Synthesis and Pharmacological Evaluation of Some New 2...

ISSN: 0973-4945; CODEN ECJHAO

E-Journal of Chemistry

http://www.e-journals.net 2009, 6(S1), S342-S346

Synthesis and Pharmacological Evaluation of

Some New 2-Phenyl benzimidazoles

Derivatives and their Schiff’s Bases

Y S. CHHONKER§, B. VEENU

§, S R. HASIM

§, NIRANJAN KAUSHIK

§,

DEVENDRA KUMAR and PRADEEP KUMAR*

§College of Pharmacy, I.F.T.M., Moradabad (UP), India.

Pharmacokinetic and Metabolic Division, CDRI, Lucknow (UP), India. *Department of Pharmaceutical Analysis,

PES College of Pharmacy, Bangalore, India.

[email protected]

Received 8 May 2009; Accepted 6 July 2009

Abstract: Some new 2- phenyl benzimidazole derivatives were synthesised by

cyclocondensation with appropriate reagents. The compounds synthesised were

identified by 1H NMR, FAB Mass and FT-IR spectroscopic techniques. All

compounds studied in this work were screened for their in vitro antimicrobial

activities against the standard strains: Staphylococcus aureus ATCC - 25923,

ATCC - 441 and Bacillus subtilis ATCC- 6633 as gram positive, Escherichia

coli ATCC - 11775 and Pseudomonas aeruginosa ATCC 10145 as gram

negative bacteria. Some of the compounds inhibited the growth of gram-

positive bacteria (B. subtilis and S. aureus) at MIC values between 25 and

200 mg/mL. Some of the compounds exhibit antimicrobial activity against

gram negative bacteria (E. coli and P. Aeruginosa) MIC values between 25

and 200 mg/mL.

Keywords: Benzimidazoles, MIC, Antimicrobial activity, Schiff’s bases.

Introduction

Benzimidazoles are very useful intermediates/subunits for the development of molecules of

pharmaceutical or biological interest. Substituted benzimidazole derivatives have found

applications in diverse therapeutic areas including anti ulcers, anti hypertensives, anti virals,

antifungals, anticancers and antihistaminics to name just a few1–3

. The widespread interest

in benzimidazole containing structures has prompted extensive studies for their synthesis.

There are two general methods for the synthesis of 2-substituted benzimidazoles. One is the

Synthesis and Pharmacological Evaluation S343

coupling of phenylenediamines and carboxylic acids4 or their derivatives (nitriles, imidates,

or ortho esters)5, which often requires strong acidic conditions and sometimes combines with

very high temperatures (i.e., PPA, 180 0C) or the use of microwave irradiation

6. The other way

involves a two-step procedure that includes the oxidative cyclo-dehydrogenation of aniline

Schiff’s bases, which are often generated in situ from the condensation of phenylenediamines

and aldehydes. Various oxidative reagents such as nitrobenzene (high-boiling point

oxidant/solvent)7, 1,4-benzoquinone

8, DDQ

9, tetracyanoethylene

10, benzofuroxan

11, MnO2

12,

Pb(OAc)4, Oxone, NaHSO3 and Na2S2O5 have been employed. Partially due to the availability

of a vast number of aldehydes, the later method has been extensively used.

The compounds with the structure of –C= N- (azomethine group) are known as Schiff

bases, which are usually synthesized from the condensation of primary amines and active

carbonyl groups. Schiff bases important class of compounds in medicinal and pharmaceutical

field. They show biological properties include antibacterial, antifungal antitumor, analgesic

and anti-inflammatory activity. Presence of –C=N- and other functional groups forms more

stable complexes compared to Schiff bases having only –C=N- coordinating moiety12

.

Experimental

Melting points were determined with an electrothermal melting point apparatus and are

uncorrected. Commercially available reagent grade chemicals were used as received. All reactions

were followed by TLC, with detection by UV light and/or spraying a 20% KMnO4 aq. solution

column chromatography was performed on silica gel (60-120 mesh, E. Merck). IR spectra were

recorded as thin films or in chloroform solution with a Shimadzu (4000-450 cm-1) FTIR

spectrophotometer. 1H NMR spectra were recorded on a Brucker AV400 in CDCl3. Chemical shift

values are reported in ppm relative to SiMe4 as internal reference, unless otherwise stated; s

(singlet), d (doublet), t (triplet), m (multiplet); J in hertz. FAB mass spectra were performed using

a mass Spectrometer Jeol SX-102 and ESI mass spectra with Quattro II (Micromass).

