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SYNTHESIS OF SOME BENZIMIDAZOLE DERIVATIVES AND EVALUATION OF THEIR ANTIMICROBIAL ACTIVITY


Amanpreet S. Kohli*, S. R. Wakode
Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, New Delhi, India

ABSTRACT

A series of nine 2-Chlormethyl-benzomimidazole derivatives were synthesized in appreciable yield. The structures of the synthesized derivatives were confirmed by IR and 1H-NMR spectra. All of these derivatives were screened for their antimicrobial activity against Staphylococcus aureus, Bacillus subtilis (Gram positive) and Escherichia coli, Pseudomonas aeruginosa (Gram negative) and showed good to moderate antimicrobial activity as compared to standard drug streptomycin.

Key words: Antimicrobial activity, carbonyl compounds, benzomimidazole, 2-Chlormethyl-benzomimidazole.

Introduction

In heterocyclic compounds the rings are not entirely composed of carbon atoms. The common hetero atoms are nitrogen, oxygen and sulphur. A great number of established drugs bear heterocyclic system with certain substitutions and functionalization1. The benzimidazole moiety is a core structure in various synthetic pharmaceuticals displaying a broad spectrum of biological activity including anti-ulcer, antitumor, antiviral and antibacterial agent 2. The benzimidazole core is classified by medicinal chemists as one of the privileged sub-structures for drug design, in light of the affinity they display towards a variety of enzymes and protein receptors 3. Benzimidazoles are heterocyclic compounds in which benzene is fused with five membered ring containg two heteroatoms. Both heteroatom’s are nitrogen (N), which are present at non-adjacent position 4. Benzimidazole are very important compounds due to their wide spectrum of biological activity such as anti-hypertensive, anti-viral, anti-fungal, anti-tumour, anti-helminthic, anti-microbial, anti-tumour , antiviral, antioxidant, antiulcer , antiamoebic and  antihistaminic activity 5-31.

Synthsis of benzimidazole: Benzimidazoles are readily formed by heating o-phenylenediamine with carboxylic acids. For example, benzimidazole itself is produced by heating o-phenylenedamine with 90% formic acid 32.

Fig 1: Scheme for Synthesis of N-substituted 2 chloromethylbenzimidazole

Materials and methods

Experimental:

Melting points were determined on a Visual melting point apparatus and were uncorrected. FTIR spectra were taken on “Jasco FT/IR-410”, using KBr pressed pellet technique. The 1H NMR spectra of the compounds was recorded on Bruker NMR spectrophotometer in DMSO or CDCl3 using TMS as internal standard (chemical shift in δ ppm. The purity of the compounds was determined by thin layer chromatography. Thin layer chromatographic analysis of the compounds was performed on silica gel G coated plates. The adsorbent silica gel G was coated to a thickness of about 1 mm on previously cleaned glass plates 20×5 cm using conventional spreader. The plates were placed in hot air oven at 110ºC for 30 min.  Chloroform: Methanol (9:1) was used as mobile phase. The spots were visualized by exposure to iodine vapours. Chemicals were purchased from Sigma-Aldrich and Lobachemie. All the reactants were identified by comparison of melting points with those reported in the literature. The year of Experimentation was 2011, at the P.G Laboratory, of the Department of pharmaceutical chemistry, DIPSAR.

Synthetic procedure:  The general scheme for the synthesis of 2-chloromethylbenzimidazole derivatives has been illustrated in Fig 1. The detailed procedures for synthesis of each compound have been described below:-

(1H-Benzoimidazol-2-yl)-methanol (L1): To a solution of o-phenylene diamine (0.05 mol) in 4N HCl (100ml), glycolic acid (0.09 mol) in 4 N HCl (50ml) was added. The reaction mixture was refluxed for 6hr. Then the reaction mixture was cooled and basified with conc. ammonia solution. The precipitate so obtained was filtered, dried and recrystallized with hot water.

2-Chlormethyl-1H-benzomimidazole (L2): To a solution of L1 (0.04mol) in chloroform (75ml), was added drop wise thionyl chloride (7.5ml). The mixture was refluxed for 10hr. The excess of thionyl chloride was evaporated under vacuum. The residue was dissolved in chloroform and washed with water (3x50ml). The organic layer was dried over sodium sulphate & solvent was evaporated to get the product.

1-(2-Chlormethyl-benzomimdazol-1-yl)-ethanone (A.P-1): To a solution of L2 (0.05 mol) and anhydrous potassium carbonate (0.04mol) in acetone (25ml), acetyl chloride (0.06 mol) was added slowly. The mixture was refluxed for about 14 hr. The mixture was then poured onto water and extracted with ethyl acetate, dried over sodium sulphate anhydrous and concentrated under vacuum to give the pure product.

