Synthesis of Bioactive Imidazoles: A Review

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. 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.


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][2][3][4][5][6][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][9][10][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].
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][19][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.

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).
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).
Pandya et al. [25] also reported a simple and concise route for the synthesis of highly substituted imidazole derivatives 12 have been presence of RCOCl they form an intermediate 32 then it is converted into the synthesized compound (Scheme 8).
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).

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 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).

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.