Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 13  |  Issue : 2  |  Page : 130-136

Synthesis and antimicrobial evaluation of some novel benzoimidazole Schiff's bases and their C-nucleoside derivatives


Department of Chemistry of Natural Products and Microbial Products, National Research Centre, Dokki, Egypt

Date of Submission05-Jul-2014
Date of Acceptance20-Jul-2014
Date of Web Publication18-Dec-2014

Correspondence Address:
Eman A Abd El-Meguid
Faculty of Pharmacy, Cairo University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-4315.147082

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  Abstract 

Background and objectives
The discovery of C-nucleosides and continuous study of their biological activities led us to construct new compounds containing 4-(5-benzoyl-benzoimidazol-2)-benzoic acid hydrazide Schiff's bases incorporated into different aldoses, thiazolidinones, and/or their C-nucleoside analogues. The aim of this study is to describe the synthesis of some new heterocycles derived from 4-(5-benzoyl-benzoimidazol-2)-benzoic acid hydrazide and to evaluate their antimicrobial activities.
Materials and methods
The starting material 4-(5-benzoyl-1H-benzoimidazol-2-yl)-benzonitrile ( 2 ) was prepared through the reaction of (3,4-diamino-phenyl)-phenyl-methanone ( 1 ) with 4-cyanobenzaldehyde in absolute ethanol. Stirring compound 2 with 70% sulfuric acid yielded benzoic acid derivative 3 , followed by esterification and refluxing with hydrazine hydrate to yield the corresponding 4-(5-benzoyl-1H-benzoimidazol-2-yl)-benzoic acid hydrazide ( 5 ). A series of Schiff's bases derivatives 6a-c and 8a-e were prepared by condensation of hydrazide 5 with different monosaccharides and/or with arenaldehydes. Treatment of 6a-c with thioglycolic acid led to the formation of the C-nucleosides ( 7a-c ), whereas treatment of 8a-e with thioglycolic acid yielded the corresponding 2-arylthiazolidin-4-one ( 9a-e ).
Results and conclusion
Compound 6b showed the highest antimicrobial activity against Bacillus subtilis, Staphylococcus aureus (gram-positive bacteria), Escherichia coli, and Pseudomonas aeuroginosa (gram-negative bacteria), and Candida albicans and Aspergillus niger (fungi) .

Keywords: Antimicrobial activity, 2-aryl-thiazolidinone-4-one, 4-benzoimidazol-2-yl, C-nucleoside, sugar-Schiff′s base


How to cite this article:
Abd El-Meguid EA, Abdelwahed NA. Synthesis and antimicrobial evaluation of some novel benzoimidazole Schiff's bases and their C-nucleoside derivatives. Egypt Pharmaceut J 2014;13:130-6

How to cite this URL:
Abd El-Meguid EA, Abdelwahed NA. Synthesis and antimicrobial evaluation of some novel benzoimidazole Schiff's bases and their C-nucleoside derivatives. Egypt Pharmaceut J [serial online] 2014 [cited 2020 Sep 18];13:130-6. Available from: http://www.epj.eg.net/text.asp?2014/13/2/130/147082


  Introduction Top


Benzoimidazole is an important pharmacophore and privileged bioactive heterocyclic structure in medicinal chemistry. Extensive biochemical and pharmacological studies have confirmed that benzoimidazole molecules are effective against various strains of microorganisms [1],[2],[3],[4],[5] and showed antioxidant [6],[7], antiparasitic [8], antiproliferative [9], anti-HIV [10], anticonvulsant [11], antidiabetic [11], anti-inflammatory [12],[13], antihypertensive [14], and antineoplastic [15],[16] activities.

On the basis of all of these findings, it was of interest to construct novel compounds containing benzoimidazole Schiff's bases and their cyclic products and/or their C-nucleoside analogues for evaluation of their antimicrobial activity.


  Materials and methods Top


Chemistry

Melting points (°C) were determined in open capillary tubes using silicon oil on a Gallen Kamp apparatus (Ultraporter Company, Walsall, United Kingdom). 1 H-NMR spectra were measured in DMSO-d 6 on a JEOL-270 MHz Spectrometer (JEOL, Canada) with tetramethylsilane as an internal standard. Mass spectra were obtained using a Schimadzu GCS-QP1000EX Spectrometer (Schimadzu Scientific Instruments, Italy) at 70 eV. The IR spectra were recorded using a Philips Infra cord Spectrophotometer Model PU 9712 (PerkinElmer, 940 Winter Street, Waltham, Massachusetts 02451, USA) in KBr discs. Elemental analysis was carried out at the Microanalytical Laboratory of the National Research Center. The antimicrobial activity of the synthesized compounds was assessed at the National Research Centre, Giza, Egypt.

