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Synthesis and therapeutic potential of imidazole containing compounds

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.

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].

Fig. 1
figure1

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].

Fig. 2
figure2

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].

Table 1 Commercially available drugs are containing Imidazole nucleus

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].

Scheme 1
scheme1

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]).

Scheme 2
scheme2

Synthesis of 2-(4-substitutedphenyl)-1-substituted-4,5-diphenyl-1H-imidazole

Table 2 Antibacterial activity of synthesized derivatives (1a-e)-zone of inhibition (mm,%) Jain et al. [28]

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]).

Scheme 3
scheme3

Synthesis of pyridin-3-yl(2-(2,3,4,5-tetrasubstitutedphenyl)-1H-imidazol-1-yl)methanone

Table 3 Antimicrobial activity of titled compounds (2a-k) Narasimhan et al. [1]

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]).

Scheme 4
scheme4

Synthesis of 3-(2,4-disubstitutedphenyl)-1-(4-substitutedphenyl)-4-(4,5-diphenyl-1H-imidazol-2-yl)-1H-pyrazole

Table 4 Antibacterial activity of tri-substituted imidazole derivatives (4a-n) Brahmbhatt et al. [2]

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]).

Scheme 5
scheme5

Synthesis of (Z)-4-((6-bromo-2-chloroquinonlin-3-yl)methylene)-2-phenyl-1-(2,3,4-trimsubstitutedphenyl)1H-imidazol-5(4H)-one

Table 5 Antimicrobial activity of synthesized compounds (5a-h) Parab et al. [29]

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]).

Scheme 6
scheme6

Synthesis of 2,3-disubstituted-3,4-dihydroimidazo[4,5-b]indole

Table 6 Antimicrobial activity of the synthesized aryl imidazole compounds (7a-t) Sharma et al. [17]

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]).

Scheme 7
scheme7

Synthesis of N-(4-substitutedphenyl)-2-(2-(2-(2-hydroxyphenyl)-4,5-diphenyl-1H-imidazol-1-yl)acetyl)hydrazinecarbothioamide

Table 7 Antibacterial and antifungal activity of titled compounds (8a-8e) Ahsan et al. [30]

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]).

Scheme 8
scheme8

Synthesis of imidazole derivatives

Table 8 Antibacterial activity of titled compounds (9a-13a) Bhade et al. [18]

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]).

Scheme 9
scheme9

Synthesis of (Z)-(4-((2-chloroquinonlin-3-yl)methylene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl)substitutedcarbamic

Table 9 (a) Antibacterial activity of the synthesized derivatives (14a-l); (b) Antifungal activity of titled compounds (14a-l) Desai et al. [31]

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]).

Scheme 10
scheme10

Synthesis of 6-substituted-3-(4,5-diphenyl-1H-imidazol-2-yl)-2-(4-substitutedphenoxy)quinoline

Table 10 (a) Antibacterial activity of the synthesized compounds (15a-f); (b) Antifungal activity of the synthesized compounds (15a-f) 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]).

Scheme 11
scheme11

Synthesis of N-(2-(1H-benzo[d]imidazol-2-yl)phenyl)substitutedformimidoyl

Table 11 Antimicrobial activity of titled compounds (16a-b) Selvan et al. [33]

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]).

Scheme 12
scheme12

Synthesis of 2-(chloroamino)-1-(2,4,5-tridiphenyl-1H-imidazol-1-yl)ethanone

Table 12 Antimicrobial activity of titled compounds (17a-f) Zala et al. [8]

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]).

Scheme 13
scheme13

Synthesis of benzimidazole-substituted-1,3-thiazolidin-4-ones

Table 13 MIC of benzimidazole-substituted-1,3-thiazolidin4-ones (18a-r) in µM/ml Yadav et al. [34]

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]).

Scheme 14
scheme14

Synthesis of 2-((1-((4-substitutedphenyl)amino)-4,5-dimethyl-1H-imidazol-2-yl)thio)-N-(6-substitutedbenzo[d]thiazol-2-yl)acetamide

Table 14 IC50 values of the synthesized compounds (20a-j) against C6 and HepG2 cancer cell line Yurttas et al. [35]

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]).

Scheme 15
scheme15

Synthesis of imidazole derivatives

Table 15 Anticancer activity of titled compounds (21a-26d) against different cancer cell lines Hsieh et al. [25]

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]).

Scheme 16
scheme16

Synthesis of 2-(5-butyl-3-chloro-1-substituted-1H-pyrrol-2-yl)-1H-benzo[d]imidazole

Table 16 IC50 values of the synthesized compounds (27a-j) Roopashree et al. [36]

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]).

Scheme 17
scheme17

Synthesis of 2-substituted-1-(3,4,5-trimethoxyphenyl)-1H-imidazole

Table 17 Antitumor activity of the synthesized compounds (28a-q) Romangoli et al. [37]

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]).

Scheme 18
scheme18

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

Table 18 (a) IC50 of the titled compounds (29a-j) against of MCF-7 and CaCo-2 cell line—benzo [d] imidazole pyrimidine derivatives; (b) IC50 of the titled compounds (30a-j) against of MCF-7 and CaCo-2 cell line—benzo [d] imidazole pyrazole derivatives Rajendran et al. [38]

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]).

