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Mini-Reviews in Medicinal Chemistry, 2019, 19, 000-000 1

REVIEW ARTICLE

Benzimidazole Derivatives as Potential Antimicrobial and Antiulcer

Agents: A Mini Review

Ali Mohd Ganie1, Ayaz Mahmood Dar2, Fairooz Ahmad Khan3 and Bashir Ahmad Dar3,*

1
Department of Chemistry, Bundelkhand University Jhansi U.P India; 2Department of Chemistry, Govt. Degree College
Kulgam 192231 J&K India; 3Department of Chemistry, Govt. Degree College (Boys) Sopore 193201 India

ARTICLE HISTORY
Received: January 07, 2018
Revised: August 07, 2018
Accepted: October 09, 2018
DOI:
10.2174/1381612824666181017102930
Abstract: Here in we report the number of strategies for the synthesis of differently substituted ben-
zimidazole derivatives. The protocols involved in the syntheses of these derivatives were one-pot or
multi-component. The characterization studies of these derivatives were carried by using different
spectroscopic techniques (1H NMR, 13C NMR and MS) and elemental analyses. The biological screen-
ing studies revealed that these benzimidazole derivatives show potential antibacterial as well as anti-
fungal behavior. These benzimidazole derivatives not only depicted potential antiulcer properties but
also showed moderate to good anticancer/cytotoxic behavior against different cancer cell lines.

Keywords: Benzimidazoles, Antimicrobial, Antiulcer, Anticancer, Escherichia coli, Pseudomonas aeruginosa.

1. INTRODUCTION
Benzimidazole is a heterocyclic aromatic organic com-
pound. The bicyclic compound consists of the fusion of ben-
zene ring and imidazole which is a five-membered ring with
two nitrogen atoms. The extensive survey of literature re-
vealed that the synthesis of benzimidazole heterocycles is
extremely important due to their biological or pharmaceuti-
cal importance. Due to the broad range of pharmacokinetic
and pharmacodynamic properties of these derivatives, vari-
ous methods were reported in the literature for the synthesis
of these benzimidazole derivatives by using different variety
of starting materials i.e. reactants [1-3]. Among these, one of
the methods is the coupling of o-phenylenediamine and car-
boxylic acid derivatives which often require high temperature
[4] or microwave irradiations [5]. The well-known two-step
methodology is also revealed in the literature which involves
the oxidative cyclohydrogenation of Schiff base, generally
prepared by the condensation of aldehydes and o-
phenylenediamine. The variety of catalytic and oxidative
reagents such as sulfamic acid [6], I2 [7], air [8] and oxane
[9] has also been employed.
K.G. Rao et al. [10] reported the synthesis of many 2-
substituted derivatives of benzimidazoles along with their 1H
NMR, IR and UV spectral characterization. These analogues
were later tested against different strains of Gram-negative
as well as Gram-positive bacteria by disk diffusion method.
*Address correspondence to this author at the Department of Chemistry,
Govt. Degree College (Boys) Sopore 193201 India;
E-mail: bashir_15_dar@yahoo.com
Results obtained from these studies showed that some com-
pounds were very much active against different bacterial
strains, as such these compounds can lay a concrete path for
the progress of potential antibacterial agents.
A. Ahmadi et al. [11] reported the synthesis of various
novel derivatives of 2-bromomethylbenzimidazole and in-
vestigated their biological activity. The structures of the
newly synthesized compounds were depicted by spectral
studies. The derivatives were later screened for antimicrobial
activity against two Gram-positive strains (Staphylococcus
aureus and Bacillus subtilis) and two Gram-negative strains
(Escherichia coli and Pseudomonas aeruginosa). These
compounds were found to show good to excellent activity
against the standard antibiotics like Streptomycin and
Ciprofloxacin.
A.E. Koronkwo et al. [12] reported the synthesis of Co-
balt(II) complexes with mercaptobenzimidazole, thiosemi-
carbazide and thiocyanate. The characterization of these
complexes by elemental analysis, conductivity, melting
point, solubility, UV-visible and IR-spectroscopic studies
depicted the formation of mono and dinuclear complexes.
The spectral studies suggest a tetrahedral geometry for the
cobalt (II) thiosemicarbazide complex and octahedral ar-
rangement for the mercaptobenzimidazole mixed ligand
complexes. A dimerized structure was proposed for the
mercaptobenzimidazole cobalt (II) complex. In these com-
plexes, the metal ion coordinates to the ligand through the
nitrogen atom and thiocyanate ion attaches via the sulphur
atom. The antimicrobial activities of these metal complexes
were carried out using agar disc diffusion method and the

