actividad de imidazoles

Send Orders for Reprints to [email protected] 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

1Guru 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: [email protected]

antibacterial potency of imidazole derivatives against various bacterial strains.

HN

N1

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 it’s 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 HAVING ANTI-BACTERIAL PROPERTY

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.

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Imidazoles as Promising Scaffolds for Antibacterial Activity: A Review Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 12 1813

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. hemolyticusand S. pyrogens [33].

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 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].

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].

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].

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].

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].

Wazeer et al. in 2007 reported that the imidazolidine-2-thione (Imt) free ligand (11) possessed significant antibacterial activity. Further its activity was enhanced after complexation with Zn(II) [41]. 2-Imidazolyl-N-(4-oxoquinazolin-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 vitro growth inhibition property of 1-substituted imidazoles was evaluated against bacteria (S. aureus, B.

N

N

O

Cl

Cl Cl

Cl

2

N NO O OO

NN

H

Cl

Cl

3

NN

N

4

Fig. (2). The chemical structure of Miconazole (2), Ketoconazole (3) and 4.

NN

5

NH

NHN N

SNO2

6

NH

OO

O

N

N

7

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

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

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

The in vitro and in vivo SAR studies of a series of 6-fluoro-and 6,8-difluoro-7-(azolesubstituted)-1,4-dihydro-4-oxo-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].

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

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-(2-alkyl-2-phenylethyl)-1H-imidazole (15) for antibacterial inhibitory property against Erysipelothrix insidiosa,S. hemolyticus and S. pyrogenes. However, ortho-parasubstitution of the phenyl ring gave favorable antibacterial compounds. It was also found that the alkyl chain should contain at least four carbon atoms [47].

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 gram-negative 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].

Cl

S

N

N

ClCl

8

Cl

O

Cl

ClN

N

9

H

O

Cl

ClN

N

10

HN NH

S11

.HNO3

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

NN

H

14

NNN

OCOOH

F

F

12

N

N

Cl

13

NN

n-C6H13

Cl Cl15

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

17

NN

O

O

Cl

Cl

Cl

18

NN

O

OCl

Cl

N

N

OCl Cl

ClCl16

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]-1H-imidazole (17 and 18).


In another report, Heeres and coworkers reported the synthesis and antibacterial property of 1-[2-(arylalkyl)-2-phenylethyl]-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].

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].

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 Zisomer against S. aureus [52].

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

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].

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].

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].

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,

HN

N20 21

NO

N

N

N

N

ClCl

Cl

19

.HCl

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

O

N

O

O

NH

N

SO

O

ONa

22

N

N

NO2

23

24

Cl

Cl

ON N

NN

N

N

Cl

Cl

Cl

25

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


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].

N

O

ONN N

O

ON N

26 27

Fig. (9). The structure of imidazole substituted piperidine-4-one, 26-27.

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].

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].

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].

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].

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].

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].

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 invivo 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].

Godefroi and Geenen reported several 2-phenethylimidazole derivatives and analyzed them for

N+N

28

N

HNH2N N

H

O

HNBr

Br29

NN

S ONO2

30

X-

Fig. (10). The chemical structure of quaternary imidazolium salt (28), oroidin (29) and disubstituted imidazole (30).


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].

HN

N

OHN

I

L-Thr-L-Ala-L-His-L-Pro-OCH335

N

HNOH

O

OOH

34 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 Co-trimoxazole [73].

Later experiments identified peptide analogues of the 2-methylimidazole 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-

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].

HN

N

O2N

OH

NO O

N O

O

36

HN

N

O2N

OH

NO O

N O

OH

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

O

O

O N

O

O O

O

OO

NOH

N

N

N

31

O

O

O N

O

O O

O

OO

NOH

N

N

N

32

O

O

O N

O

O O

O

OO

NOH

N

N

NCl

33 Fig. (11). The chemical structure of Telithromycin (31) and the C12 vinyl ketolides (32 and 33).


N

HN

NH

HN OO

NH

H2N

HNO

O

O

39

N

NO

Cl

Br

38

Fig. (14). The chemical structure of disubstituted imidazoles 38 and 39.

In 2001, Heerding and co-workers screened 1,4-disubstituted imidazole analogues against S. aureus FabI. The imidazole analogue 40 was identified as a lead (IC50=1.24�M). 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 antibacterial potency [31].

