Synthesis, Characterization and Antimicrobial Evaluation of N-Mannich Bases of (2- Substituted Phenyl) Benzimidazole Derivatives

 

Govindarao Kamala1*, N. Srinivasan2, K. Ravi Shankar3, R. Suresh4

1Department of Pharmaceutical Chemistry, Aditya Pharmacy College, Surampalem

2Department of Pharmacy, Annamalai University, Annamalai Nagar, Tamil Nadu

3Department of Pharmacology, Aditya College of Pharmacy, Surampalem

4Department of Pharmacy, Annamalai University, Annamalai Nagar, Tamil Nadu

*Corresponding Author E-mail: govindarao83@gmail.com

 

ABSTRACT:

The present study deals with synthesis of N-Mannich bases of (2- Substituted Phenyl) Benzimidazole derivatives and their spectral characterization by means of UV, IR and 1H NMR. Anti-bacterial activity and antifungal activity were carried out by cup-plate method using Bacillus Subtilis, Protease, Escherichia Coli and Staphylococcus Aeruginosa organisms for antibacterial activity, and Aspergillus Niger fungal organism for antifungal activity. The potency of the synthesized compounds was determined against standard drugs Ciprofloxacin Clotrimazole by measuring the zone of inhibition. The resulted synthesized compounds (H11 to H20) were screened for antibacterial activity and antifungal activity. The synthesized compounds were found to possess moderate to weak activity although several 2-phenyl benzimidazole derivatives (Compounds H11, H13, H17, H18 and H20) were reported for good antibacterial, antifungal activity. The compound H11, H13 and H20 were active against all organisms. Reaming compounds show moderate activity. Whereas the compounds H11, H13, H17 and H18 were active against Aspergillus Niger rest of the compounds showed only weak activity when compared to the standard Ciprofloxacin, Clotrimazole.

 

KEY WORDS: Substituted Benzimidazoles, antibacterial activity, antifungal activity, cup plate method.

 

 


 

 

INTRODUCTION:

The benzimidzole contains a phenyl ring fused to an imidazole ring; the important group of substances has found practical application in a number of fields. Recently in benzimidazole, chemistry has been revived somewhat by the discovery that the 5, 6-dimethyl benzimidazole moiety is a part of the chemical structure of vitamin B12(1-2). Benzimidazole derivatives are of wide interest because of their diverse biological activity and clinical applications, and are remarkably effective compounds both with respect to their inhibitory activity and their favorable selectivity ratio. These derivatives are found to exhibit various biological activites such as anticancer(3-4), anthelmenthic5, antiprotozoal6, antimicrobial(7-12), anti-inflammatory(13-18), analgesic(19-20), antiviral(21-22), anti ulcer acitivity23.

 

The present study utilizes the coupling phenomenon of o-phenylenediamine with substituted aromatic acids in presence of ring closing agents like glacial acetic acid to form 2-substituted phenyl benzimidazoles and then 2 hrs refluxed with di-phenyl amine in formaldehyde and followed by antibacterial and anti fungal screening by Cup-Plate method(24-26).

 

MATERIALS AND METHODS:

All the reagents used for synthesis were of analytical grade commercial products and used without further purification. The melting points of the synthesized compounds were determined using an electric melting point apparatus by open capillary method. (Expressed in degree Celsius) and are uncorrected. The progress of reactions and purity of synthesized compounds were checked on silica gel-G TLC plates using various solvent combinations of different polarity. The spots were detected with iodine vapors as visualizing agent. The λmax (in nm) of the synthesized compounds was recorded on Elico SL 164 UV-visible spectrophotometer using alcohol as solvent. The FT-IR spectra of the synthesized compounds were recorded on a FT-IR Perkin Elmer Spectrum RX-I spectrometer using KBr disc in the range of 4000-400 cm−1. The Proton NMR (1H NMR) spectra were recorded in Bruker AC-F 400 FT-NMR spectrometer at a frequency of 400 MHz. Spectra were obtained in deuterated acetone (acetone-d6) using TMS (δ 0.00 ppm) as an internal standard at room temperature. Chemical shift (δ) values are expressed in ppm relative to internal standard.

