Abstract
Novel heterocyclic compounds containing benzimidazole derivatives were synthesized from 2-(1Hbenzimidazol-2-yl) acetonitrile (1) and arylhydrazononitrile derivative 2 was obtained via coupling of 1 with 4-methyl phenyldiazonium salt, which was then reacted with hydroxylamine hydrochloride to give amidooxime derivative 3. This product was cyclized into the corresponding oxadiazole derivative 4 upon reflux in acetic anhydride. Compound 4 was refluxed in DMF in the presence of triethylamine to give the corresponding 5-(1H-benzimidazol-2-yl)-2-p-tolyl-2H-1,2,3-triazol-4-amine 6. Treatment of compound 6 with ethyl chloroformate afforded 2,6-dihydro-2-(4-methylphenyl)-1,2,3-triazolo[4″,5″-4′,5′]pyrimido[1,6-a]benzimidazole-5(4H)-one (8). 1,2-bis(2-cyanomethyl-1H-benzimidazol-1-yl)ethane-1,2-dione (10) was synthesized via the condensation reaction of 2-(1H-benzimidazol-2-yl) acetonitrile (1) and diethyloxalate. The reactivity of compound 10 towards some diamine reagents was studied. The in vitro antimicrobial activity of the synthesized compounds was investigated against several pathogenic bacterial strains such as Escherichia coli O157, Salmonella typhimurium, E. coli O119, S. paratyphi, Pseudomonas aeruginosa, Staphylococcus aureus, Listeria monocytogenes and Bacillus cereus. The results of MIC revealed that compounds 12a–c showed the most effective antimicrobial activity against tested strains. On the other hand, compounds 12a, b exhibited high activity against rotavirus Wa strain while compounds 12b, c exhibited high activity against adenovirus type 7. In silico target prediction, docking and validation of the compounds 12a–c were performed. The dialkylglycine decarboxylase bacterial enzyme was predicted as a potential bacterial target receptor using pharmacophorebased correspondence with previous leads; giving the highest normalized scores and a high correlation docking score with mean inhibition concentrations. A novel binding mechanism was predicted after docking using the MOE software and its validation.
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Akbay, A., Oren, I., Temiz-Arpaci, O., Aki-Sener, E., and Yalcin, I., Synthesis and HIV-1 reverse transcriptase inhibitor activity of some 2,5,6-substituted benzoxazole, benzimidazole, benzothiazole and oxazolo(4,5-b)pyridine derivatives. Arzneimittelforschung, 53, 266–271 (2003).
Al-Saleh, B., El-Apasery, M. A., and Elnagdi, M. H., Studies with 3-substituted 2-arylhydrazono-3-oxoaldehydes: new routes for synthesis of 2-arylhydrazono-3-oxonitriles, 4-unsubstituted 3,5-diacylpyrazoles and 4-arylazophenols. J. Chem. Res., 8, 578–580 (2004).
Alzaydi, K. M., A simplified green chemistry approaches to synthesis of 2-substituted 1,2,3-triazoles and 4-amino-5-cyanopyrazole derivatives conventional heating versus microwave and ultrasound as ecofriendly energy sources. Ultrason. Sonochem., 16, 805–809 (2009).
Andrews, J. M., Determination of minimum inhibitory concentration. J. Antimicrob. Chemother., 48, 5–16 (2001).
Ayhan-Kilcigil, G. and Altanlar, N., Synthesis and antifungal properties of some benzimidazole derivatives. Turk. J. Chem., 30, 223–228 (2006).
Bertelli, L., Biagi, G., Giorgi, I., Manera, C., Livi, O., Scartoni, V., Betti, L., Giannaccini, G., Trincavelli, L., and Barili, P. L., 1,2,3-Triazolo[1,5-a]quinoxalines: synthesis and binding to benzodiazepine and adenosine receptors. Eur. J. Med. Chem., 33, 113 (1998).
Boiani, M. and Gonzalez, M., Imidazole and benzimidazole derivatives as chemotherapeutic agents. Mini Rev. Med. Chem., 5, 409–424 (2005).
Brik, A., Alexandratos, J., Lin, Y. C., Elder, J. H., Olson, A. J., Wlodawer, A., Goodsell, D. S., and Wong, C. H., 1,2,3-triazole as a peptide surrogate in the rapid synthesis of HIV-1 protease inhibitors. Chembiochem, 6, 1167–1169 (2005).
Buchi, J., Zwieky, H., and Aebi, A., Synthese einiger 1,2-benzimidazol-derivate. Arch. Pharm., 293, 758–766 (1960).
