Abstract
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.
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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 C3H4N2 (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 (1857–1935) in 1887 [6].
Imidazole
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].
Tautomeric forms of imidazole
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].
The 1,3-diazole and it's containing compounds shows a lot of therapeutic activities such as analgesics, antifungal, antihypertensive, antiobesity, antitumor [3], antiviral, anthelmintic, antitubercular [4], antiulcer, antihistaminic [13], anti-inflammatory, antidepressant [14]. antidiabetic [15], anticonvulsant [16], antiallergic [7], antirheumatic [17], antiasthmatic, alpha-blockers [18], antiprotozoal [19], antiaging, anticoagulant, antimalarial [20], and antiamoebic activity [21] etc.
There are different examples of commercially available drugs which consist 1,3,4-oxadiazole ring (Table 1) such as clemizole (antihistaminic agent), etonitazene (analgesic), enviroxime (antiviral), irtemazole, astemizole (antihistamine), omeprazole, pantoprazole (antiulcer), thiabendazole (antihelmintic), nocodazole (antinematodal) [22], metronidazole and nitrosoimidazole (bactericidal), megazol (trypanocidal) [12], azathioprine (anti-rheumatoid arthritis), tinidazole, ornidazole (antiprotozoal and antibacterial), satranidazole (amoebiasis), cimetidine (gastric ulcer), carbimazole (against thyroid disorder), tolazoline (vasodilator action), naphazoline (vasoconstrictor), tetrahydrozoline (vasoconstrictor) [16], etomidate, lansoprazole, flumazenil, methimazole, pilocarpine [19], ketoconazole [23], dacarbazine (anticancer) [24], pimobendan (calcium sensitizer and phosphodiesterase inhibitor) [25], fenbendazole [26].
The mechanism for the formation of 2,4,5-trisubstituted imidazole
The Debus-Radziszewski reaction mechanism for the formation of the 2,4,5-trisubstituted imidazole is given by (Scheme 1) [27].
Plausible mechanism for the synthesis of imidazoles catalyzed by (4–SB)T(4–SPh)PHSO4
Main text
Antibacterial activity
Jain et al. [28] synthesized 2-(4-substituted phenyl)-1-substituted-4, 5-diphenyl-1H-imidazole (Scheme 2) and evaluated their antimicrobial activity against S. aureus, E. coli, and B. subtilis by cylinder wells diffusion method using Norfloxacin as a reference drug. Among the different derivatives, compounds 1a and 1b showed good antimicrobial potential. The conclusion of antibacterial activity was presented in (Table 2, Jain et al. [28]).
Synthesis of 2-(4-substitutedphenyl)-1-substituted-4,5-diphenyl-1H-imidazole
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, Narasimhan et al. [1]).
Synthesis of pyridin-3-yl(2-(2,3,4,5-tetrasubstitutedphenyl)-1H-imidazol-1-yl)methanone
Brahmbhatt et al. [2] synthesized 3-(2,4-disubstituted phenyl)-1-(4-substituted phenyl)-4-(4,5-diphenyl-1H-imidazol-2-yl)-1H-pyrazole (Scheme 4). The antibacterial activity of these derivatives was evaluated against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa using amikacin sulfate, ampicillin, and chloramphenicol as a reference drug. Compound 4 h shows the most potent activity as compared to the rest of the synthesized compounds. The conclusion of antibacterial activity was presented in (Table 4, Brahmbhatt et al. [2]).
Synthesis of 3-(2,4-disubstitutedphenyl)-1-(4-substitutedphenyl)-4-(4,5-diphenyl-1H-imidazol-2-yl)-1H-pyrazole
Parab et al. [29] synthesized (Z)-4-((6-Bromo-2-chloroquinolin-3-yl) methylene)-2-phenyl-1-(2, 3, 4-trisubstituted phenyl)-1H-imidazol-5(4H)-one by using Scheme 5. The antibacterial activity of synthesized derivatives was evaluated against E. coli, P. aeruginosa, B. subtilis, and B. megaterium by agar cup borer method using streptomycin as a reference drug. The antimycotic potential was evaluated for these derivatives against Candida albicans and Aspergillus niger using imidil as a reference drug and the conclusion of activity was presented in (Table 5, Parab et al. [29]).
