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Synthesis, characterization and biological activity of some novel benzimidazole derivatives.

Benzimidazole derivatives are very useful intermediates or subunits of the development of pharmaceutical or biological interest [1]. Benzimidazole derivatives are an important class of bioactive molecules in the field of drugs and pharmaceuticals [2]. Benzimidazole derivatives have found the application in diverse therapeutic areas including antiulcer, antihypertensive, antiviral, antifungal, anticancer, anti-histaminic [3], antitubercular [4], antiallergic [5, 6], antioxidant [7, 8], antimicrobial [9-11] and in vitro anti-HIV-1 [12] activities etc. A compound containing benzimidazole and benzene rings have been used extensively for pharmaceutical purpose since 1960. 1-H-Benzimidazole rings, which exhibit remarkable basic characteristics due to their nitrogen content, comprise the active substances for several drugs. A number of biological activities have been attributed to these compounds [13].

We elicited a new method for the synthesis of benzimidazoles with aromatic acid chloride. In continuation of our work on these different aromatic acid chlorides, we wish to report in the paper synthesis of 2-substituted benzimidazoles by the reaction between aromatic acid chlorides.

All the melting points were taken in open capillaries and are uncorrected. IR spectra were recorded in KBr on Shimadzu spectrometer, [sup.1]H NMR and [sup.13]C NMR in DMSO-[d.sub.6] on a Bruker AC-400 spectrometer (400 MHz for [sup.1]H and 100 MHz for [sup.13]C), using TMS as an internal standard.

N-(2-(1H-benzo[d]imidazol-2-yl) phenyl)benzamide(AB): A mixture of

compound (0.001 mol) of AOP and equivalent amount of benzoyl chloride (0.001 mol) was refluxed with pyridine (40 mL) for 3 hours. The reaction mixture was cooled, treated with cold ice and neutralized with conc. HCl. The separating solid was filtered and washed with ice cold water. The product was recrystalized from ethanol. Compound AB mp 187[degrees]C (Found C, 76.64; H, 4.7; N, 13.39; O, 5.09% [C.sub.20][H.sub.15][N.sub.3]O) IR: 3269 (N-H stretching), 3056 (aromatic C-H stretching), 1654 (C=O stretching), 1599 (C=N stretching), 1309 (C-N stretching), [sup.1]H NMR: [delta] 7.26-7.85 (13H, m, Ar-H), 8.1 (1H, s, CO-NH), 11.9 (1H, s, imidazole ring NH), [sup.13]C NMR: [delta] 115-128 (18C, Ar-C), 169 (1C, C=O), 150 (1C, C=N).

2-(2-(5-phenyl-1H-tetrazol-1-yl)phenyl)-1H-benzo[d]imidazole (ABC): A known amount of compound AB 0.01 mol (0.313 g) was taken in a beaker and added a known amount of P[Cl.sub.5] 0.01 mol (0.208 g) was heated at 100[degrees]C until the evaluation of HCl fumes ceased. The reaction mixtures contain some unreacted PO[Cl.sub.3] this was removed by distillation under reduced pressure. The resulting was treated with ice cold solution of known weight of Na[N.sub.3] 0.02 mol (0.130 g), a known volume of acetone 40 mL, known volume of sodium acetate was added. The reaction mixture was stirred over night. The acetone was removed by distillation under reduced pressure. The resulting mixture was extracted with CH[Cl.sub.3] then the organic layer was separated and evaporated we got product. The product filtered and washed with ice cold water. The product was recrystalized from benzene and pet-ether mixture. Compound ABC mp 236[degrees]C (Found C, 70.97; H, 4.14; N, 24.80; [C.sub.20][H.sub.14][N.sub.6]) IR: 3270 (N-H stretching), 3056 (aromatic C-H stretching), 1655 (C=N stretching), 1313 (C-N stretching), [sup.1]H NMR: [delta] 7.0-7.94 (13H, m, Ar-H), 11.8 (1H, s, imidazole ring NH), [sup.13]C NMR: [delta] 114-131 (18C, Ar-C), 159 (1C, C=N in tetrazole ring), 150 (1C, C=N).

