Actividad de Imidazoles

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1812
Mini-Reviews in Medicinal Chemistry, 2013, 13, 1812-1835
Imidazoles as Promising Scaffolds for Antibacterial Activity: A Review

Nidhi Rani*1, Ajay Sharma2 and Randhir Singh3
1
Guru Gobind Singh College of Pharmacy, Yamuna Nagar-135001, Haryana, India; 2Bharat Institute of Pharmacy,
Pehladpur, Kurukshetra-136132, Haryana, India; 3Department of Pharmacology, Maharishi Markandeshwar College of
Pharmacy, Maharishi Markandeshwar University, Mullana-133203, Haryana, India
Abstract: In the last few decades, a lot of work has been done on heterocycles, especially the imidazole ring, to obtain a
scaffold with potential pharmacological properties such as antibacterial, antifungal, anticancer, antiviral, antidiabetic and
others, with lesser side effects. The search for new biologically active imidazoles continues to be an interesting area of
investigation in medicinal chemistry. The present paper aims to bring together and discuss the wealth of information on
antibacterial profile of imidazoles. So it can be employed for future development to obtain new potent drug molecules.
Keywords: Bacteria, Antibacterial agent, Imidazole, Structure activity relationship study.

1. INTRODUCTION
Increasing emergence of bacterial resistance to existing
antibacterials has become a major concern among medicinal
chemists around the world. So it has sparked keen interest in
developing the new potent drugs with low toxicity and high
bioavailability. An extensive use of antibacterial and their
resistance has led to severe health problems in the hospitals
and communities [1].
In order to treat bacterial infections many heterocyclic
compounds are under study. These include furans [2],
hydrazides [3], pyrimidine [4], thiazepines [5], pyrazolines,
chalocones [6], imidazoles, etc. Imidazole, a member of
azole heterocycles, having a five membered ring with 2
nitrogen atoms present at position 1 and 3 of the ring
constitute an important pharmacophore. The imidazole
scaffold is an interesting building block in various biomolecules
such as histidine, histamine and natural products i.e.,
pilocarpine alkaloid (Pilocarpus jobarandi) [7,8]. Imidazole
analogues has generated keen interest over the years due to
their wide range of biological properties including
antimicrobial, anti-inflammatory, analgesic, antiulcerative,
histamine H3 antagonist, antioxidant, farnesyltransferase
and geranylgeranyltransferase-I inhibitor, antitumoral,
antiparasitic, antiprotozoal, and antidiabetic activities [9-21].
Some imidazole derivatives such as Cimetidine, Etomidate,
Ketoconazole, Metronidazole, Ornidazole, Azomycin,
Oxiconazole, and Clonidine have found application in drug
therapy [21-23].
A large number of review articles have been reported
over the last few decades which emphasize on various
synthetic methods and biological activities possessed by
imidazoles [24-28]. This review is an attempt to explore the
*Address correspondence to this author at the Guru Gobind Singh College

of Pharmacy, Yamuna Nagar, Haryana, India, Tel: +919034114133;
E-mail: nidhiprajapati8@gmail.com
18-57/13 $58.00+.00
antibacterial potency of imidazole derivatives against various

bacterial strains.
H
N
N
1
Fig. (1). The chemical structure of imidazole (1).
1.1. Mechanism of Action

Imidazoles act via different mechanisms. According to
one study, nitroimidazoles enter in to the cell by passive
diffusion where it undergoes reduction to yield nitro radical
anion. This anion oxidizes the DNA which results in
breakage of DNA strand and causes cell death [29].
In an another study it was found that flavohaemoglobins
present in bacteria which metabolizes nitric oxide (NO) to
nitrates and prevent NO-mediated damage, growth inhibition
and death. The imidazoles acts by coordinating the
flavohaemoglobin and inhibits its NO dioxygenase (NOD)
function, thus inhibiting the metabolism of NO and finally
leads to bacterial cell death [30]. Another group of researchers
stated that the inhibition of enoyl acyl carrier protein
reductase (FabI), an enzyme involved in the synthesis of
bacterial fatty acids is a novel target for antibacterial activity
[31].
2. REPORTED IMIDAZOLES
BACTERIAL PROPERTY
HAVING
ANTI-
As reported earlier, imidazoles possessed various

pharmacological properties. This review is an attempt to
establish the anti-bacterial potency of imidazoles and aims in
this area for further research to obtain potent anti-bacterial
imidazoles.
2013 Bentham Science Publishers
Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 12
A new potent antimicrobial agent, methyl-4-oxo-4(imidazolephenylamino)butanoate (7), was reported which

possessed moderate antibacterial activity against tested gram
positive (B. subtilis and S. aureus) and gram negative bacteria
(E. coli and P. aeruginosa) at a 1 mg/ml concentration when
determined by the agar diffusion cup plate method [37].
2.1. Monosubstituted
A detailed study of imidazoles i.e., Miconazole (2) and
Ketoconazole (3) involving minimum inhibitory concentration
(MIC), growth kinetics, viability, and intracellular K+ release
depicted that the two imidazoles work differently in the
bacterium S. aureus. Compound 2 act as a bactericidal at low
concentrations and act via release of cellular K+ while
compound 3 had no bactericidal effect at any tested
concentration but had little effect on K+ permeability and
only inhibits growth at higher concentration [32]. Another
pharmacological study was conducted and compound 3 was
found to exhibit marked growth inhibition of S. hemolyticus
and S. pyrogens [33].
Walker et al. in one of his research publication reported

1-[4-(4-chlorophenyl)-2-(2,6-dichlorophenylthio)-n-butyl]1H-imidazole nitrate (8) to be lethal against all the strains of
S. typhimurium and S. cerevisiae at a dose of 500 g/plate
and 1-500 g/plate, respectively [38].
In another attempt, carboxylic and (thio) carbonate esters
of l-[2-hydroxy(mercapto)-2-phenylethyl]-lH-imidazoles were
screened for antibacterial activity. Unfortunately, none of the
compound was active against bacteria [39].
Setzu et al. in 2002 examined the antibacterial potency of

synthesized 1H-imidazol-1-amine derivatives. Unfortunately
none of the compounds was active against Salmonella spp..
However, S. aureus was sensitive towards some derivatives.
Compound 4 was found to exhibit good potency against
S. aureus with MIC 8 M and minimum bactericidal
concentration (MBC) 40 M [34].
In accord with the identification of l-(2,4-dichlorophenyl)2-phenylpropen-l-one as a potent antibacterial agent, P. J.

Dickens and coworkers synthesized them and concluded that
the compounds 9 and 10 retained their activity against
metronidazole-resistant strains of B. fragilis. These were also
active against P. acnes. On the basis of these predictions chloro ketone 9 was revealed to be an effective agent against
anaerobic bacteria [40].
In order to obtain effective antibacterial agents, Khabnadideh

and colleagues carried out N-alkylation of imidazoles,
2-methylimidazoles and 2-methyl-4-nitroimidazoles. On
investigation, it was reported that the antibacterial potency
(against E. coil, S. aureus and P. aeruginosa) of
1-alkylimidazole derivatives increases with the increase in
alkyl chain but up to nine carbons. Moreover, substitution of
2-methyl and 2-methyl-4-nitro groups on imidazole ring
enhanced the antibacterial potency. 1-Nonylimidazole, 5,
was the most effective compound of the series with a MIC
10-39 g/ml and a MBC ranging from 19-78 g/ml against
S. aureus, P. aeruginosa and E. coli. However higher
antibacterial potency of 2-methyl-4-nitro analogues was
more significant than 2-methyl analogues [35].
Wazeer et al. in 2007 reported that the imidazolidine-2thione (Imt) free ligand (11) possessed significant
antibacterial activity. Further its activity was enhanced after
complexation with Zn(II) [41]. 2-Imidazolyl-N-(4oxoquinazolin-3(4H)-yl)-acetamide derivative was reported
to be inactive against B. subtilis, P. aeruginosa and K.
pneumoniae [42].
Further studies on imidazoles and its complexes depicted
the metal complexes possessed higher antibacterial potency
against the bacterial species of S. aureus, E. coli, K.
pneumaniae, P. vulgaris and P. aeruginosa. The copper
complex was found to be the most active synthesized
complex [43].
In another investigation, it was concluded that

2-arylamino-2-imidazoline bearing thiazole ring (6)
exhibited promising activity against S. aureus at 64 g/ml
concentration [36].
In vitro growth inhibition property of 1-substituted

imidazoles was evaluated against bacteria (S. aureus, B.
Cl
H
Cl
Cl
O
O
Cl
N
N
N
Cl
Cl
N
2
Fig. (2). The chemical structure of Miconazole (2), Ketoconazole (3) and 4.
N
5
Fig. (3). The chemical structure of compound 5-7.
H
N
NH
1813
N
S
NO2
N
H
O
7
1814 Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 12
Rani et al.
N
N
.HNO
3
N
N
Cl
Cl
S
Cl
Cl
HN
Cl
Cl
Cl
NH
Cl
S
8
10
11
Fig. (4). Chemical Structure of antibacterial imidazoles 8-11.
subtilis, S. faecalis, E. coli, S. typhi and P. aeruginosa) via

agar diffusion method at 10 and 50 g/ml. Unfortunately the
compounds were found to be weakly active or inactive
against all the tested strains [44].
provided the basis for the development of additional

antimicrobial agents to combat these pathogens [46].
Heeres and coworkers in 1976 screened a series of l-(2alkyl-2-phenylethyl)-1H-imidazole (15) for antibacterial
inhibitory property against Erysipelothrix insidiosa,
S. hemolyticus and S. pyrogenes. However, ortho-para
substitution of the phenyl ring gave favorable antibacterial
compounds. It was also found that the alkyl chain should
contain at least four carbon atoms [47].
The in vitro and in vivo SAR studies of a series of

