INTRODUCTION:

Imidazoles are an important heterocyclic structural motif in functional molecules and are utilized in a diverse range of applications.^1,2 Despite recent advances, the development of novel methods for the regiocontrolled synthesis of substituted imidazoles is of strategic importance¹.

This is due to the preponderance of applications to which this important heterocycle is being deployed, such as the traditional applications in pharmaceuticals and agrochemicals^3,4 to emerging research into dyes for solar cells and other optical applications,^5–16 functional materials,¹⁷ and catalysis¹⁸.

It is due to their versatility and utility in a number of these areas that expedient methods for the synthesis of imidazoles are both highly topical and necessary².

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. Imidazole is a highly polar compound, as evidenced by a calculated dipole of 3.61D, and is entirely soluble in water³.

Imidazole is amphoteric; that is, it can function as both an acid and a base. 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 ring has five membered ring systems that contain hydrogen binding domain, and electron donor nitrogensystem⁴.

Fischer (1882) described the first imidazole, but Freud and Kuhn (1890) demonstrated the nature of the ring system. Imidazole are important because their biological activity among their isomer, particularly the imidazole possessed abroad spectrum of biological activities including antimicrobial, antituberculosis, antioxidant, anti-inflammatory, anticonvulsants, antidepressant and anxiolytic, antihypertensive, anticancer and antifungal activity⁵.

It is aromatic heterocycles, particularly the imidazole ring, have been used in the last decades as structural skeletons to obtain different types of bioactive compounds with antibacterial, antifungal, anticancer, antiviral, antidiabetic, and other properties. The search for new potent drug molecules derived from imidazole continues to be an intense area of investigation in medicinal chemistry⁶.

Moreover, pharmaceutical research, manufacture, and regulation are enhancing the development of solid active ingredients, delivered as powders or tablets; however, many solid drugs which perform well in in vitro evaluation remain too insoluble for the body to absorb.

Most of the bioactive agents sold for pharmaceutical or food industries are salts and in this context, ionic liquids (ILs) represent a promising class of drug candidates whose physicochemical and pharmaceutical properties can be easily tuned. In this regard, the imidazolium skeleton can be transformed into ionic liquids with promisingly potent pharmacological properties. Consequently, mono-imidazolium and bis-imidazolium salts have been explored as a new generation of antibacterial agents⁷.

BACKGROUND:

In the past, such drugs containing heterocyclic nuclei have shown high chemotherapeutic value and served as therapeutic agents for new drug development. Many heterocyclic compounds are used clinically to treat infections. That is why drugs containing heterocycles are of great importance. In heterocyclic chemistry, the imidazole-containing moiety occupied a unique position⁸.

It is a 5-memberednitrogen-containing heterocyclic moiety with3carbons, 2nitrogens, 4hydrogens, and 2 double bonds with the general molecular formula C3H4N2. Nitrogensin the 1st and 3rd(non-adjacent), 4thand5thring positions are equivalent. Also called 1, 3-diazole. It contains two nitrogen atoms, one carrying a hydrogen atom and the other called apyrrole-type nitrogen. The 1, 3-diazole ring is a bioester of the pyrazole ring. It is the basic core of some natural products such as histidine, purines, histamine, and DNA-based structures. The name imidazole was first mentionedin1887 by Arthur Rudolf Hantzsch(1857–1935).1, 3-diazolesexhibit an amphoteric phenomenon. That means it can behave like both an acid and a base⁹.

There are two types of lone pairs in imidazole rings: delocalized and delocalized (non-huckle) lone pairs. Both nitrogen atomsinH.1, 3-diazolesexhibit different dissociation constants. The dissociation constants (pKa) of non-localized and non-localized lone pairs are 7 and 14.9, respectively¹⁰.

The 1, 3-diazole ring is susceptible to both electrophilic and nucleophilic attacks due to its amphoteric phenomenon. For acidic imidazoles, the dissociation constant is 5, making them less acidic than phenols, imides, and carboxylic acids, except alcohols (which are less acidic than imidazoles). For basic imidazole, the dissociation constant (pKa) is about 7 (imidazoleis 60 times more basic than pyridine)¹¹.

MECHANISM OF ACTION:

Imidazole works through different mechanisms. According to one study, nitroimidazole enters cells by passive diffusion, where it undergoes reduction to produce the nitro radical anion. This anion oxidizes DNA, causing DNA strand breaks and cell death. Another study found that flavohemoglobin is present in bacteria and metabolizes nitric oxide (NO) to nitrate, preventing NO-mediated damage, stunting, and death¹².

Imidazole acts by modulating flavohemoglobin and inhibiting its NO dioxygenase (NOD) function, thereby inhibiting NO metabolism and ultimately leading to bacterial cell death. Another research group found that inhibition of enoyl acyl carrier protein reductase (FabI), an enzyme involved in the synthesis of bacterial fatty acids, is a new target for antibacterial activity¹³.

