Synthesis and therapeutic potential of imidazole containing compounds

1Nowadays, 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.

2In past, those drugs which contain heterocyclic nuclei give high chemotherapeutic values and act as a remedy for the development of novel drugs. 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.

3In heterocyclic chemistry, imidazole containing moiety occupied a unique position. 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, position four and five are equivalent. 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. 1,3-diazole ring is a bioester of the pyrazole ring. It is the basic core of some natural products such as histidine, purine, histamine and DNA based structures, etc.. The imidazole name was first reported by Arthur Rudolf Hantzsch (1857–1935) in 1887.

41,3-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. 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.

5Due 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). 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.

6It is a white or colorless solid. The imidazole ring shows excellent solubility in water and other polar solvents. The dipole moment, melting point, and boiling point of the imidazole ring is 4.8 D in dioxane, 88.9 °C, and 267.8 °C respectively. It possesses intramolecular hydrogen bonding.

7Imidazole was first named glyoxaline because the first synthesis has been made by glyoxal and ammonia. 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.

8Due 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.

9The 1,3-diazole and it's containing compounds shows a lot of therapeutic activities such as analgesics, antifungal, antihypertensive, antiobesity, antitumor, antiviral, anthelmintic, antitubercular, antiulcer, antihistaminic, anti-inflammatory, antidepressant. antidiabetic, anticonvulsant, antiallergic, antirheumatic, antiasthmatic, alpha-blockers, antiprotozoal, antiaging, anticoagulant, antimalarial, and antiamoebic activity etc.

10There 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), metronidazole and nitrosoimidazole (bactericidal), megazol (trypanocidal), 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), etomidate, lansoprazole, flumazenil, methimazole, pilocarpine, ketoconazole, dacarbazine (anticancer), pimobendan (calcium sensitizer and phosphodiesterase inhibitor), fenbendazole.

11The Debus-Radziszewski reaction mechanism for the formation of the 2,4,5-trisubstituted imidazole is given by (Scheme 1).

12Jain et al. 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.).

13Narasimhan et al. 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.).

14Brahmbhatt et al. 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.).

15Parab et al. 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.).

16Sharma et al. 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.).

17Ahsan et al. 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.).

18Bhade et al. 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.).

19Desai et al. 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.). 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.).

20Shobhashana et al. 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.).

21Selvan et al. 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.).

22Zala et al. 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.).

23Yadav et al. 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.).

24Yurttas et al. 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.).

25Hsieh et al. 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.).

26Roopashree et al. 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.).

27Romagnoli et al. 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.).

28Rajendran et al. 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.).

29Meenakshisundaram et al. 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.).

30Sharma et al. 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.).

31Naureen et al. 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.).

32Rajasekaran et al. 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.).

33Subramaniam et al. 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.).

34Katikireddy et al. 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.).

35Subhashini et al. 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.).

36Navarrete-Vazquez et al. 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.).

37Hadizadeh et al. 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.).

38Goyal et al. 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.).

39Amini et al. 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.).

40Pandey et al. 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.).

41Makwane et al. 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.).

42Nandha et al. 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.).

43Nandha et al. 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.).

44Gising et al. 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.).

45Syed et al. 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.).

46Patel et al. 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.).

47Yadav et al. 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.).

48In 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.