAS  Google Scholar 

  43. National Committee for Clinical Laboratory Standards Approved standard Document. M27-A2, Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, National Committee for Clinical Laboratory Standards, Wayne, PA, 2002

  44. Bhattacharya A, Mishra LC, Sharma M, Awasthi SK, Bhasin VK. Antimalarial pharmacodynamics of chalcone derivatives in combination with artemisinin against Plasmodium falciparum in vitro. Eur J Med Chem, 2009, 44: 3388–3393

    Article  CAS  Google Scholar 

  45. Mishra LC, Bhattacharya A, Bhasin VK. Antiplasmodial interactions between artemisinin and triclosan or ketoconazole combinations against blood stages of Plasmodium falciparum in vitro. Am J Trop Med Hyg, 2007, 76: 497–501

    CAS  Google Scholar 

  46. Bhattacharya A, Mishra LC, Bhasin VK. In vitro activity of artemisinin in combination with clotrimazole or heat-treated amphotericin B against Plasmodium falciparum. Am J Trop Med Hyg, 2008, 78: 721–728

    CAS  Google Scholar 

  47. Berdis AJ. DNA polymerases as therapeutic targets. Biochemistry, 2008, 47: 8253–8260

    Article  CAS  Google Scholar 

  48. Rahban M, Divsalar A, Saboury AA, Golestani A. Nanotoxicity and spectroscopy studies of silver nanoparticle: calf thymus DNA and K562 as targets. J Phys Chem C, 2010, 114: 5798–5803

    Article  CAS  Google Scholar 

  49. Zhang GW, Fu P, Wang L, Hu MM. Molecular spectroscopic studies of farrerol interaction with calf thymus DNA. J Agric Food Chem, 2011, 59: 8944–8952

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China

    HuiZhen Zhang, Syed Rasheed & ChengHe Zhou

  2. Sichuan Provincial People’s Hospital, Chengdu, 610072, China

    JianMei Lin

Authors
  1. HuiZhen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. JianMei Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Syed Rasheed
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. ChengHe Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to ChengHe Zhou.

Additional information

These two authors contributed equally to this work

Postdoctoral fellow from Department of Chemistry, Hyderabad University, India

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, H., Lin, J., Rasheed, S. et al. Design, synthesis, and biological evaluation of novel benzimidazole derivatives and their interaction with calf thymus DNA and synergistic effects with clinical drugs. Sci. China Chem. 57, 807–822 (2014). https://doi.org/10.1007/s11426-014-5087-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11426-014-5087-x

Keywords

Search

Navigation