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-benzonitrile (2)

4-Cyanobenzaldehye (0.6 g, 0.21 mol) and (3,4-diamino-phenyl)-phenyl-methanone ( 1 ) (1 g, 0.21 mol) were dissolved in ethanol. This mixture was refluxed for 5 h and cooled to room temperature. Then, water was added slowly to the mixture with stirring. The suspension was maintained at -5°C overnight. The product was washed repeatedly with ethanol-water (1: 1) mixture and then recrystallized from acetone, Scheme 1 [Additional file 1]. Yield = 1.3 g (86%), m.p. = 250-252°C. Analysis for C 21 H 13 N 3 O (323.4): Calcd.: C, 78.0; H, 4.0; N, 13.0; Fd.: C, 78.0; H, 4.1; N, 13.0. IR (cm−1 ): 3340 (NH), 2225 (CN), 1705 (CO). MS: m/z (%): 323 (M + , 100). 1 H-NMR: δ, ppm (DMSO-d 6 ); 5.92 (s, 1H, NH); 7.48-8.22 (m, 12H, Ar-H).

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-benzoic acid (3)

A mixture of 2 (1 g, 0.01 mol) and 30 ml 70% sulfuric acid was stirred in a 100 ml three-necked flask at 140°C for 5 h, then suspended in 150 ml water, and the resulting precipitate was filtered off. Recrystallization from diluted ethanol yielded yellow crystals Scheme 1. Yield = 0.95 g (90%), m.p. = 280-283°C. Analysis for C 21 H 14 N 2 O 3 (342.4): Calcd.: C, 73.7; H, 4.1; N, 8.2; Fd.: C, 73.7; H, 4.2; N, 8.2. IR (cm−1 ): 3746 (NH), 3348 (OH), 1701 (COO), 1720 (CO). MS: m/z (%): 343 (M + , 16); 342 (M + , 60). 1 H-NMR: δ, ppm (DMSO-d 6 ); 5.92 (s, 1H, NH); 7.48-8.22 (m, 12H, Ar-H); 10.92 (s, 1H, OH).

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-benzoic acid ethyl ester (4)

To a solution of compound 3 (1 g; 0.073 mol) in absolute ethanol, a few drops of concentrated sulfuric acid were added and the mixture was refluxed for 4 h. The crude product was filtered, air-dried, and crystallized from ethanol Scheme 1. Yield = 0.9 g (83%), m.p. = 107-109°C. Analysis for C 23 H 18 N 2 O 3 (370.4): Calcd.: C, 74.6; H, 4.9; N, 7.6; Fd.: C, 74.5; H, 4.9; N, 7.7. IR (cm−1 ): 3746 (NH), 3348 (OH), 1717 (COO), 1705 (CO). MS: m/z (%): 371 (M + , 32); 370 (M + , 72). 1 H-NMR: δ, ppm (DMSO-d 6 ); 1.32 (t, 3H, CH 3 ); 4.32 (q, 2H, CH 2 ); 5.92 (s, 1H, NH); 7.48-8.22 (m, 12H, Ar-H).

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-benzoic acid hydrazide (5)

To a solution of ester compound 4 (1 g; 0.033 mol) in ethanol, hydrazine hydrate (98%; 2 ml) was added and heated for 5 h on a water bath. The reaction mixture was cooled. The crude product was filtered, washed with water, and dried. It was crystallized from ethanol, Scheme 1. Yield = 0.8 g (83%), m.p. = 73-78°C. Analysis for C 21 H 16 N 4 O 2 (356.4): Calcd.: C, 70.8; H, 4.5; N, 15.7; Fd.: C, 70.7; H, 4.4; N, 15.8. IR (cm−1 ): 3736 (NH), 3187 (NH 2 ), 1705 (CO), 1684 (CO). MS: m/z (%): 357 (M + , 33); 356 (M + , 49). 1 H-NMR: δ, ppm (DMSO-d 6 ); 1.96 (s, 2H, NH 2 ); 5.92 (s, 1H, NH); 7.48-8.22 (m, 12H, Ar-H); 10.45 (s, 1H, NH).

General procedure for the preparation of 4-(5-benzoyl-1H-benzoimidazol-2-yl)-benzoic acid (2, 3, 4, 5-tetrahydroxy-pentylidene)/(2, 3, 4, 5, 6-pentahydroxy-hexylidene)-hydrazide (6a-c)

A mixture of compound 5 (1 g; 0.01 mol) dissolved in ethanol (5 ml) and DMF (5 ml) and the respective monosaccharide, namely, d (+) xylose, d (+) glucose, and/or d (+) galactose (0.01 mol), dissolved in water (1.0 ml) containing a few drops of acetic acid, were heated on a water bath at 60°C for 2 h. The solid that separated after cooling was filtered off, washed with cold ethanol, and dried to yield compounds 6a-c , respectively, Scheme 2 [Additional file 2].