1-Benzyl-2-chloromethyl-1H-benzomidazole (A.P-2): To a solution of L2 (0.05 mol) and anhydrous potassium carbonate (0.04mol) in acetone (25ml), benzyl chloride (0.075 mol) was added slowly. The mixture was stirred for about 16 hr. The mixture was then poured onto water and extracted with ethyl acetate, dried over sodium sulphate anhydrous and concentrated under vacuum to give the pure product.

(2-Chloromethyl-benzomidazol-1-yl)-phenyl-methanone (A.P-3): To a solution of L2 (0.05 mol) and anhydrous potassium carbonate (0.04mol) in acetone (25ml), benzoyl chloride (0.055 mol) was added slowly. The mixture was refluxed for about 14 hr. The mixture was then poured onto water and extracted with ethyl acetate, dried over sodium sulphate anhydrous and concentrated under vacuum to give the pure product.

(2-Chloromethyl-benzoimidazol-1-yl)-(2-methoxy-phenyl)-methanone (A.P-4): To a solution of L2 (0.05 mol) and anhydrous potassium carbonate (0.04mol) in acetone (25ml), 2-methoxybenzoyl chloride (0.06 mol) was added slowly. The mixture was refluxed for about 16 hr. The mixture was then poured onto water and extracted with ethyl acetate, dried over sodium sulphate anhydrous and concentrated under vacuum to give the pure product.

(2-Chloromethyl-benzoimidazol-1-yl)-(4-chloro-phenyl)-methanone (A.P-5): To a solution of L2 (0.05 mol) and anhydrous potassium carbonate (0.04mol) in acetone (25ml), 4-chlorobenzoyl chloride (0.07 mol) was added slowly. The mixture was then refluxed for about 19 hr. The mixture was then poured onto water and extracted with ethyl acetate, dried over sodium sulphate anhydrous and concentrated under vacuum to give the pure product.

1-Benzenesulphonyl-2-chloromethyl-benzimidazole (A.P-6): To a solution of L2 (0.05 mol) and anhydrous potassium carbonate (0.04mol) in acetone (25ml), benzenesulphonylchloride (0.05 mol) was added slowly. The mixture was then stirred for about 12 hr. The mixture was then poured onto water and extracted with ethyl acetate, dried over sodium sulphate anhydrous and concentrated under vacuum to give the pure product.

2-Chloromethyl-1-(toluene-4-sulphonyl)-benzimidazole (A.P-7): To a solution of L2 (0.05 mol) and anhydrous potassium carbonate (0.04mol) in acetone (25ml), 4-methylbenzenesulphonylchlloride (0.07 mol) was added slowly. The mixture was then stirred for about 17 hr. The mixture was then poured onto water and extracted with ethyl acetate, dried over sodium sulphate anhydrous and concentrated under vacuum to give the pure product.

2-Chloromethyl-1-(naphthalene-2-sulphonyl)-benzimidazole (A.P-8): To a solution of L2 (0.05 mol) and anhydrous potassium carbonate (0.04mol) in acetone (25ml), naphthalene-2-sulphonylchloride (0.07 mol) was added slowly. The mixture was then stirred for about 22 hr. The mixture was then poured onto water and extracted with ethyl acetate, dried over sodium sulphate anhydrous and concentrated under vacuum to give the pure product.

(2-Chloromethyl-benzoimidazol-1-yl)-methanol (A.P-9): L2 (0.03mol) was placed in a two necked flask and THF was added at 15°C to give a slolution. To this, Formaldehyde (1ml, 41%) was added to give a homogenous solution. Then the reaction was stirred for 8 hr at a temp. of 15°C. After the completion of reaction, the solvent was removed under vacuum to give the pure compound. 

Anti-Microbial Activity

The antibacterial activity of newly synthesized compounds was tested by paper disc diffusion method33 using nutrient agar medium against following microorganism: Staphylococcus aureus, Bacillus subtilis, (Gram positive) and Escherichia coli, Pseudomonas aeruginosa (Gram negative)

Experimental Procedure: In the paper disc-diffusion method34, paper disc impregnated with compounds dissolved in DMSO at conc. 50 & 100 µg/ml were used. The microorganism culture was spread over nutrient agar media in petri dishes, and then the disc impregnated with the solution was placed on the surface of the media inoculated with the bacterial strain. The plates were incubated at 35°C for 24 hr. After incubation, the zones of inhibition around the disc were observed. The zones of inhibition indicate that the compounds inhibit growth of microorganism. Each testing is done in triplicate. Streptomycin at conc. 50 & 100 µg/ ml was used as standard drug for antibacterial activity. Results were interpreted in terms of diameter (mm) of zone of inhibition.