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2 Mini-Reviews in Medicinal Chemistry, 2019, Vol. 19, No. 0 Ganie et al.

results revealed that compounds were potentially active methyl-1H-benzimidazole core. Among those benzimidazole
against both bacteria and fungi species tested. derivatives, the following two were found to be most potent
against bacteria and fungi.
A. Ahmadi et al. [13] reported the synthesis of a new
series of benzimidazole derivatives. The structures of new
compounds have been confirmed by IR, 1H NMR, 13C NMR, N
MS and elemental analysis. The title compounds have been CH3
evaluated for antifungal activities against Candida albicans, N
Candida glabrata and Candida krusei. Some of these com- H
pounds have been found to exhibit moderate to good anti- C N N C

fungal activity when compared with standard antifungal O CH3

agents. CH3
N SH
C.R. Tiwari et al. [14] reported the synthesis of few tran- N N
sition metal complexes after reaction of Rabeprazole with N N
X
various metal ions like Ni(II), Co(II) and Zn(II). On the basis
of elemental analysis, the complexes have been formulated
as ML2.2H2O for Ni(II) and Co(II) complexes and ML2 for
Zn (II) complex. The ligand behaves as O, N donor and
A.K. Mishra et al. [19] synthesized 2-(triflluoromethyl)-
forms coordinate bonds through C=N and S=O groups. The
1H-benzimidazole derivatives and evaluated their biological
techniques like IR, NMR, Magnetic susceptibility and UV-
activity against several trichinella spirales and protozoa.
visible spectral studies suggest that Ni(II) and Co(II) com-
They compound (1b) was found to show maximum antipara-
plexes possess octahedral geometry whereas Zn(II) com-
sitic activity.
plexes exhibit tetrahedral geometry. The ligand and their
metal complexes have been screened for antibacterial activi-
ties against strains of Escherichia coli and Staphylococci R1 N

aurous. The results revealed that the metal chelates show CF3
more resistance as compared with parent drug.
N
R2
P. Jain et al. [15] synthesized a series of 2-substituted-5- R3
nitrobenzimidazole derivatives and screened them for anti-
microbial activity. The activity was carried out by disc diffu- Compound R1 R2 R3
sion technique using Gram-positive bacteria (S. aureus, S. 1a 2, 3-Cl2C6H3O H H
mutans and B. subtilis), Gram-negative bacterial strains (E. 1b 2, 3-Cl2C6H3O H CH3
coli, S. typhi and P. aeruginosa). The results revealed that 1c H 2, 3-Cl2C6H3O CH3
some analogues were found to show significant activity in a
comparison to that of the standard antibacterial agent. C.H.S. Subrahmanyam et al. [20] reported the synthesis of
K.F. Ansari et al. [16] reported the synthesis of a series of 1- some benzimidazole 4-(5, 6-disubstituted-2-trifluoromethyl-
(1H-Benzimidazol-2-yl)-3-substituted)-2-propen-1-one and benzimidazol-1-ylmethyl-biphenyl-2-carboxylic acid deriva-
also its 1-methyl analogous. They also reported the synthesis tive. They found that this derivative as potent antihyperten-
of benzimidazole-2-isoxazole derivatives which depicted sive agent.
potential effectiveness against HepG2 and PC12 cancer cells.
R1 N O
CF3 O
Ar
N N
R2
CN
N N
OCH2 C NH NH2
CH3 Compound R1 R2
O 1 Cl COOH
F. Hernandez-Luis et al. [17] reported an array of 2- 2 F H
3 Br CH3
substituted benzimidazole derivatives which were character-
ized by means of 1H NMR, IR, 13C NMR, MS and elemental
X. Dio et al. [21] reported the efficient synthesis and
analysis. Among these derivatives, in vitro antimicrobial activ-
biological activity of some benzimidazole derivatives.
ity was found the maximum in 1-(4-[1h-benzimidazole[d]
imidazol-2-yl)-3-chloro-4-{4-nitrophenyl)azetidinone.
N
S. Sharma et al. [18] synthesized a number of N- R
N N
(arylmethylidine)-2-[(2-methy-1H-benzimidazol-1-)]aceto-
hydrazide and 4-aryl-5-[(2- methyl-1H-benzimidazol-yl) me- N
CH3
thyl]-4H-1,2,4-triazole-3-thiol analogues by a combination O
of a variety of heterocyclic and aromatic substituents on
Benzimidazole Derivatives as Potential Antimicrobial and Antiulcer Agents Mini-Reviews in Medicinal Chemistry, 2019, Vol. 19, No. 0 3