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-benzoic acid (2, 3, 4, 5-tetrahydroxy-pentylidene)-hydrazide (6a)

Yield = 1.2 g (88%), m.p. = 144-148°C. Analysis for C 26 H 24 N 4 O 6 (488.5): Calcd.: C, 63.9; H, 5.0; N, 11.5; Fd.: C, 63.9; H, 5.1; N, 11.5. IR (cm−1 ): 3755(NH), 3220 (OH), 1705 (CO). MS: m/z (%): 489 (M + , 16); 488 (M + , 32). 1 H-NMR: δ, ppm (DMSO-d 6 ); 2.49-2.53 (s, 4H, OH); 3.29 (m, 1H, ΂H 5 ); 4.10 (m, 1H, ΂H 5 ); 4.20 (t, 1H, 1 H 2 ); 4.31 (t, 1H, 1 H 4 ); 5.16 (t, 1H, 1 H 3 ); 5.45 (s, 1H, NH); 6.52 (d, 1H, CH); 7.25 (s, 1H, NH); 7.48-8.22 (m, 12H, Ar-H). 13 C-NMR δ, ppm (DMSO-d 6 ): showed the presence of 26 signals corresponding to the 26 different carbon groups and signals appeared at δ 64.5 (CH 2 OH), 66.5-72.5 (3CHOH), 115.4-130.7 (Ar-12CH), 131.3 (C-CO), 134.1 (C-C = N), 134.7 (C-CO), 138.3 (C-N), 139.7 (C-CO), 142.3 (C-NH), 152.7 (C = N), 163.0 (CO), 167.2 (CH = N), and 196.5 (CO).

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-benzoic acid (2, 3, 4, 5, 6-pentahydroxy-hexylidene)-hydrazide (6b)

Yield = 1.3 g (89%), m.p. = 150-154°C. Analysis for C 27 H 26 N 4 O 7 (518.5): Calcd.: C, 62.5; H, 5.1; N, 10.8; Fd.: C, 62.5; H, 5.0; N, 10.8. IR (cm−1 ): 3755(NH), 3220 (OH), 1705 (CO). MS: m/z (%): 519 (M + , 13); 518 (M + , 18). 1 H-NMR: δ, ppm (DMSO-d 6 ); 1.30 (s, 5H, OH); 3.13 (m, 1H, ΂H 6 ); 3.29 (m, 1H, ΂H 6 ); 4.20 (t, 1H, 1 H 2 ); 4.31 (t, 1H, 1 H 4 ); 4.89 (m, 1H, 1 H 5 ); 5.16 (t, 1H, 1 H 3 ); 5.45 (s, 1H, NH); 6.52 (d, 1H, CH); 7.25 (s, 1H, NH); 7.48-8.22 (m, 12H, Ar-H). 13 C-NMR δ, ppm (DMSO-d 6 ): showed the presence of 27 signals corresponding to the 27 different carbon groups, and signals appeared at δ 64.5 (CH 2 OH), 66.5-72.5 (4CHOH), 115.4-130.7 (Ar-12CH), 131.3 (C-CO), 134.1 (C-C = N), 134.7 (C-CO), 138.3 (C-N), 139.7 (C-CO), 142.3 (C-NH), 152.7 (C = N), 163.0 (CO), 167.2 (CH = N), and 196.5 (CO).

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-benzoic acid (2, 3, 4, 5, 6-pentahydroxy-hexylidene)-hydrazide (6c)

Yield = 1.2 g (82%), m.p. = 157-159°C. Analysis for C 27 H 26 N 4 O 7 (518.5): Calcd.: C, 62.5; H, 5.1; N, 10.8; Fd.: C, 62.5; H, 5.0; N, 10.8. IR (cm−1 ): 3652 (NH), 3265 (OH), 1705 (CO), 1678 (CO). MS: m/z (%): 519 (M + , 23); 518 (M + , 31). 1 H-NMR: δ, ppm (DMSO-d 6 ); 1.30 (s, 5H, OH); 3.13 (m, 1H, ΂H 6 ); 3.29 (m, 1H, ΂H 6 ); 4.20 (t, 1H, 1 H 2 ); 4.31 (t, 1H, 1 H 4 ); 4.89 (m, 1H, 1 H 5 ); 5.16 (t, 1H, 1 H 3 ); 5.45 (s, 1H, NH); 6.52 (d, 1H, CH); 7.25 (s, 1H, NH); 7.48-8.22 (m, 12H, Ar-H).

General procedure for the preparation of 4-(5-benzoyl-1H-benzoimidazol-2-yl)-N-[4-oxo-2-(1, 2, 3, 4-tetrahydroxy-butyl)/(1, 2, 3, 4, 5-pentahydroxy-pentyl)-thiazolidin-3-yl]-benzamide (7a-c)

A solution of compounds 6a-c (1 g; 0.01 mol) and mercaptoacetic acid (2 ml, 0.02 mol) in dioxane (20 ml) was stirred at room temperature for 48 h. The solvent was evaporated under vacuum and the residue was washed with a 4N Na 2 CO 3 solution and then with water. The separated solid was filtered off, washed with water till carbonate free was obtained, then with cold ethanol and ether, and dried under vacuum at room temperature Scheme 2 .

