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Synthesis of Bioactive Imidazoles: A Review | OMICS International
ISSN: 2150-3494
Chemical Sciences Journal
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Synthesis of Bioactive Imidazoles: A Review

Poonam Gupta* and Jitendra K. Gupta

School of studies in Chemistry, Jiwaji University, Gwalior-474011, India

*Corresponding Author:

Poonam Gupta
School of studies in Chemistry
Jiwaji University, Gwalior-474011, India
Tel: 1800-233-1964
E-mail: [email protected]

Received dateApril 07, 2015; Accepted date April 28, 2015; Published date May 04, 2015

Citation: Gupta P, Gupta JK (2015) Synthesis of Bioactive Imidazoles: A Review. Chem Sci J 6:091. doi: 10.4172/2150-3494.100091

Copyright: © 2015 Gupta P, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Heterocyclic compounds are acquiring more importance in recent years because of their pharmacological activities. The imidazole nucleus is an important synthetic strategy in drug discovery. Imidazole is a planar fivemember ring system with N atom in 1 and 3 positions. The systemic name for the compound is 1, 3 diazole, one of the N bear an H atom and other to be regarded as a pyrrole type N. Imidazole was first named as glyoxaline. It is amphoteric in nature, susceptible to electrophilic and nucleophilic attack. It also occurs in the purine nucleus & amino acid histidine, 4-amino-imidazole-5-carboxamide occurs naturally as a riboside. This interesting group of heterocyclic compound has diverse biological activities such as antimicrobial, anticancer, analgesic, anti-inflammatory, antiviral, anthelmintic, anticonvulsant, antiulcer, anti-allergic activity etc. Numerous methods for the synthesis of imidazoles and also their various structure reactions offer enormous scope in the field of medicinal chemistry. This articles aims to review the work reported, their chemistry and pharmacological activities of imidazole during past years.

Keywords

Imidazole; Heterocyclic; Antibacterial; Antiinflammatory; Antifungal and antitumor.

Introduction

Heterocyclic compounds are also used in pharmacy and agriculture. Analysis of scientific papers in the last two decades revealed that there is a general trend in research for new drugs involving modification of existing biologically active matrices and molecular design of the structures of compounds. The imidazoles nucleus is an important synthetic strategy in drug discovery. Imidazole derivatives exhibited antimicrobial, anti-inflammatory, analgesic, anti-tubercular and anticancer activity. One of the most important application of imidazole derivatives is their use as material for treatment of denture stomatities. The high therapeutic properties of the imidazole related drugs have encouraged the medicinal chemists to synthesize a large number of novel chemotherapeutic agents. Imidazole drugs have broadened scope in clinical medicines. Medicinal properties of imidazoles include anticancer, anticoagulants, anti-inflammatory, antibacterial, antifungal, antiviral, antitubercular, antidiabetic and antimalarial [1-7]. Imidazole and its derivatives are reported to be physiologically and pharmacologically active and find applications in the treatment of several diseases. Imidazole is an organic compound with the formula (CH) 2 N (NH) CH. It is a colourless solid that dissolves in water to give mildly basic solution. In chemistry, it is an aromatic heterocycle, classified as a diazole and as an alkaloid. Imidazoles are a common component of a large number of natural products and pharmacologically active molecules (Figure 1) Imidazole was first synthesized by Heinrich Debus in 1858, but various imidazole derivatives [8-11] have been discovered as early as the 1840s, it used glyoxal [12] and formaldehyde [13,14] in ammonia to form imidazole. This synthesis, while producing relatively low yields, is still used for creating C-substituted imidazoles [15].

chemical-sciences-journal-lmidazoles

Figure 1: Imidazoles.

Imidazoles containing free imino hydrogen and a substituent in the 4- and 5- position, or two dissimilar substituents in these positions, might be expected to occur in the isomeric forms. These isomers differ in the position of the imino hydrogen which may be attached to either of the two nitrogen atoms.

Over the years, the imidazole nucleus has attracted the attention of the scientific community due to its chemical and biological properties [16,17]. For example, this nucleus is present in the structures of several natural products in the form of the essential amino-acid histidine or in alkaloids exhibiting anti-tumoral, anti-cancer (dacarbazine), antihistaminic (cimetidine), anti-parasitic (metronidazole), and antihypertensive (losartan) and anti-bacterial activities [18-20]. A great numbers of medicines contain the imidazole nucleus, including ketoconazole which are used to treat fungal infections, bacterial infections, and gastric ulcers, respectively (Figure 2) [21,22]. Due to their importance, it has become an attractive target for the synthetic and medicinal chemist. There are many synthetic methodologies that have been developed for assembling and decorating the imidazole ring with diverse functional groups.

chemical-sciences-journal-substituted-imidazoles

Figure 2: C-substituted imidazoles.