Structure and pharmacological activities:

Imidazoles are widely used and important well-known heterocyclic compounds. Characteristics of various medicinal products. Imidazole is a soluble five-membered planar ring. in water and other polar solvents. Since there are two equivalent tautomers, A hydrogen atom can be on either of the two nitrogen atoms. It is a highly polar compound It is completely soluble in water, as evidenced by the calculated dipole of 3.61D.connection is Classified as aromatic due to the presence of paired π-electrons extets electrons from the protonated nitrogen atom and electrons from the remaining four atoms ring. Imidazole is amphoteric and functions as both an acid and a base. Based on various literature searches, imidazole derivatives exhibit different pharmacological effectsactivity^{14, 15}.

Antifungal and anti-bacterial activity:

Ramya v et al. A series of novel 5-(nitro/bromo)-styryl-2-benzimidazole derivatives were synthesized and demonstrated antibacterial activity against Staphylococcus aureus, Escherichia coli, E. faecalis, Klebsiellapneumoniae, and against Candida albicans and gassed Aspergillus. Tested for fungal activity. This was comparable to ciprofloxacin¹⁶.

Deepika Sharma and colleagues have created substituted phenyl)-[2-(substituted phenyl)-imidazol-1-yl] and 2-(substituted phenyl)-1H-imidazole. equivalents of menthanone and tested for gram-positive, gram-negative, and fungal species are all targets of the antibacterial action. Norfloxacin the next chemical is the most powerful when used as the standard¹⁷.

Anti -inflammatory and analgesic activity:

Using a method called carrageenan-induced paw edoema, Puratchikody A. et al. studied 2-substituted-4, 5-diphenyl-1H-imidazoles and evaluated their antiinflammatory efficacy. This substance exhibits the greatest activity, and indomethacin is regarded as a benchmark medicine^{18, 19}.

Kavitha C.S.et al has synthesized a series of 2-methylaminibenzimidazole derivatives and newly
synthesized compounds were screened for analgesic and anti-inflammatory activities. This
compound shows analgesic activity and compared with standard nimesulide drug²⁰.

Antitubercular activity:

Ramya V et al synthesized series of novel 5-(nitro/bromo)-styryl-2-benzimidazoles derivatives and screened for in vitro anti-tubercular activity against Mycobacterium tuberculosis, and these compounds showed good antitubercular activities. Streptomycin was used as reference drug^{21, 22}.

Anticancer activity:

Synthesis of new imidazole-(benz)-azoles and imidazole-epiperazines by Yusuf Ozukai and many others Derivatives for studying anticancer activity. Anticancer activity screening results We have revealed that these are the most active compounds in the series. Cisplatin was used as a referencemedicine²³.

Clatrimazole, Misonidazole, AlpidemKetoconazole, Flumazenil, Metronidazole, Luliconazole Dacarbazine, cimetidine and clonidine contain an imidazole moiety. Active new derivatives therapeutic development²⁴.

Imidazole-based compounds have biological activity. B. Anti-cancer, anti-fungal, anti-bacterial, anti-inflammatory, anti-parasitic, anti-viral and anti-neuropathic agents. However, the synthesis of imidazoles and their derivatives has been of great interest to organic and pharmaceutical chemists. There is still a need for efficient and facile methods for constructing heterocyclic imidazole backbones^{25, 26}.

Neurodegenerative diseases (NDDs)-

Neurodegeneration has been described as a progressive, untreatable psychiatric disease in which specific types of neurons are lost, dysfunction of central nervous system (NCS)distribution, and neuronaldys regulation. Neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia are diverse in their pathophysiology and manifestations²⁷.

Cognitive impairment and memory loss and a person's ability to speak, move and breathe. Therefore, effective therapeutics are urgently needed, but only used once their mechanisms of action are understood. Most neurodegenerative diseases are detected by the intra- and extracellular aggregation of misfolded proteins²⁸.

Alzheimer disease-

Alzheimer's disease, a form of dementia, affects older people worldwide. The disease is associated with the aggregation of amyloid-β (Aβ) around tissues, forming neurofibrillary tangle NFTs through hyperphosphorylation of tau proteins associated with cellular microtubules³⁰. Aβ is a plaque membrane glycoprotein precursor protein that accumulates around neurons and causes senescent cells. Aβ has variable length truncations of ^37–42 residues, depending on the number of amino acids present²⁹.

Its cleavage, stimulated by α- or β-secretase in the presence of the γ-secretase enzyme, leads to the accumulation of neurotoxic fragments of Aβ. A 42-residue segment of Aβ42 exhibits pro-accumulation properties. Pathological increases in Aβ42 formation are associated with the presence of Alzheimer's disease³⁰.

