Divers Pharmacological Significance of Imidazole Derivatives- A Review

 

Tarani Prakash Shrivastava¹*, Umesh Kumar Patil¹, Satyendra Garg¹, Meghna A. Singh²

¹School of Pharmacy & Research, People’s University, Bhanpur, Bhopal-462037, India

²BM College of Pharmaceutical Education and Research, Khandwa Road, Indore

 

ABSTRACT:

The imidazole nucleus has proven to be an unusually fertile source of medicinal agents. Imidazoles have become an important part of many pharmaceuticals. A wide category of drugs including antitumor, antifungal, cardioprotective, alpha- blocker, CNS-depressants, anticonvulsants, antiprotozoal and anthelmintics contain the imidazole derivatives with different substituent. The imidazole ring is a constituent of several important natural products including purine, histamine, histidine and nucleic acid. Imidazole drugs have broadened scope in remedying various dispositions in clinical medicines. Since its introduction into medicine, there have been more than 1000 compounds made in an effort to find others with more potent actions combined with less toxicity. Keeping in view the increasing importance of these derivatives, a need for the review is felt. The present article aims to review the research works which are carried out in terms of the development of imidazole derivatives of pharmacological relevance and the diverse pharmacological aspects of imidazole derivatives for anti-inflammatory, anti microbial, anti cancer, antidepressant, anticonvulsant and antihypertensive activities.

 

 

INTRODUCTION:

Pharmacology is the science of drugs which deals with the interaction of exogenously administered chemicals molecules (drugs) with living system¹.  It encompasses all aspects of knowledge about dugs but most importantly with the safety and efficacy of them. For thousands of years most of the drugs were crude natural products of unknown compositions In the later part of 19^th century a great revolution has taken place in the fundamental concepts of pharmacology, since then drugs have been purified, chemically characterized and a vast variety of highly potent and selective new drugs have been developed. The mechanism of action including molecular targets of many drugs has been elucidated using the combined efforts of medicinal chemistry and pharmacology. Various biologically active synthetic compounds have five-membered nitrogen-containing heterocyclic ring in their structures². Chemistry of imidazoles began in 1858 when Heinrich Debus used glyoxyl and formaldehyde in ammonia to form imidazole, the reaction mechanism of which is explained in Figure 1. As early as 1872 several derivatives were available, in later years biological and pharmacological applications of imidazoles have been widely explored³.

 

Fig.-1

 

Imidazole is a 5-membered planar ring, which is soluble in water and other polar solvents. It exists in two equivalent tautomeric forms because the hydrogen atom can be located on either of the two nitrogen atoms. The compound is classified as aromatic due to the presence of a sextet of π-electrons, consisting of a pair of electrons from the protonated nitrogen atom and one from each of the remaining four atoms of the ring. Imidazole is amphoteric i.e. it can function as both an acid and as a base. As an acid, the pK_a of imidazole is 14.5, making it less acidic than carboxylic acids, phenols, and imides, but slightly more acidic than alcohols. The acidic proton is located on N-1. As a base, the pK_a of the conjugate acid is approximately 7, making imidazole approximately sixty times more basic than pyridine⁴. Several approaches are available for synthesis of imidazoles besides the Debus method as, Radiszewski synthesis, dehydrogenation of imidazolines, from alpha halo ketones, Wallach synthesis, from aminonitrile and aldehyde and Marckwald synthesis⁵.

Table-1: Approved marketed products containing fused imidazole derivatives

Brand Name	IUPAC Name	Structure	Pharmacological Activity	MOA
Dacarbazine	5-(3,3-Dimethyl-1-triazenyl)imidazole-4-carboxamide		Anti Cancer	Alkylating Agent
Fenflumizole	2-(2,4-Difluorophenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole		Anti-inflammatory	Non selective COX inhibitor
Miconazole	(RS)-1-(2-(2,4-Dichlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl)-1H-imidazole		Antifungal	Destruction of cell membrane
Metronidazole	2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanol		Antiprotozoal	Counteract electron transport mechanism in anaerobes
Phenytoin	5,5-diphenylimidazolidine-2,4-dione		Antiepileptic	Prolongs inactive state of voltage-activated Na+ Channels
Losartan	(2-butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazol-5-yl)methanol		Anti-hypertensive	Angiotensin II receptor antagonist
Clonidine	N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine		Anti-hypertensive	α-sympatholy-tic
Cimetidine	2-cyano- 1-methyl- 3-(2-[(5-methyl- 1H-imidazol- 4-yl)methylthio]ethyl)guanidine		Antiallergic	H2-receptor antagonist