Synthesis of imidazoles

Bunev et al. [23] have been synthesized a new series of 1,4,5-trisubstituted imidazoles 3 containing trifluoromethyl group has been developed using van Leusen reaction, which incorporates two-component condensation reaction trifluoroacetimidoyl chlorides 1 with tosylmethylisocyanide 2. This protocol provides a novel and improved method for obtaining trifluoromethyl containing 1, 4, 5-trisubstituted imidazoles in good yields (Scheme 1).

chemical-sciences-journal-trisubstituted-imidazoles

Scheme 1: Synthesis of 1, 4, 5-trisubstituted imidazoles.

Sharma et al. [24] reported two novel series of 2-(substituted phenyl)-1H-imidazole 7 and (substituted phenyl)-[2-(substituted phenyl)-imidazol-1-yl]-methanone 10 analogues it is achieved by the reaction of substituted aniline 5 in HCl/water mixture were diazotized using solution of sodium nitrite. Imidazoles were added in intermediate 6. Compound 10 were synthesized by the reaction of compound 7 in diethyl ether was added to a solution of corresponding benzoic acid 8 with substituted benzoyl chloride 9 (Scheme 2).

chemical-sciences-journal-substituted-phenyl

Scheme 2: Synthesis of 2-(substituted phenyl)-1H-imidazoles and (substituted phenyl)-[2-(substituted phenyl)-imidazol-1-yl]-methanone.

Pandya et al. [25] also reported a simple and concise route for the synthesis of highly substituted imidazole derivatives 12 have been developed by the reaction of 10 with aromatic aniline 11 via coppermediated oxidative C–H functionalization in good to high yields. The advantage of the reaction lies in its mild reaction conditions and readily available starting materials (Scheme 3).

chemical-sciences-journal-Synthesis-ethyl

Scheme 3: Synthesis of ethyl 5-methyl-1, 2-diphenyl-1H-imidazole-4-carboxylate.

Liu et al. [26] have been synthesized a series of 2-(4-(2-(substituted- 1-yl) ethoxy) phenyl)-1H-phenanthro [9, 10-d] Imidazole 15 and 2-(4-(4-(substituted-1-yl) butoxy) phenyl)-1H-phenanthro [9, 10-d] imidazole 16 by multicomponent reaction method (Scheme 4).

chemical-sciences-journal-organic-synthesis

Scheme 4: The organic synthesis of 2-(4-(2-(substituted-1-yl) ethoxy) phenyl)-1H-phenanthro [9, 10-d] Imidazole and 2-(4-(4-(substituted-1-yl) butoxy) phenyl)-1Hphenanthro [9, 10-d] imidazole.

Kathrotiya et al. [27] reported a series of some new quinoline based imidazole-5-one derivatives 19, 21 have been synthesized by the fusion of oxazol-5-ones 17, with various p-substituted anilines 18, 20 and zeolite in pyridine (Scheme 5).

chemical-sciences-journal-new-quinoline

Scheme 5: Synthesis of some new quinoline based imidazole-5-one derivatives.

Mungra et al. [28] also reported another series of some new tetrazolo[1,5-a]quinoline based tetrasubstituted imidazole derivatives 26 have been synthesized by a reaction of tetrazolo[1,5-a]quinoline- 4-carbaldehyde 22, benzyl 23, aromatic amine 25 and ammonium acetate 24 in the presence of iodine through one-pot multi-component reaction (MCR) approach (Scheme 6).

chemical-sciences-journal-new-tetrazolo

Scheme 6: Synthesis of new tetrazolo [1, 5-a] quinoline based tetrasubstituted imidazole derivatives.

Desai et al. [29] reported the synthesis of N-(4-((2-chloroquinolin- 3-yl) methylene)-5-oxo-2-phenyl-4, 5-dihydro-1H-imidazol-1-yl) (aryl) amides 30 by the reaction of 2-chloroquinoline- 3-carbaldehyde 27 and N-amino arylcarboxamides 28 in pyridine. They were react with 4-((2-Chloroquinolin-3-yl) methylene)-2-phenyloxazol-5(4H)-one 29 was heated with again an N-amino arylcarboxamides in pyridine (Scheme 7).

chemical-sciences-journal-chloroquinolin-methylene

Scheme 7: Synthesis of N-(4-((2-chloroquinolin-3-yl) methylene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl)(aryl)amides.

Li et al. [30] have been synthesized trisubstituted imidazoles 33 by the reaction of 1, 2-di (furan-2-yl)-2-oxoethyl carboxylates 31 in presence of RCOCl they form an intermediate 32 then it is converted into the synthesized compound (Scheme 8).

chemical-sciences-journal-trisubstituted-imidazoles

Scheme 8: Synthesis of trisubstituted imidazoles containing furan rings.