Synthesis of (Z)-4-((6-bromo-2-chloroquinonlin-3-yl)methylene)-2-phenyl-1-(2,3,4-trimsubstitutedphenyl)1H-imidazol-5(4H)-one
Sharma et al. [17] synthesized 2,3-disubstituted-3, 4-dihydroimidazo [4,5-b] indole (Scheme 6) and evaluated for antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Klebsiella pneumoniae by Kirby-Bauer disc technique using ciprofloxacin as reference drug. The conclusion of antimicrobial potential was presented in (Table 6, Sharma et al. [17]).
Synthesis of 2,3-disubstituted-3,4-dihydroimidazo[4,5-b]indole
Ahsan et al. [30] synthesized N-(4-substituted phenyl)-2-(2-(2-(2-hydroxyphenyl)-4, 5-diphenyl-1H-imidazol-1-yl) 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]).
Synthesis of N-(4-substitutedphenyl)-2-(2-(2-(2-hydroxyphenyl)-4,5-diphenyl-1H-imidazol-1-yl)acetyl)hydrazinecarbothioamide
Bhade et al. [18] synthesized 2,4-dichloro-6-(2-substituted-2,5-dihydro-1H-imidazol-4-yl)phenol, 6-(3, 5-dichloro-2-hydroxyphenyl)-2-substituted-2H-imidazo[1,2-a]imidazol-3(5H)-one, 1-acetyl-4-(3, 5-dichloro-2-hydroxyphenyl)-1H-imidazol-2(5H)-one, (Z)-4-(3,5-dichloro-2-hydroxyphenyl)-1-(3-(2, 3-dichlorophenyl) acryloyl)-1H-imidazol-2(5H)-one and 4-(3,5-dichloro-2-hydroxy phenyl)-1-(5-(2,3-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)-1H-imidazol-2(5H)-one by using (Scheme 8). The antibacterial activity of these derivatives was evaluated against Staphylococcus aureus, Staphylococcus epidermidis, Salmonella typhi and Pseudomonas aeruginosa using chloramphenicol as reference control. The conclusion of activity was presented in (Table 8, Bhade et al. [18]).
Synthesis of imidazole derivatives
Desai et al. [31] synthesized (Z)-(4-((2-chloroquinolin-3-yl)methylene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl)substituted carbamic (Scheme 9) and evaluated for antimicrobial potential against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Streptococcus pyogenes by serial broth dilution method using ampicillin as a reference standard and the results were summarized in (Table 9a, Desai et al. [30]). The antimycotic potential of these derivatives was evaluated against A. niger, C. albicans, and A. clavatus using griseofulvin as a reference standard. The results of the activity were summarized in (Table 9b, Desai et al. [31]).
Synthesis of (Z)-(4-((2-chloroquinonlin-3-yl)methylene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl)substitutedcarbamic
Shobhashana et al. [32] synthesized 6-substituted-3-(4,5-diphenyl-1H-imidazol-2-yl)-2-(4-substituted phenoxy) quinoline by using (Scheme 10) and evaluated for antimicrobial activity against Bacillus subtilis, Escherichia coli, Clostridium tetani, Streptococcus pneumoniae, and Salmonella typhi by using the broth dilution method. 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]).
Synthesis of 6-substituted-3-(4,5-diphenyl-1H-imidazol-2-yl)-2-(4-substitutedphenoxy)quinoline
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]).
Synthesis of N-(2-(1H-benzo[d]imidazol-2-yl)phenyl)substitutedformimidoyl
Zala et al. [8] synthesized 2-(substituted amino)-1-(2,4,5-triphenyl-1H-imidazol-1-yl) ethanone (Scheme 12) and evaluated for antimicrobial potential against Staphylococcus aureus and Escherichia coli using ciprofloxacin as a reference drug. The antimycotic potential of these derivatives was evaluated against C. albicans using Clotrimazole as a reference drug. The conclusion of antibacterial activity was presented in (Table 12, Zala et al. [8]).
Synthesis of 2-(chloroamino)-1-(2,4,5-tridiphenyl-1H-imidazol-1-yl)ethanone
Yadav et al. [34] synthesized 2-((1H-benzo[d]imidazol-2-yl)thio)-N-(4-oxo-2-(2,3,4,5,6-Penta substituted phenyl)thiazolidin-3-yl)acetamide and 2-((1H-benzo[d]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]).