 

Many of these syntheses can also be applied to different substituted imidazoles and imidazole derivatives simply by varying the functional groups on the reactants. In literature, these methods are commonly categorized by which and how many bonds form to make the imidazole rings ^5,6.  Utilizing these novel schemes, researchers have synthesized different imidazole derivatives generally substituted at 2, 4 and 5^th positions with aldehydes, ketones, amides, nitro groups and with heterocycles to have potential pharmacological activities like, anti-inflammatory, analgesics, antifungal, antiepileptic etc. examples of some approved marketed products containing fused imidazole derivatives are represented below in table 1⁷.

 

Diverse Pharmacological Properties of Imidazoles

Imidazole nucleus forms the main structure of some well-known components of human organism, i.e. the amino acid histidine, vit-B12, a component of DNA base structure and purines, histamine and biotin. In its various oxidation states, the imidazole nucleus has proven to be an unusually fertile source of medicinal agents. Imidazole has become an important part of many pharmaceuticals. Synthetic Imidazoles are present in many fungicides, antifungal, antiprotozoal and anthelmintic medications. Imidazole is part of the theophylline molecule, found in tea leaves and coffee beans, which stimulates the central nervous system. It is present in the anticancer medication mercaptopurine, which combats leukemia by interfering with DNA activities⁸.

 

The antifungal imidazole compounds, such as ketoconazole, clotrimazole, miconazole, fluconazole and itraconazole, have been reported to have anti-leishmanial activity. Experimental and clinical studies have demonstrated possible antileishmanial action of ketoconazole. Metronidazole (another imidazole derivative) is mainly used for amoebiasis, trichomoniasis and anaerobic infections. Nitro imidazoles are very often associated with antimicrobial activity, whereas imidazolines are often present in drugs acting as adrenergic agents. While nitrofurans are often prepared as anti-bacterial agents, nitroimidazole forms the basis for an extensive class of agents used in the treatment of infections by the protozoans⁹. Moreover, imidazoles are reported to show a broad spectrum of pharmacological activities and many of these have gained wide acceptance in clinical practice. Therefore imidazole and its derivatives are physiologically and pharmacologically active source of drugs and find applications in the treatment of several diseases.

 

On the basis of various literature surveys Imidazole derivatives show various pharmacological activities few of these have been reviewed in this article include:

 

Anti-inflammatory and analgesic activity:

Inflammation is characterized by edema, phagocytic emigration and accumulation (neutrophils, monocytes, macrophages), that lead to hyperalgesia and loss of tissue function.  Several researchers have reported the analgesic and anti-inflammatory activity of compounds containing imidazole derivatives¹⁰.

 

Butler et al. (1967) synthesized 2-[2-hydroxyphenyl]-4,5-diphenyl imidazole and screened the central analgesic activity by using hot plate method in rats, they have found that all the compounds at 200mg/kg p.o. doses produced significant analgesic activity¹¹.

 

Fig.-2:2-[2-hydroxyphenyl]-4,5-diphenyl imidazole.

 

2-[2-phenylethenyl] 4, diphenyl imidazole derivatives were synthesized by D. Nardi et al. (1981) and screened for the biological activity. They reported that, the derivatives shown potent anti-inflammatory activity¹².

 

Fig.-3:2-[2-phenylethenyl] 4, 5 diphenyl imidazole

 

In another study, 1-benzyl-2 substituted- 4, 5- diphenyl- 1H- imidazole derivatives were synthesized by Ucucu Umit et al. (2001). The structure elucidation of the prepared compounds was performed by IR, ¹ H-NMR and mass spectral and elemental analyses. Analgesic activity of all the compounds was screened in mice by using tail clip method at the dose of 100mg/kg i.p. Here the compounds with nitroxy substitutions have shown greater activity¹³.

R₁-OCH₃

Fig.-4: 1-benzyl-2 substituted- 4, 5- diphenyl- 1H- imidazole

 

Anti bacterial Activity:

M. W. Miller et al. (1970) synthesized some imidazole derivatives and screened for their broad spectrum antimicrobial activity. The synthesized 2-[2-chlorophenyl]-4, 5-diphenyl imidazole derivatives were found to possess significant antibacterial activity at 10-150 µg/ml concentrations in broth dilution method¹⁴.

