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Full text of "SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME BENZIMIDAZOLE DERIVATIVES"

Continental J. Pharmaceutical Sciences 2: 44 - 48, 2008 
©Wilolud Online Journals, 2008. 

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME BENZIMIDAZOLE DERIVATIVES 

D.N. Patil 1 , S.C.Chaturvedi 1 , D.L. Kale 1 , R.B. Kakde 1 and S.B. Dahikar 2 

School of Pharmacy, Devi Ahilya Vishwavidyalaya, Indore (M.P.), INDIA-452017 

'Department of Pharmaceutical Sciences, R.T.M. Nagpur University, Nagpur (M.S.), INDIA-440033 

2 Sanjivani Institute of Pharmacy and Research, Kopargaon (M.S.), INDIA-423603 

ABSTRACT 

A series of substituted benzimidazole compounds were synthesized by phase transfer 
catalyst (PTC) method using quaternary ammonium salt. Reaction has been carried out by 
conventional method in inert gas. Synthesized compounds were confirmed by IR, NMR, 
mass spectral and elemental analysis. The synthesized compounds were screened for their 
antibacterial and antifungal activity using paper disc diffusion method against some 
microorganism such as Escherichia coli, Bacillus pumilis, Staphylococcus aureus, Shigella 
sonnei, Proteus vulgaris, Pseudomonas aeruginosa, Aspergillus niger, Candida albicans. 
Almost all compounds shows potent antibacterial and antifungal activity. 

KEYWORDS: Benzimidazole derivatives, synthesis, antibacterial activity, antifungal 
activity 

INTRODUCTION 

Synthesis of benzimidazole compound is emerged as essential need for development of new pharmaceutical 
entity. It may provide scaffolds on which pharmacophores can be arranged to yield potent and selective drug 
(Cramer et al, 1988) . Every type of biological action detected, irrespective of the compounds involved in its 
induction, presents a potential lead (Cohen et al, 1990). The compounds responsible for the action have to be 
identified(Ozden et al, (2004), Rajasree et al, 2005). The range of the biological actions of potential interest is 
wide. Detection of biological action and identification of the chemical compounds involved to constitute the 
main and nearly unlimited source of leads for drug design(Natesh et al, (2003), Jarrahpour et al, (2004). The 
literature survey shows that in past recent years large number of compounds with different structures has been 
reported which exhibited antimicrobial activity (Han and Water (1998), Dunn et al, 1976). However, their 
clinical usefulness is still restricted because of their side effects. The use of antimicrobial is limited mainly due 
to development of resistance power. The aim of our paper is to synthesize benzimidazole derivatives and 
evaluation of their antimicrobial activity which can be used for antimicrobial therapy. 

MATERIALS AND METHODS 

Synthesis of benzimidazole derivative (Vogel, (2006), Seshaiah et al, (2001), Murat et al, (2005), Yingjie et al, 
(2005). 

All chemicals used in the synthesis were of synthetic grade. 

In a round bottom flask provided with efficient double surface condenser, 0.043 moles of aniline, 0.066 mol of 
carbon disulphide and 6.35 ml of ethanol were placed. The apparatus was set up in the fuming cup-board and 
heated on an electrically heated water bath for 8 hr or till content solidifies. Condenser was arranged for 
downward distillation, to remove the excess of carbon disulphide and alcohol. Residue in the flask was shaken 
with excess of dil. HC1 (1:10) to remove any aniline present, It was filtered then washed with water and dried. 
The crude drug was recrystallized with rectified spirit. 

STEP II: Synthesis of benzimidazole derivatives: 

Synthesis was carried out by phase transfer catalysis method by using quaternary ammonium salt. Six milliliter 

solution of potassium hydroxide (50% in water) and 0.25 mg of tetra butyl ammonium bromide (Q + X") were 

added in necked round bottom flask filled with inert gas and fitted with septum. The solution was then 

continuously stirred for 30 min with magnetic stirrer. First step product was added drop wise in above solvent 

and stirred for 4 hr. It was then filtered and recrystallized with solvent and dried. 