Chen et al. [31] reported a series of 1-R1-2-R-4, 5-di (furan-2-yl)- 1H-imidazole derivatives 39 were synthesized in multisteps. Reaction start with furan-2-carbaldehyde 34 and vitamin B1 to gave 1, 2-di (furan-2-yl)-2-hydroxyethanone 35. 35 react with benzyl chloride or allyl chloride and pyridine to form an intermediate 36, it were react with sodium acetate and gave substituted difuran imidazole 37. This was followed by NaH/THF to form the final compound 38 (Scheme 9).

chemical-sciences-journal-imidazole-derivatives

Scheme 9: Synthesis of 1-R1-2-R-4, 5-di (furan-2-yl)-1H-imidazole derivatives.

Ziarani et al. [32] also reported SiO2-Pr-SO3H catalyst based 1,2,4,5-tetrasubstituted imidazoles 43 by reaction with fourcomponent, one-pot reaction of 1,2-diketones 39, aryl aldehydes 40, ammonium acetate 41 and substituted aromatic amines 42 in excellent yields under solvent free conditions (Scheme 10).

chemical-sciences-journal-tetrasubstituted-imidazoles

Scheme 10: Synthesis of 1, 2, 4, 5-tetrasubstituted imidazoles in presence of SiO2-Pr-SO3H.

Jawaharlal et al. [33] reported tetrasubstituted imidazole 48 by the refluxing of 9, 10-phenenthraquinone 44 with aryl aldehyde 46, primary amines 47 and ammonium acetate 45 in the presence of glacial acetic acid (Scheme 11).

chemical-sciences-journal-tetrasubstituted-imidazole

Scheme 11: Synthesis of tetrasubstituted imidazole.

Lavanya et al. [34] also reported the synthesis of 6-bromo-2- substitutedphenyl-1H-imidazo [4, 5-b] pyridine derivatives 51 were prepared with 5-Bromopyridine-2, 3-diamine 49 underwent facile condensation with various aromatic carboxylic acid derivatives 50 in the presence of Etan’s reagent (Scheme 12).

chemical-sciences-journal-pyridine-derivatives

Scheme 12: Synthesis of 6-bromo-2-substitutedphenyl-1H-imidazo [4,5-b]pyridine derivatives.

Prabhu et al. [35] reported another series of some novel aryl imidazole derivatives 57 were prepared by the condensation of compounds containing primary aromatic amine 52 and aryl aldehydes 53 to give respective Schiff’s bases 54, which was further reacted with ammonium acetate 55 and isatin 56 in the presence of glacial acetic acid (Scheme 13).

chemical-sciences-journal-benzenesulfonamide

Scheme 13: Synthesis of 4-[2-(2-hydroxyphenyl) imidazo [4, 5 – b] indol – 3 (4H) -yl] benzenesulfonamide.

Sathe et al. [36] have synthesized 4âFluoroâ3âchloroanilline 58 treated with potassium thiocyanate in presence of glacial acetic acid and bromine was converted into 2âaminoâ6âfluoroâ7âchlorobenzothiazole 59, resulting into 2âamino benzothiazole. The synthesized compound in presence of 2âphenylâ4âbenzylidineâ5âoxazolinone 60 refluxed in pyridine to obtained 2â (2â Phenyl â 4 â benzylidenyl â 5 â oxo â imidazolin â 1 â ylamino) â 6 â fluoro â7âsubstituted (1, 3) benzothiazoles 62, 61 (Scheme 14).

chemical-sciences-journal-oxo-imidazolin

Scheme 14: Synthesis of 2 - (2 - Phenyl - 4 - benzylidenyl - 5 - oxo - imidazolin - 1 - ylamino) - 6 -fluoro-7-substituted (1, 3) benzothiazoles.

Stella et al. [37] reported an efficient and practical synthesis of imidazolyl derivatives 65 were achieved through thiocyanation of aniline derivatives 63 to gave the intermediate 64 which followed by the reaction with ethylene diamine in the presence of carbondisulphide (Scheme 15).

chemical-sciences-journal-imidazolyl-derivatives

Scheme 15: Synthesis of imidazolyl derivatives.

Lakshmanan et al. [38] also reported the synthesis of 1-(4-substitutedphenyl)-2-(2-methyl-1H-imidazol-1-yl) ethanone 67 and synthesis of 1-(4-substituted phenyl)-2-(1H-imidazol-1-yl) ethanone 68 by the reaction of para substituted phenacyl bromides 66 with imidazoles (Scheme 16).

chemical-sciences-journal-substituted-imidazoles

Scheme 16: Synthesis of 1-substituted imidazoles.

