Advertisement

Medicinal Chemistry Research

, Volume 26, Issue 11, pp 3026–3037 | Cite as

Analgesic, anti-inflammatory, and antimicrobial activities of novel isoxazole/pyrimidine/pyrazole substituted benzimidazole analogs

  • Krishna Veni Chikkula
  • Raja Sundararajan
Original Research

Abstract

From o-phenylenediamine and p-amino benzoic acid, several new 3-methylisoxazol-5(4H)-one/2-hydroxy/mercapto-6-methylpyrimidin-4(5H)-one/3-methyl-1-substituted-1H-pyrazol-5(4H)-one substituted benzimidazole derivatives 516 were synthesized through multi step synthesis based on hybrid approach. All test compounds were screened for its analgesic, anti-inflammatory, and in vitro antimicrobial activity by tail flick method, carrageenan induced foot paw edema method and agar streak dilution method, respectively. Most active compounds were examined for its ulcerogenicity by pylorus ligation method. The relationship between chemical structure and biological activities of the test compounds were discussed. Among various tested compounds, 4-(2-(4-(1H-benzimidazol-2-yl)phenyl)hydrazono)-1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5(4H)-one 10 was found to be most potent compound. This compound showed 72% analgesic activity (20 mg/kg; second hour) and 67% protection in paw edema test (20 mg/kg; second hour) which are comparable with that of standard Diclofenac [69% analgesic activity (20 mg/kg; second hour) and 65% protection in paw edema test (20 mg/kg; second hour)]. In addition, compound 10 exhibited least ulcer index which is about 1/3 of the ulcer index of reference standard and showed good antibacterial and moderate antifungal activity.

Keywords

Benzimidazole Isoxazole Pyrimidine Analgesic Anti-inflammatory Antimicrobial 

Notes

Acknowledgements

The authors gratefully acknowledge the management of Sarojini Naidu Vanita Pharmacy Maha Vidyalaya, Secunderabad, for providing infrastructure facilities to carry out this research work.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_2000_MOESM1_ESM.pdf (2.7 mb)
Supplementary Figures