A similar study conducted on substituted imidazole analogues against B. subtilis, S. aureus, P. aeruginosa and K.pneumoniae by Kirby-Bauer’s 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)-2-trifluoromethyl-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

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].

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 didnot act as antibacterial agents, but when combined with silver acetate the system exhibited excellent bacteriostatic activity [80].

In the area of development of newer antibacterial analogues of imidazoles, Paramita Das et al. synthesized the peptide and dipeptide analogues of 4-{-2�-(5�-nitro)}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].

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)2Cu–Im–Zn(Bipy)2](BF4)3 and [(Phen)2Cu–Im–Zn(Phen)2](BF4)3complexes possessed significant potency against P. vulgariswith 23.6 and 25.6 mm zone of inhibition, respectively. These complexes showed fairly good antimicrobial activity against the rest of bacteria [83].

HN

N

I

I

HN

O

4241

HN

N

I

IHN

O

N

N

O

40

Pro-Val-Pro-OMe

Leu-OH

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

HN

N

O2N

O

NThr

NHO

Thr

O

OHPhe

Phe

45

N

NH

Cl

Cl

ClCl

F

F F

43

H+C

NN

I~

44

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


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].

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].

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-

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].

2.3. Trisubstituted

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].

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-(4-piperidyl)imidazoledihydrochloride (50) possessed potent antibacterial activity at 2-4 �g/ml not only against susceptible strains, but also against multidrug resistant

ONH

N

NHCl

46

Br

N

O

O

NN+

F

F

Br-

47

Fig. (17). Chemical structure of imidazoles 46 and 47.

N

N

HONO2

48

NN

O

C6H5ONO2

49

N

N

O

H2N

H2N O

HO

HO

51

NNH

HN

Cl O

Ph

50

Fig. (18). The chemical structure of metronidazole (48), its derivative (49), 5-(3-Benzyloxy phenyl)-4-(3-chlorophenyl)-2-(4-piperidyl)imidazoledihydrochloride (50) and compound 51.

N

N

O

H2N

H2N O

HO

HO

I52

NNHS

S NH2

OOH

OH

HO

53

O

O

N

NOO

O2N54

Fig. (19). The Chemical structure of imidazoles 52-54.


strains i.e., quinolone-resistant and coumarin-resistant gram-positive bacteria. From the study it was also confirmed that imidazoles act on bacteria via inhibition of DNA gyrase and topoisomerase IV enzymes [89].

Srivastava et al. in 1975 and 1976, synthesized and screened 5-amino-1-(5-deoxy-�-D-ribo furanosyl)imidazole-4-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].

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 antibacterial potency [92].

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-5-nitro-1H-imidazol-1-yl)ethyl-5-chloro-2-(2-(5-nitro-1H-imidazol-1-yl)ethoxy)benzoate], 57, was the most potent inhibitor with IC50 of 12 �M. However, it was also found

that hydrophobic and electron-withdrawing halogeno groups were responsible for the inhibitory activity [95]. Furthermore, another study depicted thiazotropsins B to be non-antibacterial compound [96].

Sadashiva and coworkers in one of their research work depicted 2-(phenyl)-3-(2-butyl-4-chloro-1H-imidazolyl)-5-butylate 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].

OO

S

HN

N

O

O

HNO

HNN

N

NH

O

N

HO60

OH

2-adamantyl

OHN

NNO2

59

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].

NH

NPhPh

OSO

O56

N

N

SOH

O

O2N7

55O

N

O

O

N

Cl

N

N

O2N

O2N

57

N O

NHN

Cl

Bu

COOBu

58

Fig. (20). The structure of imidazole derivatives, 55-58.


HN

N N

O

N

NHO2N

61

NN

NO2

O

N N62

Fig. (22). The chemical structure of trisubstituted imidazole, 61 and 62.

Studies governing the antibacterial potency of 5-substituted-2-(2-methyl-4-nitro-1-imidazomethyl)-1,3,4-oxadiazoles 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].

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].

A study conducted on the evaluation of antibacterial efficacy of 2-(2-butyl-4-chloro-1H-imidazol-5-yl-methylene)- substituted–benzofuran-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].