 


 

Synthetic Scheme:

 

Fig.1: Synthetic Scheme for N-Mannich bases of (2- Substituted Phenyl) benzimidazole

 

 

Table.1: Different aromatic acids used in substitution reaction to get target molecules

ompound Code

H-1

H-2

H-3

H-4

H-5

H-6

H-7

H-8

H-9

H-10

R

H

2-OH

2-Cl

4-CH3

4-OH

4-Cl

4-NO2

2-benzyl

2-NH2

4-NH2

 


General method for Synthesis of N-Mannich bases of (2- Substituted Phenyl) benzimidazole derivatives:

Procedure for the preparation of 2- (substituted-phenyl) benzimidazole (Step I): A solution of benzoic acid (0.01mol) and 1,2- phenylenediamine (0.01mol) in 20ml of glacial acetic acid was stirred in 15 min with heating at 1500c the precipitate is obtained after addition of  10%NaOH in ice bath. Then the product is filtered, dried in hot air oven and recrystallized from ethanol. The compounds were identified by TLC (n-Hexane: Etheyl acetate1:1) Melting point.

 

Procedure for the Preparation of Compounds of N-Mannich Bases of 2-(Subtituted Phenyl) Benzimidazole (Step II): To a solution of 2-subtituted phenyl benzimidazole (0.005mol) in10 ml of ethanol.0.005mol of diphenylamine and 0.005 mol of formaldehyde were added and stirring for 3hour with heating. Then, the reaction mixture was refluxed for another 2 hour with 70-80 temperature. On cooling, the product formed was filtered, dried in vacuum and recrystallized from DMSO. The compounds were purified by TLC (n-Hexane: Ethyl acetate1:1), Melting point.

 

Antibacterial Evaluation:

The antibacterial activity of the synthesized compounds was evaluated systematically against Bacillus subtilis, Protease, Escherichia Coli and Staphylococcus Aeruginosa, which are the representative types of gram positive and gram-negative organisms respectively. The inhibition zones (in mm) of synthesized compounds were determined by cup-plate method. The sterilized medium (autoclaved at 121°C for 20min) was inoculated using 18 hr slant cultures of the test organisms and transferred into sterile Petri dishes and allowed to the media to solidify. Cups of 8mm diameters were made on solidified media. Solutions of the synthesized compounds at a concentration of 50μg/ml and 100μg/ml were prepared in DMSO. 50μl of each solution was placed in cups by means of sterile pipette. In each plate one cup was used for standard and other two for test solutions. The plates thus prepared were left for 90 min in a refrigerator for diffusion. The plates were incubated at 37°C for 24 hrs and examined for inhibition zones. The experiment was performed in duplicate and the average diameter of the zones of inhibition was recorded Ciprofloxacin (50μg/ml) was used as standard.

 

Antifungal Evaluation:

The anti-fungal activity of all compounds was determined on potato dextrose agar medium against Aspergillus niger.  Clotrimazole 100 μg/ml was used as a standard and DMSO was used as control. The sterile molten potato dextrose medium was cooled to 45oC and inoculated with test organisms and mixed the contents thoroughly and poured into the sterile petri dishes under aseptic conditions. All the inoculated Petri dishes were incubated at 28oC for 4 days and the extent diameter of inhibition was measured as the zone of inhibition in millimeters. Solutions of the synthesized compounds at a concentration of 50μg/ml and 100μg/ml were prepared in DMF. Clotrimazole was used as standard anti-fungal for comparison and solution were prepared by using sterile water, so that the concentration of the solution was 100 μg/ml.


 

RESULTS AND DISCUSSON:

Table No. 1: Physical Characterization data of synthesized compounds of 2-(substituted phenyl) benzimidazole- 1 (H1-H10)

 

 

 

Table No. 2: Physical Characterization data of synthesis of N-Mannich base of 2-(substituted phenyl) benzimidazole- 2 (H11-H20)

S. No

Compound code

R

Molecular formula

Mol. wt (g)

Melting point (0C)

% Yield

Rf values

1

H-1

H

C13H1ON2

194

295

85

0.85

2

H-2

2-OH

C13H10N2O

210

190

57

0.80

3

H-3

2-Cl

C13H9N2Cl

228.5

235

60

0.83

4

H-4

4-CH3

C14H12N2

208

220

58

0.85

5

H-5

4-OH

C13H10N2O

210

164

54

0.82

6

H-6

4-Cl

C13H9N2Cl

228.5

230

59

0.80

7

H-7

4-NO2

C13H9N3O2

342

250

60

0.79

8

H-8

1-CH3

C14H12N2

208

195

60

0.81

9

H-9

2-NH2

C13H11N3

209

211

52

0.65

10

H-10

4-NH2

C13H11N3

209

449

45

0.69

 