6-fluoro-and 6,8-difluoro-7-(azolesubstituted)-1,4-dihydro-4oxo-3-quinolinecarboxayacids indicated that the antibacterial
potency was better due to the presence of fluoro group at 6th
and 8th position. However the study also depicted that the
presence of 1-imidazolyl, 12, or 4-methyl-1-imidazolyl at
position-7 was essential for good antibacterial potency.
Further the pharmacokinetic profile and toxicity studies
indicated that both the imidazole derivatives possessed
excellent antibacterial activities against all the tested strains i.e.,
S. aureus, S. epidermis, B. subtilis, E. coli, K. pneumoniae,
P. vulgaris, S. paratyphi and P. aeruginosa with low toxicity
profile [45].
In 1977, the author assayed another series of l-[2(aryloxyalkyl)-2-phenylethyl]-lH-imidazole (16) derivatives

for antibacterial potency. All the compounds exhibited
excellent potency against gram-positive bacteria. However,
none of the compound was found to be active against gramnegative bacteria [48].
In extension of the above work, Heeres and coworkers
explored the antibacterial property of 1-[[2-aryl-4(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazole against
Erysipelothrix insidiosa, S. hemolyticus and S. pyrogenes.
The results depicted that the compound 17 and 18 were most
effective against gram-positive bacteria. On the other hand
all the gram-negative bacteria were resistant to the synthesized
imidazole analogues [49].
Many imidazole drugs i.e., 2, Clotrimazole (13) and

Bifonazole (14) were evaluated for antibacterial property
against Rhodococcus equi, Nocardia spp. and Gordonia spp.
The biological assay indicated that the drugs act as
bacteriostatic at 1 g/ml and bactericidal at 10 g/ml. It was
also noted that imidazoles offered the prospect for the
treatment of nocardioform infection from mycetomas. It also
O
F
COOH
N
Cl
N
n-C6H13
H
Cl
12
13
Cl
15
14
Fig. (5). The structure of imidazole derivatives 12-15.
N
N
Cl
Cl
O
O
Cl
Cl
Cl
16
Cl
Cl
Cl
17
Cl
18
Fig. (6). Structure of l-[2-(aryloxyalkyl)-2-phenylethyl]-lH-imidazole (16) and 1-[[2-aryl-4-(aryl alkyl)-1,3-dioxolan -2-yl]methyl]-1Himidazole (17 and 18).
1815
.HCl
Cl
Cl
N
Cl
H
N
N
19
21
20
Fig. (7). The chemical structure of 19-21.
In another report, Heeres and coworkers reported the

synthesis and antibacterial property of 1-[2-(arylalkyl)-2phenylethyl]-lH-imidazoles. Similar results were noted that
only the gram-positive bacteria were sensitive towards the
imidazoles. Amongst, compound 19 was found to possess
excellent potency [50].
found that replacement of imidazole ring by a guanidinium

group resulted in decrease in potency. However, compound
22, with 2-amide carbonyls group at C19 and C25 exhibited
the strongest activity [53].
Different research groups worked on the bacteriostatic
effect of 2-nitro and 4-nitro imidazole and their derivatives.
The study depicted that Azomycin (23) possessed bacteriostatic
property against B. subtilis, M. pyrogenes, E. coli, S.
dysentrica, S. paradysentrica, S. typhi, S. paratyphi and B.
anthracis. Further, all other nitro imidazoles were found to
be weakly active or completely inactive against the tested
strains [54-58].
In an attempt to obtain antibacterial agent, Sharma and

coworkers synthesized a series of 2-substituted imidazoles
and screened them for their in vitro antibacterial potency
against gram-positive bacteria (S. aureus, B. subtilis) and
gram-negative bacteria (E. coli, S. typhimurium) by filter
disc diffusion method. The imidazole 20 showed significant
inhibitory activity against the tested bacterial strains at 37.5
to 150 g/ml. However, the maximum zone of inhibition was
found at 37.5 g/ml concentration against B. subtilis [51].
Using an in vitro antibacterial activity parameter, A.

Khalafi-Nezhad et al. suggested chloroaryloxyalkyl imidazole
derivatives possessed considerable bactericidal activity.
Compound 24 exhibited significant antibacterial activity
against S. aureus but was inactive against S. typhi. All other
compounds showed moderate activity against S. aureus.
However, S. typhi was resistant to the synthesized imidazole
derivatives. QSAR studies data calculated by semiempirical
AM1 depicted that negative electrostatic potential around
chloro and phenoxy oxygen had a direct impact on
antibacterial potency of compounds towards S. aureus [59].
Karakurt et al. synthesized nafimidone [1-(2-naphthyl)-2(imidazole-1-yl)ethanone]oxime and oxime ether derivatives

(21). The synthesized derivatives were screened for
antibacterial potency against S. aureus, Enterococcus
faecalis, E. coli and P. aeruginosa by broth microdilution
method. Most of the derivatives were found to be active
against the tested strains at 0.5-64 g/ml. The nafimidone
derivative, 21, was found to exhibit excellent potency against
S. aureus at 0.5 g/ml and E. faecalis at 16 g/ml. Moreover,
it was found that antibacterial activity was affected by
stereoselectivity of the derivative which was depicted by the
fact that E isomer was more potent antibacterial than Z
isomer against S. aureus [52].
In further attempt on imidazoles as antibacterials, another

group of researchers examined the halogenated imidazoles
against S. aureus and Salmonella spp. by serial dilution
method. The observations concluded that compounds were
effective against gram positive organisms and amongst them
compound 25 was found to be the most active (25 M and
100 M MIC and MBC, respectively) [60].
Chemical investigation of a marine sponge belonging to

genera Fasciospongia had led to the isolation of interesting
imidazole sesterpene alkaloids, 19-oxofasicospongine A,
fasciospongines A, B and C along with sesterpene sulfates
and halisulfates. All imidazole alkaloids exhibited significant
inhibitory activity against Streptomyces when measured by a
hyphae-formation inhibition (HFI) assay. Moreover, it was
Na
O
O
O
S
O
A close examination of antibacterial property of

imidazole substituted piperidin-4-ones against different
bacterial strains (S. aureus, B. subtilis, S. typhi, E. coli and
K. pneumoniae) using serial dilution method depicted that
the presence of bulkier groups at C-3 like isopropyl group,
N
NO2
NH
23
Cl
Cl
O
22
Fig. (8). The chemical structure of compounds 22-25.
O
Cl
N
24
N
N
Cl
N
25
Cl
Rani et al.
26, and methyl group at C-3 and C-5, 27, on the piperidine
ring resulted in potent derivatives with good inhibitory
activity at 12.5 mg/ml against B. subtilis and 6.25 mg/ml
against E. coli, respectively [61].
O
In 2004, a survey on a quaternary imidazolium salt series

(28) was conducted. Interestingly it was observed that the
series had good antimicrobial profile against the examined
gram-negative bacteria (E. coli and S. typhimurium), and
gram positive bacteria (B. subtilis and S. aureus). The study
depicted that the antibacterial property of the salts not only
depended upon the structure of functional groups but also on
the alkyl chain length present on the imidazolium ring.
However, it was also observed that the substitution of
imidazolium salts with a long alkyl chain or hydroxyethyl
chain and the introduction of a methyl group lead to
generation of broad spectrum antimicrobial compounds
which not only possessed the bacteriostatic properties but
could also prove to be powerful bactericides [67].
O
N
26
27
Fig. (9). The structure of imidazole substituted piperidine-4-one,

