A Review Article on Recent Advances in The Pharmacological Diversification of Imidazole Derivative

Abstract

Imidazole is a nitrogen-containing heterocyclic compound that plays a vital role in biological and pharmaceutical sciences. Thus, the imidazole ring is a component of several natural products such as purine, histamine, and nucleic acid. The activity of the imidazole ring provides enormous scope in synthesizing various compounds containing pharmacological activities. In this literature, several imidazole derivatives have been described for their biological activities including antifungal, antiulcer, antiviral, anticancer, antibacterial, antitubercular, anti-inflammatory, analgesic, anthelmintic, antidepressant, antimalarial, antileishmanial, anticonvulsant, antimicrobial, antihypertensive, antidiabetic, anti-HIV, anti-hepatitis, antioxidant, anticoagulant which reveals the prospect of imidazole in the drug design and medicine.

Keywords

Heterocyclic compound, Imidazole, Antifungal, Antiviral, Antiulcer, Anticancer.

Introduction

 

 

Pharmacological Activities of Imidazole and It’s Derivatives:

1. Antifungal Activity:

1. Deepika, S. et al., have reported the synthesis of substituted-1H-imidazole and substituted imidazolyl methanone derivatives and have been shown to exhibit antifungal activity towards gram-negative, gram-positive bacteria and fungi by interfering with an enzyme that’s important creating the fungal cell membrane. Here norfloxacin is used as a reference compound and (2-(2-chlorophenyl)-1H-imidazol-1-yl) (4-nitrophenyl) methanone is found to be the most active molecule^.[2]

Fig.2: Anti-fungal activity of imidazole derivative

B. B. Bouchal, F. Abrigach, and others synthesised 34 imidazole-based compounds employing a one-pot catalytic strategy and they examined these compounds against several fungi. Among these compounds 2-(1H-imidazol-1-yl)-1 phenylethanol aromatic ester and carbamate derivatives are most active as its IC₅₀ values are 95± 7.07 compared to standard drug fluconazole against the strains of candida albicans. These compounds might be active against fungi by intervening with the lanosterol 14- methylase enzyme. ^[3]

Fig.3: Anti-fungal activity of imidazole derivative

2. Anti-Viral Activity:

1. Michele, T. et al., have synthesized many 2-phenylbenzimidazoles and found their cytotoxicity and antiviral activity against a panel of RNA and DNA viruses by inhibiting the entry of virus into the host cell and interfering with the receptor binding. The 2-(4-nitrophenyl) benzimidazole derivative was found to be a more potential drug than the standards of reference mycophenolic acid and 6-aziridine.^[4]

Fig.4: Anti-viral activity of imidazole derivative

2. D. Sharma et al., have synthesized imidazole derivatives, and the antiviral screening of substituted phenyl-[2-(substituted phenyl)-imidazol-1-yl]- methanone against viral strains compounds selected as the most potent antiviral agents.  Ribavirin was used as a standard drug. These compounds may interfere with the viral replication process by inhibiting viral enzymes such as polymerases or proteases.^[5]

Fig.5: Anti-viral activity of imidazole derivative

3. Anti-Ulcer Activity:

1. Nadeem and Khan studied to investigate the effect of 2- (pyrimidinyl sulfinyl) benzimidazole derivatives such as omeprazole are proton pump inhibitors. They show antiulcer activity by irreversible inhibition of the proton pump(H⁺/K⁺-ATPase) in parietal cells in the stomach, resulting in prolonged suppression of gastric acid secretion and increased pH, allowing ulcers to heal and preventing further damage to the gastrointestinal lining, and the compound was found to have good antiulcer activity.^[6]

     

Fig.6: Anti-ulcer activity of imidazole derivative

2. Shin et al. synthesized new aryl sulfonyl proton pump inhibitor (PPI) prodrug forms. These prodrugs provided longer residence time of an effective PPI plasma concentration, by irreversibly inhibiting the proton pump (H⁺/ K⁺ ATPase in stomach parietal cells. This reduction in acid allows ulcers to heal by minimizing acid-related damage to the gastric and duodenal lining, resulting in better gastric acid inhibition.^[7]

Fig.7: Anti-ulcer activity of imidazole derivative

4.  Anti-Cancer Activity:

1. S. Hu, W. Ma, J. Wang, et al., synthesized IPM714, 1H-Imidazole[4,5-f][1,10] phenanthroline derivative which shows inhibitory action on colorectal cancer cells with IC₅₀ 1.74µM respectively. IPM714 shows inhibitory action by triggering apoptosis in HCT116 and SW480 cells and stops the cell cycle in the S phase. ^[8]