The reactions were carried out at room temperature, using aromatic acid chloride in the presence of pyridine, accordingly with Scheme 1.

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The antimicrobial activity for the given samples was carried out by Disc Diffusion Technique (Indian Pharmacopoeia 1996, Vol II A-105). The test microorganisms of Gram positive Staphylococcus aureus and Gram negative Escherichia coli and fungus Candida albicans, Aspergillus Niger were obtained from National Chemical Laboratory (NCL), India, and maintained by periodical sub culturing on Nutrient agar and Sabourad dextrose medium both bacteria and fungus respectively. The effect produced by the sample was compared with the effect produced by the positive control (Reference standard Ciprofloxacin 5 pg/disc for bacteria and Fluconazole 10 pg/disc for fungi). The result indicated that compounds were more active against all four organisms with reference to standard. The results are shown in the Table 1.

In conclusion, we have described a simple and efficient method for the synthesis 2-substituted benzimidazoles. The easy work up procedure, non-toxic cost efficiency providing this reactions scheme, excellent yields makes this method a valuable contribution to the existing methodologies.

Acknowledgements

The authors are thankful to Principal and Management Committee of Jamal Mohamed College, for providing facilities for this work.

References and Notes

[1] Gravatt, G. L.; Baguley, B. C.; Wilson, W. R. J. Med. Chem., 1994, 37, 4338.

[2] Boyer, P. L.; Hughes, S. H.; Buckheit, R. W. J. Med. Chem. 1997, 40, 4199.

[3] Islam, I.; Skibo, E. B.; Dorr, R. T. J. Med. Chem. 1991, 34, 2954.

[4] Habernickel, V. J. Drugs made in German 1992, 35, 97.

[5] Khairnar, V. L.; Lockhande, S. R.; Patel, M. R. Chemical Abstract 1981, 95, 203833h.

[6] Fukuda, T.; Saito, T.; Tajima, S. Arzneim-Forsh./Drug Res. 1984, 34, 805.

[7] Nakano, H.; Inoue, T.; Kawasaki, N. Chem. Pharm. Bull. 1999, 47, 1573.

[8] Can-Eke, B.; Puskullu, M. O.; Iscan, M. Chemico-Biologica Interactions 1998, 113, 65.

[9] Kus, C.; Ayhan-Kicigil, G.; Iscan, M. Arch. Phar. Res. 2004, 27,156.

[10] Abdel-Rahman, A. E.; Mahmoud A. M.; El-Naggar, G. M. Pharmazie 1983, 38, 589.

[11] Soliman, F. S. G.; Rida, S. M.; Kappe, T. Arch. Pharm. 1984, 317, 951.

[12] Samia, R.; Soda, A.; El-Hesham, M.; Fahmy, T. Y. Arch. Pharm. Res. 2006, 29, 826.

[13] Popp, F. D. J. Med. Chem. 1964, 7, 210.

Ahamed A. Jafar, (a) * Kaliapillai N. Vijayakumar, (a) Bathey R. Venkatraman (b) and Govindaraj Venkatesh (a)

(a) PG & Research Dept. of Chemistry, Jamal Mohamed College, Tiruchirappalli-20, Tamil Nadu, India.

(b) PG & Research Dept. of Chemistry, Periyar EVR College, Tiruchirappalli-23, Tamil Nadu, India.

Received: 11 September 2009; accepted: 29 December 2009. Available online: 23 January 2010.

* Corresponding author: E-mail: agjafar@yahoo.co.in
Table 1. Antimicrobial screening results of the compounds.

S. No.       Microorganism       Diameter zone of
                                 inhibition in mm

                                 AB   ABC   Std.

1        Staphylococcus aureus   25   32     40
              (NCIM 2079)
2          Escherichia coli      30   36     40
              (NCIM 2065)
3          Candida albicans      15   17     20
              (NICM 3102)
4          Aspergillus Niger     14   16     20
              (NICM 105)
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Author:Jafar, Ahamed A.; Vijayakumar, Kaliapillai N.; Venkatraman, Bathey R.; Venkatesh, Govindaraj
Publication:Orbital: The Electronic Journal of Chemistry
Date:Oct 1, 2009
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