Synthesized benzimidazole derivatives with their respective yields are given in Table- 1. 



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D.N. Patil et ah Continental J. Pharmaceutical Sciences 2: 44 - 48, 2008 



General chemical scheme: 
R 



CS, 




NhL 



C 2 H 5 OH 




H H 

NU -N 
CO 



Diphenyl Urea 




Step I 




Step II 



Substituted Benzimidazole Derivatives 



STEP I: Synthesis Thiocarbanilide (Diphenyl Thiourea): 

C 2 H 5 OH 
2 QH,NH ? + CS ? 



-► S = C (NH.C 6 H 5 ) 2 +H 2 S 



STEP III: Structure Confirmation: 

Synthesized compounds were confirmed by IR, NMR, mass spectra and elemental analysis. 



Table 1: Synthesized benzimidazole derivatives. 



Comp. Code 


Substituent-R 


M.P. (°C) 


Yield (gm) 


DP-1 


H 


258-260 


2.3 


DP-2 


p-CH 3 


257-259 


1.8 


DP-3 


m-CH 3 


281-283 


1.5 


DP-4 


m-N0 2 


296-297 


2.5 


DP-5 


0-NO2 


284-286 


2.1 


DP-6 


p-OCH 3 


274-276 


1.2 


DP-7 


o-Br 


282-284 


1.8 


DP-8 


p-Cl 


285-287 


2.3 


DP-9 


m-Cl 


285-287 


1.1 


DP-10 


COOH 


291-293 


1.4 


Where DP-Benzimidazole Derivatives with substituent R 



STEP-IV: Antimicrobial screening: 

The standard pathogenic microorganism was procured from School of Life Sciences, Devi Ahilya 
Vishwavidyalaya, Indore, India and used in the study is given in table-2. 0.1ml of broth was inoculated in 10ml 
sterile nutrient broth and incubated at 37°C for 3hr. Turbidity of culture was measured with the help of Nephelo- 
turbidimeter. Viable count (10 s ) was measured by standard plate and used in the study. 



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D.N. Patil et ah Continental J. Pharmaceutical Sciences 2: 44 - 48, 2008 



Disc diffusion method as described by the National Committee of Clinical Laboratory Standards (2002) was 
used to determine the antibacterial activity of the various synthesized compounds. For antibacterial properties, 
0.1ml bacterial suspension of 10 5 CFU/ml was uniformly spread on Muller Hinton agar and Potato Dextrose 
Agar plate to form lawn cultures. The solutions of synthesized compounds were prepared lOOug/ml in 
tetrahydrofuran (THF). The blotting paper discs (6 mm diameter) were soaked in prepared solutions, and tested 
for their antibacterial and antifungal activity by disc diffusion technique (NCCS 2000). After incubation of 24 hr 
at 37°C, zone of inhibition of growth was measured in mm. The antibacterial activity was classified as highly 
active (>21mm), mild active (15-21mm) and slightly active (12-15mm) and less than 12mm was taken as 
inactive. Gentamycin lOmcg/disc (Hi -Media disc) for antibacterial and Griseofulvin for antifungal was used as 
positive control, while discs soaked in THF were placed on lawns as negative control. Experiment was 
performed in triplet to obtain persistent result. 

Table 2: Standard pathogenic microorganism with ATCC No. (American type culture collection) 



Microorganism 


ATCC No. 


Escherichia coli 


2109 


Bacillus pumilis 


2327 


Staphylococcus aureus 


2079 


Shigella sonnei 


-- 


Proteus vulgaris 


2813 


Pseudomonas aeruginosa 


2036 


Aspergillus niger 


545 


Candida albicans 


-- 



RESULTS AND DISCUSSION 

In this work, series of compounds were synthesized and evaluated for biological activity against micro 

organism. 