 

 

 

S. No

Compound Code

Molecular Formula

Molecular Weight

Melting Point (0c)

% of Yield

Rf Values

1

H11

C26H21N3

375

180

60

0.95

2

H12

C26H21N3O

391

150

55

0.92

3

H13

C26H20N3Cl

411.5

230

75

0.90

4

H14

C27H23N3

389

175

54

0.89

5

H15

C26H21N3O

391

120

57

0.93

6

H16

C26H20N3Cl

411.5

232

51

0.90

7

H17

C26H20N5O

418

242

60

0.91

8

H18

C27H23N3

389

180

58

0.92

9

H19

C26H22N4

362

130

45

0.89

10

H20

C26H22N4

362

122

52

0.90

 

 


Spectral data of Synthesized Compounds (Compounds H1-H10 and H11-H20):

Compound H1:

1H NMR Spectra (δ ppm): 12.9 Singlet (1H), 7.09-8.1 Multiplet (9H)

IR Spectra (cm-1): 3230 (N-H Streching), 2989 (Ar-CH Stretching), 1675 (C=C Streching), 1459 (C=N Streching)

 

Compound H2:

1H NMR Spectra (δ ppm): 4.59 Singlet (1H), 6.92-8.06 Multiplet (8H), 13.1 Singlet (1H)

IR Spectra (cm-1): 3178 (NH stretching), 3048 (Ar-H Stretching), 2986 (C=N Stretching), 1602 (C-N Stretching)

 

Compound H3:

1H NMR Spectra (δ ppm): 12.1 Singlet (1H), 7.03-7.70 Multiplet (8H)

IR Spectra (cm-1): 3421 (NH stretching), 3056 (Ar-H Stretching), 1602 (C=N Stretching), 1418 (C-N Stretching), 750 (C-Cl stretching).

 

Compound H4:

1H NMR Spectra (δ ppm): 2.4 singlet (3H),5.2 singlet (1H),7.27 triplet (2H), 7.70 doublet (2H),7.30 doublet (1H), 7.12 doublet (1H).

IR Spectra (cm-1): 3431 (NH stretching), 3054 (Ar-H Stretching), 1602 (C=N Stretching), 1418 (C-N Stretching), 2800 (CH stretching).

 

Compound H5:

1H NMR Spectra (δ ppm):  5.0 singlet (1H),7.7 doublet (2H), 7.26 triplet (2H),7.31 doublet (2H), 6.78 doublet (2H).

IR Spectra (cm-1): 3167 (NH stretching), 3032 (Ar-H Stretching), 2980 (C=N Stretching), 1601 (C-N Stretching), 2800 (C-H stretching), 1240 (C-O stretching).

 

Compound H6:

1H NMR Spectra (δ ppm):  5.0 singlet (1H),7.7 doublet (2H), 7.26 triplet (2H),7.41 doublet (2H), 7.33 doublet (2H).

IR Spectra (cm-1): 3433 (NH stretching), 3054 (Ar-H Stretching), 1601 (C=N Stretching), 1418 (C-N Stretching), 2800 (CH stretching), 750 (C-Cl stretching).

 

Compound H7:

1H NMR Spectra (δ ppm):  5.0 singlet (1H),7.7 doublet (2H), 7.26 triplet (2H),7.74 doublet (2H), 8.25 doublet (2H).

IR Spectra (cm-1): 3167 (NH stretching), 3032 (Ar-H Stretching), 2980 (C=N Stretching), 1601 (C-N Stretching), 2800 (C-H stretching), 1530 (C-N stretching).

 

Compound H8:

1H NMR Spectra (δ ppm): 5.0 singlet (1H),7.7 doublet (2H), 7.26 triplet (2H),1.54 singlet (1H), 5.8 doublet (1H),5.9 triplet (2H),5.82 triplet (1H), 2.5 singlet (1H).

IR Spectra (cm-1): 3430 (NH stretching), 3054 (Ar-H Stretching), 1600 (C=N Stretching), 1418 (C-N Stretching), 2803 (CH stretching).