Husain et al. [39] reported a series of 1,2,4âtrisubstitutedâ1 Himidazoles 72 were synthesized by the 2,4âdisubstitutedâ1 Hâ imidazoles 71 and the title compounds were synthesized from 4âmethoxyphenyl glyoxal 70 with following multistep synthesis (Scheme 17).

chemical-sciences-journal-trisubstituted-imidazoles

Scheme 17: Synthesis of 1, 2, 4 trisubstituted 1-H-imidazoles.

Pharmacological Profile of Imidazoles

Imidazole and their derivatives are still the most widely used in the therapeutic areas and have shown a broad spectrum of activity against various pathogens. Since the discovery of various drugs contain the imidazole nucleus, including ketoconazole, metronidazole and cimetidine, which are used to treat fungal infections, bacterial infections and gastric ulcers, respectively. On the basis of various literature surveys imidazole derivatives shows various pharmacological activities (Table 1).

S.No. Chemical Structure Chemical Name Activity Ref.
1 image 2-Cyano-3-(4-fluorophenyl)-N’-[1-(5-methyl-2-phenyl-1H-imidazol-
4-yl)ethylidene]acrylohydrazie
antimicrobial, antioxidant, anti-hemolytic and cytotoxic 40
2 image 1-[2-(1H-imidazol-1-yl)acetyl]-3-methyl-2,6-
diphenylpiperidin-4-one
antibacterial and antifungal 41
3 image 2,4-Dichloro-N-(4-(4-chloro-1H-imidazol-1-yl)-3-
methoxyphenyl)benzamide
antimicrobial and antitubercular 42
4 image transition metal(II) complexes of imidazole-2-carbaldehyde semicarbazone (H2L) antimicrobial 43
5 image (2-aryl-1H-imidazol-
4-yl)methanone
antiproliferative 44
6 image 3-(4-((4-(1H-phenanthro[9,10-d]imidazol-2-yl)phenoxy)
methyl)-1H-1,2,3-triazol-1-yl)propan-1-amine
alzheimer's disease 21
7 image 2,4,5-triphenyl-1H-imidazole antimicrobial 45
8 image 2-[4-(4,5-Diphenyl-1H-imidazol-2-yl)-phenyl]-6-(40-
mathoxy-biphenyl-4-yl)-pyridine (MPBI)
antibacterial, antifungal 46
9 image methyl(2Z)-[3-
({(E)-[3-aryl-1H-pyrazol-4-yl]methylidene}amino)-5-oxo-2-
thioxoimidazolidin-4-ylidene]ethanoate
antibacterial 47
10 image 3-(1-(4-methoxybenzyl)-2-butyl-4-chloro-1H-imidazol-5-yl-1-arylprop-2-en-1-one antibacterial, antifungal 48
11 image (5Z)-5-[4-
(dimethylamino)benzylidene]-3-(5-
substituted -1,3,4-oxadiazol -2-yl)-2-phenyl-
3,5-dihydro-4H-imidazol-4-one
anthelmintic                               49
12         image 4-[2-(2-hydroxyphenyl)imidazo[4,5-b]indol-3(4H)-yl]benzenesulfonamide antibacterial and antihelmintic 35
13 image 2[2’â  Phenyl  â4’â  benzidinylâ  5’â  oxoâ imidazolineâ  1ylâ amino]  â6  fluoroâ  7â  chloro  (1,3)  benzothiazole  anti-inflammatory 36
14 image 4-(4methoxyphenyl)-1,2-diphenyl-1 H-imidazole anti-inflammatory, antifungal 39
15 image 2,3-dihydroimidazo[1,2-b][1,4,2]benzodithiazines anti-HIV 50
16 image N-(2,4-dihydroxybenzylidene)-
2-(2-(phenylthiomethyl)-1H-benzo[d]-imidazol-1-yl)acetohydrazide
antitumor 51
17 image 3-bromo-3-deazaneplanocin antiviral 52

Table 1: Various imidazole derivatives show various pharmacological activities.

Conclusion

Imidazole is a five membered heterocyclic compound. There were so many different conventional methods to synthesize imidazole and its derivatives. On the basis of the literature it was found that imidazole was synthesized under solvent free condition and refluxing method with the help of efficient and different catalyst and without catalyst with good yield. Imidazole is a base in nature due to nitrogen atom. It under goes electrophilic substitution but nucleophilic substitution is rare one. From the extensive literature survey it was found that it has antimicrobial, anticancer, analgesic , antiinflammatory, anticonvulsant, antiviral, anthelmintic, antiulcer, antiallergic activity etc. So from the above discussion it can be concluded that imidazole is a therapeutically active versatile moiety, which had been exploited in the past years for synthesizing various compounds having diverse pharmacological activities, and still imidazole can be further utilized for the future prospective against various diseases or disorders.

Acknowledgements

We are grateful to the Head of the Department, School of studies in Chemistry, Jiwaji University Gwalior and Dean, Birla Institute of Medical Research and College of Life Sciences, Gwalior.

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