Carta, A., Sanna, P., Gherardini, U. D., and Zanetti, S., Novel functionalized pyrido[2,3-9]quinoxalinones as antibacterial, antifungal and anticancer agents. Il Farmaco, 56, 933–938 (2001).
Cook, G. C., Use of benzimidazole chemotherapy in human helminthiases: indication and efficacy. Parasitol. Today, 6, 133–136 (1990).
Eslam, R. S., Fatma, A. B., Sherifa, A. B., Hanaa, M. R., and Mohamed, M. A., Synthesis and biological activity of some new 1-benzyl and 1-benzoyl-3-heterocyclic indole derivatives. Acta Pharm., 60, 55–71 (2010).
Fan, W. Q. and Katritzky, A. R., Comprehensive Heterocyclic Chemistry II, Elsevier, New York, (1996).
Fatma, A. B., Sherifa, M., Abu-B., Abdel Salam, O. I., and Abdel Rehim, M., Synthesis and anticancer activity of some diazepine and diazocine derivatives. Egypt Pharm. J., 8, 107–120 (2009).
Garuti, L., Roberti, M., and Cermelli, C., Synthesis and antiviral activity of some N-benzene sulphonyl benzimidazoles. Bioorg. Med. Chem. Lett., 9, 2525–2530 (1999).
Ghozlan, S. A., Badahdah, K. O., and Abdelhamid, I. A., An easy synthesis of 5-functionally substituted ethyl 4-amino-1-aryl-pyrazolo-3-carboxylates: interesting precursors to sildenafil analogues. Belistien J. Org. Chem., 3, 15–16 (2007).
Goker, H., Alp, M., and Yildiz, S., Synthesis and potent antimicrobial activity of some novel N-(alkyl)-2-phenyl-1H-benzimidazole-5-carboxamidines. Molecules, 10, 1377–1386 (2000).
Hanaa, A. T., Fatma, A. B., Amira, M. G., Mona, A. A., and Wageeh, S. H., Tumor anti-initiating activity of some novel 3,4-dihydropyrimidinones. Pharmacol. Rep., 61, 1153–1161 (2009).
Hatem, A. A, Tamer, S. S, and Heba, S. A., Facile synthesis and in-vitro antitumor activity of some pyrazolo[3,4-b]pyridines and pyrazolo[1,5-a]pyrimidines linked to a thiazolo [3,2-a]benzimidazole moiety. Arch. Pharm. (Weinheim), 343, 24–30 (2010).
Haugwitz, R. D., Martinez, A. J., Venslavsky, J., Angel, R. G., Maurer, B. V., Jacobs, G. A., Narayanan, V. L., Cruthers, L. R, and Szanto, J., Antiparasitic agents. 6. Synthesis and anthelmintic activities of novel isothiocyanatophenyl-1,2,4-oxadiazoles. J. Med. Chem., 28, 1234–1241 (1985).
He, Y., Wu, B., Yang, J., Robinson, D., Risen L., Ranken, R., Blyh, L., Sheng, S., and Swayze, E. E., 2-piperidin-4-yl-benzimidazoles with broad spectrum antibacterial activities. Bioorg. Med. Chem. Lett., 13, 3253–3256 (2003).
Jaso, A., Zarranz, B., Aldana, I., and Monge, A., Synthesis of new 2-acetyl and 2-benzoylquinoxaline 1,4-di-N-oxide derivatives as antimycobacterium tuberculosis agents. Eur. J. Med. Chem. 38, 791–800 (2003).
Kazimierczuk, Z., Upcroft, J. A., Upcroft, P., Gorska, A., Starosciak, B., and Laudy A., Synthesis, antiprotazoal and antibacterial activity of nitro and halogeno-substituted benzimidazole derivatives. Acta Biochim. Polon., 49, 185–195 (2002).
Kerwin, S. M., ChemBioOffice Ultra suite 2010. J. Am. Chem. Soc., 132, 2466–2467 (2010).
Khalafi-Nezhad, A., Rad, M. N. S., Mohabatkar, H., Asrari, Z., and Hemmateenejad, B., Design, synthesis, antibacterial and QSAR studies of benzimidazole and imidazole chloroaryloxyalkyl derivatives. Bioorg. Med. Chem., 13, 1931–1938 (2005).
Liu, X., Ouyang, S., Yu, B., Liu, Y., Huang, K., Gong, J., Zheng, S., Li, Z., Li, H., and Jiang, H., PharmMapper server: a web server for potential drug target identification using pharmacophore mapping approach. Nucleic Acids Res., 38, 609–614 (2010).
Mosmann, T., Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 65, 55–63 (1983).
Nguyen, P. T. M., Baldeck, J. D., Olsson, J., and Marquis, R. E., Antimicrobial actions of benzimidazoles against oral streptococci. Oral Microbiol. Immunol., 20, 93–100 (2005).