P. Saha et al. [22] reported the synthesis of benzimidaz- H.K. Ibrahim et al. [27] reported the synthesis of deriva-
ole derivative from o-phenylenediamine and aldehyde by tives of benzimidazole in one pot under neat and green con-
using a Lewis acid as a catalyst Yttrium(III) chloride com- ditions by the simple grinding method and evaluated their
pared with many other methods has many advantages of ex- biological activity.
cellent yields and short reaction time.
A series of substituted benzimidazole compounds were
synthesized by K. Niknam et al. [28] by using quaternary
N ammonium salts as phase transfer catalyst (PTC). And all the
R derivatives of benzimidazole synthesized so far were
screened for antimicrobial activity
R
H. Xiangmng et al. [29] reported the synthesis of a series
J. She et al. [23] reported the synthesis of benzimidazole of 2-substituted benzimidazole derivative via condensation
and its derivative by CuI/Proline catalyzed coupling of 2- of ethyl-2-thionylpyruvate and hydrazidoyl derivatives with
iodoacetanilides and 2-iodophenyl carbamate with aqueous an o-phenylene diamine in acetic acid. Some the synthesized
ammonia at room temperature which gives aryl amination benzimidazole derivative is as under.
product. This, in turn, undergoes in-situ addition and cycliza-
tion under an acidic condition or by heating to produce sub-
C6H4CH3
stituted 1H-benzimidazole derivatives and 1,3-dihydro-
C6H5 HN
benzimidazole-2-one. O N
HN H
N
J. Sluiter et al. [24] reported the synthesis of substituted N
N S
benzimidazole, 2-aminobenzimidazoles and benzoxazoles N
S N N
through CuO nanoparticles catalyzed intramolecular cycliza-
N O H2N H2N
tion of o-bromoaryl derivatives in DMSO under ligand-free O
conditions. They also reported recyclability of the heteroge-
neous catalyst without the loss of activity.
A.S. Alan et al. [30] reported the synthesis of microwave
N
assisted addition reaction of 2-benzimidazole and bis-
R' benzimidazole in the presence of Alumina-Methane sulfonic
acid.

R R'' H
N N
Y
R'' = Me, Ph, NR2
R' = Bu, Ar, CH3 N N
H
H. Thakuri et al. [25] reported one-pot synthesis of func- Y = H2C=CH2, H2CSCH2, H2COCH2
tionalized benzimidazole and β-1H-pyrimidines from with
terminal alkynes and p-tolylsulfonyl with o-aminoanilines or
naphthalene-1,8-diamine. K. Bahrami et al. [31] reported the synthesis of 2-aryl
substituted benzimidazole derivative by using p-TsOH as a
catalyst.
N
R
R''
N N
R R' R R = C6H5, ClC6H4, O2N C6H4, Furfuryl
N
R'' = Me, H H
R' = Ar, CH3
R = H, CH2Cl
L.H. Du et al. [32] reported the synthesis of benzimidaz-
D.N. Patil et al. [26] reported the synthesis of N- ole derivatives which are active as inhibitors of type I DNA
methylbenzimidazoles by the reaction of carbonitriles and N- Topoisomerase. In this study he reported three 1H- benzimid-
methyl -1, 2-phenylenediamine mediated by NaH. azole derivative with different electronic characteristics at 5th
position namely 5-chloro-4-[1H-benzimidazole-2yl]phenol
N (cpd I), 5-methyl-4-[1H-benzimidazole-2-yl]phenol (cpd II)
and 4-[1H-benzimidazole-2yl]phenol(cpd III) were synthe-
R'' sized and evaluated for their effect on mammalian type I
N Topoisomerase activity. The compound 5-methyl-4-[1H-
R' benzimidazole-2-yl] phenol (cpd II) was found to show
comparatively potent Topoisomerase I inhibition.
R'' = Me, H
4 Mini-Reviews in Medicinal Chemistry, 2019, Vol. 19, No. 0 Ganie et al.