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-N-[4-oxo-2-(1, 2, 3, 4-tetrahydroxy-butyl)-thiazolidin-3-yl]-benzamide (7a)

Yield = 0.9 g (78%), m.p. = 114-117°C. Analysis for C 28 H 26 N 4 O 7 S (562.6): Calcd.: C, 59.8; H, 4.7; N, 10.0; S, 5.7; Fd.: C, 59.8; H, 4.8; N, 10.0; S, 5.7. IR (cm−1 ): 3786 (NH), 3208 (OH), 1718 (CO), 1705 (CO), 1679 (CO). MS: m/z (%): 562 (M + , 34). 1 H-NMR: δ, ppm (DMSO-d 6 ); 2.30 (s, 4H, OH); 3.76 (s, 2H, CH 2 ); 4.20 (t, 1H, 1 H 2 ); 4.31 (t, 1H, 1 H 4 ); 4.89 (m, 1H, 1 H 5 ); 5.16 (t, 1H, 1 H 3 ); 5.36 (d, 1H, CH); 5.45 (s, 1H, NH); 7.19 (s, 1H, NH); 7.48-8.22 (m, 12H, Ar-H).

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-N-[4-oxo-2-(1, 2, 3, 4, 5-pentahydroxy-pentyl)-thiazolidin-3-yl]-benzamide (7b)

Yield = 0.85 g (75%), m.p. = 92-95°C. Analysis for C 29 H 28 N 4 O 8 S (592.6): Calcd.: C, 58.8; H, 4.8; N, 9.5; S, 5.4; Fd.: C, 58.9; H, 4.8; N, 9.4; S, 5.4. IR (cm−1 ): 3755 (NH), 3220 (OH), 1718 (CO), 1705 (CO), 1669 (CO). MS: m/z (%): 592 (M + , 34). 1 H-NMR: δ, ppm (DMSO-d 6 ); 2.30 (s, 5H, OH); 3.13 (m, 1H, ΂H 6 ); 3.29 (m, 1H, ΂H 6 ); 3.76 (s, 2H, CH 2 ); 4.20 (t, 1H, 1 H 2 ); 4.31 (t, 1H, 1 H 4 ); 4.89 (m, 1H, 1 H 5 ); 5.16 (t, 1H, 1 H 3 ); 5.36 (d, 1H, CH); 5.45 (s, 1H, NH); 7.19 (s, 1H, NH); 7.48-8.22 (m, 12H, Ar-H).

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-N-[4-oxo-2-(1, 2, 3, 4, 5-pentahydroxy-pentyl)-thiazolidin-3-yl]-benzamide (7c)

Yield = 0.8 g (70%), m.p. = 85-88°C. Analysis for C 29 H 28 N 4 O 8 S (592.6): Calcd.: C, 58.8; H, 4.8; N, 9.5; S, 5.4; Fd.: C, 58.9; H, 4.8; N, 9.4; S, 5.4. IR (cm−1 ): 3755 (NH), 3220 (OH), 1718 (CO), 1705 (CO), 1669 (CO). MS: m/z (%): 592 (M + , 34). 1 H-NMR: δ, ppm (DMSO-d 6 ); 2.30 (s, 5H, OH); 3.13 (m, 1H, ΂H 6 ); 3.29 (m, 1H, ΂H 6 ); 3.76 (s, 2H, CH 2 ); 4.20 (t, 1H, 1 H 2 ); 4.31 (t, 1H, 1 H 4 ); 4.89 (m, 1H, 1 H 5 ); 5.16 (t, 1H, 1 H 3 ); 5.36 (d, 1H, CH); 5.45 (s, 1H, NH); 7.19 (s, 1H, NH); 7.48-8.22 (m, 12H, Ar-H).

General procedure for the preparation of 4-(5-benzoyl-1H-benzoimidazol-2-yl)-benzoic acid-[(un)substituted-benzylidene]-hydrazide (8a-e)

A mixture of the arenaldehydes, namely, benzaldehyde, 4-fluoro benzaldehyde, 4-cyanobenzaldehyde, 4-dimethylaminobenzaldehyde, and/or 4-nitro benzaldehyde (0.01 mol) and compound 5 (1 g; 0.01 mol) in ethanol (30 ml) containing a few drops of glacial acetic acid was refluxed for 3 h. Then, the hot mixture was filtered off. After cooling, the filtrate was diluted with 50 ml of water and the resulting precipitate was filtered off and recrystallized from methanol to yield 8a-e , respectively Scheme 3 [Additional file 3].

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-benzoic acid benzylidene-hydrazide (8a)

Yield = 1.1 g (88%), m.p. = 292-295°C. Analysis for C 28 H 20 N 4 O 2 (444.5): Calcd.: C, 75.6; H, 4.5; N, 12.6; Fd.: C, 75.6; H, 4.6; N, 12.6. IR (cm−1 ): 3322 (NH), 3286 (NH), 1705 (CO), 1683 (CO). MS: m/z (%): 445 (M + , 36); 444 (M + , 59). 1 H-NMR: δ, ppm (DMSO-d 6 ); 4.99 (s, 1H, NH); 6.48 (s, 1H, CH); 7.43-8.46 (m, 17H, Ar-H); 7.99 (s, 1H, NH). 13 C-NMR δ, ppm (DMSO-d 6 ): showed the presence of 28 signals corresponding to the 28 different carbon groups, and signals appeared at δ 118.4-130.7 (Ar-17CH), 131.3 (C-CO), 134.1 (C-C = N), 134.7 (C-CO), 138.3 (C-N), 139.7 (C-CO), 142.3 (C-NH), 152.7 (C = N), 163.0 (CO), 167.2 (CH = N), and 196.5 (CO).