 

Compound H9:

1H NMR Spectra (δ ppm): 5.0 singlet (1H), 4.0 singlet (1H), 7.7 doublet (2H), 7.26 triplet (2H), 6.5 doublet (1H),6.9 triplet (1H),6.682 triplet (1H), 7.23 doublet (1H).

IR Spectra (cm-1): 3430 (NH stretching), 3054 (Ar-H Stretching), 1600 (C=N Stretching), 1418 (C-N Stretching), 2803 (CH stretching), 3341 (N-H stretching).

 

Compound H10:

1H NMR Spectra (δ ppm): 5.0 singlet (1H), 4.0 singlet (1H), 7.7 doublet (2H), 7.26 triplet (2H), 7.23 doublet (2H), 6.52 doublet (2H).

IR Spectra (cm-1): 3430 (NH stretching), 3054 (Ar-H Stretching), 1600 (C=N Stretching), 1418 (C-N Stretching), 2803 (CH stretching), 3345 (N-H stretching). 

 

Compound H11:

1H NMR Spectra (δ ppm): 7.7 doublet (2H),7.26 triplet (2H),7.48 doublet (2H),7.32 triplet (2H),7.22 triplet (1H),6.81 doublet (1H),6.50 triplet (1H), 4.9 singlet (2H), 6.82 triplet (1H),6.6 doublet (1H),4.1 singlet (1H),6.46 doublet (2H),7.01 triplet (2H),6.62 triplet (1H).

IR Spectra (cm-1): 3232 (N-H Streching), 2988 (Ar-CH Stretching), 1674 (C=C Streching), 1459 (C=N Streching), 2803 (CH stretching), 2230 (C-N stretching).

 

Compound H12:

1H NMR Spectra (δ ppm): 7.7 doublet (2H),7.26 triplet (2H),5.1 singlet(OH),6.79 doublet (1H),7.05 triplet (1H),6.88 triplet (1H),7.31 doublet (1H), 4.9 singlet (2H), 6.82 triplet (1H),6.6 doublet (1H),4.1 singlet (1H),6.46 doublet (2H),7.01 triplet (2H),6.62 triplet (1H).

IR Spectra (cm-1): 3178 (NH stretching), 3048 (Ar-H Stretching), 2986 (C=N Stretching), 1602 (C-N Stretching), 2803 (CH stretching), 2230 (C-N stretching), 1020 (C-O stretching).

 

Compound H13:

1H NMR Spectra (δ ppm): 7.7 doublet (2H),7.26 triplet (2H),7.33 doublet (1H),7.15 triplet (1H),7.20 triplet (1H),7.41 doublet (1H), 4.9 singlet (2H), 6.82 triplet (1H),6.6 doublet (1H),4.1 singlet (1H),6.46 doublet (2H),7.01 triplet (2H),6.62 triplet (1H).

IR Spectra (cm-1): 3421 (NH stretching), 3056 (Ar-H Stretching), 1602 (C=N Stretching), 1418 (C-N Stretching), 2803 (CH stretching), 2230 (C-N stretching), 750 (C-Cl stretching).

 

Compound H14:

1H NMR Spectra (δ ppm): 7.7 doublet (2H),7.26 triplet (2H),7.36 doublet (2H),7.12 doublet (2H),2.33 singlet (3H) , 4.9 singlet (2H), 6.81 doublet (1H),6.50 triplet (1H),6.82 triplet (1H),6.6 doublet (1H),4.1 singlet (1H),6.46 doublet (2H),7.01 triplet (2H),6.62 triplet (1H).

IR Spectra (cm-1): 3431 (NH stretching), 3054 (Ar-H Stretching), 1602 (C=N Stretching), 1418 (C-N Stretching), 2800 (CH stretching), 2230 (C-N stretching).

 

Compound H15:

1H NMR Spectra (δ ppm): 7.7 doublet (2H),7.26 triplet (2H),7.31 doublet (2H),6.79 doublet (2H), 5.0 singlet (1H) , 6.81 doublet (1H),6.50 triplet (1H), 4.9 singlet (2H) ,6.82 triplet (1H),6.6 doublet (1H),4.1 singlet (1H),6.46 doublet (2H),7.01 triplet (2H),6.62 triplet (1H).