Fig.8: Anti-cancer activity of imidazole derivative

2. S. Meenakshisundaran, Manickam et al., synthesized bis-imidazoles and bis imidazo[1,2-a] pyridines for anticancer activity. These compounds were tested using 3 cancer line cells such as HeLa[cervical], breast [MDA-MB-231], and renal cancer. Imidazo[1,2-a] pyridines show outstanding cytotoxic activity and exhibit the strongest inhibitory effects on all cell lines especially on breast cancer cell lines.^[9]

Fig.9: Anti-cancer activity of imidazole derivative

5. Anti-Bacterial Activity:

1. A. Agarwal, S. Juneja, et al., synthesized N-(4-([benzyl]) oxy) phenyl) acetamide derivatives. Their conjugates are antibacterial against gram-positive and gram-negative bacteria such as methicillin-resistant Staphylococcus aureus and extended-spectrum beta-lactamases by inhibiting cell wall and protein synthesis.^[10]

Fig.10: Anti-bacterial activity of imidazole derivative

2. D.G. Daraji, D.P. Rajani, et al., synthesized 1-(furan-2-yl) methyl)-4,5-diphenyl-2-p-tolyl-1H-imidazole (FMDI) molecules. The antibacterial properties of these compounds are examined then these compounds have higher binding energies than mitomycin and ciprofloxacin Binding energy: -11.69kcal/mol and 15.40kcal/mol shows better activity when compared to standard drug mitomycin with binding energy of -24.47 kcal/mol. ^[11]

Fig.11: Anti-bacterial activity of imidazole derivative

6. Anti-Tubercular Activity:

1. P.G. Shobha Shana, Prasad, et al., identified 2,4,5-trisubstituted imidazole derivatives in a single pot using Benzil, ammonium acetate, and ceric ammonium citrate as a catalyst then pyrido[1,2-a] imidazo-chalcones have been synthesized and tested for anti-tubercular activity against mycobacterium TB H37Rv and cytotoxicity in Vero cells. The compounds with MIC values 7.89, 6.42, and 6.59 mg/L are the most active anti-tubercular activity.^[12]

Fig.12: Anti-tubercular activity of imidazole derivative

2. J. Gising, M.T. Nilsson, L.R. Odell, et al., studied the targeting ATP binding sites of MTGS [Mycobacterium tuberculosis glutamate synthetase inhibitors] compounds. The 2-amino group was introduced into the 4-pyridyl ring and it gives the best inhibitory activity with IC₅₀ =0.049 µM on MtGS and MIC= 2µg/ml against M. tuberculosis.^[13]

Fig.13: Anti-tubercular activity pf imidazole derivative

7. Anti-Inflammatory Activity:

1. Hussain, A, et al., identified the biological evaluation of di- and tri-substituted imidazoles, in those 4-(4-methoxyphenyl)-1,2-diphenyl -1H-imidazole exhibited good and safer anti-inflammatory with MIC- 12.5µg mL^-1 by the inhibition of cyclooxygenase, particularly COX-2 which is responsible for conversion of arachidonic acid into prostaglandins. Prostaglandins play an important role in inflammation by promoting vasodilation, edema, and pain.^[14]

Fig.14: Anti-inflammatory activity of imidazole derivative

2. Achar et al. synthesized 2-methyl amino benzimidazole derivatives with aromatic amines. The synthesized compounds were screened and tested for analgesic and anti-inflammatory activities by carrageenan-induced paw edema. They showed a potent anti-inflammatory activity (100% at 100 mg/kg.) compared to standard drug nimesulide (100% at 50mg/kg) by the inhibiting COX-2, derivatives these reduce the production of prostaglandins, leading to decreased inflammation, pain, and swelling.^[15]                                     

Fig.15: Anti-inflammatory activity of imidazole derivative

8. Analgesic Activity:

1.  Shukla A. synthesized benzimidazole derivatives such as 4-(2-chloro-ethoxy)-benzaldehyde. These synthesized benzimidazole compounds were screened for analgesic activity by using mice. Some derivatives or compounds showed significant analgesic activity by inhibiting pro-inflammatory mediators which inhibit writhing more than 70% are considered to be more active.^[16]

Fig.16: Analgesic activity of imidazole derivative

2. Gaba, M, et al., have synthesized novel 5- substituted-2-methyl benzimidazoles using carrageenan-induced rat paw edema in-vivo test and found analgesic properties compared with standard drug indomethacin by COX enzyme inhibition, ion channel modulation, and GABAergic system enhancement. The following derivative showed good analgesic activity.^[17]