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-benzoic acid (4-fluoro-benzylidene)-hydrazide (8b)

Yield = 1.2 g (92%), m.p. = 277-279°C. Analysis for C 28 H 19 FN 4 O 2 (462.5): Calcd.: C, 72.7; H, 4.1; N, 12.1; Fd.: C, 72.7; H, 4.0; N, 12.1. IR (cm−1 ): 3422 (NH), 3286 (NH), 1705 (CO), 1683 (CO). MS: m/z (%): 462 (M + , 59). 1 H-NMR: δ, ppm (DMSO-d 6 ); 4.99 (s, 1H, NH); 6.48 (s, 1H, CH); 7.43-8.46 (m, 16H, Ar-H); 7.99 (s, 1H, NH).

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-benzoic acid (4-cyanobenzylidene)-hydrazide (8c)

Yield = 1.2 g (91%), m.p. = 250-253°C. Analysis for C 29 H 19 N 5 O 2 (469.5): Calcd.: C, 74.2; H, 4.1; N, 14.9; Fd.: C, 74.3; H, 4.1; N, 14.8. IR (cm−1 ): 3421 (NH), 3216 (NH), 2219 (CN), 1705 (CO), 1683 (CO). MS: m/z (%): 469 (M + , 27). 1 H-NMR: δ, ppm (DMSO-d 6 ); 4.99 (s, 1H, NH); 6.48 (s, 1H, CH); 7.43-8.46 (m, 16H, Ar-H); 7.99 (s, 1H, NH). 13 C-NMR δ, ppm (DMSO-d 6 ): showed the presence of 29 signals corresponding to the 29 different carbon groups, and signals appeared at δ 114.9 (C-CN), 115.8 (C°N), 118.4-130.7 (Ar-16CH), 131.3 (C-CO), 134.1 (C-C = N), 134.7 (C-CO), 138.3 (C-N), 139.7 (C-CO), 142.3 (C-NH), 152.7 (C = N), 163.0 (CO), 167.2 (CH = N), and 196.5 (CO).

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-benzoic acid (4-dimethylamino-benzylidene)-hydrazide (8d)

Yield = 1.3 g (95%), m.p. = 287-289°C. Analysis for C 30 H 25 N 5 O 2 (487.5): Calcd.: C, 73.9; H, 5.2; N, 14.4; Fd.: C, 73.9; H, 5.2; N, 14.4. IR (cm−1 ): 3421 (NH), 3216 (NH), 2219 (CN), 1705 (CO), 1683 (CO). MS: m/z (%): 487 (M + , 24). 1 H-NMR: δ, ppm (DMSO-d 6 ); 2.37 (s, 6H, CH 3 ); 4.99 (s, 1H, NH); 6.48 (s, 1H, CH); 7.43-8.46 (m, 16H, Ar-H); 7.99 (s, 1H, NH).

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-benzoic acid (4-nitro-benzylidene)-hydrazide (8e)

Yield = 1.3 g (95%), m.p. = 180-184°C. Analysis for C 28 H 19 N 5 O 4 (489.5): Calcd.: C, 68.7; H, 3.9; N, 14.3; Fd.: C, 68.6; H, 3.9; N, 14.4. IR (cm−1 ): 3421 (NH), 3216 (NH), 2219 (CN), 1705 (CO), 1683 (CO). MS: m/z (%): 489 (M + , 47). 1 H-NMR: δ, ppm (DMSO-d 6 ); 4.99 (s, 1H, NH); 6.48 (s, 1H, CH); 7.43-8.46 (m, 16H, Ar-H); 7.99 (s, 1H, NH).

General procedure for the preparation of 4-(5-benzoyl-1H-benzoimidazol-2-yl)-N-[4-oxo-2-(un)substituted-phenyl)-thiazolidin-3-yl]-benzamide (9a-e)

The foregoing method is the same as described for the preparation of C-nucleosides 7a-c , but with the use of the Schiff's bases 8a-e instead of 6a-c derivatives, Scheme 3.

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-N-(4-oxo-2-phenyl-thiazolidin-3-yl)-benzamide (9a)

Yield = 0.9 g (77%), m.p. = 145-148°C. Analysis for C 30 H 22 N 4 O 3 S (518.6): Calcd.: C, 69.5; H, 4.3; N, 10.8; S, 6.2; Fd.: C, 69.5; H, 4.4; N, 10.8; S, 6.2. IR (cm−1 ): 3322 (NH), 3188 (NH), 1720 (CO), 1706 (CO), 1689 (CO). MS: m/z (%): 518 (M + , 24). 1 H-NMR: δ, ppm (DMSO-d 6 ); 3.45 (s, 2H, CH 2 ); 4.32 (s, 1H, NH); 5.97 (s, 1H, CH); 7.43-8.46 (m, 17H, Ar-H); 10.42 (s, 1H, NH).