Synthesis of benzimidazole-substituted-1,3-thiazolidin-4-ones
Anticancer activity
Yurttas et al. [35] developed 2-((1-((4-substituted phenyl) amino)-4,5-dimethyl-1H-imidazol-2-yl)thio)-N-(6-substitutedbenzo[d]thiazol-2-yl)acetamide by using (Scheme 14) and evaluated for antitumor potential by MTT assay against two different cancer cell lines such as C6 (rat glioma) and HepG2 (human liver) using cisplatin as a reference drug. Among the synthesized derivatives compound 20g shows good cytotoxic potential. The conclusion of antitumor potential was presented in (Table 14, Yurttas et al. [35]).
Synthesis of 2-((1-((4-substitutedphenyl)amino)-4,5-dimethyl-1H-imidazol-2-yl)thio)-N-(6-substitutedbenzo[d]thiazol-2-yl)acetamide
Hsieh et al. [25] synthesized (E)-1-(1-allyl-1H-benzo[d]imidazol-2-yl)-3-(4-substituted phenyl) prop-2-en-1-one by using (Scheme 15) and evaluated for anticancer activity against different cell lines such as A549, MCF-7, HepG2, and OVCAR-3 by MTT assay using cisplatin as a reference drug. The conclusion of anticancer activity was presented in (Table 15, Hsieh et al. [25]).
Synthesis of imidazole derivatives
Roopashree et al. [36] synthesized 2-(5-butyl-3-chloro-1-substituted-1H-pyrrol-2-yl)-1H-benzo[d]imidazole (Scheme 16) and evaluated for antitumor activity against HeLa cancer cell line by using MTT assay. Each compound was tested to calculate the inhibitory concentration and the results of the activity were presented in (Table 16, Roopashree et al. [36]).
Synthesis of 2-(5-butyl-3-chloro-1-substituted-1H-pyrrol-2-yl)-1H-benzo[d]imidazole
Romagnoli et al. [37] developed 2-substituted-1-(3,4,5-trimethoxyphenyl)-1H-imidazole (Scheme 17) and evaluated for anticancer activity against different cancer cell lines such as HeLa, HT-29, A549, MCF-7, Jurkat, and HL-60 using C-A4 as a reference standard. Compounds 28k, 28n, and 28o showed maximum cytotoxicity as compared to others. The conclusion of antitumor potential was presented in (Table 17, Romagnoli et al. [37]).
Synthesis of 2-substituted-1-(3,4,5-trimethoxyphenyl)-1H-imidazole
Rajendran et al. [38] synthesized 1-substituted-2-(5-substituted-1-phenyl-1-H-pyrazol-3-yl)-1H-benzo[d]imidazole and 4-(1-chloro-1H-benzo[d]imidazol-2-yl)-6-fluoropyrimidin-2-amine by using (Scheme 18) and evaluated for antitumor potential against different cell lines such as MCF-7 and CaCo-2 using Fluorouracil as reference drug. Each compound was tested to calculate inhibitory concentration and the conclusion of activity was presented in (Table 18a, b, Rajendran et al. [38]).
Synthesis of 1-substituted-2-(5-substituted-1-phenyl-1H-pyrazol-3-yl)-1H-benzo[d]imidazole and 4-(1-chloro-1H-benzo[d]imidazole-2-yl)-6-fluoropyrimidin-2-amine
Meenakshisundaram et al. [39] synthesized 3-(4-substitutedbenzyl)-6,7-disubstituted-2-(4-(6,7-disubstituted-3-(4-substitutedbenzyl) imidazo[1,2-a] pyridin-2-yl)phenyl)imidazo[1,2-a]pyridine, 3-(4-substituted benzyl)-2-(3-(6,7-disubstituted-3-(4-substitutedbenzyl)imidazo[1,2-a]pyridin-2-yl)phenyl)-6,7-disubstitutedimidazo[1,2-a]pyridine and 6,7-disubstituted-3-(4-substitutedbenzyl)-2-phenylimidazo[1,2-a] pyridine (Scheme 19a–c) and evaluated for antitumor potential against different cell lines such as HeLa, MDA-MB-231 and ACHN by SRB method using adriamycin as a reference drug. The conclusion of antitumor potential was presented in (Table 19, Meenakshisundaram et al. [39]).
a Synthesis of substituted Schiff base; b Synthesis of substituted imidazole derivatives; c. Synthesis of substituted phenyl imidazole pyridine derivatives
Sharma et al. [40] synthesized 1,2-disubstituted-4, 5-diphenyl-1H-imidazole (Scheme 20), and evaluated for antitumor potential by using the tryphan blue dye exclusion technique against different cancer cell lines such as DLA and EAC at different concentration. The conclusion of antitumor potential was presented in (Table 20, Sharma et al. [40]).