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 Mconcentration. The rest of the derivatives also possessed moderate to good potency [104].

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].

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].

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 series of imidazole derivatives, 2-(5-nitro-2-imidazolylmethylene)-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

N

N

N N

O

COCH3

H

NO2

O

63

N

N

N N

O

COCH3

NO2O

O

64

N

N

N N

O

COCH3

NO2

NO2

65

Fig. (23). Structure of imidazole derivatives having oxadiazoline moiety (63-65).

N

NO2N

Cl

N

NO

NH

NN

HN

HS

NO2

67

N

NO2N

Cl

N

NO

NH

NN

HN

HS

Br

OHN

N

OI

Cl

Cl66 68

Fig. (24). The chemical structure of compounds 66-68.


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].

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].

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. coliwas 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-1H-imidazol-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

possessed stronger antibacterial activity with compound 75to 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].

OO

N

N

O

OO

ON

N

NN NO2

O2N

O2N

76

N NS

N

NH

N

BrOH

Cl

Cl

Cl

75

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

N

N S

N N

NH2O2N

70

NO

NHN

Cl

Bu

R

COOBu69

NN

C6H5

NO

NN

C6H5

NO2

71 72

Fig. (25). Structure of trisubstituted imidazoles, 69-72.

N

NO2N

O

O

N

73

H2SO4

N

N

O2N

NO

O

74

Fig. (26). The structure of nitroimidazole derivatives 73 and 74.


against all the tested bacterial strains. However, the synthesized imidazoles showed variation in activity towards gram-positive 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].

80

N

N

O2N

OH

SN

NN

O

Cl

NN

NO2

81

N

N

O2N

CHO82

Fig. (29). The chemical structure of compounds 80-82. 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 invitro antibacterial activity [119,120].

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 2-mercaptoimidazoles 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].

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

N

NHN

HN

NN

O2N

Cl78

N

NH

OH

77

NN

N

NO279

Fig. (28). Chemical structure of substituted imidazoles, 77-79.


MIC of 21.9 �g/ml against all the strains except B. subtilis (43.8 �g/ml) and K. pneumoniae (weakly active) [127].

N

HN

Ph N NH

O

CN

F

86

NN

O2N

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 vitroantimicrobial 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 haveconsiderable 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

NN

S

O O

NO2

88

N

N

N

HN

N

N

HN

NHPh

Ph

N

NPh

Ph

N N

PhPh

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 6.25-100 �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 Kirby-Bauer disc diffusion technique [135]. In 2010 1-acetyl-5-(substitutedphenyl)-{3-[4-(2-methyl-4-benzylidene-5-oxo-imidazol-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].

NH

NS

HN

O

N

N83

NN

O2N

OS

O

O

84

NN

O2N

OS

O

O

Cl

85

Fig. (30). The structure of imidazole analogues, 83-85.


In a work reported in 2009, potent antibacterial imidazolinone derivatives were explained. Compound 97showed 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 2,4,5-substituted triphenyl-N-alkylimidazole derivatives by Wen-Long 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-[(5-benzylidene-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. aureusand P. aeruginosa, respectively [142].

NN

NN

Cl

Ph

CN

Cl

91

O

O

N

NNH

NN

O

HN

92

OO

NN

HN

N

N

O

ON

N

NO

Cl

HO

OBr

Cl

90 93

Fig. (33). Chemical structure of bis-heterocycles bearing imidazole moiety, (90 and 91), clathridimine (92) and clathridine (93).

NN N

S

NH

O

O

94

NN

ON N

O

O

OO

95

Fig. (34). The structure of tetra aryl imidazole analogue (94) and 1-acetyl-5-(substitutedphenyl)-{3-[4-(2-methyl-4-benzylidene-5-oxo-imidazol-1-yl)] phenyl}-4,5-dihydropyrazole (95).

N

N

ON

N

O

Cl

96

N

SClNH

NHS N

NO

C6H5

97

O

ON

NC6H5

C6H5F98

Fig. (35). Chemical structure of antibacterial imidazaoles, 96-98.


In a recent investigation, Baldaniya observed that the 5-arylidine-3-(6,7-dichloro-1,3-benzothiazol-2-yl)-2-phenyl-3,5-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].