26-27.
Recently, in 2010, it was observed that oroidin (29) a

natural alkaloid possessed antibiotic and biofilm inhibitory
activity [68]. Further, Tweit and coworkers synthesized a
series of substituted imidazoles with alkyl and aralkyl sulfur
groups at position 2 along with their 5- and 4-nitro analogues.
All the synthesized derivatives were quantified for
antibacterial potency against B. subtilis, E. coli, Salmonella
paratyphi A and Erwinia spp. by serial dilution method. All
the strains were sensitive towards 30 at 1 ppm concentration.
However, it was also observed that 5-nitro benzyl sulfoxides
and sulfones were proved to be more potent antibacterials
than the uninitrated sulfides [69].
Rodriguez-Arguelles et al. synthesized and evaluated the

antibacterial potency of Ni(II), Co(II) and Co(III) complexes
of imidazole-2-carbaldehyde thiosemicarbazone (H2L1).
Unfortunately, all of the complexes and ligands were found
to be inactive against the tested strains upto 100 g/mL [62].
In order to obtain a good antibacterial, an imidazole
complex was generated from organic ligand containing both
imidazole and carboxylic functional groups. Preliminary
examination demonstrated that it completely inhibited the
growth of Achromobacter xylosoxidans and B. subtilis at 100
g/ml. As compared to free ligand, the complex was more
potent, which can be attributed to the coordination interactions
[63].
A recent study was conducted on the antibacterial

property of an Australian sponge (Cistronia astra). The two
new tetrapeptides i.e., Citronamide A and B were isolated
and evaluated for the antibacterial potency against S. albus
and E. coli. The antimicrobial data revealed that the
citronamides A were inactive against S. albus but possessed
weak activity against E. coli [70].
In a similar attempt, Ag(I)-containing imidazole complexes

were evaluated against MRSA and E. coli. The results
showed that [Ag2(imH)4](salH)2 [(imH= imidazole), (SalH2=
salicylic acid)] possessed significantly better antibacterial
potency than silver sulfadiazine [64].
With increasing utilization of antibacterials in both

human and veterinary medicines, emerging resistance of
these agents is becoming a growing concern. These findings
ponder upon the need for the discovery of new antibacterial
agents, therefore a novel series of C12 vinyl Erythromycin
derivatives were prepared and evaluated for in vitro and in
vivo potency against key respiratory pathogens. The data
depicted that the substitution of C12 methyl group with vinyl
resulted in compounds with significant potency against
macrolide-sensitive and -resistant bacteria. Further, the
activity was equi-potent to the Telithromycin (31). However,
in vivo studies indicated that compound 32 and 33 have
higher lung-to-plasma ratios, larger volumes of distribution,
and longer half-life when determined in rat lung infection
models against S. pneumoniae and H. influenzae [71].
As part of ongoing efforts into development of new

metal-based antimicrobial complexes, metal cephalothin
complexes were prepared and screened for antibacterial
activity. It was noticed that [Cu(cephalo)(Im)Cl] possessed
higher activity than Cephalothin against S. aureus, P.
mirabilis, K. pneumonia, S. enteriditis, E. coli and can be
used as a bactericide. However, all the compounds were
inactive against P. aeruginosa [65].
2.2. Disubstituted
In later studies, the antibacterial activity of
thiosemicarbazides, 4-thiazolidinones and 1,3,4-thiadiazoles
substituted imidazoles were assayed against S. aureus, B.
subtilis and E. coli using disc diffusion method. The
synthesized analogues were found to possess weak
antibacterial property against all the tested strains [66].
Godefroi
and
Geenen
reported
several
2phenethylimidazole derivatives and analyzed them for
O
N
XN+
N
H
H 2N
HN
NO2
Br
HN
Br
28
S
N
29
Fig. (10). The chemical structure of quaternary imidazolium salt (28), oroidin (29) and disubstituted imidazole (30).
30
N
N
N
N
O
O
OH N
O
O
Cl
N
O
O
OH N
O
O
31
OH N
O
O
1817
32
33
Fig. (11). The chemical structure of Telithromycin (31) and the C12 vinyl ketolides (32 and 33).
antibacterial efficacy against P. mirabilis, P. aeruginosa, and

E. coli. Unfortunately none of the compounds were active.
From the study it was found that the antibacterial properties
peculiar to 2 and its analogues were due to the location of the
benzyloxyphenethyl side chain on N. The study also clearly
demonstrated that transposition of this substituent to C-2 or
replacement of it by a methyl group leads to the loss of
antibacterial potency [72].
salicylic acids and evaluated them for antibacterial property

against P. aeruginosa, K. pneumoniae. The results depicted
that the compound 36 and its hydrolyzed analog 37 exhibited
good antibacterial potency [75].
O
N
OH
HN
OH
O
34
O2N
H
N
N
O
O2N
N
O
O
N
H
N
OH
N
O
O
N
H
N
OH
OH
N
36
37
Fig. (13). The structure of compounds 36 and 37.

HN L-Thr-L-Ala-L-His-L-Pro-OCH3
35
Fig. (12). Chemical structure of the imidazole hydrazinium salt (34)

and methylimidazole peptide analogue (35).
An antibacterial study depicted that the hydrazinium salt

of imidazole 34 possessed promising inhibitory activity
against E. coli, S. typhi and Vibrio cholera at 1%, 2% and
2% concentrations, respectively. It was also found to exhibit
higher potency against the microorganisms with reference to
their corresponding free acids and the standard Cotrimoxazole [73].
Later experiments identified peptide analogues of the 2methylimidazole 35 to possess potent antimicrobial activity
against gram-negative bacteria (P. aeruginosa and K.
pneumoniae). SAR studies revealed that the introduction of
iodo group at position-5 of the benzoic acid moiety resulted
in increase in antimicrobial activity against all the tested
microorganisms except gram-positive bacterium B. subtilis.
Imidazolopeptides displayed good activity towards P.
aeruginosa and K. pneumoniae. A comparison of biological
activity data further proved that hydrolyzed peptide
derivatives possessed slightly increased antibacterial potency
in comparison to corresponding methyl ester derivatives [74].
In a similar attempt on imidazoles as antibacterial,
Dahiya and coworkers synthesized 2-substituted imidazolyl-
A logical interpretation of antibacterial activity of

2-(substitutedphenyl)-1H-imidazole and (substitutedphenyl)[2-(substitutedphenyl)-imidazol-1-yl]-methanone analogues
revealed that the compound 38 exhibited appreciable
antibacterial activity against S. aureus, B. subtilis and E. coli
with MIC of 2 X 10-3 M/ml when determined by tube
dilution method. The SAR study of these compounds
indicated that the presence of electron withdrawing group
was necessary for their activity. The results also indicated
that compound might be of interest for the identification of
new antimicrobial molecules as their antibacterial activity
was equivalent to the standard drug Norfloxacin [76].
In order to fight antibiotic resistant microbial infections,
a series of synthetic peptide analogues based on Trp-His and
His-Arg structural frameworks were synthesized and
evaluated against Methicillin resistant S. aureus (MRSA),
Methicillin resistant S. epidermis (MRSE), E. coli, K.
pneumonia and P. aeruginosa by modified broth microdilution
method. The results obtained from the assay revealed
compounds possessed significant antibacterial potency with
MIC of 5-20 g/mL and IC50 of 1-5 g/mL. It was also
found that substitution of a bulky and hydrophobic group at
C2 position of imidazole ring with NHBzl or cyclohexyl or
adamantan-1-yl groups enhanced the antibacterial potency as
shown by 39 [77].
Rani et al.
H 2N
NH
HN
Cl
two aryl rings, the imidazole NH and an electron

withdrawing group or an aldehyde or amino group at C-2
were essential for activity against MRSA [79].
O
O
O
HN
O
Br
N
H
O
38
The antibacterial potency of imidazolium salts, 44, with

different substituents at the 4 and 5 positions of the
imidazole ring and their silver complexes were evaluated.
From this study it was concluded that imidazolium salts did
not act as antibacterial agents, but when combined with
silver acetate the system exhibited excellent bacteriostatic
activity [80].
H
N
39
Fig. (14). The chemical structure of disubstituted imidazoles 38 and

39.
In 2001, Heerding and co-workers screened 1,4disubstituted imidazole analogues against S. aureus FabI.
The imidazole analogue 40 was identified as a lead
(IC50=1.24M). The Topliss analysis decision studies
revealed that the electron-rich benzyl rings at the position 1
of the imidazole ring (R2) were required for FabI inhibition.
Additionally, small electron-donating groups such as methyl
and methoxy groups, on position 4 of the aromatic ring were
preferred. Replacement with larger phenyl groups lead to
decrease in activity. Similarly, moving the methyl group
from the 4-position to 2- and 3-position yielded less active
compounds. It was also depicted that electron-rich aromatic
group at position-4 of imidazole ring are important for
A similar study conducted on substituted imidazole
analogues against B. subtilis, S. aureus, P. aeruginosa and K.
pneumoniae by Kirby-Bauers disk diffusion method
indicated compounds possessed mild to moderate antibacterial
property. However analogues 41 and 42 were found to
exhibit maximum potency at MIC values ranging from 6-25
g/ml [78].
A preliminary exploration of 4,5-bis(3,5-dichlorophenyl)-2trifluoromethyl-1H-imidazoles, 43, as novel antibacterial
agents were carried out to determine the basic features of the
structure responsible for antibacterial activity. From a
perusal of the results, it was concluded that the presence of
In a study it was concluded that the polysulfobetaines

