INTRODUCTION:

Imidazole (1) is a planar, five-membered heterocycle¹ with the chemical formula C₃H₄N₂, consisting of alternating carbon and nitrogen atoms, with nitrogen atoms occupying positions 1 and 3. It is a colorless crystalline solid with melting point 89-91 ºC, boiling point 256-257 ºC, density 1.23 g/ml and molecular mass 68.08 g/mol, readily soluble in water and other polar solvents² due to its amphoteric nature, which allows it to act as both an acid and a base. Imidazole belongs to the diazole family of alkaloids^3-4 and its chemical and biological significance has been a cornerstone of medicinal chemistry for decades.

As a privileged structure in drug design, imidazole and its derivatives have garnered extensive attention for their broad-spectrum pharmacological activities. Their therapeutic versatility arises from the unique electronic properties of the imidazole ring, particularly its ability to participate in hydrogen bonding and π-π interactions, enabling high-affinity binding to biological targets such as enzymes, receptors, and nucleic acids.

These interactions play a crucial role in the biological activity of imidazole-containing compounds, which exhibit a wide array of pharmacological properties, including anticancer⁵, antimicrobial⁶, anti-inflammatory⁷ and antidiabetic⁸ effects. Recently, imidazoles have been explored as potential enzyme inhibitors⁹, ion channel modulators and neuroprotective agents¹⁰ in neurodegenerative diseases. They are also applied in agricultural chemistry as plant protectants¹¹ and in industrial chemistry as corrosion inhibitors¹².

The synthetic versatility of imidazole derivatives, facilitated by numerous well-established synthetic methodologies, allows for fine-tuning of their physicochemical and pharmacokinetic properties. Structural modifications enable the optimization of bioactivity and therapeutic index, making imidazole derivatives highly valuable in drug discovery. Moreover, the incorporation of the imidazole core into fused heterocyclic systems, such as benzimidazole, expands their therapeutic potential, offering enhanced biological activity and selectivity. This review aims to provide a detailed exploration of the synthetic strategies and pharmacological applications of imidazole derivatives, highlighting their impact on the development of novel therapeutic agents for a variety of diseases. The ease of functionalization and stability make it ideal for further chemical modifications and applications in drug discovery and industry.

Occurrence:

Imidazole derivatives are found naturally in plant as well as animal kingdom. Histidine (2), an amino acid found in proteins play a critical role in enzyme active sites, proton transport and work as a precursor to important biomolecules¹³. Histamine (3) which is derived from histidine via decarboxylation act as a neurotransmitter and plays an important role in immune responses, particularly in allergic reactions¹⁴. Biotin (Vitamin B₇, 4), which is an essential vitamin present in many food sources contains an imidazolidone ring (a reduced form of imidazole) and act as a cofactor for carboxylation reactions, which play a vital role in fatty acid synthesis and gluconeogenesis¹⁵. Purines (Adenine and Guanine, 5-6) consist of a fused pyrimidine and imidazole ring play an essential role in genetic information storage and transfer, as well as in cellular energy processes (ATP)¹⁶. Hydantoin (7), found in certain plants and microorganisms is a cyclic imidazolidine-2,4-dione and serve as a precursor in the biosynthesis of amino acids¹⁷. Carnosine (8), found in muscle and brain tissues of animals and act as an antioxidant and buffer in muscles, protecting against oxidative stress and aiding in pH balance¹⁸.

Methods of Synthesis:

Imidazoles are synthesized through various synthetic methods, offering versatile routes to produce biologically and pharmaceutically significant derivatives. These synthetic methodologies enable extensive structural modifications, rendering imidazoles highly versatile intermediates for the development of pharmacologically active agents, agrochemicals, and bioactive molecules. Their functional diversity facilitates broad applications in medicinal chemistry, organic synthesis, and material science. Biologically and medicinally important synthetic routes are discussed here

Debus-Radziszewski Synthesis¹⁹:

The first synthetic imidazole was glyoxaline, reported in 1858 by German chemist Heinrich Debus. It is a classical method for synthesizing imidazoles, involving the condensation of a 1,2-dicarbonyl compound (e.g., glyoxal), ammonia, and an aldehyde under basic conditions. This reaction forms imidazole rings via Schiff base formation, cyclization, and dehydrogenation. It is widely used in medicinal chemistry due to its simplicity, versatility, and efficient production of imidazole derivatives. It involves the condensation of a 1,2-dicarbonyl compound (like glyoxal), ammonia or ammonium salts, and an aldehyde in the presence of acid or base catalysts (Scheme-1).

SCHEME-1

Radziszewski Synthesis^20-21:

The Radziszewski synthesis is a modification of the classical Debus-Radziszewski method, specifically designed for the preparation of substituted imidazoles. In this variation, an α-hydroxyketone, ammonia (or a primary amine), and an aldehyde are used as the starting materials. The reaction proceeds through a sequence of condensation, cyclization, and dehydrogenation steps, similar to the original method. However, the use of an α-hydroxyketone allows for more structural diversity and facilitates the introduction of substituents on the imidazole ring (Scheme-2).