Synthesis of 1,2-disubstituted-4,5-diphenyl-1H-imidazole
Antioxidant activity
Naureen et al. [41] synthesized 3-(4,5-diphenyl-1-(substituted phenyl)-1H-imidazol-2-yl)-substituted-2-(substituted phenyl)-1H-indole (Scheme 21) and evaluated for antioxidant potential by DPPH method using Quercetin as reference drug. Compound 61d shows the highest antioxidant activity as compared to others. The conclusion of antioxidant potential was presented in (Table 21, Naureen et al. [41]).
Synthesis of 3-(4,5-diphenyl-1-(substitute phenyl)-1H-imidazol-2-yl)-sunstituted-2-(substitutedphenyl)- 1H-indole
Rajasekaran et al. [42] synthesized (E)-(1H-benzo[d]imidazol-1-yl)(4-((substituted benzylidene)amino)phenyl)methanone (Scheme 22a), 2-(1H-benzo[d]imidazol-1-yl)-N-(5-phenyl-1,3,4-oxadiazol-2-yl)acetamide (Scheme 22b) and 1-(1H-benzo[d]imidazol-1-yl)-2-((substituted-1,3,4-oxadiazol-2-yl)thio)ethanone (Scheme 22c) and evaluated for antioxidant potential by using DPPH assay. All the synthesized derivatives showed good scavenging potential as compared to ascorbic acid (positive control) and the conclusion of activity was presented in (Table 22, Rajasekaran et al. [42]).
a Synthesis of (E)-(1H-benzol[d]imidazole-1-yl)(4-(substitutedbenzylidene)amino)phenyl)methanone. b Synthesis of 2-(1H-benzol[d]imidazole-1-yl)-N-(5-phenyl-1,3,4-oxadiazol-2-yl)acetamide. c Synthesis of substituted imidazole linked 1,3,4-oxadiazole derivatives
Subramaniam et al. [43] synthesized (Z)-3-(2-(5-(3-methyl benzylidene)-4-oxo-2-phenyl-4, 5-dihydro-1H-imidazol-1-yl) ethyl)-2-phenyl quinazolin-4(3H)-one derivatives (Scheme 23) and evaluated for antioxidant potential by using DPPH assay. These compounds showed good scavenging potential as compared to ascorbic acid (positive control). The conclusion of scavenging potential was presented in (Table 23, Subramaniam et al. [43]).
Synthesis of (Z)-3-(2-(5-(3-methyl benzylidene)-4-oxo-2-phenyl-4, 5-dihydro-1H-imidazol-1-yl) ethyl)-2-phenyl quinazolin-4(3H)-one and 3-(3-mercapto-5-(susbstituted phenyl)-4H-1,2,4-triazol-4-yl)-2-phenylquinazolin-4(3H)-one
Katikireddy et al. [21] developed (E)-N'-(7-methyl-2-propyl-1H-benzo[d]imidazole-5-carbonyl) substituted formohydrazonoyl (Scheme 24) and evaluated for antioxidant activity using ascorbic acid as a reference drug. Compound 64n shows the most potent antioxidant activity as compared to others and the results of activity were presented in (Table 24, Katikireddy et al. [21]).
Synthesis of (E)-N'-(7-methyl-2-propyl-1H-benzo[d]imidazole-5-carbonyl)substituted formohydrazonuyl
Subhashini et al. [44] synthesized 4-((4-(4,5-diphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1-(2,3,4-trisubstituted phenyl)-1H-1,2,3-triazole derivatives (Scheme 25a, b) and evaluated for antioxidant activity by using four different methods such as Hydrogen peroxide scavenging, Nitric oxide scavenging, DPPH, and FRAP assay. The conclusion of antioxidant potential was presented in (Table 25a–d, Subhashini et al. [44]).
a Synthesis of 4-((4-(4,5-diphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1-(2, 3, 4-trisubstituted phenyl)-1H-1, 2, 3-triazole; b Synthesis of 4-((4-(4,5-diphenyl-1-((1-(2, 3, 4-trisubstituted phenyl)-1H-1, 2, 3-triazole-4-yl)methyl)-1H-imiidazol-2-yl)phenoxy)methyl)-1-(2,3,4-trisubstitutedphenyl)-1H-1,2,3-triazole
Antihypertensive activity
Navarrete-Vazquez et al. [45] synthesized 5-(trifluoromethyl)-2-(2,3,4-trisubstituted phenyl)-1H-benzo[d] imidazole and 5-nitro-2-(2,3,4-trisubstituted phenyl)-1H-benzo [d] Imidazole (Scheme 26) and evaluated for antihypertensive potential in SHR by using the tail-cuff method and the results of antihypertensive activity were summarized in (Table 26, Navarrete-Vazquez et al. [45]).
