One-pot Multi-component Synthesis of Some Pharmacologically Significant 2,4,5-Tri and 1,2,4,5-Tetrasubstituted Imidazoles: A Review

Heterocyclic compounds are acquiring more importance in recent years because of their pharmacological activities. Compounds containing imidazole moiety have many pharmacological properties and play important role in biochemical processes. Imidazole is a natural compound which exists in many important natural molecules such as the amino acid histidine, vitamin B12, histamine, biotin and purines like adenine and guanine. Imidazole derivatives play significant roles in various pharmacological activities such as anticancer, antibacterial, antifungal, antiviral, anti-HIV and antitubercular. This article aims to review the work in the methods of synthesis using various catalytic system, solvent condition and pharmacological potential of 2,4,5-tri and 1,2,4,5tetrasubstituted imidazoles reported during last 15 years. Review Article Bansal et al.; IRJPAC, 11(4): 1-26, 2016; Article no.IRJPAC.24493 2


INTRODUCTION
The chemistry of imidazole units is very important due to their potent biological activity and synthetic utilities. The potency and wide applicability of the imidazole pharmacophore can be attributed to its hydrogen bond donoracceptor capability as well as its high affinity for metals, present in many protein active sites. [1] Appropriately substituted imidazoles are extensively used as glucagon receptors [2] and cannabinoid receptor antagonists [3], modulators of P-glycoprotein (P-gp) mediated multidrug resistance (MDR) [4], anti-tumour [5], antibacterial [6] and anti-inflammatory agents. These can also be utilized as fungicides [7] and plant growth regulators [8].
The research and development of imidazolebased chemistry have become a rapidly developing and increasingly active topic, towards their feasible applications in diverse areas, such as medicinal drugs, agrochemicals, man-made materials, artificial acceptors, supra molecular ligands and biomimetic catalysts [9][10][11][12]. Numerous imidazole-based compounds have playing a vital role in the treatment of various types of diseases and encouraged medicinal chemists to synthesize a large number of novel chemotherapeutic agents [13][14][15].
In recent years, alkylated imidazoliums have been used as ionic liquids [16] providing an approach to the 'Green Chemistry' protocol. The imidazole compounds have also been used in photography as photosensitive compounds [17].
Thus the main intention of this report is to survey the methods reported in the literature up to 2016 for the synthesis of tri-and tetrasubstituted 1Himidazoles. In addition, this review outlines and discusses the biological activities of these heterocycles to make it more useful for medicinal chemists, pharmacists and pharmacologists.

MULTICOMPONENT REACTIONS
Multi-component reactions (MCRs) are convergent reactions, in which three or more starting materials react to form a product, where basically all or most of the atoms contribute to the newly formed product [18]. In an MCR, a product is assembled according to a cascade of elementary chemical reactions. Thus, there is a network of reaction equilibria, which finally flow into an irreversible step yielding the product. The challenge is to conduct an MCR in such a way that the network of pre-equilibrated reactions channel into the main product and do not yield side products. The result is clearly dependent on the reaction conditions: solvent, temperature, catalyst, concentration, the kind of starting materials and functional groups. Such considerations are of particular importance in connection with the design and discovery of novel MCRs [19].
In the drug discovery process, MCR offers many advantages over traditional approaches. With only a limited number of chemists and technicians, more scaffold synthesis programs can be achieved within a shorter time. With onepot reactions, each synthesis procedure (weighing of reagents, addition of reagents, reaction time, control) and work-up procedure (quenching, extraction, distillation, chromatography, weighing, and analysis) needs to be performed only once, in contrast to multistep synthesis. MCRs are compatible with a solution phase approach, thus enabling a simple monitoring and they are easily amenable to automation. Moreover, each scaffold is expandable from a low number of compounds (scouting library) to a larger library. Thus, "hit-tolead" transitions are normally accomplished easily and promptly. Certain physicochemical properties can be built into a library, e.g. lipophilicity and aqueous solubility, molecular weight, numbers of hydrogen donors and acceptors and the number of rotatable bonds, as well as the polar surface area. Finally, scale-up is often possible from a preclinical lab-scale (mg, gram) to clinical exploratory amounts (kg) using the same type of chemistry [20]. Drug molecules derived from MCR are very cost effective which, is the need of the hour.
MCRs have received considerable attention because of the complexity of the molecules that can be easily achieved from readily available starting materials in one reaction sequence [21]. MCRs generally occur in one pot and exhibit high atom economy and product selectivity. In most of the cases, they yield a single product and thus MCRs are advantageous over linear stepwise synthesis because of operational simplicity, reduction in reaction time, ecological friendliness, saving of money and raw materials, inexpensive purification, and avoidance of protection and deprotection processes [22].