Fig.17: Analgesic activity of imidazole derivative

9. Anti-Helmintic Activity:

1. Sreenivasa, G. M. et al., identified the synthesis of (5Z)-5-[4-(dimethylamino) benzylidene]-3-(5-substituted-1,3,4-oxadiazol-2-yl)-2-phenyl-3,5-dihydro-4H-imidazol-4-one having different functional groups using aromatic aldehydes and semi carbazide and tested for anthelmintic activity against Pheritima posthuma. These compounds inhibit enzymes crucial for parasitic worms' energy metabolism, which are involved in glycolysis and ATP production. By disrupting the worm’s energy supply, they can paralyze or kill the parasite.^[18]                                                                                                                                                                     

Fig.18: Anti-helminthic activity of imidazole derivative

2. S. Datta et al., synthesized series of 2-substituted-4,5-diphenyl imidazoles. They were synthesized by refluxing Benzil with various modified aldehydes with ammonium acetate present and glacial acetic acid and examined for anthelmintic properties. Test findings showed that substances displayed a 0.24 to 1.54 minutes paralysis time and death time of 0.39 to 4.40 minutes, as compared to the standard medicines piperazine citrate and albendazole showed a paralysis time of 0.54 and 0.58 min, and death time of 2.16 and 2.47 min, respectively, at the same concentration of 10 mg/ml. ^[19]

Fig.19: Anti-helminthic activity of imidazole derivative

10. Anti-Depressant Activity:

1. F. Hadizadeh et al. described that moclobemide is a selective and reversible monoamine oxidase-A inhibitor used as an antidepressant. 4-aryl piperazine derivatives of moclobemide analogs were synthesized by replacing the moclobemide phenyl ring with substituted imidazoles. So, N-[2-(4-morpholinyl) ethyl)-1-benzyl-2-(alkylthio)-1H-imidazole-5-carboxamides synthesized and studied for antidepressant activity using a forced swimming test in mice. These analogs were found to be more potent than moclobemide.^[20]

Fig.20: Antidepressant activity of imidazole derivative

2. J. Subbarao, et al., synthesized 2,4,5-trisubstituted imidazole derivatives taking different aldehydes as substitutions. These derivatives have been screened for their antidepressant activities using a forced swimming test in mice in which tri-phenyl imidazole derivative showed good activity and in those substitutions with C₆H₅, -4-hydroxy phenyl, and -3-hydroxy phenyl are found to be most significant while as compared to standard drug fluoxetine.^[21]

Fig.21: Antidepressant activity of imidazole derivative

11. Anti-Malarial Activity:

1. Sharma et al., reported a series of pyrido[1,2-a] benzimidazole compounds with IC₅₀ values of 0.02-0.95µM against P. falciparum showing antimalarial activity among which compounds with IC₅₀ values of 0.69, 1.60 and 1.61 µM, showed excellent activity respectively against chloroquine-sensitive 3D7 strain compared to standard chloroquine (IC₅₀ = 1.53 µM) ^[22]

Fig.22: Anti-malarial activity of imidazole derivative

2. Mueller et al., identified a benzimidazole drug lerisetron (IC₅₀ NF54 = 0.81 µM) and its methyl substituted compound with (IC₅₀ NF54 = 0.098µM). Among them, the identification of chloro-substituted analogs having IC₅₀ values of 0.098µM and 0.062 µM have high potency against the NF54 strain of human malarial parasite Plasmodium falciparum.^[23]

Fig.23: Anti-malarial activity of imidazole derivative

12. Anti-Leishmanial Activity:

1. Kalpana, B. et al., have prepared a series of aryloxy alkyl/aryl alkyl imidazoles that were synthesized and determined their in vitro activity as antileishmanial against leishmania donovani. All the synthesized compounds exhibited excellent high inhibition with an IC50 of 0.47-4.85µg/ml against antileishmanial of leishmania donovani.^[24]

Fig.24: Anti-leishmanial activity of imidazole derivative

13. Anti-Convulsant Activity:

1. D. Bhragual et al., have tested the anticonvulsant activity by Maximal Electroshock Method (MES). Substitution of chloro and nitro group at the second position in the substituted ring showed significant anticonvulsant activity without showing neurotoxicity.^[25]

