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2-(2′-Pyridyl) benzimidazole derivatives and their urease inhibitory activity

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Abstract

Pyridyl-benzimidazole analogues 1–11 with variable substituent on phenyl ring of phenacyl moiety were synthesized and evaluated for their urease inhibitory activity. The compounds exhibited urease inhibition with IC50 between 19.22 and 77.31 µM. Compounds 4 (IC50 = 19.22 ± 0.49 µM) showed a urease inhibition comparable to thiourea (IC50 = 21.00 ± 0.01 µM) and twofold more active than acetohydroxamic acid (IC50 = 42.00 ± 1.26 µM) (standards), respectively. Moreover, compounds 5 (IC50 = 21.55 ± 0.36 µM), 1 (IC50 = 24.37 ± 0.41 µM), 7 (IC50 = 25.44 ± 0.19 µM), 6 (IC50 = 27.62 ± 0.25 µM), 3 (IC50 = 31.32 ± 0.75 µM), 8 (40.88 ± 0.36 µM) and 9 (41.22 ± 0.42 µM) also exhibited excellent activities when compared to the standards. Compounds 2 (IC50 = 65.46 ± 0.75 µM), 10 (68.99 ± 0.33 µM) and 11 (77.31 ± 0.51 µM) showed a moderate activity. The size of the substituents and their electron donating or withdrawing affects as well as their position on phenyl apparently modulates the enzyme inhibitory activity.

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References

  • Achar KCS, Hosamani KM, Seetharamareddy HR (2010) In-vivo analgesic and anti-inflammatory activities of newly synthesized benzimidazole derivatives. Eur J Med Chem 45:2048–2054

    Article  CAS  PubMed  Google Scholar 

  • Akhtar T, Khan MA, Iqbal J, Jones PG, Hameed S (2014) A facile one pot synthesis of 2-arylamino-5-aryloxylalkyl-1,3,4-oxadiazoles and their urease inhibition studies. Chem Biol Drug Des. doi:10.1111/cbdd.12297

  • Arfan M, Ali M, Ahmad H, Anis I, Khan A, Choudhary MI, Shah MR (2010) Urease inhibitors from Hypericum oblongifolium WALL. J Enzyme Inhib Med Chem 25:296–299

    Article  CAS  PubMed  Google Scholar 

  • Arjmand F, Mohani B, Ahmad S (2005) Synthesis, antibacterial, antifungal activity and interaction of CT-DNA with a new benzimidazole derived Cu(II) complex. Eur J Med Chem 40:1103–1110

    Article  CAS  PubMed  Google Scholar 

  • Barker HA, Smyth RD, Weissbach H, Toohey JI, Ladd JN, Volcani BE (1960) Isolation and properties of crystalline cobamide coenzymes containing benzimidazole or 5,6-dimethylbenzimidazole. J Biol Chem 235:480–488

    CAS  PubMed  Google Scholar 

  • Biron KK, Harvey RJ, Chamberlain SJ, Godd SS, Smith AA III, Davis MG, Talarico CL, Miller WH, Ferris R, Dornsife RE, Stanat SC, Drach JC, Townsend LB, Koszalka GW (2002) Potent and selective inhibition of human cytomegalovirus replication by 1263W94, a benzimidazole l-Riboside with a unique mode of action. Antimicrob Agent Chemother 46:2365–2372

    Article  CAS  Google Scholar 

  • Boiani M, González M (2005) Imidazole and benzimidazole derivatives as chemotherapeutic agents. Mini Rev Med Chem 5:409–424

    Article  CAS  PubMed  Google Scholar 

  • Budow S, Kozlowska M, Gorska A, Kazimierczuk Z, Eickmeier H, Colla PL, Gosselin G, Seela F (2009) Substituted benzimidazoles: antiviral activity and synthesis of nucleosides. Arkivoc 3:225–250

    Google Scholar 

  • Cheng, X-S, Zhang J-C, You Z-L, Wang X, Li, H-H (2014) Synthesis, structures, and Helicobacter Pylori urease inhibition of hydroxamate-coordinated oxovanadium complexes with benzohydrazone ligands. Trans metal Chem. doi:10.1007/s11243-014-9802-4

  • Czerwonka G, Arabski M, Wasik S, Jablonska-Wawrzycka A, Rogala P, Kaca W (2014) Morphological changes in Proteus mirabilis O18 biofilm under the influence of a urease inhibitor and a homoserine lactone derivative. Arch Micro 196:169–177

