Synthesis of Some New Benzimidazole Derivatives Containing Chlorine and Investigation of Their Antioxidant and Anti-urease Activities

Abstract

In this work, the synthesis of 2-substituted benzimidazole compound containing chlorine (1) was carried out and then converted to the ester (2) and hydrazide (3) derivatives respectively. In the next steps, the hydrazide compound (3) was reacted with the appropriate reagents to give the thiadiazole (8-10) and triazole (11-13) derivatives. Synthesis of the compound 4 was carried out as a result of the interaction of the ester derivative compound (2) with morpholine. The structures of all synthesized compounds were elucidated by FT-IR, ¹H NMR, ¹³C NMR and elemental analysis spectroscopic methods. Also, the antioxidant and urease enzyme inhibition properties of these compounds were also investigated.

Keywords

• Benzimidazole,triazole,thiadiazole

References

1. Neelima S, Naim MJ, Alam J, Nawaz F, Shujauddin A, Alam O. Benzimidazole Scaffold as Anticancer Agent: Synthetic Approachesand Structure–Activity Relationship. Arch Pharm Chem Life Sci. 2017;350:1-80.
2. Ozkay Y, Tunai Y, Karaca H, Isikdag I. Antimicrobial activity and a SAR study of some novel benzimidazole derivatives bearing hydrazone moiety. Eur J Med Chem. 2010;45: 3293–98.
3. Achar KC, Hosamani KM, Seetharamareddy HR. In-vivo analgesic and anti-inflammatory activities of newly synthesized benzimidazole derivatives. Eur J Med Chem. 2010;45:2048-54.
4. Ramya VS, Kallappa MH, Rangappa SK, Mallinath HH. Derivatives of benzimidazole pharmacophore: Synthesis, anticonvulsant, antidiabetic and DNA cleavage studies. European Journal of Medicinal Chemistry. 2010;45:1753–59.
5. Ajania O, Olayinka O, Tolu B, Shade JO, Yuxia Z, Damilola VA. Structure-based design of functionalized 2-substituted and 1,2-disubstituted benzimidazole derivatives and their in vitro antibacterialefficacy. Journal of Advanced Research. 2017;8(6):703-12.
6. Kumar JR, Jawaharand J, Pathak DP. Synthesis of Benzimidazole Derivatives: As Anti-hypertensive Agents. E-J Chem. 2006;3:278-85.
7. Yeong KY, Mohamed AA, Ang CW, Tan SC, Kooi YK, Vikneswaran M, Hasnah O, Vijay HM. Synthesis, characterization, and molecular docking analysis of novel benzimidazole derivatives as cholinesterase inhibitors. Bioorganic Chemistry. 2013;49:33–39.
8. Patricia T, Hugo AK, Bruno P, Fernando L, Aurélie P, Christophe B, Rodrigo A. Organometallic benzimidazoles: Synthesis, characterization and antimalarial activity. Inorganic Chemistry Communications. 2013;35:126–29.