Therefore, prevention of Aβ42 production and accumulation, or at least clearing of accumulated Aβ42, along with elimination of tau-associated toxicity, is of critical importance. The protein tau is important for microtubule stabilization, which depends on inhibition of tau phosphorylation, which is accompanied by stabilization of microtubules and inhibition of tau oligomerization³¹.

Parkinson’s disease-

Parkinson's disease(PD) is another common type of NDD, affecting about 4% of people over the age of 85 and about 1% of people over the age of 60. Patients with Parkinson's disease suffer from characteristic symptoms such as cognitive impairment, gradual memoryloss, etc., due to the loss of dopamine-containing neurons in the substantia nigra neurons leading to reduced dopamine levels in the striatum³².

Loss of these neurons and uptake of the insoluble protein 'Lewybodies'(LBS) are key pathologies in the end stages of diseases in which α-sinkre in protein accumulates. Amyloid aggregation, cholinergic dysfunction, andα-synucle in accumulation cause cognitive impairment in Parkinson's disease patients. Some studies have shown that occupational exposure to some chemicals, such as heavy metals and pesticides, increases the risk of developing Parkinson's disease³³.

Table No 1- List of Patents Applied for Antibacterial Potency of Imidazoles

Patent Name	Patent Date	Descriptions	Ref.
US 3, 575, 999	20.04.1971	The patent disclosed the antibacterial potential of 1-(-aryl)ethyl imidazoleketals.	34
US 3, 679, 697	25.07.1972	In 1972, explained the antibacterial property of 1-[ halophenethyl ]imidazoles	35
US 3, 682, 951	08.08.1972	Kreider discovered 1-[-(1-Adamantyloxy) halophenethyl]imidazoles as potent antibacterial agents	36
US 3, 927, 017	16.12.1975	1-(-aryl--R-ethyl)imidazoles possessing antibacterial potency was described	37
US 3, 991, 201	09.11.1976	Heeres and co-workers reported 1-(-aryl--R-ethyl)imidazoles having antibacterial activity	38
US 2005/0020586 A1	27.01.2005	Patent disclosed new class of imidazolines with potential antibacterial potency	39
WO 2005/033119 A1	14.04.2005	The patent disclosed antibacterial imidazoles	40
WO 2007/133790 A2	22.11.2007	Patent disclosed new class of imidazolines with potential antibacterial potency	41
WO 2007/144286 A1	21.12.2007	The patent enclosed the antibacterial compositions having imidazole as main component	42
WO 2008/059258 A2	22.05.2008	The researcher disclosed the Imidazoles for the treatment of infection caused by multidrug resistant microorganisms.	43
WO 2009/070304 A1	04.06.2009	Imidazole derivatives possessing biofilm inhibition property had been reported.	44

Chemical aspects of imidazole:

Glyoxal and ammonia were used in 1858 to create imidazoles. The synthesis of imidazoles can be accomplished in a number of ways, including the Radiszewski method, dehydrogenation of imidazolines, the Wallach method, the method using aminonitrile and aldehyde, and the Marckwald method. Below are specifics of the synthetic processes^{45, 46}-

Radiszewski synthesis:

It involves combining a dicarbonyl chemical, such as glyoxal, a-keto aldehyde, or a-diketone, with an aldehyde in the presence of ammonia. For example, when benzyl is combined with benzaldehyde, two molecules of ammonia react to produce 2, 4, 5-triphenylimidazole. A convenient alternative to ammonia is frequently found to be formamide⁴⁸.

Dehydrogenation of Imidazoline:

Barium managanate has been described as a gentler reagent for the conversion of imidazolines to imidazoles when sulphur is present by Knapp and colleagues. When alkyl nitriles and 1, 2 ethanediamine are combined, the resulting imidazolines produce 2-substituted imidazoles⁴⁹.

From a- Haloketone:

The interaction between an imidine and alpha halo ketones is what causes this reaction. This technique has been successfully used to produce 2, 4- or 2, 5-biphenyl imidazole from phenacylbromide and benzimidine, which in turn produces 2, 4-diphenyl imidazole. Similar to this, amidine produces imidazoles when it interacts with acyloin or alpha halo ketones^{50, 51}.

Table No 2- Commercially available drugs are containing Imidazole nucleus.