    Article  CAS  Google Scholar 

  • Devesa SS, Blot WJ, Fraumeni JF (1998) Changing patterns in the incidence of esophageal and gastriccarcinoma in the United States. J Cancer 83:2049–2053

    Article  CAS  Google Scholar 

  • Elnima EI, Zubair MU, Al-Badr AA (1981) Antibacterial and antifungal activities of benzimidazole and benzoxazole. Antimicrob Agents Chemothe 19:29–32

    Article  CAS  Google Scholar 

  • Garuti L, Roberti M, Gentilomi G (2001) Synthesis and antiviral assays of some benzimidazole nucleosides and acyclonucleosides. II Farmaco 56:815–819

    Article  CAS  Google Scholar 

  • Göker H, Tunçbilek M, Ayhan G, Altanlar N (1998) Synthesis of some new benzimidazolecarboxamides and evaluation of their antimicrobial activity. II Farmaco 53:415–420

    Article  Google Scholar 

  • Göker H, Ozden S, Yıldız S, Boykin DW (2005) Synthesis and potent antibacterial activity against MRSA of some novel 1,2-disubstituted-1H-benzimidazole-N-alkylated-5-carboxamidines. Eur J Med Chem 40:1062–1069

    Article  PubMed  Google Scholar 

  • Grimmett M (1996) Comprehensive heterocyclic chemistry: the structure, reactions, synthesis and uses of heterocyclic compounds, vol 3. Pergamon, Oxford, p 77

    Google Scholar 

  • Horn J (2000) The proton-pump inhibitors: similarities and differences. Clin Ther 22:266–280

    Article  CAS  PubMed  Google Scholar 

  • Howson CP, Hiyama T, Wynder EL (1986) The decline of gastric cancer: epidemiology of an unplanned triumph. J Epidemiol Rev 8:1–27

    CAS  Google Scholar 

  • Iemura R, Kawashima T, Fukuda T, Ito K, Tsukamoto G (1986) Synthesis of 2-(4-substituted-1-piperazinyl)benzimidazoles as H1-antihistaminic agents. J Med Chem 29:1178–1183

    Article  CAS  PubMed  Google Scholar 

  • Ishida T, Suzuki T, Hirashima S, Mizutani K, Yoshida A, Ando I, Ikeda S, Adachi T, Hashimoto H (2006) Benzimidazole inhibitors of hepatitis C virus NS5B polymerase: identification of 2-[(4-diarylmethoxy)phenyl]-benzimidazole. Bioorg Med Chem Lett 16:1859–1863

    Article  CAS  PubMed  Google Scholar 

  • Kamal A, Kumar PP, Sreekanth K, Seshadri BN, Ramulu P (2008) Synthesis of new benzimidazole linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates with efficient DNA-binding affinity and potent cytotoxicity. Bioorg Med Chem Lett 18:2594–2598

    Article  CAS  PubMed  Google Scholar 

  • Kazimierczuk Z, Upcroft JA, Upcroft P, Górska A, Starooeciak B, Laudy A (2002) Synthesis, antiprotozoal and antibacterial activity of nitro- and halogeno-substituted benzimidazole derivatives. Acta Biochem Polon 49:185–195

    CAS  Google Scholar 

  • Khan KM, Rahim F, Halim SA, Taha M, Khan M, Perveen S, Zaheer-Ul-Haq, Mesaik MA, Choudhary MI (2011a) Synthesis of novel inhibitors of β-glucuronidase based on benzothiazole skeleton and study of their binding affinity by molecular docking. Bioorg Med Chem 9:4286–4294

    Article  Google Scholar 

  • Khan KM, Taha M, Naz F, Khan M, Rahim F, Samreen, Perveen S, Choudhary MI (2011b) Synthesis and in vitro leishmanicidal activity of disulfide derivatives. Med Chem 7:704–710

    Article  CAS  PubMed  Google Scholar 

  • Khan KM, Shah Z, Ahmad VU, Ambreen N, Khan M, Taha M, Rahim F, Noreen S, Perveen S, Choudhary MI, Voelter W (2012a) 6-Nitroben-zimidazole derivatives: potential phosphodiesterase inhibitors: synthesis and structure-activity relationship. Bioorg Med Chem 20:1521–1526