9. Kahveci B, Yilmaz F, Mentese E, et al. Design, Synthesis, and Biological Evaluation of Coumarin-Triazole Hybrid Molecules as Potential Antitumor and Pancreatic Lipase Agents. Archiv Der Pharmazie. 2017;350(8):1-9.
10. Mentese E, Bektas H, Sokmen BB, Emirik M, Cakir D, Kahveci B. Synthesis and molecular docking study of some 5,6-dichloro-2cyclopropyl-1H-benzimidazole derivatives bearing triazole, oxadiazole, and imine functionalities as potent inhibitors of urease. Biorganic & Med Chem Lett. 2017;27(13):3014-18.
11. Yogita B, Om S. The therapeutic journey of benzimidazoles: A review. Bioorg & Med Chem. 2012;20:6208-36.
12. Erb KL, Ravula SB, Yu J, Kord SZ, Moree WJ, Petroski RE, Wen J, Malany S, Hoare S RJ, Madan A, Crowe PD, Beaton G. The discovery and structure–activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles as selective, CNS penetrating H1-antihistamines for insomnia. Bioorg Med Chem Lett. 2010;20:2916- 19.
13. Kus C, Kılcıgil GA, Ozbey S, Betu F, Kaynak I, Kaya M, Coban T, Eke BC. Synthesis and antioxidant properties of novel N-methyl-1,3,4-thiadiazol-2-amine and 4-methyl-2H-1,2,4-triazole-3(4H)-thione derivatives of benzimidazole class. Bioorg Med Chem. 2008;16, 4294-303.
14. Desai KG, Desai KR. Green route for the heterocyclization of 2-mercaptobenzimidazole into β-lactum segment derivatives containing –CONH– bridge with benzimidazole: Screening in vitro antimicrobial activity with various microorganisms. Bioorg Med Chem. 2006;14:8271-79.
15. Menteşe E, Karaali N, Yilmaz F, Ulker S, Kahveci K. Microwave‐Assisted Synthesis and Biological Evaluation of Some Benzimidazole Derivatives Containing a 1,2,4‐Triazol Ring. Archiv der Pharmazie. 2013;346:556-61.
16. Menteşe E, Yilmaz F, Baltaş N, Bekircan O, Kahveci B. Synthesis and antioxidant activities of some new triheterocyclic compounds containing benzimidazole, thiophene, and 1,2,4-triazole rings. J Enzy Inh and Med Chem. 2015;30:435-441.
17. Schulz WG, Islam I, Skibo EB. Pyrrolo[1,2-a]benzimidazole-Based Quinones and Iminoquinones. The Role of the 3-Substituent on Cytotoxicity. Jour Med Chem. 1995; 38:109-18.
18. Pinner A. Die Imidoäther und ihre Derivate, 1. Auflage, R. Oppenheim, Berlin (1892), S. 2.
19. Apak R, Guclu K, Ozyurek M, Karademir SE. Novel total antioxidant capacity index for dietary polyphenols and vitamins C and E, using their cupric ion reducing capability in the presence of neocuproine: CUPRAC method. J Agr Food Chem. 2004;52(26):7970-7981.
20. Mentese E, Yilmaz F, Emirik M, Ulker S, Kahveci B. Synthesis, molecular docking and biological evaluation of some benzimidazole derivatives as potent pancreatic lipase inhibitors. Bioorg Chem. 2018;76:478-486.
21. Yilmaz F, Menteşe E, Baltaş N. Synthesis and Antioxidant Evaluation of Some Novel Benzimidazole Derivatives Containing a Triazole Nucleus. Letters in Drug Design & Discovery. 2017;14:201-208.
22. Brandwilliams W, Cuvelier ME, Berset C. Use of a Free-Radical Method to Evaluate Antioxidant Activity. Food Sci Technol-Leb. 1995;28(1):25-30.
23. Usta A, Yılmaz F, Kapucu G, Baltaş N, Menteşe E. Synthesis of Some New Benzimidazole Derivatives with their Antioxidant Activities. Lett Org Chem. 2015; 12: 227-32.
24. Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice-Evans C. Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radical Bio Med. 1999;26(9-10):1231-37.
25. Weatherburn MW (1967) Phenol-hypochlorite reaction for determination of ammonia. Anal Chem 1967, 39(8):971-974.
26. Baltaş N, Yılmaz F, Menteşe E. Synthesis, Antioxidant, Xanthine Oxidase and Urease Inhibitory Activities of Some Chlorine Containing Benzimidazoles. Hacettepe J Biol & Chem. 2016;44(3):293–305.
27. Bekircan O, Baltaş N, Menteşe E, Gültekin E. Synthesis of new fluorine-containing 1,2,4-triazole-5-on derivatıves with their anti-urease, anti-xanthine oxidase and antioxidant activities. Revue Roumaine de Chimie. 2016;61(10):733-746.
28. Mentese E, Karaali N, Yilmaz F, Ulker S, Kahveci B. Microwave- Assisted Synthesis and Biological Evaluation of Some Benzimidazole Derivatives Containing a 1,2,4-Triazol Ring. Arch Pharm. 2013;346:556-61.