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Bisbenzimidazole Derivatives as Potential Antimicrobial Agents: Design, Synthesis, Biological Evaluation and Pharmacophore Analysis

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Pharmaceutical Chemistry Journal Aims and scope

In an attempt to design and synthesize a potent class of antimicrobials, 1,2-phenylenediamine derivatives were reacted with various aliphatic and heteroaliphatic dicarboxylic acids to generate a small library of 26 head-to-head bisbenzimidazole compounds (16 – 42) using the polyphosphoric acid method. These compounds were screened for their antibacterial activity and their antifungal activity. Compound 25 showed maximum potency against both Gram-positive and Gram-negative bacterial strains with minimum inhibitory concentration (MIC) values in the range of 7.81 – 31.25 μg/mL. In particular, it showed the maximum MIC values of 7.81 μg/mL against Gram-negative bacteria, which was four-fold more active than the standard drug ampicillin (MIC = 32.25 μg/mL). Compound 19 was found to be the most active against S. aureus with a MIC value of < 3.90 μg/mL, whereas the remaining compounds showed only low-to-moderate activity. Furthermore, all compounds exhibited low activity against all fungal strains in comparison to the standard drug fluconazole. I addition, pharmacophore hypotheses were generated to analyze structure–activity relationships between the molecular structures and antimicrobial activities on E. coli. This pharmacophore model can be useful in order to design new antimicrobial drugs. It can be suggested that the substitution of a phenyl ring at the 5/6 and 5′/6′ positions in symmetric bisbenzimidazole derivatives produces compounds with promising antimicrobial activity.

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References

  1. European Centre for Disease Prevention and Control. https: //www.ecdc.europa.eu/en/news-events/33000-people-die-every-year-due-infections-antibiotic-resistant-bacteria

  2. S. Kurakata, K. Fujiwara, and T. Fujita, 2000-JP4858 2001005402, 20000719 (2001).

  3. D. Carcanague, Y. K. Shue, M. A. Wuonola, et al., J. Med. Chem., 45(19), 4300 – 4309 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. O. Algul and N. Duran, Asian J. Chem., 19(4), 3145 – 3151 (2007).

    CAS  Google Scholar 

  5. N. M. Aghatabay, M. Somer, M. Senel, et al., Eur. J. Med. Chem., 42(8) 1069 – 1075 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. V. A. Mamedov, RSC Adv., 6(48) 42132–42172 (2016).

    Article  CAS  Google Scholar 

  7. A. K. Tewari and A. Mishra, Indian J. Chem., Sect. B: Org. Med. Chem., 45, 489 – 493 (2006).

    Google Scholar 

  8. S. Demirayak, A. C. Karaburun, I. Kayagil, et al., Phosphorous, Sulfur, Silicon Relat. Elem., 180(8), 1841 – 1848 (2005).

    Article  CAS  Google Scholar 

  9. J. M. Gardiner and C. R. Loyns, Tetrahedron, 51(42), 11515 – 11530 (1995).

    Article  CAS  Google Scholar 

  10. Y. Bansal, O. Silakari, Bioorg. Med. Chem., 20(21), 6208 – 6236 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. N. Ranjan, S. Story, G. Fulcrand, et al., J. Med. Chem., 60(12) 4904 – 4922 (2017).

    Article  CAS  PubMed  Google Scholar 

  12. R. Patil, A. Kulshrestha, A. Tikoo, et al., Molecules, 22(9), 1559 (2017).

    Article  PubMed Central  Google Scholar 

  13. V. S. Koval, A. F. Arutyunyan, V. L. Salyanov, et al., Bioorg. Med. Chem., 26(9), 2302 – 2309 (2018).

    Article  CAS  PubMed  Google Scholar 

  14. A. Mayence, A. Pietka, M. S. Collins, et al., Bioorg. Med. Chem. Lett., 18(8), 2658 – 2661(2008).

    Article  CAS  PubMed  Google Scholar 

  15. M. P. Barrett, C. G. Gemmell, and C. J. Suckling, Pharmacol. Ther., 139(1), 12 – 23 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. L. Hu, M. L. Kully, D. W. Boykin, and N. Abood, Bioorg. Med. Chem. Lett., 19(13), 3374 – 3377 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. L. Hu, M. L. Kully, D. W. Boykin, and N. Abood, Bioorg. Med. Chem. Lett., 19(5), 1292 – 1295 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. L. Hu, M. L. Kully, D. W. Boykin, and N. Abood, Bioorg. Med. Chem. Lett., 19(16), 4626 – 4629 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. J. Mann, P.W. Taylor, C. R. Dorgan, et al., Med. Chem. Comm., 6(8), 1420 – 1426 (2015).

    Article  CAS  Google Scholar 

  20. Y. He, J. Yang, B. Wu, et al., Bioorg. Med. Chem. Lett., 14(5), 1217 – 1220 (2008).

    Article  Google Scholar 

  21. J. B. Moreira, J. Mann, S. Neidle, et al., Int. J. Antimicrob. Agents, 42(4), 361 – 366 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. G. Bashiardes, Benzothiazole-2-thiol, in: e-EROS Encyclopedia of Reagents for Organic Synthesis, 1 – 7 (2005).