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-N-[2-(4-fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-benzamide (9b)

Yield = 0.85 g (73%), m.p. = 112-115°C. Analysis for C 30 H 21 FN 4 O 3 S (536.6): Calcd.: C, 67.2; H, 3.9; N, 10.4; S, 6.0; Fd.: C, 67.2; H, 3.9; N, 10.4; S, 6.0. IR (cm−1 ): 3322 (NH), 3188 (NH), 1720 (CO), 1706 (CO), 1689 (CO). MS: m/z (%): 536 (M + , 29). 1 H-NMR: δ, ppm (DMSO-d 6 ); 3.45 (s, 2H, CH 2 ); 4.32 (s, 1H, NH); 5.97 (s, 1H, CH); 7.43-8.46 (m, 16H, Ar-H); 10.42 (s, 1H, NH).

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-N-[2-(4-cyano-phenyl)-4-oxo-thiazolidin-3-yl]-benzamide (9c)

Yield = 0.95 g (82%), m.p. = 92-95°C. Analysis for C 31 H 21 N 5 O 3 S (543.6): Calcd.: C, 68.5; H, 3.9; N, 12.9; S, 5.9; Fd.: C, 68.5; H, 4.0; N, 13.1; S, 5.8. IR (cm−1 ): 3329 (NH), 3183 (NH), 2219 (CN), 1720 (CO), 1706 (CO), 1689 (CO). MS: m/z (%): 543 (M + , 32). 1 H-NMR: δ, ppm (DMSO-d 6 ); 3.45 (s, 2H, CH 2 ); 4.32 (s, 1H, NH); 5.97 (s, 1H, CH); 7.43-8.46 (m, 16H, Ar-H); 10.42 (s, 1H, NH).

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-N-[2-(4-dimethylamino-phenyl)-4-oxo-thiazolidin-3-yl]-benzamide (9d)

Yield = 0.85 g (74%), m.p. = 134-137°C. Analysis for C 32 H 27 N 5 O 3 S (561.6): Calcd.: C, 68.4; H, 4.9; N, 12.5; S, 5.7; Fd.: C, 68.4; H, 4.9; N, 12.5; S, 5.7. IR (cm−1 ): 3322 (NH), 3188 (NH), 1720 (CO), 1706 (CO), 1689 (CO). MS: m/z (%): 561 (M + , 29). 1 H-NMR: δ, ppm (DMSO-d 6 ); 2.37 (s, 6H, CH 3 ); 3.45 (s, 2H, CH 2 ); 4.32 (s, 1H, NH); 5.97 (s, 1H, CH); 7.43-8.46 (m, 16H, Ar-H); 10.42 (s, 1H, NH).

4-(5-Benzoyl-1H-benzoimidazol-2-yl)-N-[2-(4-nitro-phenyl)-4-oxo-thiazolidin-3-yl]-benzamide (9e)

Yield = 0.9 g (78%), m.p. = 92-95°C. Analysis for C 30 H 21 N 5 O 5 S (563.6): Calcd.: C, 63.9; H, 3.8; N, 12.4; S, 5.7; Fd.: C, 63.9; H, 3.8; N, 12.4; S, 5.7. IR (cm−1 ): 3322 (NH), 3188 (NH), 1720 (CO), 1706 (CO), 1689 (CO). MS: m/z (%): 563 (M + , 19). 1 H-NMR: δ, ppm (DMSO-d 6 ); 3.45 (s, 2H, CH 2 ); 4.32 (s, 1H, NH); 5.97 (s, 1H, CH); 7.43-8.46 (m, 16H, Ar-H); 10.42 (s, 1H, NH).

Antimicrobial activity test

The in-vitro antimicrobial activity was assessed against Bacillus subtilis NRRL 543, Staphylococcus aureus NRRL B-313 (gram-positive bacteria),  Escherichia More Details coli NRRL B-210 and Pseudomonas aeuroginosa NRRL B-23 (gram-negative bacteria), Candida albicans NRRL Y-477, and Aspergillus niger NRRL 599 (fungi) using the agar diffusion method [17]. A suspension of the organisms was added to sterile nutrient agar media at 45°C and the mixture was transferred to sterile  Petri dish More Detailses and allowed to solidify. Holes of 10 mm in diameter were made using a cork borer; 0.1 ml of the synthesized compounds was poured into the holes. A hole filled with DMSO was also used as a control. The plates were left for 1 h at room temperature for a period of preincubation diffusion to minimize the effects to variation in time between the applications of the different solutions. The plates were then incubated at 37°C for 24 h and observed for antibacterial activity. The diameters of zone of inhibition were measured and compared with that of the standard, and the values were tabulated. Ciprofloxacin and fluconazole were used as standards for antibacterial and antifungal activity, respectively.