RESULTS AND DISCUSSION

TLC was used to monitor the completion of the reaction; the structures of products were assessed by interpretation of IR and NMR spectra obtained. The spectroscopic data of IR and 1H-NMR are in agreement with the structure of the synthesized compounds.

(1H-Benzoimidazol-2-yl)-methanol (L1): Rf value: 0.85 (Chloroform: Methanol, 9:1); IR (KBr) : 3430cm-1(O-H str), 3270cm-1 (N-H str), 3012cm-1 (Ar-C-H str), 2919 cm-1 (aliphatic- C-H str) , 1620 cm-1  (C=N str), 1457 cm-1 (C=C str), 1310cm-1 (C-N str); NMR (CDCL3) δ: 4.57 (s, 2H, CH2), 6.44 (s, 1H, OH), 7.20-7.25 (m, 2H, Ar-H), 7.54-7.57 (m, 2H, Ar-H), 8.41 (s, 1H, NH).

2-Chlormethyl-1H-benzomimidazole (L2): Rf value: 0.85 (Chloroform: Methanol, 9:1); IR (KBr) : 3345cm-1 (N-H str), 3045cm-1 (Ar-C-H str), 2952 cm-1(aliphatic- C-H str) , 1682 cm-1  (C=N str), 1448 cm-1 (C=C str), 1292 cm-1 (C-N str), 764-672cm-1  (C-Cl); NMR (CDCL3) δ: 4.64 (s, 2H, CH2), 7.20-7.25 (m, 2H, Ar-H), 7.54-7.57 (m, 2H, Ar-H), 8.41 (s, 1H, NH).

1-(2-Chlormethyl-benzomimdazol-1-yl)-ethanone (A.P-1): Rf value: 0.81 (Chloroform: Methanol, 9:1); IR (KBr) : 3078cm-1 (Ar-C-H str), 2971 cm-1(aliphatic- C-H str), 1640 cm-1 (C=O str), 1570(C=N str) 1468 cm-1 (C=C str), 1315cm-1 (C-N str), 764-672cm-1  (C-Cl); NMR (CDCL3) δ: 2.65 (s, 3H, CH3), 4.62 (s, 2H, CH2 ), 7.20-7.58 (m, 2H, Ar-H), 7.54-7.57 (m, 2H, Ar-H).

1-Benzyl-2-chloromethyl-1H-benzomidazole (A.P-2): Rf value: 0.71 (Chloroform: Methanol, 9:1); IR (KBr) :            3050cm-1 (Ar-C-H str), 2945 cm-1(aliphatic- C-H str) , 1662 cm-1  (C=O str),1598 cm-1(C=N str), 1467 cm-1 (C=C str), 1292 cm-1 (C-N str), 764-672cm-1  (C-Cl); NMR (CDCL3) δ: 4.56 (s, 2H, CH2), 4.91 (s, 2H, CH2), 7.21-7.39 (m, 7H, Ar-H), 7.72-7.73 (m, 2H, Ar-H).

(2-Chloromethyl-benzomidazol-1-yl)-phenyl-methanone (A.P-3): Rf value: 0.64 (Chloroform: Methanol, 9:1); IR (KBr) : 3088 cm-1 (Ar-C-H str), 2955 cm-1(aliphatic- C-H str) , 1725 cm-1  (C=O str),1585 cm-1(C=N str), 1478 cm-1 (C=C str), 1245 cm-1 (C-N str), 764-672cm-1  (C-Cl); NMR (CDCL3) δ: 4.56 (s, 2H, CH2), 7.20-7.22 (m, 2H, Ar-H), 7.23-7.25 (m, 2H, Ar-H), 7.54-7.55 (m, 2H, Ar-H), 7.56-7.57 (m, 2H, Ar-H).

(2-Chloromethyl-benzoimidazol-1-yl)-(2-methoxy-phenyl)-methanone (A.P-4): Rf value: 0.62 (Chloroform: Methanol, 9:1); IR (KBr) : 3057 cm-1 (Ar-C-H str), 2925 cm-1(aliphatic- C-H str) , 1725 cm-1  (C=O str),1552 cm-1(C=N str), 1492 cm-1 (C=C str), 1197 cm-1 (C-N str),1111 cm-1 (C-O str) 764-672cm-1  (C-Cl); NMR (CDCL3) δ: 3.69 (s, 3H, CH3), 4.62 (s, 2H, CH2), 7.12-7.18 (m, 2H, Ar-H), 7.54-7.56 (m, 2H, Ar-H), 7.82-7.85 (m, 3H, Ar-H).