(PSBs) exhibited potential anti-bacterial property.
[PSB]+OH- was observed to be very potent anti-bacterial
agent as compared to the standard Penicillin with high MIC
(0.25 mg/mL) against B. coagulans. Other PSBs also
exhibited strong anti-bacterial action against B. coagulans.
The [PSB]+Cl-, [PSB]+Br-, [PSB]+BF-4, [PSB]+OH- and
[PSB]+CH3COO- were found to have the same potential as
that of Penicillin against P. aeruginosa, i.e., (4 mg/mL).
While the polymers with anions F-, SH- and NO-3 possessed
stronger bactericidal activity against P. aeruginosa than the
standard [82].
In an investigation it was observed that [(Bipy)2CuIm
Zn(Bipy)2 ](BF4)3 and [(Phen)2 CuImZn(Phen)2 ](BF4) 3
complexes possessed significant potency against P. vulgaris
with 23.6 and 25.6 mm zone of inhibition, respectively.
These complexes showed fairly good antimicrobial activity
against the rest of bacteria [83].
H
N
O
In the area of development of newer antibacterial

analogues of imidazoles, Paramita Das et al. synthesized
the peptide and dipeptide analogues of 4-{-2-(5nitro)}imidazolyl benzoyl (N-methyl) and screened them for
antibacterial efficacy against S. aureus, B. subtilis, P.
aeruginosa and E. coli at 50 g/ml by disc diffusion
technique. The compounds were found to possess mild to
moderate antibacterial potency against all the tested strains.
However, 45 was found to possess excellent antibacterial
activity against all the tested strains [81].
H
N
HN Pro-Val-Pro-OMe
40
H
N
O
I
41
42
Fig. (15). Structure of 40-42.
Cl
N
Phe
Thr
NH
Cl
I~H+
C
N
N
Cl
Cl
43
OH
44
Fig. (16). Chemical structure of imidazole analogues, 43-45.
O2N
NH
H
N
Thr Phe
45
Leu-OH
O
N+
NH
Cl
Br
N
Br-
N
H
46
1819
47
Fig. (17). Chemical structure of imidazoles 46 and 47.
A preliminary study on antibacterial potency of synthesized

amido linked imidazole compounds were carried out against
S. aureus, B. subtilis, P. aeruginosa and K. pneumoniae by
Padmavati et al. The study indicated compound 46 to be the
most potent with MIC and MBC of 12.5 g/ml and 25 g/ml
against B. subtilis, respectively [84].
4(or5)-carboxylate in experimentally infected mice with

S. aureus. The results depicted that the analogues possessed
an in vivo chemotherapeutic activity comparable to that
observed with Penicillin [87].
In a similar attempt another group of researchers from

Laboratory of Bioorganic and Medicinal Chemistry,
synthesized and evaluated naphthalimide-derived azoles. The
title compounds were screened against S. aureus, MRSA, B.
subtilis, M. luteus, B. proteus and E. coli using two fold
serial dilution technique. All the compounds exhibited good
antibacterial efficacy. However, compound 47 was found to
be the most active with a MIC of 4-8 g/ml against all the
strains [85].
In order to improve the physicochemical properties of

Metronidazole (48), various novel aliphatic and aromatic
esters of 48 were synthesized and evaluated for antibacterial
property against C. perfringens. The pharmacological screening
data involving a serial dilution assay revealed that the
antibacterial property of 49 was maximum with a MIC of 0.4
g/ml. However, a further increase in chain length or the
introduction of bulky groups in ester chain leads to reduction
in potency [88].
2.3. Trisubstituted
Some new imidazole derivatives were evaluated for their

in vitro antibacterial activity by Singh et al. using a
microdilution method against S. aureus and E. coli. The
compound 5-(3-benzyloxyphenyl)-4-(3-chlorophenyl)-2-(4piperidyl)imidazoledihydrochloride (50) possessed potent
antibacterial activity at 2-4 g/ml not only against
susceptible strains, but also against multidrug resistant
Hertiani et al. explored marine sponges Agelas linnaei

and A. nakamurai in order to obtain potent antibacterial
imidazole alkaloids. Unfortunately the imidazole alkaloid,
hymenidin was inactive against biofilm formation [86].
A preliminary study was carried out on the antibacterial
potency of methyl-5(or4)-(3,3-dimethyl-1-triazeno)-imidazole-
Ph
O
Cl
O
N
H2N
C6H5
HO
N
NO2
NO2
H2N
NH
48
N
O
HO
HO
HN
49
51
50
Fig. (18). The chemical structure of metronidazole (48), its derivative (49), 5-(3-Benzyloxy phenyl)-4-(3-chlorophenyl)-2-(4piperidyl)imidazoledihydrochloride (50) and compound 51.
NH2
O
N
H 2N
H2N
HS
O
HO
HO
HO
52
Fig. (19). The Chemical structure of imidazoles 52-54.
OH
OH
53
O
O
O2N
54
N
N
S
7
Rani et al.
OH
O2N
O2N
55
N
H
Cl
Ph Ph
N
N
O2N
O
Cl
56
COOBu
NH
Bu
57
58
Fig. (20). The structure of imidazole derivatives, 55-58.
strains i.e., quinolone-resistant and coumarin-resistant grampositive bacteria. From the study it was also confirmed that
imidazoles act on bacteria via inhibition of DNA gyrase and
topoisomerase IV enzymes [89].
that hydrophobic and electron-withdrawing halogeno groups

were responsible for the inhibitory activity [95]. Furthermore,
another study depicted thiazotropsins B to be nonantibacterial compound [96].
Srivastava et al. in 1975 and 1976, synthesized and

screened 5-amino-1-(5-deoxy--D-ribo furanosyl)imidazole4-carboxamide and 1--ribofuranosyl-4,5-disubstituted
imidazoles against S. aureus. Among the synthesized
imidazole derivatives, derivatives 51-53 were found to
exhibit significant anti S. aureus properties at 0.01, 0.02 and
0.05 g/mol concentrations, respectively [90,91].
Sadashiva and coworkers in one of their research work

depicted 2-(phenyl)-3-(2-butyl-4-chloro-1H-imidazolyl)-5butylate isoxazoline (58) to exhibit good antibacterial
properties against E. coli, B. subtilis and S. aureus at 7-10
g/ml concentration when determined by turbidometric
technique [97].
A study conducted on the antibacterial profile of 5-nitro

and 4-nitro imidazole analogues revealed that 5-nitroimidazoles
possessed wide spectrum of inhibitory property against
gram-positive bacteria (S. aureus, S. epidermis, MRSA and
B. subtilis) and gram-negative bacteria (K. pneumoniae). On
the other hand 4-nitroimidazole analogues were inactive. The
most active compound, 54, had low CASA (negative charge
weighted surface area, times maximum negative charges),
medium Dipole-X and high value of Kier descriptors,
suggesting that large non-polar functional group on 7
position seemed to be good for the antibacterial potency.
However, changing the position of the substituents on the
benzofuran ring appeared to have little influence on the
Tweit et al. proposed that nitroimidazoles possessed mild
to moderate antibacterial activity against N. gonorrhoeae and
amongst them compound 55 was most potent. Furthermore,
presence of 5-nitro group and a free carboxyl group at side
chain of the nitroimidazole ring at position 2 resulted in
compounds with optimum activity. These compounds were
weakly active against other aerobic or facultative bacteria
[93].
Another investigation reported 2-(4,5-dihydro-5-oxo-4,4(diphenyl-1H-imidazole-2-ylthio)acetic acid (56) to possess
moderate antibacterial activity against B. subtilis, P.
aeruginosa and S. aureus. However, the activity increased
on cyclization of the side chain [94].
Apart from this, in vitro and molecular docking
investigation of metronidazole derivatives against H. pyroli
urease were described by Anthony et al.. [2-(2-Methyl-5nitro-1H-imidazol-1-yl)ethyl-5-chloro-2-(2-(5-nitro-1Himidazol-1-yl)ethoxy)benzoate], 57, was the most potent
inhibitor with IC50 of 12 M. However, it was also found
N
H
N
O
OH
O
N
N
2-adamantyl
59
NO2
NH
OH
N
HN
O
HN
60
HO
Fig. (21). The chemical structure of compounds 59 and 60.
In order to achieve potent imidazole antibacterial agent

substituted imidazole derivatives were synthesized. The
synthesized imidazole derivatives were screened against B.
subtilis, Peptostreptococcus anaerobicus, P. magnus, B.
vulgates, Prevotella melaninogenica and C. perfringens
using the serial dilution method. Out of these only compound
59 was found to be the most active candidate due to its
superior activity (with MIC of 0.52-2.6 mol/l) and lack of
mutagenicity [98].
In a recent report, Wenhao and coworkers described new
analogues with improved activity against drug resistant S.
aureus. Amongst them analogue 60 exhibited good potency
against both MRSA and Vancomycin-resistant S. aureus
(VRSA). It also possessed remarkable potency against all
gram-positive bacteria with relatively good efficacy and
bactericidal action against E. coli [99].
A series of 4-diazoimidazole-5-carboxamides bearing
lipophilic substituent at position 2 were screened against
gram positive and gram negative bacteria. It was concluded
that compound 61 exhibited significant inhibitory activity
against S. aureus at 10 g/ml [100].
To optimize Metronidazole, Atia synthesized 7 series of

Metronidazole derivatives and evaluated them for inhibitory
activity against S. aureus, E. coli and P. mirabilis by agar
disc-diffusion method. The derivatives, 67 and 68 showed
highest potency against all the tested strains at a 10-3 M
concentration. The rest of the derivatives also possessed
moderate to good potency [104].
N
H
N
N
O2N
N
N
NO2 N
NH
61
62
A literature survey revealed that 5-imidazolyl substituted

isoxazolidines exhibited moderate inhibitory properties
against S. aureus, E. coli and B. subtilis at 10 mg/ml
concentration when determined by the bolter disc method.
Compound 69 was found to be most active among the series
[105].
Fig. (22). The chemical structure of trisubstituted imidazole, 61 and