To evaluate the activity of synthesized compounds against bacteria and fungi, minimum inhibitory concentration (MIC) was determined using the agar streak dilution method; 100 mg/ml stock solution of the synthesized compounds was prepared using DMSO as the solvent. From this stock solution, a range of concentrations from 5 to 0.05 mg/ml of the tested compounds' solutions were mixed with known quantities of molten sterile agar media aseptically. About 20 ml of nutrient agar medium for bacteria and Sabouraud dextrose agar medium for fungi containing the tested compound under study were dispensed into each sterile Petri dish. Then, the media were allowed to solidify. Microorganisms were then streaked one by one on the agar plates aseptically. After streaking, all the plates were incubated at 30°C for 24 h/48 h for bacteria and fungi, respectively. Then, the plates were observed for the growth of microorganisms. The lowest concentration of the synthesized compounds inhibiting the growth of the given bacteria/fungus was considered the MIC of the test compounds against that bacteria or fungi on the plate.


  Results and discussion Top


Chemistry

The starting material 4-(5-benzoyl-1H-benzoimidazol-2-yl)-benzonitrile ( 2 ) was prepared through the reaction of (3,4-diamino-phenyl)-phenyl-methanone ( 1 ) with 4-cyanobenzaldehyde in absolute ethanol. Stirring of compound 2 with 70% sulfuric acid yielded benzoic acid derivative 3 , followed by esterification and refluxing with hydrazine hydrate to form the corresponding 4-(5-benzoyl-1H-benzoimidazol-2-yl)-benzoic acid hydrazide ( 5 ) (Scheme 1).

Thus, the reaction of 4-(5-benzoyl-1H-benzoimidazol-2-yl)-benzoic acid hydrazide ( 5 ) dissolved in DMF containing a few drops of acetic acid with various monosaccharide (aldoses) namely, d (+) xylose, d (+) glucose, and/or d (+) galactose dissolved in water yielded the corresponding Schiff's bases 6a-c . Cyclocondensation of Schiff's bases 6a-c with thioglycolic acid in dry dioxane yielded the corresponding C-nucleosides 7a-c as shown in Scheme 2.

Also, the reaction of 4-(5-benzoyl-1H-benzoimidazol-2-yl)-benzoic acid hydrazide ( 5 ) with different arenaldehydes, namely, benzaldehyde, 4-fluorobenzaldehyde, 4-cyanobenzaldehyde, 4-dimethylaminobenzaldehyde, and/or 4-nitrobenzaldehyde in the presence of a few drops of acetic acid yielded Schiff's bases 8a-e . Cyclocondensation of Schiff's bases 8a-e with thioglycolic acid in dry dioxane yielded the corresponding thiazolidinones 9a-e as shown in Scheme 3.

Antimicrobial activity test

The results indicated that compounds 4 , 5 , 6b , 8a , 8b , and 8d showed the best antimicrobial activity against the tested microorganisms. Compounds 2 , 7b , 9a , 9b , and 9d showed less activity against all the tested microorganisms. Compounds 3 , 6a , and 7a showed moderate activity. The antifungal activities shown in [Table 1] indicates that compounds 4 and 6b showed good activity against C. albicans and A. niger, followed by compounds 5 , 8a , 8b , and 8d, which were moderately active, whereas compounds 6a , 7a , 7b , 9a , 9b , and 9d showed the lowest antifungal activities.
Table 1: Inhibition zone (mm) as a criterion of antibacterial and antifungal activities of the newly synthesized compounds

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Structure-activity relationship

The MIC of synthesized compounds, which are shown in [Table 2], was in accordance with the results obtained in the primary screening. The structure-activity relationship indicated that the attachment of 4-(5-benzoyl-1H-benzoimidazol-2-yl)-benzoic acid hydrazide ( 5 ) with different monosaccharides and/or with aromatic aldehydes moieties through Schiff's linkage resulted in a marked increase in antimicrobial activity. The ethyl ester 4 and compound 6b showed high activity against gram-positive bacteria (B. subtilis and S. aureus), gram-negative bacteria (E. coli and P. aeuroginosa), and the yeast-like pathogenic fungus (C. albicans and A. niger). Furthermore, compound 6b showed higher activity than ciprofloxacin and fluconazole, which were used as the standard for antibacterial and antifungal activity, respectively. In addition, the antimicrobial activity observed for the thiazolidinones 7a , 7b , 9a , 9b , and 9d indicated the importance of the free Schiff's linkage as the activity was reduced when this group was cyclized to yield the corresponding thiazolidinone. Moreover, the antibacterial activity observed for the thiazolidinone derivative 7a was relatively higher than that of the corresponding thiazolidinone 7b , 9a, 9b , and 9d . In addition, benzylidene 8d showed high activity against tested gram-positive bacteria and gram-negative bacteria and showed moderate activity against the yeast-like pathogenic fungus (C. albicans and A. niger).
Table 2: MIC (mg/ml) of the newly synthesized compounds against microorganisms

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  Conclusion Top


The preliminary in-vitro antibacterial and antifungal screening results of novel benzoimidazole derivatives reported here have indicated the antimicrobial activity of the synthesized compounds. SAR observation has shown the importance of free Schiff's linkage. The presence of substituents on the aromatic ring has increased the activity of the compounds compared with that of unsubstituted benzylidene. Findings from SAR have encouraged us to make some modifications on the basic structure of the compounds obtained to obtain selective and more active derivatives in ongoing studies.