IR Spectra (cm-1): 3167 (NH stretching), 3032 (Ar-H Stretching), 2980 (C=N Stretching), 1601 (C-N Stretching), 2800 (C-H stretching), 1240 (C-O stretching), 2230 (C-N stretching).

 

Compound H16:

1H NMR Spectra (δ ppm): 7.7 doublet (2H),7.26 triplet (2H),7.42 doublet (2H),7.33 doublet (2H) , 4.9 singlet (2H),6.81 doublet (1H),6.50 triplet (1H) ,6.82 triplet (1H),6.6 doublet (1H),4.1 singlet (1H),6.46 doublet (2H),7.01 triplet (2H),6.62 triplet (1H).

IR Spectra (cm-1): 3433 (NH stretching), 3054 (Ar-H Stretching), 1601 (C=N Stretching), 1418 (C-N Stretching), 2800 (CH stretching), 750 (C-Cl stretching), 2230 (C-N stretching).         

 

Compound H17:

1H NMR Spectra (δ ppm): 7.7 doublet (2H),7.26 triplet (2H),7.74 doublet (2H),8.25 doublet (2H), 4.9 singlet (2H),6.81 doublet (1H),6.50 triplet (1H) ,6.82 triplet (1H),6.6 doublet (1H),4.1 singlet (1H),6.46 doublet (2H),7.01 triplet (2H),6.62 triplet (1H).

IR Spectra (cm-1): 3167 (NH stretching), 3032 (Ar-H Stretching), 2980 (C=N Stretching), 1601 (C-N Stretching), 2800 (C-H stretching), 1530 (C-N stretching), 2230 (C-N stretching).

 

Compound H18:

1H NMR Spectra (δ ppm): 7.7 doublet (2H),7.26 triplet (2H),2.53 singlet (3H),2.28 doublet (2H),5.8 doublet (1H) , 5.8 triplet (1H) , 5.9 triplet (2H) ,4.9 singlet (2H),6.81 doublet (1H),6.50 triplet (1H) ,6.82 triplet (1H),6.6 doublet (1H),4.1 singlet (1H),6.46 doublet (2H),7.01 triplet (2H),6.62 triplet (1H).

IR Spectra (cm-1): 3430 (NH stretching), 3054 (Ar-H Stretching), 1600 (C=N Stretching), 1418 (C-N Stretching), 2803 (CH stretching) ,2230 (C-N stretching).

 

Compound H19:

1H NMR Spectra (δ ppm): 7.7 doublet (2H),7.26 triplet (2H),4.0 singlet (2H),6.52 doublet (1H),6.97 triplet (1H) , 6.68 triplet (1H) , 7.23 doublet (2H) ,4.9 singlet (2H),6.81 doublet (1H),6.50 triplet (1H) ,6.82 triplet (1H),6.6 doublet (1H),4.1 singlet (1H),6.46 doublet (2H),7.01 triplet (2H),6.62 triplet (1H).

IR Spectra (cm-1): 3430 (NH stretching), 3054 (Ar-H Stretching), 1600 (C=N Stretching), 1418 (C-N Stretching), 2803 (CH stretching), 3341 (N-H stretching), 2230 (C-N stretching).

 

Compound H20:

1H NMR Spectra (δ ppm): 7.7 doublet (2H),7.26 triplet (2H),4.0 singlet (2H),7.23 doublet (2H),6.52 doublet (2H) ,4.9 singlet (2H),6.81 doublet (1H),6.50 triplet (1H) ,6.82 triplet (1H),6.6 doublet (1H),4.1 singlet (1H),6.46 doublet (2H),7.01 triplet (2H),6.62 triplet (1H).

IR Spectra (cm-1): 3430 (NH stretching), 3054 (Ar-H Stretching), 1600 (C=N Stretching), 1418 (C-N Stretching), 2803 (CH stretching), 3345 (N-H stretching), 2230 (C-N stretching).

 

Biological Evaluation of Synthesized Compounds (H11-H20):

Anti-bacterial activity:

In the study of antibacterial activity, all the synthesized compounds could show the activity. Among these the compounds H11 (2 phenyl benzimidazole derivative), H13 (2 phenyl [2-chloro] benzimidazole derivative), H18 (2phenyl [benzyl] benzimidazole derivative), H20 (2phenyl [4-amino] benzimidazole derivative) show maximum significance against all the organisms. But the maximum significance shows against E.Coli and S.Aeroginosa the data given in the Table No-3. Rest of the compounds shows poor to moderate activity when compared to standard drug.