X
N S.V. Ryabukhin et al. [39] reported the synthesis of a set
OH of benzimidazoles, 3H-imidazo(4, 5-b) pyridines, purines,
N
xanthenes and benzothiazoles from orthodiamines or 2-
H aminothiophenol and aldehydes using chlorotrimethylsilane
cpd I = Cl, cpd II =CH3, cpd III = H in DMF, as a promoter and water acceptor.

N
A.K. Teawari et al. [33] reported an easy and competent
method for the preparation of benzimidazole analogues
through a single pot synthesis from o-phenylenediamines N
Y H
with aryl aldehyde in the presence of HCl and H2O2 in
CH3CN at room temperature with excellent yields. Y = CN, H

N G. Micheal et al. [40] reported the synthesis of a series of

R 2-substituted N-H, N-alkyl and n-aryl benzimidazoles
N
R'
R.K. Jat [34] reported the synthesis of various 2-
arylbenzimidazoles from phenylenediamines and aldehydes
via a one-step process using hyper-valent iodine as an oxi-
dant. This method features mild conditions, short reaction
times, high yields and a simple procedure.
R. Rahul et al. [35] reported the synthesis and antiviral
activities of N-substituted-2-substituted-benzimidazole de-
rivative viz.1-benzyl-2-substituted benzimidazole and 1-(p-
chlorophenyl)-2substituted benzimidazole.
possessing different functional groups was achieved in a
one-step via the Na2S2O4 reduction of o- nitroanilines in the
presence of an aldehyde.
H. Cotton et al. [41] reported the synthesis of 2-n-propyl,
5(N-methyl-3, 4-cyclohexane-4-amino piperidine Keto-6-
ethoxybenzimidazole, which exhibit good anti-ulcer activity.
O
N C3H7
N NH
EtO

N
B.B. Lohray et al. [42] reported the preparation of 1-(3-
R
pyridylsulfinyl) [3- methyl, 4 trifluoroethoxy-2-pyridyl, me-
N
R'
thyl, sulfinyl]-benzimidazole that was found very effective in
the curing of disease caused by gastric acid secretion and
R = CH2CH2COOH, -CH=CH-C6 H5, Rʹ = H, C6 H5Cl shows proton pump inhibitory activity.
S.V. Ryabukhin et al. [36] reported the synthesis of ben-
CH3
zimidazole derivatives as anti-hypertensive agents. D. Yang O
et al. [37] also reported the solvent-free synthesis of benzim- N
CH3
idazole derivative by using BF3OEt2. S

N
Cl
N S
O

N
H
N

M.L. Lopez-Redriguez et al. [43] reported synthesis of

N
H substituted pyridine which exhibits anti-ulcer activity.

R
G. Reddy et al. [38] reported the synthesis and antifungal
activity of some benzimidazole derivative. N
S

N HN
R2
R = -S-CH2-CH2-OH, -S-CH2-CH2-OCONH-Ph
N
O2N R1
R1 R2 Hanna et al. [44] reported the efficient synthesis of
Esomeprazole through asymmetric oxidation of prochiral
C3 H7 H
C3 H7 F
sulphide of omperazole. Preparation of 2-[3-methyl, 4-
C6 H5 Br methoxy-2-pyridyl) methyl, sulfinyl] 5-piperidine, 6-
fluorobenzimidazole was by reported R.P. Ananthnarayan et
Benzimidazole Derivatives as Potential Antimicrobial and Antiulcer Agents Mini-Reviews in Medicinal Chemistry, 2019, Vol. 19, No. 0 5

al. [45]. These compounds were found to exhibit good bio- CONFLICT OF INTEREST
logical activity.
The authors declare no conflict of interest, financial or
otherwise.

H3 C
OCH3 ACKNOWLEDGEMENTS
H O Declared none.
N

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PMID: 30332950