62.
Studies governing the antibacterial potency of 5substituted-2-(2-methyl-4-nitro-1-imidazomethyl)-1,3,4oxadiazoles possessing nitroimidazole moiety revealed that
the synthesized compounds possessed excellent activity
against E. coli, P. aeruginosa, K. pneumoniae and S. aureus
at 10 g/ml. Moreover, Compound 62 was found to be the
most active [101].
Systematic optimization of the nitroimidazoles resulted

in 1-methyl-2-nitro-5-imidazolyl derivatives which were
screened in vivo against S. gallinarum in chicks, S. aureus
and E. coli in mice. A derivative 70 was found to be
effective against all the strains. It was also observed that an
electronic effect play a very important role in antimicrobial
potency which was explained by the decrease in potency due
to a reduction in basicity from the 2-nitro group [106].
In further studies, Frank and Kalluraya reported that

imidazole derivatives having oxadiazoline moiety possessed
significant antibacterial activity at 0.25-5 g/ml against S.
aureus, P. aeruginosa, E. coli and B. subtilis. However,
derivatives 63-65 were found to be the most potent [102].
Ehlhardt and coworkers in 1988 evaluated the antibacterial

potency of 5-nitroimidazoles and discovered 71 which was
20 times more potent than Metronidazole against E. coli. It
was also observed that on reduction of nitro group to nitroso
group, potent bactericidal nitroimidazoles were obtained.
Amongst them compound 72 was the most active derivative
against E. coli at 0.06 mM concentration [107].
A study conducted on the evaluation of antibacterial

efficacy of 2-(2-butyl-4-chloro-1H-imidazol-5-yl-methylene)substitutedbenzofuran-3-ones depicted that the compounds
possessed good inhibitory property against all the tested
strains (B. subtilis, K. pneumoniae, P. vulgaris and S.
aureus) at 25 g/ml. Moreover, SAR studies indicated that
the antimicrobial activity can be enhanced by substituting
halogen groups at the 6 and 8 position of the benzofuran
ring. Furthermore, benzofuran ring of imidazole, 66, having
methyl group at position 7 or 8 and I or Br at 6 yielded
potent analogues [103].
COCH3
N
N
O H
N
A series of imidazole derivatives, 2-(5-nitro-2imidazolylmethylene)-l-indanones, 1-tetralones, and acetophenones were synthesized and tested in vitro against
Proteus species and P. aeruginosa by a serial dilution assay.
The results of biological test indicated that compound 73
COCH3
N
N
COCH3
N
N
O
N
NO2
NO2
NO2
NO2
64
63
65
Fig. (23). Structure of imidazole derivatives having oxadiazoline moiety (63-65).
Cl
Cl
Br
NO2
Cl
N
I
O
H
N
O 2N
N
NH
N
HN
N
Cl
66
1821
N
N
O 2N
N
NH
N
HN
N
N
HS
HS
67
68
Rani et al.
Bu
NH
N
N
Cl
O
COOBu
O2N
69
N
NO2
NO
C6H5
NH2
70
C6H5
72
71
Fig. (25). Structure of trisubstituted imidazoles, 69-72.
O
O2N
N
N
H2SO4
O 2N
N
N
N
O
73
74
Fig. (26). The structure of nitroimidazole derivatives 73 and 74.
exhibited a broad spectrum antibacterial activity against the

tested strains i.e., S. aureus, S. faecalis, E. coli, P. mirabilis,
K. pneumoniae and P. aeruginosa. The SAR study depicted
that substitution with a dimethylamino group and a diallyl
amino group decreases the activity. Furthermore, lengthening
of the side chain and replacement of methyl group by ethyl
group led to reduction in potency. However, replacement of
indanone moiety by tetralone or acetophenone moieties results
in elimination of the antibacterial property [108].
possessed stronger antibacterial activity with compound 75

to be the most potent among the series. However, substitution
of hydroxyl group at position 2 and halo group at position 3
and 5 resulted in active analogue which can be used for the
development of lead compounds [112].
Br
However, the antibacterial potency evaluation of chitosan

and CMCh grafted poly(N-vinyl imidazole), revealed them
to cause decreased viable cell counts of S. aureus and E. coli.
The antibacterial activity of these derivatives against E. coli
was stronger than against S. aureus [110].
Furthermore, Gursoy and coworkers depicted that
imidazolylmercaptoacetylthiosemicarbazide analogues were
inactive against S. aureus, K. pneumoniae, P. aeruginosa, E.
coli [111].
Dawane et al. synthesized and assayed 1-(4-(4'chlorophenyl)-2-thiazolyl)-3-aryl-5-(2-butyl-4-chloro-1Himidazol-5yl)-2-pyrazoline derivatives against E. coli, S.
typhi, S. aureus and B. subtilis by agar diffusion method. The
data reported in the paper concluded that all the derivatives
O2N
Cl
Cl
In the mid twentieth century, R. E. Bambury et al.

reported that nitroimidazolyl nitrones possessed significant
activity against S. schottmuelleri the gram-negative bacteria.
However, variation of the nitrone side chain (R2) i.e., from
lower alkyl to higher alkyl or aryl group led in a reduction of
activity. Moreover, introduction of side chain with hydroxyl
group did not increase the potency while other functional
groups except the ethoxy group resulted in a decrease in
potency. However, 74 was one of the most active
nitroimidazole nitrones [109].
NO2
N
OH
N
O
N
H
N N
S
O
O
O2N
Cl
75
76
Fig. (27). Structure of 1-(4-(4'-chlorophenyl)-2-thiazolyl)-3-aryl-5(2-butyl-4-chloro-1H-imidazol-5yl)-2-pyrazoline derivatives (75)

and metronidazole trimesate (76).
Bowden and Izadi in 1998 presented a report involving

the design, synthesis and antibacterial activity of a series of
multifunctional Metronidazole esters. The trimester,
metronidazole trimesate (76) was exceptionally active as
antibacterial compound, which appeared to be associated
with a rigid and three-point attachment [113].
Some novel chemically synthesized 2,4,5-trisubstituted
imidazoles which were screened against different human
pathogenic bacteria (S. aureus, P. vulgaris, Streptococci,
Bacillus spp., E. coli, K. pneumoniae, P. aeruginosa and
Serratia morganii) via disc diffusion and microdilution
method. Amongst, compound 77 was found to be active
OH O2N
NH
N
N
N
77
H
N
N NH
78
1823
N
Cl
NO2
79
Fig. (28). Chemical structure of substituted imidazoles, 77-79.
against all the tested bacterial strains. However, the synthesized

imidazoles showed variation in activity towards grampositive as well as gram-negative bacteria [114].
Furthermore, antibacterial potency of 3-arylamino-5-[2(substituted-1-imidazolyl)ethyl]-1,2,4-triazole derivative was
determined against S. aureus, M. luteus, E. coli and P.
aeruginosa by the tube dilution method. The synthesized
imidazole derivative 78 possessed excellent antibacterial
property against M. luteus and S. aureus at 6.25 and 31.25
g/ml concentrations, respectively [115].
In analogy to above work, Demirayak and co-workers
designed some new 5-nitroimidazole derivatives 79 as
antibacterial agents. It was depicted that these compounds
were notably active against the tested strains i.e., S.aureus
and E. coli. Further, S. aureus was found to be sensitive
towards all the compounds at 8 g/ml [116].
In view of the wide interest in the activity spectrum and
profile of the nitroimidazoles. Various derivatives were
designed and evaluated against S. aureus, S. epidermis, E.
coli, K. pneumoniae, S. flexneri, P. aeruginosa, P. mirabilis
and S. typhi via the microbroth dilution technique. Among
the derivatives, 80 was most effective against all the tested
strains [117].
Similarly, di- and trisubstituted imidazoles were screened
for in vitro antibacterial activity at the concentration of 100
and 200 g/ml. All the synthesized imidazoles showed mild
to moderate activity against E. coli and B. subtilis at 100
g/ml. However, compound 81 was most potent with zone of
inhibition of 16 and 14 mm at 100 g/ml against E. coli and
B. subtilis, respectively [118].
N
Cl
OH
N
O2N
QSAR study of a series of N-alkyl imidazole analogues

using combination of various thermodynamic electronic and
spatial descriptors suggested that substitution of hydrophobic
group and less bulky group at position 1 was favorable for
the antibacterial activity [121].
Another report explained the development of antibacterial
agent involving the evaluation of free Imt ligand. The results
suggested that free ligand possessed significant antibacterial
property. However complexation with Zn(II) led to increase
in potency which was maintained by complexation with
ZnCl2. Further study involving N-iPrImt potency indicated
the ligand to have remarkable and superior activity against
gram negative bacteria P. aeruginosa and E. coli [122].
In a similar attempt, 2,4-dithioxo and 2-thioxoimidazolidene
derivatives were evaluated against P. solaniserum, Erwinia
carotovora and Ralstonia salanceanum. But none of the
compound was active [123].
Furthermore, in an effort to synthesize imidazole
analogues which retained biological activity but no toxicity,
4-nitroimidazoles were synthesised and their structure
mutagenicity relationship was studied against S. typhimurium
TA98 and TA100. The study concluded that active imidazoles
were weak-direct-acting mutagens. However, presence of a
methyl or benzylic group on the imidazole ring and
substituents at N1 and N3 positions determined the mutagenicity
of compounds [124].
Later, in 2004, Salama and Almotabacani found
2-mercaptoimidazoles to possess some antibacterial activity.
In order to confirm, the authors synthesized 2mercaptoimidazoles and evaluated them for antibacterial
potency by cup plate method. The results indicated all the
tested strains i.e., B. subtilis, S. aureus, E. Coli and P.
Mirabilis were sensitive to compound 83, the most active
compound of the series [125].
N
N
S
N
N
80
O2N
O
NO2
N
81
N
82
CHO
In continuation of already reported work on nitroimidazoles,