 

Fig.-5: 2-[2-chlorophenyl]-4, 5-diphenyl imidazole

 

V.H. Shah et al. (1993) synthesized 2-(2’-phenyl-2’,3’-diaryl-4’-thizolidinon-5’-yl)methyl-4,5-dihyro-imidazole  derivatives, these derivatives shown significant zone of inhibition at 50 µg/ml after 24 h.¹⁵.

 

Fig.-6: 2-(2’-phenyl-2’,3’-diaryl-4’-thizolidinon-5’-yl)methyl-4,5-dihyro-imidazole

 

Antifungal Activity:

1,4-bis-(4,5-diphenyl-2-imidazolyl)-benzene derivatives were synthesized and screened for antifungal activity by Harold A. Green and coworkers (1962) compounds with nitro substitutions have shown greater activity than others when compared to standard¹⁶.

 

Fig.-7: 1,4-bis-(4,5-diphenyl-2-imidazolyl)-benzene

 

In another study, K. Ruckmani et al. (2003)¹⁷ synthesized 2-[4-flourophenyl]-4, 5-diphenyl imidazole and screened for antifungal activity against strains of Candida albicans and Aspergillus fumigates, the compounds have shown significant antifungal activity when tested at concentrations from 20-150 µg/ml.

 

Fig.-8: 2-[4-flourophenyl]-4, 5-diphenyl imidazole

 

Dorota Olender et al (2009) synthesized nitroimidazole derivatives and tested for their antifungal activity using the standard nutrient method against sclerophoma pityophila. This compound shows more potent fungistatic activity¹⁸.

 

Fig.-9: 2-(3,4-dimethoxystyryl)-6-bromo-1H-benzo[d]imidazole

 

Antiviral activity:

Michele Tonelli et al (2010) synthesized seventy six 2-phenylbenzimidazole derivatives and evaluated for cytotoxicity and anti viral activity against a panel of RNA and DNA viruses. Compound 5,6- dichloro-2-(4-nitrophenyl) benzimidazole exhibited a high activity resulting more potent than reference drugs smycophenolic acid and 6-azauridine¹⁹.

 

Fig.-10: 5,6-dichloro-2-(4-nitrophenyl)-1H-benzo[d]imidazole

 

Deepika Sharma et al (2009) synthesized imidazole derivatives and the antiviral screening of (substituted phenyl)-[2-(substituted phenyl)-imidazol-1-yl]-methanones against viral strains indicated that compounds A and B selected as the most potent antiviral agents. Ribavirin was used as standard drug²⁰.

 

 

Fig.-11

AntiLeishmanial activity:

Kalpana bhandari et al (2010) synthesized a series of substituted aryloxy alkyl and aryloxy aryl alkyl imidazole and evaluated in vitro antileishmanial activity against Leshmania donovani. Among all compounds exhibited 94–100% inhibition²¹.

 

Fig.-12.

 

 

Anticancer activity:

Yusuf Ozkay et al (2010) synthesized many novel imidazole-(Benz) azole and imidazole epiperazine derivatives in order to investigate the anticancer activity. Anticancer activity screening results revealed that these were the most active compounds in the series. Cisplatin was used as reference drug²².

 

Fig.-13

Cenzo congiu et al (2008) synthesized a series of 1, 4-diarylimidazole-2(3H)-one derivatives and their 2-thione analogues and evaluated antitumor activity. This Compound show potent antitumor activity²³.

 

Fig.-14: 1-(4-chlorophenyl)-4-(3,4,5-trimethoxyphenyl)-1H-imidazol-2(3H)-one

 

Anti-epileptic activity:

Several antiepileptic drugs are present for the treatment of convulsive diseases but in spite of this, many patients suffer from both the inadequate control of seizures and the toxic side effects of anticonvulsant drugs. The research for new antiepileptic drugs with more selective anticonvulsant effects and /or lower toxicity is therefore essential. 2-(lH-l-imidazolyl)-N-(p-tolyl) acetamide, 3-(lH-l-imidazolyl)-N-(p-tolyl) propionamide and 4-(lH-l -imidazolyl)-N-(p-tolyl) butyramide were synthesized by U. Levent et al. (1989) the anticonvulsant actions by using maximum electroshock induced convulsions method were studied, results showed that nitro-p- tolyl substitutions were responsible for the anticonvulsant actions²⁴.