Synthesis of 5-(trifluoromethyl)-2-(2, 3, 4-trisubstituted phenyl)-1H-benzo[d] imidazole and 5-nitro-2-(2, 3, 4-trisubstituted phenyl)-1H-benzo[d]imidazole
Hadizadeh et al. [46] synthesized 2-(2-(1H-imidazol-1-yl)ethyl)-4-(1-benzyl-2-(substituted thio)-1H-imidazol-5-yl)-5-(substituted carbonyl)-6-methyl-1, 4-dihydropyridine-3-substituted carboxylic acid (Scheme 27) and evaluated for antihypertensive potential in rats and the results of anti-hypertensive activity were summarized in (Table 27, Hadizadeh et al. [46]).
Synthesis of 2-(2-(1H-imidazol-1-yl)ethyl)-4-(1-benzyl-2-(substituted thio)-1H-imidazol-5-yl)-5-(substituted carbonyl)-6-methyl-1, 4-dihydropyridine-3-substituted carboxylic acid
Goyal et al. [22] synthesized 2-substituted-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazole derivatives (Scheme 28) and evaluated for antihypertensive potential and the results of activity were summarized in (Table 28, Goyal et al. [22]).
Synthesis substituted imidazole derivatives
Antitubercular activity
Amini et al. [47] synthesized N3-(substituted phenyl)-N5-(substituted phenyl)-4-(4,5-dichloro-1H-imidazol-2-yl)-2-methyl-1, 4-dihydropyridine-3,5-dicarboxamide (Scheme 29) and evaluated for anti-tubercular activity against Mycobacterium tuberculosis strain using rifampicin as reference drug. The conclusion of the anti-tubercular activity was presented in (Table 29, Amini et al. [47]).
Synthesis of N3-(substituted phenyl)-N5-(substituted phenyl)-4-(4, 5-dichloro-1H-imidaVol-2-yl)-2-methyl-1, 4-dihydropyridine-3, 5-dicarboxamide
Pandey et al. [48] synthesized (E)-3-(4-(7-substituted-3-(substituted amino)imidazo[1,2-a] pyridin-2-yl)phenyl)-1-(substituted phenyl)prop-2-en-1-one (Scheme 30) and evaluated for anti-tubercular potential against Mycobacterium tuberculosis strain by MB 7H10 agar medium using Ethambutol and Pyrazinamide as a reference drug. The conclusion of the activity was presented in (Table 30, Pandey et al. [48]).
Synthesis of (E)-3-(4-(7-substituted-3-(substituted amino)imidazo[1,2-a] pyridin-2-yl)phenyl)-1-(substituted phenyl)prop-2-en-1-one
Makwane et al. [49] synthesized 10-(2-(substituted phenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-10H-phenothiazine by using (Scheme 31) and evaluated for antitubercular activity by (L.J) agar method against Mycobacterium tuberculosis H37Rv strain using Isoniazid as reference drug and MIC values of these derivatives were calculated. The conclusion of anti-tubercular activity was presented in (Table 31, Makwane et al. [49]).
Synthesis of 10-(2-(substituted phenyl)imidazo[2,1-b][1, 3, 4]thiadiazol-6-yl)-10H-phenothiazine
Nandha et al. [23] synthesized 2-((1H-imidazol-1-yl)methyl)-6-substituted-5-fluoro-1H-benzo[d]imidazole (Scheme 32) and evaluated for anti-tubercular activity against Mycobacterium tuberculosis strain by MABA assay using Isoniazid as a reference drug. The conclusion of anti-tubercular activity was presented in (Table 32, Nandha et al. [23]).
Synthesis of 2-((1H-imidazol-1-yl)methyl)-6-substituted-5-fluoro-1H-benzo[d]imidazole
Nandha et al. [50] synthesized 6-(benzo[d][1,3]dioxol-5-yloxy)-2-substituted-5-fluoro-1H-benzo[d] imidazole (Scheme 33) and evaluated for anti-tubercular activity against Mycobacterium tuberculosis (ATCC27294) by MABA assay using streptomycin, ciprofloxacin, and pyrazinamide as a reference drug. The conclusion of the activity was presented in (Table 33, Nandha et al. [50]).