only 1-methyl-2-nitroimidazole-5-carboxaldehyde (82) was
found to possess a broad spectrum in vitro activity [54].
In 1971 Rufer and his colleagues synthesized and
evaluated antibacterial potency of 5-nitroimidazoles. But
unfortunately none of the compounds showed interesting in
vitro antibacterial activity [119,120].
In an attempt to resolve the problem of growing bacterial

resistance to drugs, 2-substituted imidazoles (84, 85) were
synthesized and evaluated for anti-bacterial potency. All the
synthesized compounds were active against C. sporogenus at
>20 g/ml and B. fragilis at 10 g/ml when measured by the
macro broth dilution method [126].
In order to obtain an efficient antibacterial agent, a series
of imidazole was synthesized and evaluated against B.
megaterium, B. subtilis, S. aureus, K. pneumoniae, P.
aeruginosa and E. coli via agar well diffusion and serial
dilution methods. Among the synthesized compounds, 86
was found to possess significant anti-bacterial property with
Rani et al.
N
S
O
N
N
H
HN
O2N
83
S
N
N
O2N
84
Cl
85
Fig. (30). The structure of imidazole analogues, 83-85.
Ph
MIC of 21.9 g/ml against all the strains except B. subtilis

(43.8 g/ml) and K. pneumoniae (weakly active) [127].
O
Ph
N NH
CN
O2N
N
HN
NO2
87
Fig. (31). The chemical structure of compounds 86 and 87.
Another study was conducted for in vivo antibacterial

evaluation of vinyl substituted 2-nitroimidazoles against S.
aureus, S. haemolyticus, S. typhimorium, Diplococcus
pneumoniae, K. pneumoniae, C. perfringens, P.vulgaris, P.
aeruginosa and E. coli by tube dilution method. All the
synthesized imidazoles exhibited significant antibacterial
potency but compound 87 was most active against the tested
strains. Further, from a SAR study, it was found that the
insertion of a vinyl group between substituent groups and the
imidazole nucleus did not substantially enhance the in vitro
antimicrobial activity. However, introduction of a nitro or
nitrone group onto the vinyl chain of compound 87 strongly
enhanced the activity towards gram-positive bacteria. While,
on placing vinyl group at position 1 of the imidazole
nucleus, the antibacterial activity disappeared completely
[128].
In order to evaluate the antibacterial property of Co(III)
complexes, these complexes were synthesized and assayed.
The MBC data of Co(III) complexes presented in the study
clearly indicated that the complex [Co(en)2(mimd)2]+3
showed little antimicrobial activity, while complex
[Co(en)2(imd)2]+ did not show any activity [129].
2.4. Tetrasustituted
Furthermore, in 2006 imidazol-5-ones were screened for
antibacterial efficacy which indicated compound 88 to have
considerable antibacterial activity against B. subtilis at 3.175
g/ml by 2-fold serial dilution technique [130].
From antibacterial activity studies, it was known that an
imidazole substituted with s-triazines possessed significant
antibacterial activity against gram-positive (B. subtilis, S.
aureus, B. sphaericus) and gram negative (C. violaceum, K.
aerogenes and P. aeruginosa) species. Furthermore, 89 was
found to be most effective derivative against all the tested
strains with maximum potency (12.5 g/ml) against B.
sphaericus and C. violaceum [131].
N
N
N
88
H
N
N
N
HN
86
Ph
N
NH
Ph
Ph
Ph
N
N
N
Ph
89
Fig. (32). The structure of substituted imidazol-5-one, 88 and

imidazole having substituted-s-triazine, 89.
An observation on the antibacterial activity of a novel

series of bis-heterocycles bearing isoxazoline and imidazole
moieties indicated 90 and 91 exhibited significant
antibacterial properties against all the tested strains. The
study also depicted that the antibacterial property of the
compounds may be due to the presence of chloro and bromo
group in the synthesized derivatives [132,133].
Recently, large amounts of a 2-aminoimidazole alkaloid,
named clathridimine (92), along with the known clathridine
(93) and their zinc complexes isolated from the sponge C.
clathrus 92 displayed selective anti-E. coli activity while the
zinc complex of 93 exhibited selective anti-S. aureus activity
[134].
It had been postulated that tetra aryl imidazole analogues
possessed a significant potent antibacterial activity against E.
coli and K. pneumonia at concentration ranging from 6.25100 g/ml. Analogue 94 was also found to be active against
S. aureus, B. subtilis, E. coli and K. pneumoniae at 25, 50,
6.25 and 12.5 g/ml, respectively when measured by KirbyBauer disc diffusion technique [135]. In 2010 1-acetyl-5(substitutedphenyl)-{3-[4-(2-methyl-4-benzylidene-5-oxoimidazol-1-yl)]phenyl}-4,5-dihydropyrazol (95) was
synthesized and screened against E. coli and S. aureus. The
study revealed that the compound possessed good antibacterial
property [136].
In view of the antibacterial investigation, quinazoline
substituted imidazole analogues were synthesized and
evaluated for antibacterial potency by cup plate method.
Compound 96 with a para chloro group showed convincing
antibacterial activity against S. aureus, B. subtilis, E. coli and
K. pneumonia at 10 g/ml [137].
1825
HN
Cl
Cl
Cl
Ph
NH
92
Cl
N
O N
O
Br
HN
CN
93
91
90
Fig. (33). Chemical structure of bis-heterocycles bearing imidazole moiety, (90 and 91), clathridimine (92) and clathridine (93).
O
O
O
S
N
N
N
H
N
N N
O
O
95
94
Fig. (34). The structure of tetra aryl imidazole analogue (94) and 1-acetyl-5-(substitutedphenyl)-{3-[4-(2-methyl-4-benzylidene-5-oxoimidazol-1-yl)] phenyl}-4,5-dihydropyrazole (95).
Cl
O
O
N
O
S
N
NH
96
Cl
97
N
N
NH
C6H5
N
C6H5
N
C6H5
98
Fig. (35). Chemical structure of antibacterial imidazaoles, 96-98.
In a work reported in 2009, potent antibacterial

imidazolinone derivatives were explained. Compound 97
showed excellent antibacterial property against E. coli, S.
aureus and P. aeruginosa. The compound at 50 g/ml
concentration exhibited 81-94% inhibition. However, all the
other derivatives also showed significant inhibition against
all the 3 strains [138].
Study conducted at Indian Institute of Chemical
technology reported that C-linked imidazole conjugates
exhibited mild to moderate activity against B. subtilis, S.
aureus, S. epidermis, E. coli, P. aeruginosa and K.
pneumoniae. Compound 98 possessed significant antibacterial
property towards E. coli and P. aeruginosa [139].
In an attempt, Jain and coworkers synthesized 2,4,5substituted triphenyl-N-alkylimidazole derivatives by WenLong Pan reaction. The synthesized compounds were
assayed for antibacterial potency against S. aureus, B.
subtilis and E. coli by the agar disc diffusion method.

Amongst the series, compound 99 possessed maximum
activity against E. coli with 12 mm zone of inhibition [140].
A similar investigation suggested that the 3-[(5benzylidene-2-phenyl)-3,5-dihydro-4-H-imidazol-4-one-3(4-benzoylhydrazono)]-indole-2-ones (100) possessed moderate
activity against S. aureus, E. coli, S. typhi and B. subtilis. An
antibacterial study revealed that substitution of halogens at
the 5 position of isatin produced active compounds [141].
On assaying a series of 2,4,5- triphenylimidazoles for
antibacterial activity, it was found that all the compounds
possessed mild to moderate activities towards S. aureus and
P. aeruginosa at 30 g/ml when measured by disc diffusion
technique. Compound 101 was the most active imidazole
having 32 and 16 mm zone of inhibition against S. aureus
and P. aeruginosa, respectively [142].
Rani et al.
H
N
O
N NH
Ph
Ph
Ph
O
O2N
100
99
101
Fig. (36). The chemical structure of 2,4,5-substituted triphenyl-N-alkylimidazole derivative (99), 3-[(5-benzylidene-2-phenyl)-3,5-dihydro-4H-imidazol-4-one-3-(4-benzoylhydrazono)]-indole-2-ones (100) and 2,4,5-triphenyl imidazole (101).
Cl
Cl
S
H 2N
CN
N
H 2N
Ph
OH
O
Ph
O
N
O
S
N
H
O
Cl
102
103
104
Fig. (37). The chemical structure of imidazoles, 102-104.