Name	Structure	Activity	Reference
Clemizole		Anti-histaminic	52
Etonitazene		agent	53
Enviroxime		Antiviral	54
Irtemazole		For the promotion of excretion of uric acid	55
Astemizole		Anti-histaminic agent	56
Omeprazole		Antiulcer	57
Ketoconazole		Antifungal	58
Dacarbazine		Anticancer	59
Pimobendan		Calcium sensitizer and phosphor diesterase inhibitor	60
Fenbendazole		Antihelmintic	61

LITERATURE REVIEW:

Title of article	Author	Description	Ref.
Imidazoles as Promising Scaffolds for Antibacterial Activity: A Review	Nidhi Rani	Many studies have been conducted on heterocycles recently, particularly the imidazole ring, in an effort to create a scaffold with potential pharmacological qualities such as antibacterial, antifungal, anticancer, antiviral, and antidiabetic, among others, with fewer side effects. Finding novel physiologically active imidazoles is still a fascinating field of research. analysis of medicinal chemistry. It can therefore be used for future research to produce new, potent medicinal compounds.	62
A Literature Review on the Imidazole	Muhammed Abdel Hasan Shallal	In this article, some information is provided regarding the imidazole ring as a (ligand, complex, antibacterial, antimalarial, anticancer, uses, applications, coupled with active groups such as Schiff base, azo group The five-membered ring systems of the midazole ring feature an electron donor nitrogen system and a hydrogen-binding domain.Particularly the imidazole possessed a broad spectrum of biological properties, including antibacterial, antituberculosis, antioxidant, antiinflammatory, anticonvulsant, antidepressant and anxiolytic, antihypertensive, anticancer, and antifungal action.	63
Synthesis, characterization and antibacterial activity of imidazole derivatives of 1, 10 phenan- throline and their cu(ii), co(ii) and ni(ii) complexes	Mesut Gomleksiz	The structures of the compounds were determined by elemental analyses, IR, UV-visible, 1H-NMR, TGA, magnetic susceptibilities and molar conductance measurements. It is observed that the synthesized complexes have tetragonal and distorted square pyramidal geometrical structures. Antibacterial activity of the ligands and their metal complexes were tested against selected bacteria by disc diffusion method.synthesized and characterized Cu(II), Co(II) and Ni(II) complexes with phen imidazole derivatives, which are 4-bromo-2-(1H-imidazo[4, 5-f] phenanthroline-2-yl)phenol (L1) and 2-(1H-imidazo[4, 5-f] phenanthroline-2-yl)-5 methoxyphenol (L2)	64
Imidazole Antifungals: A Review of Their Action Mechanisms on Cancerous Cells	BernaKavakcıoğluYardımcı	The azole subgroup of antifungal medications, which includes imidazoles and triazoles, works by preventing the cytochrome P450-dependent enzyme lanosterol 14-demethylase from doing its job. Clotrimazole, econazole, and ketoconazole have emerged as the most effective imidazoles for extra anti-cancer action beyond their core usage. The disruption of the glycolytic route, blocking of Ca2+ influx, and nonspecific inhibition of CYP450 enzymes might be regarded as the primary mechanisms behind the antineoplastic actions of the aforementioned medicines, notwithstanding their disparate effects.	65
Imidazole and Imidazolium Antibacterial Drugs Derived from Amino Acids	Elena Atrián-Blasco	The lipophilicity of imidazole and imidazolium salts, which may be adjusted by adding various hydrophobic substituents to the nitrogen atoms of the molecule's imidazole or imidazolium ring, is a key factor in their antibacterial action. In light of this, we created a variety of imidazole and imidazolium salts from L-valine and L-phenylalanine that contained various hydrophobic groups, described them, and then assessed their efficacy against two model bacterial strains: Gram-negative E. coli and Gram-positive B. subtilis.	66
Reaction strategies for synthesis of imidazole derivatives: a review	Sylvia Atanasova-Stamova	Modern synthetic organic chemistry places a strong emphasis on the creation of a methodical directing synthesis of complex organic compounds with the goal of getting the physiologically active substance with selective action. Many bioactive substances, both natural and manufactured, have imidazole derivatives as a significant ingredient. In recent years, they have drawn the attention of numerous researchers in the fields of pharmaceutical chemistry and pharmacology. This is as a result of the remarkable chemical characteristics and biological functions they exhibit. Making changes to existing imidazole derivatives and synthesising new ones is extremely difficult for scientists.	67

CONCLUSION:

On the basis of various literature survey imidazole derivatives show various activity against antimicrobial, anti-inflammatory, analgesic, antitubercular, anticancer etc. 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. Furthermore, some imidazole drugs, at high concentrations, could exert direct inhibitory effects on membranes, without interference with sterols and sterol esters. Various recent new drugs developments in imidazole derivatives show better effect and less toxicity.

CONFLICTS OF INTEREST:

There are no conflicts of interest and disclosures regarding the manuscript.

ACKNOWLEDGMENT:

The authors express their sincere gratitude to Pravara Rural College of Pharmacy, Pravaranagar, (Loni BK), University Libraries, and all other sources for their cooperation and advice in writing this review.

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Received on 13.10.2022 Modified on 16.11.2022

Asian J. Research Chem. 2023; 16(1):71-78.

DOI: 10.52711/0974-4150.2023.00012