Synthesis of 6-(benzo[d][1, 3]dioxol-5-yloxy)-2-substituted-5-fluoro-1H-benzo[d] imidazole and 2-(((6-bromobenzo[d][1,3]dioxol-5-yl)methyl)thio)-6-substituted-5-fluoro-1 h-benzo[d]imidazole
Gising et al. [51] synthesized 2,5-disubstituted-4-(6-methoxynaphthalen-2-yl)-1H-imidazole by using (Scheme 34). The anti-tubercular potential of these derivatives was evaluated against Mycobacterium tuberculosis strain and MIC values of these derivatives were calculated. The conclusion of anti-tubercular activity was presented in (Table 34, Gising et al. [51]).
Synthesis of 2,5-disubstituted-4-(6-methoxynaphthalen-2-yl)-1H-imidazole
Syed et al. [52] synthesized 6-(4-substituted phenyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)imidazo [2,1-b][1,3,4] thiadiazole (Scheme 35) and evaluated for anti-tubercular potential against Mycobacterium tuberculosis strain. Compounds 80a, 80b, 81a, 82a, and 83a showed the most potent anti-tubercular activity as compared to others. The conclusion of anti-tubercular activity was presented in (Table 35, Syed et al. [52]).
Synthesis of substituted phenyl imidazole derivatives
Patel et al. [53] synthesized 6-(substituted phenyl)-2-(1-methyl-1H-imidazol-2-yl) imidazo [2,1-b] [1,3,4] thiadiazole (Scheme 36) and evaluated for anti-tubercular activity against Mycobacterium tuberculosis and MIC values of these derivatives were calculated. The conclusion of anti-tubercular activity was presented in (Table 36, Patel et al. [53]).
Synthesis of 6-(substituted phenyl)-2-(1-methyl-1H-imidazol-2-yl) imidazo [2,1-b] [1,3,4] thiadiazole
Yadav et al. [54] synthesized 2-((1-benzoyl-1H-benzo[d]imidazol-2-yl) thio)-N-(substituted phenyl) acetamide (Scheme 37) and evaluated for anti-tubercular activity against Mycobacterium tuberculosis strain and MIC values of these derivatives were calculated. Streptomycin was used as a reference drug and the results of anti-tubercular activity were presented in (Table 37, Yadav et al. [54]).
Synthesis of 2-((1-benzoyl-1H-benzo[d]imidazol-2-yl) thio)-N-(substituted phenyl) acetamide
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 antioxidant, etc. This review article established the fact that 1,3-diazole act as useful templates for further modification or derivatization to design more potent biologically active compounds.
Availability of data and materials
All data are provided in the manuscript or cited in the references.
Abbreviations
- AMR:
-
Antimicrobial resistance
- DNA:
-
Deoxyribonucleic acid
- DMF:
-
Dimethylformamide
- TEBA:
-
Triethyl benzyl ammonium chloride
- MTT:
-
3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- C-A4:
-
Combretastatin-A4
- SRB:
-
Sulforhodamine B assay
- DLA:
-
Dalton’s Lymphoma Ascites cell line
- EAC:
-
Ehrlich’s ascites carcinoma cell lines
- DPPH:
-
2,2-Diphenyl-1-picrylhydrazyl
- FRAP:
-
Ferric reducing ability of plasma
- SHR:
-
Spontaneously hypertensive rats
- MB:
-
Middle brook
- MABA:
-
Microplate Alamar blue assay
- L.J:
-
Lowenstein-Jensen
- IC50 :
-
Half maximal inhibitory concentration
- HeLa:
-
Henrietta Lacks
- TEA:
-
Triethanolamine
- DMSO:
-
Dimethyl sulphoxide
- MIC:
-
Minimum inhibitory concentration
- TBAB:
-
Tetrabutylammonium bromide
- NCFT:
-
National Centre of Fungal Taxonomy
- MLC:
-
Minimum Lethal concentration
- p-TSA:
-
P-Toluenesulfonic acid
- MW:
-
Microwave
- CAN:
-
Cerric ammonium nitrate
- (4-SB) T (4-SPh)PHSO4:
-
(4-Sulfobutyl)tris(4-sulfophenyl) phosphonium hydrogen sulfate
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Siwach, A., Verma, P.K. Synthesis and therapeutic potential of imidazole containing compounds. BMC Chemistry 15, 12 (2021). https://doi.org/10.1186/s13065-020-00730-1
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DOI: https://doi.org/10.1186/s13065-020-00730-1