  Acknowledgements Top


The authors are grateful to the Microanalytical Center, Faculty of Science, Cairo University, Egypt, for carrying out elemental analyses, IR, 1 H-NMR, and mass spectra.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Kazimierczuk Z, Upcroft JA, Upcroft P, Gorska A, Starosciak B, Laudy A. Synthesis and antiprotozol activity of some 2-(trifluoromethyl)-1H-benzimidazole bioisosteres. Acta Biochim Pol 2002; 49:185-195.  Back to cited text no. 1
    
2.
Goker H, Kus C, Boykin DW, Yildiz S, Atlanlar N. Synthesis of some new 2-substituted-phenyl-1H-benzimidazole-5-carbonitriles and their potent activity against Candida species. Bioorg Med Chem 2002; 10:2589-2596.  Back to cited text no. 2
    
3.
Klimesova V, Koci J, Pour M, Stachel J, Waisser K, Kaustova J. Synthesis and preliminary evaluation of benzimidazole derivatives as antimicrobial agents. Eur J Med Chem 2002; 37:409-418.  Back to cited text no. 3
    
4.
Pawer NS, Dalal DS, Shimpi SR, Mahulikar PP. Studies of antimicrobial activity of N-alkyl and N-acyl-2-(4-thiazolyl)-1H-benzimidazoles. Eur J Pharm Sci 2004; 21:115-118.  Back to cited text no. 4
    
5.
Guven OO, Erdogan T, Goker H, Yildiz S. Synthesis and antimicrobial activity of some novel phenyl and benzimidazole substituted benzyl ethers. Bioorg Med Chem Lett 2007; 17:2233-2236.  Back to cited text no. 5
    
6.
Ayhan-Kilcigil G, Kus C, Ozdamar ED, Can-Eke B, Iscan M. Synthesis and antioxidant capacities of some new benzimidazole derivatives. Arch Pharm 2007; 34:607-611.  Back to cited text no. 6
    
7.
Ates-Alagoz Z, Kus C, Coban T. Synthesis and antioxidant properties of novel benzimidazoles containing substituted indole or 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-napthalene fragments. J Enzyme Inhib Med Chem 2005; 20:325-331.  Back to cited text no. 7
    
8.
Navarrete-Vazquez G, Cedillo R, Hernandez-Campos A, Yepez L, Hernandez-Luis F, Valdez J, et al. Synthesis and antiparasitic activity of 1H-benzimidazole derivatives. Bioorg Med Chem 2001; 11:187-190.  Back to cited text no. 8
    
9.
Garuti L, Roberti M, Malagoli M, Rossi T, Castelli M. Synthesis and antiproliferative activity of some thiazolyl benzimidazole-4,7-diones. Bioorg Med Chem Lett 2000; 10:2193-2195.  Back to cited text no. 9
    
10.
Miller JF, Turner EM, Gudmundsson KS, Jenkinson S, Spaltenstein A, Thomson M, et al. Novel N-substituted benzimidazole CXCR4 antagonists as potential anti-HIV agents. Bioorg Med Chem Lett 2010; 20:2125-2128.  Back to cited text no. 10
    
11.
Shingalapur RV, Hosamani KM, Keri RS, Hugar MH. Derivatives of benzimidazole pharmacophore: synthesis, anticonvulsant, antidiabetic and DNA cleavage studies. Eur J Med Chem 2010; 45:1753-1759.  Back to cited text no. 11
    
12.
Thakurdesai PA, Wadodkar SG, Chopade CT. Synthesis and anti-inflammatory activity of some benzimidazole-2-carboxylic acids. Pharmacology Online 2007; 1:314-329.  Back to cited text no. 12
    
13.
Gaba M, Singh S, Mohan C. Benzimidazole: an emerging scaffold for analgesic and anti-inflammatory agents. Eur J Med Chem 2014; 76:494-505.  Back to cited text no. 13
    
14.
Kubo K, Inada Y, Kohara Y, Sugiura Y, Ojima M, Itoh K, et al. Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazoles. J Med Chem 1993; 36:1772-1784.  Back to cited text no. 14
    
15.
Abdel-monem Abdel-hafez A. Benzimidazole condensed ring systems: new synthesis and antineoplastic activity of substituted 3,4-dihydro- and 1,2,3,4-tetrahydro-benzo[4,5]imidazo[1,2-a]pyrimidine derivatives. Arch Pharm Res 2007; 30:678-684.  Back to cited text no. 15
    
16.
Ram S, Wise DS, Wotring LL, McCall JW, Townsend LB. Synthesis and biological activity of certain alkyl 5-(alkoxy carbonyl)-1H-benzimidazole-2-carbamates and related derivatives: a new class of potential antineoplastic and antifilarial agents. J Med Chem 1992; 35:539-547.  Back to cited text no. 16
    
17.
Cruikshank R, Duguid JP, Marion BP, Swain RHA. Medicinal microbiology. 12th ed. London, UK: Churchill Livingstone; 1975. II:196-202.  Back to cited text no. 17
    



 
 
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