References

  1. Abdel Tawab M, Zettl H, Schubert Zsilavecz M (2009) Non steroidal anti-inflammatory drugs: a critical review on current concepts applied to reduce gastrointestinal toxicity. Curr Med Chem 16:2042–2063CrossRefPubMedGoogle Scholar
  2. Anderson K, Carlsson E (2005) Potassium competitive acid blockade: a new therapeutic strategy in acid related diseases. Pharmacol Ther 108(3):294–307CrossRefGoogle Scholar
  3. Avinash P, Swastika G, Sanjay S (2008) A systematic review of benzimidazole derivatives as an antiulcer agent. Rasayan J Chem 1:447–460Google Scholar
  4. Bergh MS, Budsberg SC (2005) The coxib NSAIDs: Potential clinical and pharmacologic importance in veterinary medicine. J Vet Intern Med 19:633–643CrossRefPubMedGoogle Scholar
  5. Bhimanna K, Hesham F (2016) Thiazolo[4,5-d]pyrimidines as a privileged scaffold in drug discovery. Eur J Med Chem 113:198–213CrossRefGoogle Scholar
  6. Chelucci RC, Dutra LA, Lopes Pires ME, de Melo TR, Bosquesi PL, Chung MC, Dos Santos JL (2014) Antiplatelet and antithrombotic activities of non-steroidal anti-inflammatory drugs containing an N-acyl hydrazone subunit. Molecules 19:2089–2099CrossRefPubMedGoogle Scholar
  7. D’Amour FE, Smith DL (1941) A method for determining loss of pain sensation. J Pharmacol Exp Ther 72:74–79Google Scholar
  8. Dannhardt G, Kiefer W (2001) Cyclooxygenase inhibitors—current status and future prospects. Eur J Med Chem 36:109–126CrossRefPubMedGoogle Scholar
  9. Dhikav V, Singh S, Pande S, Chawla A, Anand KS (2003) Non steroidal drug induced gastrointestinal toxicity: Mechanisms and management. J Indian Acad Clin Med 4:315–322Google Scholar
  10. Feldman B, Zinkl J, Jain N (2000) Veterinary hematology. Lippincott Williams and Wilkins, Philadelphia, p 213Google Scholar
  11. Ganguly AK, Bhatnagar OP (1973) Effect of bilateral adrenalectomy on production of restraint ulcers in the stomach of albino rats. Can J Physiol Pharmacol 51:748–750CrossRefPubMedPubMedCentralGoogle Scholar
  12. Govindaraj S, Veerachamy A, Pandurangan D (2013) Synthesis, analgesic, anti-inflammatory and in vitro antimicrobial activities of some novel isoxazole coupled quinazolin-4(3H)- one derivatives. Arch Pharm Res doi: 10.1007/s12272-013-0262-8
  13. Goyal RK, Chakrabarti A, Sanyal AK (1985) The effect of biological variables on the anti ulcerogenic effect of vegetable plantain banana. Planta Med 29:85–88CrossRefGoogle Scholar
  14. Hawkey PM, Lewis DA (1994) Medical bacteriology—a practical approach. Oxford University Press, Oxford, p 181–194Google Scholar
  15. Immadisetty SK, Govindaraj S, Janga V, Pamidipamula S, Jarugula UB, Mittineni VSK (2014) Synthesis, characterization and antimicrobial activity of some novel benzimidazole derivatives. J Adv Pharm Technol Res 5:21–27CrossRefGoogle Scholar
  16. Javed NM, Ozair A, Farah N, Jahangir AM, Perwaiz A (2016) Current status of pyrazole and its biological activities. J Pharm Bioallied Sci 8:2–17CrossRefGoogle Scholar
  17. Kulkarni SK (1980) Heat and other physiological stress-induced analgesia: catecholamine mediated and naloxone reversible response. Life Sci 27:185–188CrossRefPubMedGoogle Scholar
  18. Mona MH (2012) New pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines: synthesis, 2D-QSAR, anti-inflammatory, analgesic and ulcerogenicity studies. Eur J Med Chem 55:12–22CrossRefGoogle Scholar
  19. Monika G, Punam G, Deepika U, Neelima D, Malkeet SB, Om S, Chander M (2015) Benzimidazole derivatives: Search for GI friendly anti-inflammatory analgesic agents. Acta Pharm Sin B 5:337–342CrossRefGoogle Scholar
  20. Monika G, Sarbjot S, Chander M (2014) Benzimidazole: An emerging scaffold for analgesic and anti-inflammatory agents. Eur J Med Chem 76:494–505CrossRefGoogle Scholar
  21. Olfert ED, Cross BM, McWilliam AA (1993) Guide to the care and use of experimental animals, vol 1, 2nd edn. Canadian council of animal care, Canada, p 1–201Google Scholar
  22. Panneer Selvam T, Saravanan G, Prakash CR, Dinesh Kumar P (2011) Microwave assisted synthesis, characterization and biological activity of novel pyrazole derivatives. Asian J Pharm Res 1:126–129Google Scholar
  23. Penning TD, Talley JJ, Bertenshaw SR, Carter JS, Collins PW, Docter S, Graneto MJ, Lee LF, Malecha JW, Miyashiro JM, Rogers RS, Rogier DJ, Yu SS, Anderson GD, Burton EG, Cogburn JN, Gregory SA, Koboldt CM, Perkins WE, Seibert K, Veenhuizen AW, Zhang YY, Isakson PC (1997) Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methyl phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, celecoxib). J Med Chem 40:1347–1365CrossRefPubMedPubMedCentralGoogle Scholar
  24. Shay M, Komarov SA, Fels D, Meranze D, Grunstein H, Siplet H (1945) A simple method for the uniform production of gastric ulceration in the rats. Gastroenterology 5:43–61Google Scholar
  25. Surendra KR, Ibrahim AA, Anish A, Akbar I (2016) Anti-inflammatory and antimicrobial activities of novel pyrazole analogs. Saudi J Bio Sci 23:614–620CrossRefGoogle Scholar
  26. Thais RFM, Rafael CC, Maria ELP, Luiz AD, Karina PB, Priscila LB, Gustavo HGT, Man CC, Jean LS (2014) Pharmacological evaluation and preparation of nonsteroidal anti-inflammatory drugs containing an N-acyl hydrazone subunit. Int J Mol Sci 15:5821–5837CrossRefGoogle Scholar
  27. Theivendren PS, Palanirajan VK, Govindaraj S, Chinnasamy RP (2014) Microwave assisted synthesis, characterization and biological activity of novel pyrazole derivatives. J Saudi Chem Soc 18:1015–1021CrossRefGoogle Scholar
  28. Trepanier LA (2002) Mechanisms of drug associated hepatotoxicity in the dog and cat. In: Proceedings on 20th Annual Forum of the ACVIM. Dallas 669–671Google Scholar
  29. Winter CA, Risley EA, Nuss GW (1962) Carrageenin induced edema in hind paw of the rat as an assay for anti-inflammatory drugs. Exp Biol Med 111:544–547CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Sarojini Naidu Vanita Pharmacy Maha VidyalayaSecunderabadIndia
  2. 2.Department of Pharmaceutical ChemistryGITAM Institute of Pharmacy, GITAM UniversityVisakhapatnamIndia

Personalised recommendations