(2-Chloromethyl-benzoimidazol-1-yl)-(4-chloro-phenyl)-methanone (A.P-5): Rf value: 0.59 (Chloroform: Methanol, 9:1); IR (KBr) : 3098 cm-1 (Ar-C-H str), 2967 cm-1 (aliphatic- C-H str), 1644 cm-1  (C=O str),1505 cm-1(C=N str), 1450 cm-1 (C=C str), 1276 cm-1 (C-N str), 764-672cm-1  (C-Cl); NMR (CDCL3) δ: 4.62 (s, 2H, CH2), 7.21-7.22 (m, 2H, Ar-H), 7.39-7.41(m, 2H, Ar-H), 7.58-7.60 (m, 2H, Ar-H), 7.70-7.72 (m, 2H, Ar-H).

1-Benzenesulphonyl-2-chloromethyl-benzimidazole (A.P-6): Rf value: 0.67 (Chloroform: Methanol, 9:1); IR (KBr) : 3312 cm-1 (S=O str), 3075 cm-1 (Ar-C-H str), 2923 cm-1 (aliphatic-C-H str), 1556 cm-1(C=N str), 1485 cm-1 (C=C str), 1276 cm-1 (C-N str), 764-672cm-1  (C-Cl); NMR (CDCL3) δ: 4.56 (s, 2H, CH2), 7.21-7.25 (m, 4H, Ar-H ), 7.39-7.40 (m, 1H, Ar-H), 7.55-7.57 (m, 2H, Ar-H), 7.70-7.73(m, 2H, Ar-H).

2-Chloromethyl-1-(toluene-4-sulphonyl)-benzimidazole (A.P-7): Rf value: 0.57 (Chloroform: Methanol, 9:1); IR (KBr) : 3330 cm-1 (S=O str), 3063 cm-1 (Ar-C-H str), 2923 cm-1 (aliphatic-C-H str), 1559 cm-1(C=N str), 1455 cm-1 (C=C str), 1244 cm-1 (C-N str), 764-672cm-1  (C-Cl); NMR (CDCL3) δ: 2.65(s, 3H, CH3), 4.61(s, 2H, CH2), 7.20-7.25 (m, 2H, Ar-H), 7.55-7.57(m, 2H, Ar-H).

2-Chloromethyl-1-(naphthalene-2-sulphonyl)-benzimidazole (A.P-8): Rf value: 0.54 (Chloroform: Methanol, 9:1); IR (KBr) : 3315 cm-1 (S=O str), 3030 cm-1 (Ar-C-H str), 2940 cm-1 (aliphatic-C-H str), 1587 cm-1(C=N str), 1455 cm-1 (C=C str), 1230 cm-1 (C-N str), 764-672cm-1  (C-Cl); NMR (CDCL3) δ:  4.56 (s, 2H, CH2), 7.21-7.37 (m, 7H, Ar-H), 7.55-7.57(m, 2H, Ar-H), 7.70-7.73(m, 2H, Ar-H).

(2-Chloromethyl-benzoimidazol-1-yl)-methanol (A.P-9): Rf value: 0.79 (Chloroform: Methanol, 9:1); IR (KBr) : 3450cm-1(O-H str), 3025cm-1 (Ar-C-H str), 2905 cm-1(aliphatic- C-H str) , 1595 cm-1  (C=N str), 1457 cm-1 (C=C str), 1283cm-1 (C-N str); NMR (CDCL3) δ: 4.62 (s, 2H, CH2), 5.87 (s, 2H, CH2), 6.41(s, 1H,), 7.20-7.25 (m, 2H, Ar-H), 7.54-7.57(m, 2H, Ar-H). 

Anti-microbial activity: The anti-microbial activity of synthesized compounds is summarized in table-1and table-2 respectively.

Table 1:- Zone of inhibition (mm ± S.D) of test sample and Standard Drug (Streptomycin) against B. subtilis & E. coli.