    Article  CAS  PubMed  Google Scholar 

  • Khan KM, Shah Z, Ahmad VU, Khan M, Taha M, Ali S, Perveen S, Choudhary MI, Voelter W (2012b) 2,4,6-Trichlorophenylhydrazine schiff bases as DPPH radical and super oxide anion scavengers. Med Chem 8:452–461

    Article  CAS  PubMed  Google Scholar 

  • Khan KM, Khan M, Karin A, Taha M, Ambreen N, Gojayev A, Perveen S, Choudhary MI (2013a) Xanthine oxidase inhibition by 5-aryledene N,N′-dimethylbarbituric acid derivatives. J Pak Chem Soc 35:495–498

    Google Scholar 

  • Khan KM, Khan M, Saleem M, Taha M, Perveen S, Choudhary MI (2013b) Benzimidazoles: a new class of carbonic anhydrase inhibitors. J Pak Chem Soc 35:901–904

    Google Scholar 

  • Khan KM, Taha M, Rahim F, Fakhri MI, Jamil W, Khan M, Rasheed S, Karim A, Perveen S, Choudhary MI (2013c) Acylhydrazide schiff bases: synthesis and antiglycation activity. J Pak Chem Soc 35:929–937

    Google Scholar 

  • Khan KM, Naz F, Taha M, Khan A, Perveen S, Choudhary MI, Voelter W (2014a) Synthesis and in vitro urease inhibitory activity of N,N′-disubsituted thioureas. Eur J Med Chem 74:314–323

    Article  CAS  PubMed  Google Scholar 

  • Khan KM, Jamil W, Ambreen N, Taha M, Perveen S, Morales GA (2014b) An expeditious synthetic approach towards the synthesis of bis-schiff bases (Aldazines) using ultrasound. Ultrason Sonochem 21:1200–1205

    Article  CAS  PubMed  Google Scholar 

  • Kühler TC, Swanson M, Shcherbuchin V, Larsson H, Mellgard B, Sjöström JE (1998) Structure-activity relationship of 2-[[(2-pyridyl)methyl]thio]-1H- benzimidazoles as anti Helicobacter pylori agents in vitro and evaluation of their in vivo efficacy. J Med Chem 41:1777–1788

    Article  PubMed  Google Scholar 

  • Kumara D, Jacobb MR, Reynoldsa MB, Sean M, Kerwin SM (2002) Synthesis and evaluation of anticancer benzoxazoles and benzimidazoles related to UK-1. Bioorg Med Chem 10:3997–4004

    Article  Google Scholar 

  • Mansoor F, Anis I, Khan A, Marasini BP, Choudhary MI, Shah MR (2014) Urease inhibitory constituents from Daphne retusa. J Asian Nat Prod Res 16:210–215

    Article  CAS  PubMed  Google Scholar 

  • Martelli A, Buli P, Cortecchia V (1981) Urease inhibitor therapy in infected renal stones. Eur Urol 7:291–293

    CAS  PubMed  Google Scholar 

  • Merino G, Jonker JW, Wagenaar E, Pulido MM, Molina AJ, Alvarez AI, Schinkel AH (2005) Transport of anthelmintic benzimidazole drugs by breast cancer resistance protein (BCRP/ABCG2). Drug Metab Dis 33:614–618

    Article  CAS  Google Scholar 

  • Mobley HLT, Hausinger RP (1989) Microbial ureases: significance, regulation, and molecular characterization. J Microbial Rev 53:85–108

    CAS  Google Scholar 

  • Nguyen PT, Baldeck JD, Olsson J, Marquis RE (2005) Antimicrobial actions of benzimidazoles against oral streptococci. Oral Microbiol Immunol 20:93–100

    Article  CAS  PubMed  Google Scholar 

  • Orjales A, Mosquera R, Labeaga L, Rodes R (1997) New 2-piperazinylbenzimidazole derivatives as 5-HT3 antagonists. Synthesis and pharmacological evaluation. J Med Chem 40:586–593

    Article  CAS  PubMed  Google Scholar 

  • Ozden S, Atabey D, Yildiz S, Göker H (2005) Synthesis and potent antimicrobial activity of some novel methyl or ethyl 1H-benzimidazole-5-carboxylates derivatives carrying amide or amidine groups. Bioorg Med Chem 13:1587–1597