  23. O. Algul, A. Kaessler, Y. Apcin, et al., Molecules, 13(13), 736 – 748 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. H. A. Elagab and H. G. Alt, Inorg. Chim. Acta, 437, 26 – 35 (2015).

    Article  CAS  Google Scholar 

  25. U. Yilmaz and H. Kucukbay, Phosphorus, Sulfur, Silicon Relat. Elem., 191(1), 140 – 143 (2016).

    Article  CAS  Google Scholar 

  26. M. R. Grimmett, Sci. Synth., 12, 529 – 612 (2002).

    CAS  Google Scholar 

  27. S. Mao, K. Shen, X. Shi, et al., Inorg. Chim. Acta, 471, 82 – 90 (2018).

    Article  CAS  Google Scholar 

  28. H. Wu, F. Wang, F. Shi, et al., Transit. Met. Chem., 40(5), 555 – 564 (2015).

    Article  CAS  Google Scholar 

  29. P. Kopel, D. Wawrzak, V. Langer, et al., Molecules, 20(6), 10360 – 10376 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. K. Dimroth, N. Greif, and A. Klapproth, Justus Liebigs Annalen der Chemie, 2, 373 – 86 (1975).

    Article  Google Scholar 

  31. P. A. Levin, Zh. Obshch. Khim., 26, 2543 – 4 (1956).

    CAS  Google Scholar 

  32. G. Cakir, U. Ucucu, and U. Abbasoglu, Gazi Universitesi Eczacilik Fakultesi Dergisi, 5(1), 105 – 10 (1988).

    CAS  Google Scholar 

  33. R. T. Stibrany, ACS Symposium Series, 857, 210 – 221 (2003).

    Article  CAS  Google Scholar 

  34. Y. Sun, G. Duan, J. Liu, and J. Wang, Youji Huaxue, 26(7), 942 – 945 (2006).

    CAS  Google Scholar 

  35. S. Akihama and K. Takahashi, Yakugaku Zasshi, 90(10), 1305 – 9 (1970).

    Article  CAS  PubMed  Google Scholar 

  36. C. Mukhopadhyay, S. Ghosh, and R. J. Butcher, ARKIVOC, 9, 75 – 96 (2010).

    Article  Google Scholar 

  37. M. Berrada, Z. Anbaoui, N. Lajrhed, et al., Chem. Mater., 9(9), 1989 – 1993 (1997).

    Article  CAS  Google Scholar 

  38. D. Castillo, R. Cervantes, C. Frontana, et al., J. Phys. Org., 27(8), 701 – 706 (2014).

    Article  CAS  Google Scholar 

  39. G. Bhave, B. A. Chauder,W. Liu, et al., Mol. Pharmacol., 79(1), 42 – 50 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. N. S. El-Gohary and M. I. Shaaban, Eur. J. Med. Chem., 137, 439 – 449 (2017).

    Article  CAS  PubMed  Google Scholar 

  41. D. Gilbert, European Patent Application, EP 121326 (1984).

  42. G. L.Woods and J. A.Washington, Manual of Clinical Microbiology, 6th ed., American Society for Microbiology, Washington, DC (1995), pp. 1327–1341.

  43. J. H. Jorgensen and M. J. Ferraro, Clin. Infect. Dis., 26(4) 973–80 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Schrödinger Release 2018 – 2: LigPrep, Schrödinger LLC, New York (2019).

  45. S. L. Dixon, A. M. Smondyrev, and S. N. Rao, Chem. Biol. Drug Des., 67(5), 370 – 372 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. D. Song and S. Ma, ChemMedChem, 11(7), 646 – 659 (2016).

    Article  CAS  PubMed  Google Scholar 

  47. H. Nimesh, S. Sur, D. Sinha, et al., J. Med. Chem., 57(12), 5238 – 5257 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. N. Mani, C. H. Gross, J. D. Parsons, et al., Antimicrob. Agents Chemother., 50(4), 1228 – 1237 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. A. G. Dale, J. Hinds, J. Mann, et al., Biochemistry, 51(29), 5860 – 5871 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. N. T. Chandrika, S. K. Shrestha, H. X. Ngo, and S. Garneau-Tsodikova, Bioorg. Med. Chem., 24(16), 3680 – 3686 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by 2015-AP3-1228 BAP Projects of Mersin University.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mersin University, Mersin, Turkey

    Ronak Haj Ersan & Oztekin Algul

  2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey

    Kayhan Bolelli

  3. Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Mersin University, Mersin, Turkey

    Serpil Gonca & Aylin Dogen

  4. Department of Chemistry, Faculty of Science, Ataturk University, Erzurum, Turkey

    Serdar Burmaoglu

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  1. Ronak Haj Ersan
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  2. Kayhan Bolelli
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  6. Oztekin Algul
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Correspondence to Oztekin Algul.

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Ersan, R.H., Bolelli, K., Gonca, S. et al. Bisbenzimidazole Derivatives as Potential Antimicrobial Agents: Design, Synthesis, Biological Evaluation and Pharmacophore Analysis. Pharm Chem J 55, 149–158 (2021). https://doi.org/10.1007/s11094-021-02389-x

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  • DOI: https://doi.org/10.1007/s11094-021-02389-x

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