Fig.25: Anti-convulsant activity of imidazole derivative

2. V. P. Arya et al, have synthesized several imidazole compounds such as imidazo [1,2- a] imidazole, imidazo[1,2-a] pyrimidine and imidazo [1,2-a]-1,3-diazepine derivatives. Imidazoimidazoles showed good anticonvulsant activity. The most active compound of this series is Imidazoimidazoles derivative having an ED₅₀ of 24 mg/kg in protecting against electroshock-induced seizures one hour after oral administration.^[26]

Fig.26: Anti-convulsant activity of imidazole derivative

14. Anti-Microbial Activity:

1. Sharma et al., have synthesized 2- (substituted phenyl)-1H-imidazole and (substituted phenyl)- [2-(substituted phenyl)-imidazol-1-yl]- methanone analogs and screened for their invitro antimicrobial activity against two gram-positive bacteria (S. aureus, B. subtilis), 2 Gram-negative (E. coli, A. niger), and fungal species (C. albicans) using norfloxacin as a standard drug. All these synthesized substituted imidazole derivatives showed good anti-microbial activity against tested microorganisms. Among those most active antimicrobial agents have MIC values of 2×10^-3µM/ml against S. aureus.^[27]

Fig.27: Anti-microbial activity of imidazole derivative

2. N.C. Desai synthesized N-(4-((2-chloroquinolin-3-yl) methylene)-5-oxo-2- phenyl-4, 5-dihydro-1H-imidazole-1-yl) (aryl) amides using conventional and microwave-assisted methods. Anti-microbial activity of newly synthesized compounds were screened in vitro on the various microbial species such as Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 1688), Staphylococcus aureus (MTCC 96), Streptococcus pyogenes (MTCC 442), Candida albicans (MTCC 227), Aspergillus niger (MTCC 282), Aspergillus clavatus (MTCC 1323). Among these compounds MIC with approximately 100µM/ml shows excellent antimicrobial activity against these microbial species.^[28]

Fig.28: Anti-microbial activity of imidazole derivative

15. Anti-Hypertensive Activity:

1. Arunkumar, S. S. has reported that imidazole derivatives act as antagonists against the Angiotensin II receptor. The hydroxymethyl substituents at the 4^th and carboxy substituents at the 5^th position in the imidazole nucleus are favorable for bioactivity.^[29]                                                                                                                                                               

Fig.29: Anti-hypersensitive activity of imidazole derivative

2. Yang et al. established the promising pulmonary hypotensive effect of the below imidazole derivatives [a] with an excellent pharmacokinetic profile in comparison with tadalafil. Wu et al. reported that this compound [b] showed superior inhibition of AT1 receptor [IC₅₀ (mean ±SEM):0.8± 0.1 and 2.3 ± 0.7, respectively than both standard losartan and telmisartan.^[30]   

Fig.30: Anti-hypersensitive activity of imidazole derivative

16. Anti-Diabetic Activity:

1. Mehdi Adib et al., designed and synthesized a series of fused carbazole-imidazole derivatives. These agents are evaluated for their α-glucosidase activities. Based on the inhibition assay, all of these synthesized compounds were revealed to be more potent than the standard drug, acarbose. The compound [IC₅₀ = 74.0 ± 0.7 µM] was found to be the most active inhibitor better than the standard drug.^[31]

Fig.31: Anti-diabetic activity of imidazole derivative

2. Chaudhary et.al. demonstrated the design and synthesis of tetra-substituted imidazole hybrids attached to pyrazole moiety as potential antidiabetic agents. Results of in vitro α-glucosidase inhibitory assay showed that hybrids [IC₅₀ -25.19 µM] and [IC₅₀ -33.62 µM] exhibited the most potent inhibition of the enzyme α- α-glucosidase.^[32]

Fig.32: Anti-diabetic activity of imidazole derivative

17. Anti-HIV Activity:

1. Zhan, P. et al., have reported the synthesis of 2-(1-aryl-1H-imidazol-2-yl-thio) acetamide [imidazole thioacetanilides (ITA) derivatives and evaluated as potent inhibitors of HIV-1. They found that most potent HIV-1 inhibitors were [EC₅₀=0.18µM] and [EC₅₀= 0.20µM] which were more effective than the lead compound [EC₅₀= 2.053µM] and reference drugs nevirapine and delaviridine, all these newly synthesized imidazole thioacetanilides showed higher anti-HIV-1 activity. HIV-1 virus destroys the helper cells: lymphocytes which fight infections and diseases in human beings.^[33]

Fig.33: Anti-HIV activity of imidazole derivative

2. Serrao, et al., discovered novel 5-formyl-1H-imidazole-4-carboxamides with potent inhibitor activity for HIV-1 integrase-LEDGF/p75. The 5-formyl group and the carboxamide moiety may contribute to the molecule’s ability to bind to these enzyme targets or disrupt viral replication by affecting the viral life cycle.^[34]

