Synthesis and therapeutic potential of imidazole containing compounds

Imidazole is a five-membered heterocyclic moiety that possesses three carbon, two nitrogen, four hydrogen atoms, and two double bonds. It is also known as 1, 3-diazole. It contains two nitrogen atoms, in which one nitrogen bear a hydrogen atom, and the other is called pyrrole type nitrogen. The imidazole name was reported by Arthur Rudolf Hantzsch (1857–1935) in 1887. 1, 3-diazole is an amphoteric in nature i.e. it shows both acidic and basic properties. It is a white or colorless solid that is highly soluble in water and other polar solvents. Due to the presence of a positive charge on either of two nitrogen atom, it shows two equivalent tautomeric forms. Imidazole was first named glyoxaline because the first synthesis has been made by glyoxal and ammonia. It is the basic core of some natural products such as histidine, purine, histamine and DNA based structures, etc. Among the different heterocyclic compounds, imidazole is better known due to its broad range of chemical and biological properties. Imidazole has become an important synthon in the development of new drugs. The derivatives of 1, 3-diazole show different biological activities such as antibacterial, antimycobacterial, anti-inflammatory, antitumor, antidiabetic, anti-allergic, antipyretic, antiviral, antioxidant, anti-amoebic, antihelmintic, antifungal and ulcerogenic activities, etc. as reported in the literature. There are different examples of commercially available drugs in the market which contains 1, 3-diazole ring such as clemizole (antihistaminic agent), etonitazene (analgesic), enviroxime (antiviral), astemizole (antihistaminic agent), omeprazole, pantoprazole (antiulcer), thiabendazole (antihelmintic), nocodazole (antinematodal), metronidazole, nitroso-imidazole (bactericidal), megazol (trypanocidal), azathioprine (anti rheumatoid arthritis), dacarbazine (Hodgkin's disease), tinidazole, ornidazole (antiprotozoal and antibacterial), etc. This present review summarized some pharmacological activities and various kinds of synthetic routes for imidazole and their derived products.


Background
Nowadays, Public health problems were increasing due to AMR in drug therapy. So, there is necessary for the development of a new drug that overcomes the AMR problems [1].
In past, those drugs which contain heterocyclic nuclei give high chemotherapeutic values and act as a remedy for the development of novel drugs [2]. There are lots of heterocyclic compounds that are in clinical use to treat infectious diseases. So, there is a great importance of heterocyclic ring containing drugs [3].
In heterocyclic chemistry, imidazole containing moiety occupied a unique position [4]. It is a five-membered nitrogenous heterocyclic moiety that possesses three carbon, two nitrogen, four hydrogen atoms, and two double bonds having general molecular formula is C 3 H 4 N 2 (Fig. 1). The nitrogen atoms present at the first and third positions (non-adjacent position) of the ring [5], position four and five are equivalent [6]. It is also known as 1,3-diazole. It contains two nitrogen atoms, one nitrogen bear a hydrogen atom, and the other is called pyrrole type nitrogen [7]. 1,3-diazole ring is a bioester of the pyrazole ring [8]. It is the basic core of some natural products such as histidine, purine, histamine and DNA based structures, etc. [4]. The imidazole name was first reported by Arthur Rudolf Hantzsch  in 1887 [6].
1,3-diazole shows an amphoteric phenomenon i.e. it can behave like acid as well as a base. Two types of lone pair are present in the imidazole ring, delocalized and non-delocalized (non-Huckle) lone pair, i.e. both nitrogen of 1,3-diazole shows different dissociation constant. The dissociation constant (pKa) of delocalized lone pair and non-delocalized lone pair is 7 and 14.9 respectively. 1,3-diazole ring is susceptible to both electrophilic and nucleophilic attacks due to its amphoteric phenomenon [7]. For an acid imidazole, the dissociation constant is 14.5, which makes it less acidic than phenol, imides, and carboxylic acid except for alcohols (which is less acidic than imidazole). For a basic imidazole, the dissociation constant (pKa) is approximately 7 (which makes imidazole 60 times more basic than pyridine). The acidic proton is present on the first nitrogen atom of the imidazole ring [6].
Due to the presence of a positive charge on either of the two nitrogen atoms, 1,3-diazole ring shows two equivalent tautomeric forms (Fig. 2) [9]. The presence of a sextet of π-electrons on the ring makes it an aromatic compound. The nitrogen atom on the third position in the imidazole ring is more reactive to the electrophilic compound due to the availability of unshared pairs of electron on the second nitrogen atom since the second nitrogen is a part of aromatic sextet [6].
It is a white or colorless solid. The imidazole ring shows excellent solubility in water and other polar solvents [10]. The dipole moment, melting point, and boiling point of the imidazole ring is 4.8 D in dioxane [6], 88.9 °C , and 267.8 °C [7] respectively. It possesses intramolecular hydrogen bonding [9].
Imidazole was first named glyoxaline because the first synthesis has been made by glyoxal and ammonia [9]. There is a different kind of synthetic route from which we can synthesize 1,3-diazloes, and its derivatives. Common methods are Debus-Radiszewski synthesis, Wallach synthesis, from dehydrogenation of imidazolines, from alpha halo-ketones, Marckwald synthesis, and amino nitrile [11].
Due to the polar nature of the imidazole ring, the pharmacokinetic parameters of the imidazole containing compounds should be improved to a great extent. Thus, this moiety helps to overcome the solubility problems of poorly soluble drug entities [12].