SYNTHESIS OF 1,2,4,5-TETRA AND 2,4,5-TRISUBSTITUTED IMIDAZOLES VIA ONE-POT MULTI-COMPONENT REACTIONS
The development of new MCRs with a variety of catalyst is an interesting area of current research. Owing to the wide range of pharmacological and biological activities, the synthesis of various imidazoles and their derivatives are important targets in current years, among these tri-and tetra substituted imidazoles have received much attention [23]. Several methods have been reported in literature exploiting the utility of MCRs. have reported to achieve a simple, highly versatile and an efficient synthesis of 1,2,4,5tetrasubstituted imidazoles by four-component cyclocondensation of benzil, aromatic aldehyde, aminoethylpiperazine and ammonium acetate using sulphated yttria (SO 4 -2 /Y 2 O 3 ) as a catalyst in ethanol medium. An attractive synthetic protocol by the aspect of condensation in the presence of supported reagents with operational simplicity, inexpensive reagents, high yield of products and the use of non-toxic reagents have been reported by Sivakumar et al. [67] in which Cu(II) nitrate impregnated zeolite was used as an efficient reagent for rapid one-pot synthesis of 2,4,5-tri and 1,2,4,5-tetrasubstituted imidazoles with excellent yields. An operationally simple, metal-free and economical one-pot threecomponent cycloaddition reaction for the synthesis of 1,2,4-trisubstituted imidazoles using aldehydes, α-amino carbonyl compounds and ammonium acetate has been developed successfully by Tang et al.
[68] This environment friendly transformation by employing I 2 (10 mol %) as a catalyst and EtOH as a solvent with wide range of functional groups and heterocycles giving rise from moderate to good yields (Scheme 16).
[69] Cu/SAPO-34 catalyst has been reported with highest activity in improving the efficiency of the heterogeneous cyclocondensation of an aldehyde, benzil, ammonium acetate and a primary aromatic amine in water under ultrasonic irradiation. An efficient and eco-friendly procedure for shorter reaction time, recyclable catalyst and excellent yields has been developed by Safari et al. [ This naturally occurring and widely produced fatty acid exhibited remarkable catalytic activity which was easily separated by extraction. The reusability of this catalytic medium was tested by recovering the catalyst and using it again in the reaction up to four times with no significant drop in activity. The catalyst is commercially available, low cost and eco-friendly, offering short reaction times, good to excellent yields and a straightforward work-up procedure.  [118] have reported a reliable synthesis method for 2,4,5trisubstituted imidazole from benzil, ammonium acetate and aromatic aldehyde using BiCl 3 as a catalyst in solvent CH 3 CN.
Over the years the imidazole nucleus has attracted the attention of the scientific community due to its chemical and biological properties [145] e.g. nucleus is present in the structures of several natural products in the form of the essential amino-acid histidine or in alkaloids exhibiting anti-tumour, anti-cancer (dacarbazine), antihistaminic (cimetidine), anti-parasitic (metronidazole), and antihypertensive (losartan) and anti-bacterial activities [146][147][148]. A great numbers of medicines containing the imidazole nucleus, including ketoconazole have used to treat gastric ulcers, fungal and bacterial infections [149,150].
Imidazoles have many applications in pharmacological and biochemical development [151] e.g. the hypnotic agent (etomidate), [152] the proton push inhibitor (omeprazole) [153] and the benzodiazepine antagonist (flumazenil) [154] are imidazole derivatives. For all above applications the synthesis of imidazoles has become very vital objective in present duration. 2,4,5-triaryl-1H-imidazole is harmful towards human life also for animal because it reduces platelet aggregation in some animal and humans.
A series of 1-substituted 2,4,5-triphenyl imidazoles (13) were synthesized by Yashoda et al. [169] and screened for mild to moderate anti-inflammatory and antimicrobial activities. Many drugs have imidazole nucleus in their structure have been found in medicinal field like dacarbazine as anticancer, metronidazole as antifungal, cimetidine as anti-histamics and flumazenil as benzodiazepine antagonist [170]. Imidazole-containing antifungal drug (ketoconazole) was also found to have anti-inflammatory activity in addition to its antifungal activity [171]. Flutrimazole another imidazole-based wide spectrum antifungal agent was found to be a good topical anti-inflammatory agent [172]. Therefore, imidazole nucleus seems to be an important pharmacophore for designing of new drug candidates.
Jain et al. [180] have synthesized 2-substituted-4,5-diphenyl-N-alkylimidazoles and evaluate their antibacterial activity. All the synthesized compounds were evaluated for antibacterial activity against S. aureus, B. subtilis, and E. coli the results showed some short of activity but none of them had considerable activity compared with that of the standard. 4,5-triphenyl-1Himidazole-1-yl derivatives (14) have been synthesized and tested for their anti-inflammatory activity in-vitro using phenylbutazone as a reference drug and antimicrobial activity using clotrimazole and ciprofloxacin as a standard drug by Shailesh et al. [181].

CONCLUSION
MCRs are a useful class of reactions for never ending hunt for biologically active compounds and complimentarily add into the large arsenal of tools available to the modern chemists. The literature survey reveals that great biological potential and easy routes for synthesis of imidazoles have attracted the attention of chemists, pharmacologists and researchers. The therapeutically active moiety 2,4,5-tri and 1,2,4,5tetrasubstituted imidazoles had been exploited in the recent past for the synthesis of various pharmacologically active compounds. By the present scenario it can be concluded that imidazoles have a great potential for further research and novel derivatives can be synthesized containing this core fragment and can be explored for various biological activities.

ACKNOWLEDGEMENT
Authors acknowledge gratefully the help rendered by Head, SOS in Chemistry, for providing library facilities and Central Library, Jiwaji University, Gwalior, for providing online access of journals.