    Article  PubMed  Google Scholar 

  • Serafin B, Borkowska G, Główczyk J, Kowalska I, Rump S (1989) Potential antihypertensive benzimidazole derivatives. Pol J Pharmacol Pharm 41:89–96

    CAS  PubMed  Google Scholar 

  • Taha M, Baharudin MS, Ismail NH, Khan KM, Jaafar FM, Samreen, Siddiqui S, Choudhary MI (2013) Synthesis of 2-methoxybenzoylhydrazone and evaluation of their antileishmanial activity. Bioorg Med Chem Lett 23:3463–3466

    Article  CAS  PubMed  Google Scholar 

  • Taha M, Naz H, Rasheed S, Ismail NH, Rahman AA, Yousuf S, Choudhary MI (2014) Synthesis of 4-methoxybenzoylhydrazones and evaluation of their antiglycation activity. Molecules 19:1286–1301

    Article  PubMed  Google Scholar 

  • Tiwari AK, Mishrab AK, Bajpai A, Mishra P, Singh S, Sinha D, Singh VK (2007) Synthesis and evaluation of novel benzimidazole derivative [Bz-Im] and its radio/biological studies. Bioorg Med Chem Lett 17:2749–2755

    Article  CAS  PubMed  Google Scholar 

  • Veerakumari L, Munuswamy N (2000) In vitro effect of some antihelminthics on lactate dehydrogenase activity of Cotylophoron cotylophorum (Digenea: Paramphistomidae. Vet Parasitol 91:129–140

    Article  CAS  PubMed  Google Scholar 

  • Wank SA (1998) G protein-coupled receptors in gastrointestinal physiology. I. CCK receptors: an exemplary family. Am J Physiol 274:G607–G613

    CAS  PubMed  Google Scholar 

  • Weatherburn MW (1967) Phenol–hypochlorite reaction for determination of ammonia. Anal Chem 39:971–974

    Article  CAS  Google Scholar 

  • Zhao Z, Arnaiz DO, Griedel B, Sakata S, Dallas JL, Whitlow M, Trinh L, Post J, Liang A, Morrissey MM, Shaw KJ (2000) Design, synthesis, and in vitro biological activity of benzimidazole based factor Xa inhibitors. Bioorg Med Chem Lett 10:963–966

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are thankful to the OPCW, The Netherlands, for their financial support for Project No. L/ICA/ICB/173681/12.

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Authors and Affiliations

  1. International Center for Chemical and Biological Sciences, H. E. J. Research Institute of Chemistry, University of Karachi, Karachi, 75270, Pakistan

    Zafar Saeed Saify, Ajmal Khan, Khalid Mohammed Khan & M. Iqbal Choudhary

  2. Department of Pharmaceutical Chemistry, Federal Urdu University of Arts, Science and Technology, Karachi, 75300, Pakistan

    Arfa Kamil & Sarwat Jahan

  3. Department of Pharmaceutical Chemistry, University of Karachi, Karachi, 75270, Pakistan

    Shamim Akhtar

  4. Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300, Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia

    Muhammad Taha

  5. Faculty of Applied Science, Universiti Teknologi MARA, 40450, Shah Alam, Malaysia

    Muhammad Taha

  6. Department of Chemistry, Hazara University, Mansehra, Pakistan

    Fazal Rahim

  7. PCSIR Laboratories Complex, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi, 75280, Pakistan

    Shahnaz Perveen

  8. Department of Biochemistry, Faculty of Science, King Abdul-Aziz University, Jeddah, 21412, Saudi Arabia

    M. Iqbal Choudhary

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  1. Zafar Saeed Saify
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  2. Arfa Kamil
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  3. Shamim Akhtar
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  4. Muhammad Taha
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  5. Ajmal Khan
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  6. Khalid Mohammed Khan
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  7. Sarwat Jahan
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  8. Fazal Rahim
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  9. Shahnaz Perveen
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  10. M. Iqbal Choudhary
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Correspondence to Khalid Mohammed Khan.

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Saify, Z.S., Kamil, A., Akhtar, S. et al. 2-(2′-Pyridyl) benzimidazole derivatives and their urease inhibitory activity. Med Chem Res 23, 4447–4454 (2014). https://doi.org/10.1007/s00044-014-1015-z

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  • DOI: https://doi.org/10.1007/s00044-014-1015-z

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