Anesthetic agent
Narasimhan et al.
[1] synthesized pyridin-3-yl (2-(2,3,4,5-tetra substituted phenyl)-1H-imidazol-1-yl) methanone (Scheme 3). The tube dilution method was used for the determination of antimicrobial potential against S. aureus, B. subtilis, and E. coli using ciprofloxacin as a reference drug. The antifungal activity of these derivatives was also evaluated against A. niger and C. albicans using Fluconazole as a reference standard. The conclusion of antimicrobial potential was presented in (Table 3

Pilocarpine
Cholinergic agent
Ahsan et al. [30] synthesized N-(4-substituted phenyl)-2- acetyl) hydrazine carbothioamide (Scheme 7). The antibacterial activity of synthesized derivatives was evaluated against Escherichia coli, Bacillus subtilis, and Staphylococcus aureus using Ofloxacin as a reference drug. The antimycotic potential was evaluated for these derivatives against C. albicans using Voriconazole as a positive control. Compounds 8a, 8b, and 8d showed good antifungal activity against C. albicans. The conclusion of antimicrobial activity was presented in (Table 7, Ahsan et al. [30]).
Ampicillin, chloramphenicol, and ciprofloxacin were used as a positive control. The antimycotic activity of these derivatives was evaluated against Candida albicans and Trichophyton rubrum using Nystatin and Griseofulvin as reference drugs. The conclusion of antimicrobial activity was presented in (Table 10a, b, Shobhashana et al. [32]).
Selvan et al. [33] developed N-(2-(1H-benzo[d]imidazol-2-yl)phenyl)substituted formimidoyl by using (Scheme 11). The disc diffusion technique was used for the determination of antimicrobial activity against S. aureus using ciprofloxacin as a positive control. The antimycotic activity of these derivatives was evaluated against A. niger using Nystatin as a reference drug and the conclusion of antimicrobial potential was presented in (Table 11, Selvan et al. [33]).
Yadav et al.
imidazol-2-yl)thio)-N-(2-substituted-4-oxothiazolidin-3-yl) acetamide by using (Scheme 13). The antibacterial activity of these derivatives was evaluated against different bacterial strains (Staphylococcus aureus, Escherichia coli, and Bacillus subtilis) using Norfloxacin as a reference drug. The antimycotic activity of these derivatives was evaluated against different fungal (Candida albicans and Aspergillus niger) strains using Fluconazole as a reference drug. The conclusion of the activity was presented in (Table 13, Yadav et al. [34]).

Conclusion
In this present review article, we have summarized different pharmacological activities of 1,3-diazole containing compounds. From this study, we have found that 1,3-diazole containing compounds can be synthesized by various kinds of synthetic routes, and these derivatives having a wide range of biological activities such as antitumor, antitubercular, antimicrobial, antihypertensive and