HNN

O

O

F

R1

F

108

NN

O

NHCl109

Fig. (39). Chemical structure of substituted imidazolidinedione (108) and 1,4-diaryl-5-imino-3-imidazolin-2-ones (109).

HN

N

O

NH

O NN

O

100

N

N

O2N99

NN Ph

Ph

PhO

101 Fig. (36). The chemical structure of 2,4,5-substituted triphenyl-N-alkylimidazole derivative (99), 3-[(5-benzylidene-2-phenyl)-3,5-dihydro-4-H-imidazol-4-one-3-(4-benzoylhydrazono)]-indole-2-ones (100) and 2,4,5-triphenyl imidazole (101).

N

N

SN

Cl

Cl

O

Cl102

N

N

SO

Ph

NH

O

OO

O N

CNH2N

H2NN

N

S

OH

O

Ph

103 104 Fig. (37). The chemical structure of imidazoles, 102-104.

NN

O

FNN

O

NH2

106

N

NO

I

HOO

R105 107

Fig. (38). Chemical structure of imidazole derivatives, 105-107.


On investigating the antimicrobial property of 1,4-diaryl-5-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].

N

N

SO

O

O

H

OH

110

N

N

S

EtOOC

O

O O

O

OO

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 111possessed 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-1H-pyrazole-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) viawell 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 118was 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].

NN

C6H5

C6H5C6H5

O

NHN

112

N

NNN

SHN

O

113

O O

N

HNS

O

N

NHN

S

114

Fig. (41). The structure of tetrasubstituted imidazoles, 112-114.


N N

O

S NH

SCN

115

N N

O

S O

Cl

I

116

N N

OO

S NH117

Fig. (42). Chemical structure of compounds 115-117.

NN

O

O

Cl

Cl

Cl

118

NN

O

SNH

S

119

NN

O

S

HN

O

O

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

1 US 3,575,999 20.04.1971 The patent disclosed the antibacterial potential of 1-(�-aryl)ethyl imidazoleketals [160].

2 US 3,679,697 25.07.1972 In 1972, explained the antibacterial property of 1-[�-halophenethyl]imidazoles [161].

3 US 3,682,951 08.08.1972 Kreider discovered 1-[�-(1-Adamantyloxy) halophenethyl]imidazoles as potent antibacterial agents [162].

4 US 3,927,017 16.12.1975 1-(�-aryl-�-R-ethyl)imidazoles possessing antibacterial potency was described [163].

5 US 3,991,201 09.11.1976 Heeres and co-workers reported 1-(�-aryl-�-R-ethyl)imidazoles having antibacterial activity [164].

6 US 4,036,973 19.06.1977 The author disclosed imidazol-1-yl derivatives to be useful as antibacterial agents [165].

7 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].

8 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].

9 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].


(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-hydroxy-1,2-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].


33 US 2003/0232998 A1 18.12.2003 Patent disclosed new class of imidazolines with potential antibacterial potency [192].

34 WO 2004/016086 A2 26.02.2004 Antimicrobial 2,4,5-trisubstituted imidazoles [193].

35 US 2005/0020586 A1 27.01.2005 Patent disclosed new class of imidazolines with potential antibacterial potency [194].

36 WO 2005/033119 A1 14.04.2005 The patent disclosed antibacterial imidazoles [195].


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 Imidazole derivatives possessing biofilm inhibition property had been reported [200].

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 Imidazole derivatives possessing biofilm inhibition property had been reported [202].

44 WO 2010/077603 08.07.2010 Imidazole derivatives possessing biofilm inhibition property had been reported [203].

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

The authors confirm that this article content has no conflicts of interest.

ACKNOWLEDGEMENTS

The authors wish to thank Maharishi Markandeshwar University, Mullana, India for financial support.

ABBREVIATIONS

ANN = Artificial Neural Network

DNA = Deoxyribo Nucleic Acid

HFI = Hyphae Formation Inhibition

ICU’s = 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

PSB’s = Polysulfobetaines

QSAR = Quantitative Structure Activity Relationship

SAR = Structure Activity Relationship

VRSA = Vancomycin-Resistant S. aureus

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Received: October 05, 2012 Revised: August 26, 2013 Accepted: September 09, 2013

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