NH2

NH2

HOOC

H2N

PPA

190-195 CReflux N

H

N

NH2

CHO

R

NH

N

N

CH

R

I, YS-A

II

O-PhenylenediamineAnthranilic cid

1

Scheme 1.

o-Phenylenediamine

190-195 oC

Reflux

S.No. R

1. H

2. 2-OH

3. 3-NO2

4. 3-OCH3, 4-OH

5. 4-OCH3

S344 PRADEEP KUMAR et al.

General procedure for the preparation of the 2-(2- aminophenyl) benzmidazole (YS-

A, I) and Schiff bases (II)

o-Phenylenediamine was condensed with anthranilic acid in poly phosphoric acid at

190-195 0C for 4 h. The reaction mixture was poured into crushed ice. Filtered, washed,

dried and recrystalized. The product 2-(2-aminophenyl) benzimidazole (YS-A, I) was then

treated with various aromatic aldehydes to obtain the Schiff bases compounds (II).

Table 1. Schiff bases derived from 2-(2- amino phenyl) benzimidazole (YS-A).

NH2

NH2

+

NH2

OOH

PPANH

N

NH2

OHCPhenylenediamine

p-anino benzoic acid

IV

R

NH

N

N

R

YS-B

Preparation of 2-(4- aminophenyl) benzmidazole (YS-B, IV) and Schiff bases (V)

In another sequence of reactions, o-phenylenediamine was condensed with p-amino benzoic

acid in poly phosphoric acid at 190-195 0C for 4 hours. The reaction mixture was poured

into crushed ice. The product was filtered, washed, dried, and recrystalized. The product

2-(4-aminophenyl) benzimidazole (YS-B, IV) was then treated with various aromatic

aldehydes to obtain the Schiff bases compounds (V).

S.No. Compd

code

Substitution

(R)

Molecular

Formula

Molecular

Weight

Melting

Point, OC

%

yield

Rf

Value

1. YS-7 H C20H15N3 297.13 198-200 47 0.78

2. YS-1 2-OH C20H15N3O 313.35 259-260 66 0.65

3. YS-6 3-NO2 C20H14N4O2 342.35 218-220 73 0.72

4. YS-5 3-OCH3, 4-OH C21H21N3O2 343.13 268-270 60 0.69

5. YS-5a 4-OCH3 C21H17N3O 327.13 240-242 50 0.52

S.No. R

1. H

2. 2-OH

3. 3-NO2

4. 3-OCH3, 4-OH

5. 4-OCH3

V

Phenylenediamine

p-Aminobenzoic acid

∆

Scheme 2

Synthesis and Pharmacological Evaluation S345

Table 2. Schiff bases derived from 2-(4- aminophenyl) benzimidazole (YS-B).

S.No. Compd

code

Substitution

(R)

Molecular

Formula

Molecular

Weight

Melting

Point, 0C

%

yield

Rf

Value

1. YS-10 H C20H15N3 297.13 210-211 40 0.73

2. YS-8 2-OH C20H15N3O 313.35 245-246 77 0.60

3. YS-2 3-NO2 C20H14N4O2 342.35 255-256 81 0..67

4. YS-9 3-OCH3,

4-OH C21H21N3O2 343.13 230-232 60 0.63

5. YS-4 4-OCH3 C21H17N3O 327.13 220-221 56 0.58

Results and Discussion

The antibacterial activity of all of the compounds against S. aureus and B. subtilis as gram

positive and E. coli and P. aeruginosa as gram negative bacteria showed lower potencies

than the control drug ampicillin. Some of the compounds (YS-1, YS-2, YS-5, YS-6 and YS-

8) showed good activity with a MIC value of 25 µg/mL against P. aeruginosa, which was

comparable to ampicillin.Compound YS-2 and YS-10 exhibited significant activity against

B. subtilis with a 25 µg/mL. As a result of antimicrobial activity, substitution of amine

function to anilide at the 2-phenyl moiety of benzimidazole ring increases the activity

against B.subtilis. It was also observed that the presence of N=CH-group (azomethine)

increase the potencies of the synthesized.

Conclusion

The present work has demonstrated the use of a simple cyclocondensation method for the

synthesis of 2-(2-amino phenyl) benzimidazole and 2-(4-amino phenyl) benzimidazole. This

method was able to give reasonably good and clean yields. Ten derivatives were prepared

and biologically evaluated for antibacterial activity. The basic N=C group believed to

enhance antimicrobial activity. Nevertheless, some of the compounds were found to possess

good antimicrobial activity. Therefore they may be used as lead compounds for further

development.

Acknowledgements

Thanks to RSIC, CDRI Lucknow for providing Mass spectra and Panjab Technical

University for NMR spectra. The authors gratefully acknowledge Dr. A.K. Wai, for his

constant encouragement and support.

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