Test samples Diameter of zone of inhibition in mm [mean ± SD (n=3)]
  B. subtilis E.coli
  50µg/ml 100µg/ml 50µg/ml 100µg/ml
L1 6.53±0.44 10.31±0.44 4.40±0.20 8.50±0.42
L2 6.67±1.60 11.32±1.60 4.65±0.50 7.86±0.60
A.P-1 9.30±0.95 13.32±1.00 5.64±0.84 8.90±0.40
A.P-2 9.35±0.54 14.46±1.32 3.00±1.00 6.46±0.26
A.P-3 8.33±0.91 12.34±1.20 6.33±1.28 10.60±0.36
A.P-4 8.00±0.16 12.68±0.19 6.72±0.60 11.22±0.20
A.P-5 9.36±0.56 14.40±0.38 3.16±0.28 7.76±0.52
A.P-6 8.67±0.50 13.61±0.14 4.30±0.50 8.06±1.22
A.P-7 8.51±0.45 12.68±1.20 5.32±0.61 9.50±1.00
A.P-8 9.12±0.55 14.10±0.48 5.13±0.50 10.32±0.18
A.P-9 8.10±0.18 12.54±0.82 4.70±0.20 8.75±0.38
Std 13.35±0.34 18.27±0.42 10.50±0.44 15.50±0.29
Test samples Diameter of zone of inhibition in mm [mean± SD (n=3)]

 

 

Table 2:- Zone of inhibition (mm ± S.D) of test sample and Standard Drug (Streptomycin) against S. Aureus & P. aeureginosa

  S. aureus P. aeureginosa
  50µg/ml 100µg/ml 50µg/ml 100µg/ml
L1 6.32±0.68 11.04±0.33 4.53±0.83 7.31±0.44
L2 7.30±0.32 14.30±1.00 7.50±0.46 12.61±0.88
A.P-1 6.30±0.65 12.64±0.44 8.30±0.95 14.31±1.00
A.P-2 5.00±0.88 11.42±1.10 6.30±0.54 12.46±1.32
A.P-3 8.24±0.12 14.00±0.24 8.33±0.91 14.64±1.20
A.P-4 7.30±0.90 12.32±0.16 6.00±0.16 12.68±0.19
A.P-5 4.67±1.50 9.66±0.86 3.36±0.56 7.46±0.38
A.P-6 6.00±0.66 12.20±0.54 8.67±0.50 11.65±0.12
A.P-7 6.12±0.66 13.30±0.50 8.64±0.48 12.64±0.14
A.P-8 7.67±0.32 13.78±0.21 7.32±0.91 11.68±1.20
A.P-9 5.25±0.38 10.24±0.68 4.67±0.20 9.32±1.60
Std 12.00±0.48 17.28±0.34 14.20±0.42 19.60±0.54

Fig 2:- Zone of inhibition (mm) of Test samples and Standard Drug (Streptomycin) at a conc. of 50µg/ml.

Thus, the above data revealed that all compounds showed good to moderate antimicrobial activity as compared to standard drug streptomycin. The result shows that:-

  • Compounds 1-(2-Chlormethyl-banzimidazol-1-yl)-ethanone (A.P-1), 1-Benzyl-2-Chlormethyl-1H-benzimidazole (A.P-2), (2-Chloromethyl-benzimidazol-1-yl)-(4-chloro-phenyl)-methanone (A.P-5) and 2-Chloromethyl-1-(naphthalene-2-sulphonyl)-benzimidazole (A.P-8) showed best activity against B. subtilis.
  • Compounds (2-Chloromethyl-benzimidazole-1-yl)-phenyl-methanone (A.P-3) and (2-Chloromethyl-benzimidazol-1-yl)-(2-methoxy-phenyl)-methanone (A.P-4) showed best activity against E.coli.
  • Compound (2-Chloromethyl-benzimidazole-1-yl)-phenyl-methanone (A.P-3) showed best activity against S. aureus.
  • Compounds 1-Benzenesulphonyl-2-chloromethyl-benzimidazole(A.P-6) & 2-Chloromethyl-1-(toluene-4-sulphonyl)-benzimidazole (A.P-7)showed best activity against P. aeureginosa.

CONCLUSION

A series of 2(chlormethyl) benzimidazole derivatives were synthesized and evaluated for their potential as anti-inflammatory and antimicrobial activity. Based upon the work done, it can be concluded that:

  • Compounds were synthesized in appreciable yield.
  • Spectral data and elemental analysis were found to be in agreement with the assigned structures.
  • All the synthesized compounds showed good to moderate anti-microbial activity.

Future Scope: The compounds synthesized can be further explored for their potential against different activities. Moreover the scheme can be further extended to synthesize new molecule and evaluate their different activities.

 

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