 

Antifungal activity:

From the antifungal data Table No: 3 H11 (2phenylbenzimidazolederivative), H13 (2phenyl [2-chloro] benzimidazole derivative), H17 (2phenyl [4nitro] benzimidazole derivative) and H18 (2phenyl [benzyl] benzimidazole derivative) shown good significant against A.Niger. H19 (2phenyl [2-amino] benzimidazole derivative), H20 (2phenyl [4-amino] benzimidazole derivative) shown poor activity when compared to standard drug. Reaming compounds had shown poor to moderate activity.


 

Fig No 1:  Structures of Synthesized Compounds (from H11 to H20)


Table No-3: Antibacterial and Antifungal Activities of Synthesized Compounds (H11-20)

Sample Code

*Inhibition zone diameter in cm

 

B.Subtilis

Protease

E.Coli

S.Aeroginosa

A.Niger

100

μg/ml

50

μg/ml

100 mg/ml

50μg/ml

100 mg/ml

50

μg/ml

100

mg/ml

50

μg/ml

100 μg/ml

50 μg/ml

H11

13

10

14

11

18

13

20

12

19

11

H12

13

8

12

13

18

8

19

14

12

10

H13

15

13

16

14

19

14

17

15

23

20

H14

10

8

6

7

10

9

12

10

9

9

H15

14

10

6

9

19

11

13

12

8

7

H16

12

11

10

9

15

12

13

11

7

6

H17

18

14

15

14

16

13

19

15

19

18

H18

10

8

6

4

8

6

13

14

21

20

H19

7

5

11

10

14

9

12

8

6

5

H120

17

15

14

13

19

17

18

16

5

4

Ciprofloxacin

20

19

22

18

19

18

20

21

-

-

Clotrimazole

-

-

-

-

-

-

-

-

25

23

DMSO

-

-

-

-

-

-

-

-

 

 

*Each value is an average of three independent determinations ± Standard deviation

Note: ‛-denotes no activity, 4-6 poor activity, 7-9cm moderate activity, 10mm and above 10mm good activity.

 

 


CONCLUSION:

The synthesized compounds from H11 to H20 were screened for antibacterial and antifungal activity. The antimicrobial activity shown by the compounds inferior to that of standard drug, it is described in respective table, among the synthesized compounds H11, H13, H17, H18 and H20 shown good results in antimicrobial activity. From the results one can establish that the synthesized substituted benzimidazoles derivatives can rich source of exploitation. Therefore, the search of new generation of active compounds, it may worthwhile  to explore the possibility in this area by making or introducing different functional group as  substituted secondary amine moieties or phenyl benzimidazole moiety which may result in better pharmacological agents with higher potency.

 

REFERENCES:

1.     Wright JB. The chemistry of benzimidazoles. Chem Rev., 1951; 48: 397-541.

2.     Walther RV, Kessler A. Zur kenntnis einiger benzimidazole 2, 4-nitramido    diphenylamine. J Prakt Chem., 1906; 74: 241-8.

3.     Selvem et al synthesis, anti-viral and cytotoxicity studies of some novel N-substituted benzimidazole derivatives. (39). IJPSR (2010).Vol.1 Issue 9:105- 109, ISSN: 0975-8232.

4.     K.Vijayakumar and A.Jafar Ahamed synthesis, anti tumor, anti-diabetic, anti-asthmatic activities of some novel benzimidazole derivatives (37). J. Chem. pharm. Res., 2010, (2)4:215-224 ISSN No: 0975-7384.

5.     Ramesh Sawant et al Synthesis and biological evalution of some novel 2- phenyl benzimidazole-1-acetamide derivatives as potential antihelminthic agents. Acta pharm.61 (2011), 353-361.

6.     Zygmunt Kazimierczuk et al synthesis, antiprotazoal and antibacterial activity of nitro-and halogeno substituted benzimidazole derivatives (55) .Ac. Biochem. Polonica, Vol. 49 No. 1/2002, 185- 195.