 

Fig.-15: 2-(lH-l-imidazolyl)-N-(p-tolyl) acetamide, 3-(lH-l-imidazolyl)-N-(p-tolyl) propionamide

 

Some new triphenyl imidazoles of biological interest were synthesized by A. Puratchikody et al. (2004). Maximum electro shock induced convulsions method was used to screen anti-epileptic activity. The synthesized compounds at the dose levels of 100 mg/kg b.w. have shown significant activity²⁵.

 

Fig.-16: 2-(methyl) 4, 5 diphenyl 1H-imidazole

 

Anti-depressant Activity:

In the field of the antidepressant drugs, today efforts are focused towards the development of selective and reversible MAO-A inhibitors. The MAO-A inhibitors such as moclobemide are effective in the treatment of depression. A few structure activity relationship studies have been previously reported regarding moclobemide. In previous works, researchers studied the effect of replacing morpholine ring with other heterocyclic rings and synthesis of the 4-arylpiperazine derivatives of moclobemide has also been reported. In another work, the pyrrole-2-carboxamides including moclobemide analogue, N-[2-(4-morpholinyl) ethyl)] pyrrole-2-carboxamide, has been reported as monoamine oxidase inhibitor. Fardin Hadizadeh et al. (2008) synthesized N-[2-(4-morpholinyl) ethyl)-1-benzyl-2-(alkylthio)-1H-imidazole-5-carboxamides and tested as antidepressant by forced swimming test model in mice. Investigation demonstrated that three analogues were more potent than moclobemide in forced swimming test model at the dose level of 20 mg/kg i.p.²⁶.

Fig.-17

 

Antihypertensive Activity:

Hypertension is became an endemic disorder during last decade covering majority of population throughout the world. More advanced and intense research work has been resulted in more selective and advanced drug therapies like angiotensin blockers, RAAS inhibitors and many others. Clonidine, 2-(2,6-dichlorophenylamino) imidazoline hydrochloride is a potent centrally acting antihypertensive agent. Several approaches have been made to synthesize novel imidazole derivatives with antihypertensive activity. In this regard certain 2-substitued 4,5 dihydroimidazoles were synthesized by V.P. Arya et al. (1977)²⁷. Antihypertensive effects of the synthesized compounds were studied using rat renal hypertensive model at the doses of 50 and 100 mg/kg p.o. blood pressure was measured plethysmographically from the tail of the rats significant results were exhibited by the compounds.

 

Fig.-18

 

In another study, Neeraj Bhatnagar et al. (1994) synthesized some 2substituted -(4,5-diphenyl imidazo)-benzene imidazole derivatives and screened anti-hypertensive activity of these  biphenyl derivatives they have found that more alkali substitutions at 2^nd  position have resulted in the more potent antihypertensive agents²⁸.

 

Fig.-19

Toxicity and Adverse effects:

Imidazole derivatives are readily absorbed and excreted in humans and in test animals after oral and rectal administration²⁹. Peak plasma levels are reached within 15 to 30 minutes in rats and within approx. 3 hours in humans. Elimination half-life in humans is approx. 2 to 3 hours³⁰. Therefore a potential for bioaccumulation is unlikely. Induction of microsomal P450 enzyme in the liver cells of rats and rabbits is restricted to certain isoenzymes such as 7-ethoxycoumarin-O-deethylase and isoenzyme 3a³¹. However, no such induction was seen in Syrian golden hamster³². Imidazoles are of moderate oral toxicity in a scientifically valid study. No studies concerning the long-term toxicity and/or carcinogenic potential of imidazoles are available. It is, however, mentioned that imidazole derivatives were negative in the mouse fibroblast cell transformation test³³.

 

 

CONCLUSION:

Imidazole is an entity which is being synthesized in many of its derivative forms from several years. Imidazoles are reported to show a broad spectrum of pharmacological activities, the possible improvements in the activity can be further achieved by slight modifications in the substituents on the basic imidazole nucleus. Having structural similarity with histidine imidazole compound can bind with protein molecules with ease compared to the some other heterocyclic moieties. Thus imidazole offers better pharmacodynamic characteristics. The imidazole derivatives while being relatively low toxic have provided potent therapeutic agents to serve the mankind. Being innovative and resourceful newer techniques of drug discovery are being utilized in the more extensive researches to explore the versatile nature of imidazole derivatives.

 

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Received on 20.11.2012       Modified on 23.11.2012

Accepted on 28.11.2012      © RJPT All right reserved