The anti-bacterial activity of the ten compounds was evaluated by paper disc diffusion method using 
Gentamycin as a standard. The minimum inhibitory concentration of the compound was determined. 
Compounds DP-1, DP-3 and DP- 10 were good activity against E. coli, while DP-2 and DP-6 were moderately 
active. Compounds DP-1, DP-2, DP-4 and DP-10 have greatest activity against B. pumilus, while DP-3 and DP- 
5 were moderately active where as DP-6, DP-7 and DP-8 shows zero activity. All Compounds have moderate 
activity against S. aureus, except DP-6 and DP-7 which are poorly active and DP-8 with zero activity. DP-10 
was active, while DP-5, DP-6 and DP-7 show zero activity and rest were poorly active against S. sonnei. 
Compounds DP-1, DP-2, DP-3, DP-7, DP-8 and DP-9 have moderate activity against P. vulgaris, while DP-4 
and DP-6 were moderately active where as DP-5 and DP-10 shows zero activity. Compounds DP-3, DP-9, and 
DP-10 have moderate activity against P. aeruginosa, where DP-5 has zero activity and rest shows poor activity. 
The anti-fungal activity of the ten compounds was evaluated by paper disc diffusion method using Griseofulvin 
as a standard. All compounds except DP-8, DP-9 and DP-10, which has zero activity shows moderate activity 
against A. niger as well as C. albicans. Detail results are depicted in Table-3. 

Synthesized Compounds DP-1 to DP-10, were confirmed by IR, NMR, mass spectral and elemental analysis. 

CONCLUSION 

Our finding suggests that the compounds DP2 and DP8 with methyl and CI substitute at para position are active 
molecule comparing to the previously synthesized derivatives. One can also synthesize the different substitute 
on methyl moiety to increase antimicrobial activity with minimal side effect. More potent benzimidazole 
derivative with substitute on methyl group at para position may find the active drug candidate in antimicrobial 
activity. The area of research on this molecule is still open to develop very potent agent in antimicrobial therapy. 



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D.N. Patil et ah Continental J. Pharmaceutical Sciences 2: 44 - 48, 2008 



ACKNOWLEDGEMENT 

The authors are thankful to the Panacea Biotech India Ltd. for providing NMR, Mass structural analysis report 
and Head of Department, School of Life Sciences, Devi Ahilya Vishwavidyalaya, Indore, India for providing 
pathogenic microorganisms. Authors are also thankful to Head of Department, School of Pharmacy, Devi 
Ahilya Vishwavidyalaya, Indore, India for providing necessary facilities to carry out experimental work. 

Table 3: Antimicrobial activity of benzimidazole Derivatives against microorganism with zone of inhibition (mm) 



Compounds code 


E. coli 


B. pumilis 


S. aureus 


S. sonnei 


P. vulgaris 


P. aeruginosa 


A. niger 


C. albicans 


DP-1 


18 


17 


16 


15 


14 


11 


18 


17 


DP-2 


17 


18 


17 


14 


14 


12 


17 


16 


DP-3 


18 


15 


14 


16 


15 


14 


16 


14 


DP-4 


15 


16 


16 


13 


12 


10 


15 


16 


DP-5 


- 


14 


15 


- 


- 


- 


15 


14 


DP-6 


17 


- 


11 


- 


11 


12 


16 


11 


DP-7 


14 


- 


09 


- 


14 


09 


16 


13 


DP-8 


15 


- 


- 


14 


13 


10 


- 


- 


DP-9 


14 


13 


14 


15 


14 


13 


- 


- 


DP- 10 


18 


16 


15 


18 


- 


14 


- 


- 


Gentamycin 


19 


16 


18 


19 


15 


16 


- 


- 


Griseofulvin 


- 


- 


- 


- 


- 


- 


22 


21 


Negative control 


- 


- 


- 


- 


- 


- 


- 


- 



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D.N. Patil et ah Continental J. Pharmaceutical Sciences 2: 44 - 48, 2008 



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Received for Publication: 04/1 1/2008 
Accepted for Publication: 20/12/2008 

Corresponding Author: 

Deepak N. Patil 

Sanjivani Institute of Pharmacy and Research, Kopargaon (M.S.), INDIA-423603 

E-Mail: dnp_pharma@ yahoo. coin 



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