I
HO
NH2 F
N
N
O
R
105
107
106
Fig. (38). Chemical structure of imidazole derivatives, 105-107.
In a recent investigation, Baldaniya observed that the

5-arylidine-3-(6,7-dichloro-1,3-benzothiazol-2-yl)-2-phenyl3,5-dihydro-4H-imidazole-4-ones 102 possessed good
antibacterial potency against S. aureus [143].
Further development led to pendant imidazole system
based on cyanoacetic 2-[(benzoylamino)thioxomethyl]
hydrazides. Evaluation of their antibacterial efficacy
indicated that most of the synthesized systems exhibited
noticeable antimicrobial activity towards E. coli and X. citri.
Analysis and evaluation of the antimicrobial spectra of the
synthesized systems revealed that compounds 103 and 104
demonstrated excellent inhibitory activity against both the
strains [144].
In 2001 imidazole-5-one derivatives were designed and
screened against E. coli, Azotobacteria, B. subtilis, S. typhi
and Salmonella dysentrae by the disc diffusion method. The
pharmacological investigation depicted that 105 was active
against all the tested strains with zone of inhibition ranging
from 15-18 mm at 150 ppm concentration [145].
A study was carried out involving antibacterial screening
of imidazolinones 106 against B. subtilis and K. pneumoniae
by paper disc diffusion method. The compounds were found
to be weakly active towards both the strains [146].
Recent report described the antibacterial efficacy of

5-substituted imidazolones against E. coli, B. subtilis,
S. flexneri, S. aureus, P. aeruginosa and S. typhi. All the
compounds possessed moderate activity towards some
strains but compound 107 was found to be active against
most of the strains at 1 mg/ml concentration except B.
subtilis [147].
However, in 1999 a group of researchers evaluated the
substituted imidazolidinediones for antibacterial activity
against S. aureus, M. flavus, B. ceresus, P. vulgaris, S.
enteritidis and E. coli. The pharmacological screening data
revealed, compound 108 possessed significant antibacterial
potency against B. cereus at 16 g/ml [148].
O
F
HN
O
N
N
O
R1
NH
108
109
Cl
Fig. (39). Chemical structure of substituted imidazolidinedione

(108) and 1,4-diaryl-5-imino-3-imidazolin-2-ones (109).
On investigating the antimicrobial property of 1,4-diaryl5-imino-3-imidazolin-2-ones, e.g. 109, it was found that
most of the compounds were resistant to the tested microbes
(S.aureus, S. epidermis, E. coli, K. pneumoniae, P. aeruginosa,
Citrobacter freundii, P. vulgaris, Providencia rettgeri,
Edwardsiella tarda, S. typi, S. typhimorium, Strigella dysentrica,
V. cholera, V. parahaemolyticus, Aerominas hydrophila and
Plesimonas shigelloides). Only some compounds were found
to be active against some microorganisms. It was also found
that compounds having a chloro substituent at meta position
of the phenyl ring were most effective as compared with
those at ortho or para position [149].
Bucinski et al. employed artificial neural network (ANN)
for QSAR studies of imidazole derivatives for antibacterial
property against E. coli, Serratia marcescens, P. vulgaris, K.
pneumoniae and P. aeruginosa. The results concluded that
size of the molecule to be the most important parameter for
biological activity which was reflected by the length of
substituent, the electron charge on the oxygen and/or sulphur
atoms and the overall energy of the molecule [150].
O H
N
O
O
110
O
H
O
N
S
O N
EtOOC
O
O
O
O
111
Fig. (40). Chemical structure of compound 110 and 111.
Furthermore, in order to obtain a more effective

chemotherapeutic agent, antibacterial activity of
2-benzylthio- and 2-benzylsulfonyl-1H-imidazoles was
evaluated against S. aureus, B.subtilis, P. vulgaris and K.
pneumonia. The result described compounds 110 and 111
possessed excellent inhibitory activity against all the tested
microorganisms at a 100 g/ml concentration [151].
Satyanarayana and coworkers synthesized a series of
schiff bases having an imidazole moiety and screened them
for antibacterial efficacy against E. coli, P. aeruginosa and
S. aureus using agar well diffusion method. The data
concluded that the compound 112 was the most potent
derivative with MIC of 0.5 and 1 g/ml against all the tested
strains [152].
In continuation of work on antibacterial imidazoles, Amir

et al. synthesized another series of azole derivatives with
2,4,5-triphenylimidazole moiety and screened them for
antibacterial property using agar diffusion technique. The
preliminary analysis data revealed, compound 113 to be the
most potent compound with 80.6% and 78.6% inhibition
against E. coli and S. aureus, respectively at 100 g/ml
concentration [153].
Furthermore, novel imidazole derivatives substituted
with pyrazoles were synthesized from 3-substituted-1Hpyrazole-4-carbaldehydes. The preliminary screening data
depicted that the compound 114 possessed good antibacterial
activity at 500 g/ml with zone of inhibition ranging from
5-15 mm against all the tested strains (S. aureus, B. subtilis,
C. profingens, E. coli, S. typhimorium and P. aeruginosa) via
well plate method [154].
2.5. Pentasubstituted
Some new imidazolidine derivatives were synthesized by
reacting iso(thio)cyanates, aldehydes and dibenzylideneacetone
and assayed for antibacterial potency against B. subtillus,
S.aureus, E. coli and S. typhi. The compounds 115 and 116
were found to possess high antimicrobial activities [155].
In 2009 El-Sharief and Mousa together synthesized and
evaluated various mono- and bis-imidazolidine-iminothiones
and imidazolidine iminodithiones against gram negative
(E. coli and S. typhi) and gram positive (B. subtilis and
S. aureus) bacteria by disc diffusion method. All the
synthesized derivatives exhibited significant antibacterial
activity. However, 117 was found to possess excellent
activity towards all the strains with zone of inhibition ranging
from 17-19 mm at 100 l concentration. Furthermore, SAR
study depicted that ethoxy group was essential for activity.
Replacement with a bromine group led to drop in the activity
[156].
In another attempt pentasubstituted imidazolidinediones
were evaluated. The results depicted that the compound 118
was active against M. flavus at 32 g/ml [157].
In an effort to optimize imidazoline bis compounds,
Ghorab and coworkers synthesized and evaluated the
compounds. Most of them showed remarkable activity against
the gram-negative (E. coli and S. typhi), gram-positive
(S. aureus and B. subtilis) bacteria. But their potency was
less active than the standard Chloramphenicol [158].
HN
O
S
N
C6H5
N NH
N
N
O
C 6H 5
112
C6H5
N N
HN
Fig. (41). The structure of tetrasubstituted imidazoles, 112-114.
N
N
S
N NH
113
1827
114
SCN
N
NH
Rani et al.
115
Cl
N
S
N
NH
117
116
Fig. (42). Chemical structure of compounds 115-117.

O
Cl
Cl
N
N
N
NH
O
118
N
N
Cl
119
HN
120
Fig. (43). The structure of imidazole derivatives 118-120.

Table 1.
List of Patents Applied for Antibacterial Potency of Imidazoles.
S. No.
Patent Name
Patent Date
Descriptions
US 3,575,999
20.04.1971
The patent disclosed the antibacterial potential of 1-(-aryl)ethyl imidazoleketals [160].
US 3,679,697
25.07.1972
In 1972, explained the antibacterial property of 1-[-halophenethyl]imidazoles [161].
US 3,682,951
08.08.1972
Kreider discovered 1-[-(1-Adamantyloxy) halophenethyl]imidazoles as potent antibacterial agents

[162].
US 3,927,017
16.12.1975
1-(-aryl--R-ethyl)imidazoles possessing antibacterial potency was described [163].
US 3,991,201
09.11.1976
Heeres and co-workers reported 1-(-aryl--R-ethyl)imidazoles having antibacterial activity [164].
US 4,036,973
19.06.1977
The author disclosed imidazol-1-yl derivatives to be useful as antibacterial agents [165].
US 4,039,677
02.08.1977
The author described the antimicrobial activity of novel 1-phenylimidazole substituted to the imidazole
ring by optionally substituted hydrocarbyl carbonate or a mono-, di, or trithiocarbonate [166].
US 4,055,652
25.10.1977
The patent revealed to the invention of novel 1-[-(R-thio)phenethyl]-imidazoles and the

corresponding 1-[-(R-sulfinyl)phenethyl]-imidazoles and 1-[-(R-sulfonyl)phenethyl]-imidazoles,
which possessed antibacterial property [167].
US 4,078,071
07.03.1978
The researcher described N-alkyl imidazole derivatives as antibacterial agent [168].
10
US 4,101,666
18.07.1978
Author disclosed the antibacterial property of 1-(2-Ar-4-R-1,3-dioxolan-2-ylmethyl) [169].
11
US 4,101,664
18.07.1978
Heeres described substituted imidazoles as potent antibacterial agents [170].
12
US 4,101,665
18.07.1978
1-(2-Ar-4-aryloxymethyl-1,3-dioxolan-2-yl methyl)imidazoles possessed significant anti-bacterial