Scheme 19
scheme19scheme19

a Synthesis of substituted Schiff base; b Synthesis of substituted imidazole derivatives; c. Synthesis of substituted phenyl imidazole pyridine derivatives

Table 19 Anticancer activity of the synthesized derivatives (31–59) against three different cancer cell lines Meenakshisundaram et al. [39]

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]).

Scheme 20
scheme20

Synthesis of 1,2-disubstituted-4,5-diphenyl-1H-imidazole

Table 20 Antitumor activity of the synthesized derivatives (60a-j) Sharma et al. [40]

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]).

Scheme 21
scheme21

Synthesis of 3-(4,5-diphenyl-1-(substitute phenyl)-1H-imidazol-2-yl)-sunstituted-2-(substitutedphenyl)- 1H-indole

Table 21 Antioxidant activity of the synthesized derivatives (61a-j) Naureen et al. [41]

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]).

Scheme 22
scheme22

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

Table 22 Antioxidant activity of the synthesized compounds (62a-f) Rajasekaran et al. [42]

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]).

Scheme 23
scheme23

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

Table 23 Antioxidant activity of the synthesized derivatives (63a-h) Subramaniam et al. [43]

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]).

Scheme 24
scheme24

Synthesis of (E)-N'-(7-methyl-2-propyl-1H-benzo[d]imidazole-5-carbonyl)substituted formohydrazonuyl

Table 24 Antioxidant activity of synthesized derivatives (64a-r) Katikireddy et al. [21]

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]).

Scheme 25
scheme25

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

Table 25 (a) DPPH radical scavenging activity of (65a-h) and (66a-h); (b) Hydrogen peroxide radical scavenging activity of (65a-h) and (66a-h); (c) Nitric oxide radical scavenging activity of (65a-h) and (66a-h); (d) FRAP oxide radical scavenging activity of (65a-h) and (66a-h) Subhashini et al. [44]

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]).

Scheme 26
scheme26

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

Table 26 Antihypertensive activity of the synthesized derivatives (67a-o) in SHR Navarrete-Vázquez et al. [45]

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]).

Scheme 27
scheme27

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

Table 27 Antihypertensive activity of titled compounds (68a-f) in normotensive and hypertensive rats Hadizadeh et al. [46]

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]).

Scheme 28
scheme28

Synthesis substituted imidazole derivatives

Table 28 Antihypertensive activity of the synthesized compounds (70a-j) Goyal et al. [22]

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]).

Scheme 29
scheme29

Synthesis of N3-(substituted phenyl)-N5-(substituted phenyl)-4-(4, 5-dichloro-1H-imidaVol-2-yl)-2-methyl-1, 4-dihydropyridine-3, 5-dicarboxamide

Table 29 Antitubercular activity of the synthesized compounds (71a-j) against Mycobacterium tuberculosis (H37Rv strain) Amini et al. [47]

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]).

Scheme 30
scheme30

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

Table 30 Antitubercular activity of synthesized compounds (72a-q) against M. tuberculosis H37Rv Pandey et al. [48]

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]).

Scheme 31
scheme31

Synthesis of 10-(2-(substituted phenyl)imidazo[2,1-b][1, 3, 4]thiadiazol-6-yl)-10H-phenothiazine

Table 31. Antitubercular activity of the synthesized compounds (73a-j) Makwane et al. [49]

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]).

Scheme 32
scheme32

Synthesis of 2-((1H-imidazol-1-yl)methyl)-6-substituted-5-fluoro-1H-benzo[d]imidazole

Table 32 Antitubercular activity of synthesized derivatives (74a-e) against M. tuberculosis H37Rv strain Nandha et al. [23]

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]).

Scheme 33
scheme33

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

Table 33 Antitubercular activity of synthesized derivatives (77a-f) and (78a-i) Nandha et al. [50]

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]).

Scheme 34
scheme34

Synthesis of 2,5-disubstituted-4-(6-methoxynaphthalen-2-yl)-1H-imidazole

Table 34 Antitubercular activity of synthesized derivatives (79a-m) Gising et al. [51]

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]).

Scheme 35
scheme35

Synthesis of substituted phenyl imidazole derivatives

Table 35 Antitubercular activity of synthesized compounds (80a-83e) Syed et al. [52]

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]).

Scheme 36
scheme36

Synthesis of 6-(substituted phenyl)-2-(1-methyl-1H-imidazol-2-yl) imidazo [2,1-b] [1,3,4] thiadiazole

Table 36 Antitubercular activity of synthesized compounds (84a-j) Patel et al. [53]

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]).

Scheme 37
scheme37

Synthesis of 2-((1-benzoyl-1H-benzo[d]imidazol-2-yl) thio)-N-(substituted phenyl) acetamide

Table 37 Antitubercular activity of synthesized compounds (85a-t) Yadav et al. [54]

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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Acknowledgements

Thanks to Head Prof. Sanju Nanda, Department of Pharmaceutical Sciences, M.D.U, Rohtak for providing library and internet facilities, etc.

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PKV-endeavored and accomplished the scheme; AS-completed review work and wrote the manuscript. Both authors read and approved the final manuscript.

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Correspondence to Prabhakar Kumar Verma.

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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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Keywords

  • 1
  • 3-diazole
  • Antibacterial
  • Antitumor
  • Antioxidant
  • Antitubercular
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