Fig.34: Anti-HIV activity of imidazole derivative

18. Anti-Hepatitis Activity:

1. Ujjinamatada, et al. synthesized 4-carbamoyl-5-(4,6-diamino-2,5-dihydro-1,3,5-triazin-2-yl) imidazole-1-β-D-ribofuranoside and evaluated their in vitro activity against NTPase/helicases Flaviviridae family viruses such as hepatitis C virus [HCV], the Japanese encephalitis virus [JEV], Dengue virus [DENV], and West Nile virus [WNV] by employing RNA and DNA substrate. The compound below exhibited maximum activity against WNV and HCV with an IC₅₀ value of 23 and 37µM respectively in the presence of DNA substrate activity on the RNA substrate and no activity against JEV and DENV virus.^[35]

Fig.35: Anti-hepatitis activity of imidazole derivative

2. Windisch and co-workers synthesized 2-iminobenzimidazole [IBI] derivatives bearing a benzyl moiety exhibited good anti-HCV activities [EC₅₀ = 0.17-0.46µM] but had narrow selectivity index and compounds substituted with acetophenone exhibits excellent HCV activity [EC₅₀ = 0.073 and 0.079µM] with good selectivity index which blocks the enzymatic activity of the HCV NS3 protease region. It showed maximum inhibition and a novel mechanism of action.^[36]

Fig.36: Anti-hepatitis activity of imidazole derivative

19. Anti-Oxidant Activity:

1. Naureen et al., synthesized a series of tetra-substituted imidazoles containing 2-aryl indole substituents in those 3-(4,5-diphenyl-1-(substituted phenyl)-1H-indole evaluated for antioxidant potential by DPPH (1,1-diphenyl-2-picrylhydrazyl) assay method which showed good inhibition activity with 44.21 ± 0.7% at 0.5 M using quercetin as a reference drug.^[37]

Fig.37: Anti-oxidant activity of imidazole derivative

2. Rajasekaran et al., synthesized (E)- (1H-benzo[d]imidazole-1-yl) (4-substituted benzylidene) amino) phenyl) methanone, 2-(1H-benzo[d]imidazole-1-yl-N-(5-phenyl-1,3,4-oxidiazol-2-yl) acetamide and 1-(1Hbenzo[d]imidazole-1-yl-2-((substituted-1,3,4-oxadiazol-2yl)thio)ethenone and evaluated for antioxidant potential by using DPPH assay method. The concentration of 30µg/ml showed maximum absorbance of 0.903. Hence, the compound with pyridyl-substituted oxadiazole has good antioxidant activity within the series. All the synthesized derivatives showed good scavenging potential as compared to ascorbic acid.^[38]

Fig.38: Anti-oxidant activity of imidazole derivative

20. Anti-Coagulant Activity:

1. Haul et al., designed and synthesized a series of new benzimidazole derivatives bearing structural similarity to α-NAPAP a benzamidine-based powerful inhibitor of thrombin, trypsin, and other serine proteases with the addition of ethyl esters and hexyloxycarbonyl carbamide hydrophobic side chains improved pharmacokinetic profile was obtained leading to the invention of an orally absorbed prodrug, (Dabigatran etexilate). The prodrug reached clinical trials, and its active form Dabigatran was discovered with excellent thrombin inhibitory potency and tolerability.^[39]

Fig.39: Anti-coagulant activity of imidazole derivative

2. Ren et al., designed a series of benzimidazole derivatives and tested them for thrombin inhibitory effects. A compound with an IC₅₀ value of 3.11 ± 0.21 µM appeared to be a potent thrombin inhibitor exhibiting better activity than the standard argatroban (IC₅₀ 9.88 ± 2.26 µM).^[40]

Fig.40: Anti-coagulant activity of imidazole derivative

CONCLUSION: The above study of imidazole derivatives shows promising results in most of the pharmacological activities like antifungal, antiulcer, antiviral, anticancer, antibacterial, antitubercular, anti-inflammatory, analgesic, anthelmintic, antidepressant, antimalarial, antileishmanial, anticonvulsant, antimicrobial, antihypertensive, antidiabetic, anti-HIV, anti-hepatitis, antioxidant, anticoagulant. It has been noticed so far that modifications in imidazole nuclei show promising biological activities and can be taken as a lead for future development to get safer and more effective compounds with decreased toxicity and less side effects.

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