properties [171].
13
US 4,123,542
31.10.1978
Walker disclosed the antibacterial potency of N-alkyl imidazole derivatives [172].
14
US 4,213,991
22.07.1980
Patent disclosed antibacterial potency of N-alkyl imidazoles [173].
15
US 4,215,220
29.07.1980
Antibacterial compounds of 1-(3-anilinopropyl)imidazoles class [174].
16
US 4,333,947
08.06.1982
Imidazole derivatives having remarkable antibacterial activity [175].
17
US 4,423,046
27.12.1983
1-Methyl-5-nitro-2-(2-phenylvinyl)imidazoles to be useful as antibacterial agents [176].
18
US 4,483,865
20.11.1984
The patent presented series of novel dithioketal derivatives of 1-(2-aryl-2-oxoethyl)-1H-imidazoles

and corresponding sulfones and sulfoxides to possess antibacterial potency [177].
1829
(Table 1) Contd.
S. No.
Patent Name
Patent Date
Descriptions
19
US 4,458,079
03.07.1984
Antibacterial mercaptal imidazoles had been reported [178].
20
US 4,539,330
03.09.1985
Trager and Chylinski discussed anti-bacterial potencies of imidazolidinyl urea derivatives [179].
21
US 4,608,438
26.08.1986
Patent disclosed antibacterial imidazole derivatives [180].
22
US 4,632,933
30.12.1986
Sulfur-containing imidazole derivatives possessing anti-bacterial potency [181].
23
US 4,675,315
23.06.1987
Antimicrobial salt of fosfomycin with imidazole [182].
24
EP 0270316 A2
08.06.1988
Patent described 1-substituted imidazoles having antibacterial activity against Propionibacterium

acnes [183].
25
US 4,814,332
21.031989
Antibacterial 1,3-disubstituted imidazolium salts [184].
26
US 4,902,705
20.02.1990
The patent disclosed new imidazole derivatives having antibacterial activity [185].
27
US 5,082,948
21.01.1992
The inventors reported the novel imidazoles and their acid adducts having antimicrobial activities
especially against gram positive bacteria [186].
28
US 5,112,844
12.05.1992
The author disclosed the anti-bacterial potency of imidazole derivatives [187].
29
US 5,283,271
01.02.1994
Patent explored the antibacterial property of 3,5-diphenyl and substituted-3,5-diphenyl-1-hydroxy1,2-dihydro imidazole-2-thiones [188].
30
EP 0609099 A1
03.08.1994
The inventor disclosed the antibacterial compositions for use in agriculture and horticulture
containing imidazoles as major component [189].
31
WO 03/101954 A2
11.12.2003
Patent disclosed new class of imidazolines with potential antibacterial potency [190].
32
WO 2003/101969 A1
11.12.2003
33
US 2003/0232998 A1
18.12.2003
34
WO 2004/016086 A2
26.02.2004
Antimicrobial 2,4,5-trisubstituted imidazoles [193].
35
US 2005/0020586 A1
27.01.2005
36
WO 2005/033119 A1
14.04.2005
The patent disclosed antibacterial imidazoles [195].
37
WO 2007/133790 A2
22.11.2007
38
WO 2007/144286 A1
21.12.2007
The patent enclosed the antibacterial compositions having imidazole as main component [197].
39
WO 2008/059258 A2
22.05.2008
The researcher disclosed the Imidazoles for the treatment of infection caused by multidrug resistant
microorganisms [198].
40
WO 2009/070304 A1
04.06.2009
Imidazole derivatives possessing biofilm inhibition property had been reported [199].
41
WO 2009/123753
08.10.2009
42
WO 2009/127615 A1
22.10.2009
Dumeunier explored novel imidazole derivatives for bactericidal efficacy in his patent [201].
43
WO 2010/058402 A1
27.05.2010
44
WO 2010/077603
08.07.2010
Recently, a series of imidazolidineiminothiones were

investigated for anti-bacterial potency against E. coli,
Sarcina lutea, B. subtilis and S. aureus using agar diffusion
technique. The bioassay data showed that derivatives 119
and 120 were the most active against all the tested strains.
Compounds of the series exhibited a zone of inhibition of
22-25 mm at 100 g/ml concentration [159].
3. PATENTS
The anti-bacterial profile of imidazoles had been patented
by various research groups some of which are described in
Table 1.
CONCLUSION
With the advent of increasing resistance to antibiotics
there is an urgent need of drug molecules with potent anti-
bacterial profile. This review illustrates the chemical

structures and antibacterial property of the most interesting
heterocyclic compound i.e., imidazole. Additional screening
of these analogues might lead to the identification of
compounds that are significantly potent to be useful as
antibacterials. In addition to the structural alteration of weak
and moderately active imidazoles, investigation of
mechanism of action of these compounds is likely to be a
productive area of research. Although imidazoles are
currently used in clinical practice for treatment of various
diseases but yet clinical studies are required to confirm the
antibacterial potency of imidazoles so as to obtain a potential
antibacterial agent.
CONFLICT OF INTEREST
Rani et al.
[6]
[7]
[8]
[9]
[10]
[11]
The authors confirm that this article content has no

conflicts of interest.
ACKNOWLEDGEMENTS
[12]
The authors wish to thank Maharishi Markandeshwar

University, Mullana, India for financial support.
[13]
ABBREVIATIONS
[14]
ANN
= Artificial Neural Network
DNA
= Deoxyribo Nucleic Acid
HFI
= Hyphae Formation Inhibition
ICUs
= Intensive Care Units
MBC
= Minimum Bactricidal Concentration
MIC
= Minimum Inhibitory Concentration
MRSA
= Methicillin Resistant Staphyococcus aureus
MRSE
= Methicillin Resistant S. epidermidis
NO
= Nitric Oxide
NOD
= Nitric Oxide Dioxygenase
PSBs
= Polysulfobetaines
QSAR
= Quantitative Structure Activity Relationship
SAR
= Structure Activity Relationship
VRSA
= Vancomycin-Resistant S. aureus
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Mini-Reviews in Medicinal Chemistry, 2013, 13, 1812-1835

Imidazoles as Promising Scaffolds for Antibacterial Activity: A Review

Keywords: Bacteria, Antibacterial agent, Imidazole, Structure activity relationship study.

*Address correspondence to this author at the Guru Gobind Singh College

antibacterial potency of imidazole derivatives against various

1.1. Mechanism of Action

As reported earlier, imidazoles possessed various

2013 Bentham Science Publishers

Imidazoles as Promising Scaffolds for Antibacterial Activity: A Review

Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 12

A new potent antimicrobial agent, methyl-4-oxo-4(imidazolephenylamino)butanoate (7), was reported which

Walker et al. in one of his research publication reported

Setzu et al. in 2002 examined the antibacterial potency of

In accord with the identification of l-(2,4-dichlorophenyl)2-phenylpropen-l-one as a potent antibacterial agent, P. J.

In order to obtain effective antibacterial agents, Khabnadideh

In another investigation, it was concluded that

In vitro growth inhibition property of 1-substituted

Fig. (3). The chemical structure of compound 5-7.

1814 Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 12

Fig. (4). Chemical Structure of antibacterial imidazoles 8-11.

subtilis, S. faecalis, E. coli, S. typhi and P. aeruginosa) via

provided the basis for the development of additional

The in vitro and in vivo SAR studies of a series of

In 1977, the author assayed another series of l-[2(aryloxyalkyl)-2-phenylethyl]-lH-imidazole (16) derivatives

Many imidazole drugs i.e., 2, Clotrimazole (13) and

Fig. (5). The structure of imidazole derivatives 12-15.

Imidazoles as Promising Scaffolds for Antibacterial Activity: A Review

Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 12

Fig. (7). The chemical structure of 19-21.

In another report, Heeres and coworkers reported the

found that replacement of imidazole ring by a guanidinium

In an attempt to obtain antibacterial agent, Sharma and

Using an in vitro antibacterial activity parameter, A.

Karakurt et al. synthesized nafimidone [1-(2-naphthyl)-2(imidazole-1-yl)ethanone]oxime and oxime ether derivatives

In further attempt on imidazoles as antibacterials, another

Chemical investigation of a marine sponge belonging to

A close examination of antibacterial property of

Fig. (8). The chemical structure of compounds 22-25.

1816 Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 12

In 2004, a survey on a quaternary imidazolium salt series

Fig. (9). The structure of imidazole substituted piperidine-4-one,

Recently, in 2010, it was observed that oroidin (29) a

Rodriguez-Arguelles et al. synthesized and evaluated the

A recent study was conducted on the antibacterial

In a similar attempt, Ag(I)-containing imidazole complexes

With increasing utilization of antibacterials in both

As part of ongoing efforts into development of new

Imidazoles as Promising Scaffolds for Antibacterial Activity: A Review

Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 12

antibacterial efficacy against P. mirabilis, P. aeruginosa, and

salicylic acids and evaluated them for antibacterial property

Fig. (13). The structure of compounds 36 and 37.

Fig. (12). Chemical structure of the imidazole hydrazinium salt (34)

An antibacterial study depicted that the hydrazinium salt

A logical interpretation of antibacterial activity of

1818 Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 12

two aryl rings, the imidazole NH and an electron

The antibacterial potency of imidazolium salts, 44, with

Fig. (14). The chemical structure of disubstituted imidazoles 38 and

In a study it was concluded that the polysulfobetaines

In the area of development of newer antibacterial

Fig. (15). Structure of 40-42.

Fig. (16). Chemical structure of imidazole analogues, 43-45.