7.     M. Vijey Aanandhi et al synthesis and characterization of novel mannich bases of benzimidazole derivatives for antibacterial and anti fungal activity. Int J of pharmacy and pharm sci., 0 vol 5, issue 2; 2013.

8.     Balram soni et al Synthesis and antimicrobial activity of some novel N- substituted benzimidazole derivatives (26). J. Ph. Res., 2012, 5(7), 3523-3526, ISSN: 0974-6943.

9.     Hasan KUCUKBAY et al synthesis and antimicrobial activities of some bridged bis-benzimidazole derivatives Turk J Chem, 35(2011), 561-571.

10.   Ibrahim and begum synthesis and antimicrobial activity of some benzimidazole derivative with i

11.   buprofen (31).IJPSR, 2011; Vol-2(2):298-302 ISSN: 0975-8232.

12.   K.Anandrajogopal et al synthesis, antimicrobial evalution of 2- mercaptobenzimidazole derivatives (40). Int Jof Chem and ana Sci., 2010, 1(19), 214-216.

13.   Parmender Singh Rathee et al Synthesis and antimicrobial studies of substituted 2-phenylbenzimidzole derivatives (29). J. of applied ph. Sci., 01, (10); 2011:140-142, ISSN: 2231-3354.

14.   Rashmi Arora et al analgesic and anti-inflammatory activity of some newly synthesized novel pyrazole derivatives of benzimidazole (22). Current research in chemistry, 2012, ISSN: 1996-5052.

15.   Julee.p et al structure activity relationship studies of synthesized pyrazolone derivatives of imidazole, benzimidazole and benzatriazole moiety for anti inflammatory activity. J. of app. Pharm.sci. 01(04); 2011:115-120, ISSN: 2231-3354.

16.   Abidin ayalp the derivatives of 3-(1h benzimidazole -2) propanoic acid synthesis and analgesic and anti-inflammatory activity, Pakistan J. pharm. Sci, 2(1) 7-12, 1989.

17.   J.T.Leonard et al synthesis, anti-inflammatory and antibacterial activities of 4-substituted phenyl benzimidazoles. Asian j. of chemistry vol.18, no.2 (2006), 1104-1108.

18.   Thakurdesi et al Synthesis and anti inflammatory activity of some benzimidazole-2 carboxylic acids pharmcologyonline 1:314-329(2007).

19.   Gummadi Sridhar babu et al characterization and evalution of novel N-(1H-benzimidazol-2-yl)-2-isatinylidene-hydrazinecaroxamide derivatives as anti-inflammatory agents. Der pharm Chem, 2010, 2(3):196-204.

20.   Ranjith u. s. et al microwave assisted synthesis of fluro, chloro 2-subtituted benzimidazole thiazine derivatives, for analgesic activities. IJRPS 2012, 2(3), 146-158.

21.   Sravanthi M. et al Synthesis, characterization and evaluation of analgesic activity of some 5-nitro benzimidazole derivatives (27). J.of Chem. and Ph. Res., 2012, 4(8):3836, ISSN: 0975- 7384.

22.   Simone Budow et al substituted benzimidazoles: Antiviral activity and synthesis of nucleosides9 (45) (46). ARKTVOC 2009 (iii) 225-250.

23.   Ashush Kumar et al  synthesis and antiviral activities of N-substituted-2-substituted-benzimidazole derivatives .Ind. J. of Chem., Vol. 4, Feb 2006, pp. 489-493.

24.   Khan et al synthesis and anti ulcer, anti secretory activity of some new substituted 2-(pyrimidinylsulfinyl) benzimidazoles derivatives. Int. J. of Res. In Pharm. And Biomed. SCI., Vol 2(2) Apr –jun -2011, ISSN: 2229-3701.

25.   Hawkey PM, Lewis DA. Medical bacteriology-a practical approach, Oxford University press, 1994.

26.   Cruickshank R, Duguid JP, Marmion BP, Swam HA. The practice of medical microbiology. 12th ed. Churchill Livingstone London, 1975: 2544.

27.    S.K Kullkarni Hand Book of Experimental Pharmacology, 1st Ed. Vallabh Prakashan, Dehli, 72; 1987.

 

 

 

 

 

 

 

 

Received on 11.02.2018       Accepted on 16.04.2018

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2018; 8(2): 87-93.

DOI:  10.5958/2231-5691.2018.00015.1