Podunavac-Kuzmanović, S. O., Leovac, V. M., Perišiæ-Janjić, N. U., Rogan, J., and Balaž, J., Complexes cobalt (II), zinc (II) and copper (II) with some newly synthesized benzimidazole derivatives and their antibacterial activity. J. Serb. Chem. Soc., 64, 381–388 (1999).
Podunavac-Kuzmanović, S. O., Cvetković, D., Podunavac-Kuzmanović, S. O., and Cvetković, D., Antibacterial evaluation of some benzimidazole derivatives and their zinc (II) complexes. J. Serb. Chem. Soc., 75, 459–466 (2007).
Rybak, M. J. and Akins, R. L., Emergence of methicillin-resistant Staphylococcus aureus with intermediate glycopeptide resistance: clinical significance and treatment options. Drugs, 61, 1–7 (2001).
Sanjeevkumar, G., Hanumanagoud, H., and Basavaraja, K. M., Analgesic and anti-inflammatory activity of 3-methoxy-5-nitro-2-(1′,3′,4′-oxadiazolyl,1′,3′,4′-thiadiazolyl and 1′,2′,4′-triazolyl)benzofurans. J. Chem. Pharm. Res., 2, 387–392 (2010).
Sarges, R., Howard, H. R., Browne, R. G., Lebel, L. A., Seymour, P. A., and Koe, B. K., 4-Amino[1,2,4]triazolo[4,3-a]quinoxalines. A novel class of potent adenosine receptor antagonists and potential rapid-onset antidepressants. J. Med. Chem., 33, 2240–2254 (1990).
Sgouras, D., Maragkoudakis, P., Petraki, K., Martinez-Gonzalez, B., Eriotou, E., Michopoulos, S., Kalantzopoulos, G., Tsakalidou, E., and Mentis, A., In vitro and in vivo inhibition of Helicobacter pylori by Lactobacillus casei strain Shirota. Appl. Environ. Microbiol., 70, 518–526 (2004).
Shivi, B. and Monika, G., 1, 3, 4-Oxadiazole as antimicrobial agents: an overview. J. Chem. Pharm. Res., 3, 137–147 (2011).
Simões, C. M. O., Amoros, M., and Girre, L., Mechanism of antiviral activity of triterpenoid saponins. Phytother. Res., 13, 323–328 (1999).
Tamer, S., Saleh, A., Al-Omar Mohamed, A., and Abdel-Aziz, H., One-pot synthesis of enaminones using gold’s reagent. Lett. Org. Chem., 7, 483–486 (2010).
Valdez, J., Cedillo, R., Hernández-Campos, A., Yépez, L., Hernández-Luis, F., Navarrete-Vázquez, G., Tapia, A., Cortés, R., Hernández, M., and Castillo, R., Synthesis and antiparasitic activity of 1H-benzimidazole derivatives. Bioorg. Med. Chem. Lett., 12, 2221–2224 (2002).
Vijayakumar, K. and Jafar, A. A., Synthesis, anti-tumor, antidiabetic, and anti-asthmatic activitives of some novel benzimidazole derivatives. J. Chem. Pharm. Res., 2, 215–224 (2010).
Vlietinck, J., Van Hoof, L., Totté, J., Lasure, A., Vanden Berghe, D., Rwangabo, P. C., and Mvukiyumwami, J., Screening of hundred Rwandese medicinal plants for antimicrobial and antiviral properties. J. Ethnopharmacol., 46, 31–473 (1995).
Walum, E., Strenberg, K., and Jenssen, D., Principles and Pratice. Ellis Howood, NewYork, (1990).
Whiting, M., Tripp, J. C., Lin, Y. C., Lindstorm, W., Olson, A. J., Elder, J. H., Sharpless, K. B., and Fokin, V. V., Rapid discovery and structure-activity profiling of novel inhibitors of human immunodeficiency virus type 1 protease enabled by the copper(I)-catalyzed synthesis of 1,2,3-triazoles and their further functionalization. J. Med. Chem., 49, 7697–7710 (2006).
Wiart, C., Goniothalamus species: a source of drugs for the treatment of cancers and bacterial infections? Evid. Based Complement. Alternat. Med., 4, 299–311 (2007).
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Bassyouni, F.A., Saleh, T.S., ElHefnawi, M.M. et al. Synthesis, pharmacological activity evaluation and molecular modeling of new polynuclear heterocyclic compounds containing benzimidazole derivatives. Arch. Pharm. Res. 35, 2063–2075 (2012). https://doi.org/10.1007/s12272-012-1204-6
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DOI: https://doi.org/10.1007/s12272-012-1204-6