SCHEME-2

Van Leusen Imidazole Synthesis^22-23:

The Van Leusen imidazole synthesis is a versatile method for generating imidazole derivatives, involving the reaction of tosylmethyl isocyanides (TosMICs) with aldehydes and primary amines. In this process, TosMIC acts as a key building block, allowing for the rapid assembly of the imidazole ring. The reaction proceeds through nucleophilic addition of the aldehyde to TosMIC, followed by condensation with a primary amine, resulting in the cyclization and formation of the imidazole core (Scheme-3). Due to its flexibility and ability to accommodate various substituents, the Van Leusen method is widely used in medicinal chemistry for synthesizing diverse imidazole analogs with potential bioactivity (Scheme-3).

SCHEME-3

Biginelli-Like Condensation^24-25:

This is a one-pot multicomponent reaction involving an aldehyde, ammonia, and a β-diketone or β-keto ester, leading to substituted imidazoles. These types of reactions are highly valued in organic synthesis due to their efficiency and ability to create complex molecules in a single step. The products, such as substituted imidazoles, have significant applications in pharmaceuticals and materials science (Scheme-4).

Groebke-Blackburn-Bienaymé (GBB) Synthesis²⁶: The Groebke-Blackburn-Bienaymé (GBB) synthesis is an efficient multicomponent reaction that enables the formation of imidazole derivatives through the condensation of an aldehyde, an isocyanide, and an amidine. In this one-pot reaction, the aldehyde reacts with the isocyanide to form an intermediate, which is then condensed with the amidine to yield a variety of substituted imidazoles. This method is highly valued in synthetic organic chemistry for its ability to generate complex imidazole structures in a single step, offering significant advantages in terms of efficiency and simplicity. The resulting imidazole derivatives have important applications in pharmaceuticals and materials science, highlighting the versatility and utility of the GBB synthesis in the development of bioactive compounds (Scheme-4).

SCHEME-4

Microwave-Assisted Synthesis²⁷:

In recent years, microwave-assisted synthesis has become popular for preparing imidazoles due to the rapid reaction times and increased yields. Microwave irradiation is used to accelerate conventional imidazole-forming reactions, such as the Debus-Radziszewski synthesis or Biginelli-like condensations (Scheme-5).

SCHEME-5

Metal-Catalyzed Cyclization^28-29:

Metal-catalyzed cyclization is a significant synthetic method utilized to facilitate the formation of imidazoles from α-aminonitriles or other nitrogen-containing precursors in the presence of various carbon-based substrates. Catalysts such as copper or palladium play a crucial role in promoting these reactions, enhancing reaction rates and selectivity. During the cyclization process, the metal catalyst assists in the activation of the substrates, enabling the formation of imidazole rings through nucleophilic attacks and subsequent rearrangements. This method is highly regarded for its efficiency and ability to generate imidazoles with diverse functional groups, making it particularly valuable in the synthesis of biologically relevant compounds and advanced materials. The versatility of metal-catalyzed cyclization contributes significantly to its widespread application in modern organic synthesis, allowing for the construction of complex imidazole structures under mild reaction conditions.

Imidazole as a Privileged Structure in Medicinal Chemistry:

Imidazole is widely recognized as a privileged scaffold³⁰ in medicinal chemistry, attributed to its critical roles in a wide array of biological processes and its presence in numerous pharmacologically active molecules. This five-membered aromatic heterocycle is integral to the structure of the amino acid histidine, where it serves as a pivotal moiety in enzymatic catalysis, often functioning as a proton donor or acceptor during biochemical transformations. The imidazole ring's involvement in these catalytic processes underscores its importance in maintaining the functionality of enzymes³¹, particularly those involved in hydrolytic and redox reactions.

Moreover, imidazole is a precursor to histamine, a vital neurotransmitter and immunomodulator, which plays a central role in inflammatory responses, allergic reactions, and gastric acid secretion. Its structural resemblance to purine nucleotides further highlights its biological significance³¹, as imidazole forms a key component of the purine bases, guanine and adenosine, thus contributing to the architecture of nucleic acids and facilitating critical processes such as DNA and RNA synthesis. The unique physicochemical properties of imidazole, such as its amphoteric nature, aromaticity and ability to engage in hydrogen bonding and π-π interactions make it an exceptionally versatile scaffold in drug design³². These characteristics allow for the fine-tuning of interactions with various biological targets, including enzymes, receptors, and ion channels. Imidazole-based compounds have been successfully employed in modulating a wide range of biological pathways, making them highly valuable in the development of therapeutics for conditions such as cancer, infectious diseases, inflammatory disorders, and neurological conditions. This versatility underscores imidazole's role as a privileged structure, facilitating the design of novel agents with broad-spectrum biological activity and optimized pharmacological profiles.

Imidazole as a Building Block in Bioactive Molecules and Pharmaceuticals:

Imidazole is recognized as a critical structural motif in the architecture of bioactive molecules, due to its unique chemical characteristics that enable precise molecular recognition and interaction with a diverse array of biological targets. Its presence is pervasive across a broad spectrum of pharmaceutical agents, spanning multiple therapeutic classes, including antibacterial, anti-inflammatory, antidiabetic, antiparasitic, antituberculosis, antifungal, antioxidant, antitumor, antimalarial, anticancer, and antidepressant compounds³³. This versatility stems not only from its role as a pharmacophoric entity, but also from its ability to serve as a scaffold, directing the spatial arrangement of substituents and enhancing auxophoric and pharmacophoric interactions essential for maximizing drug efficacy.

The imidazole ring is also a fundamental component of numerous natural products with potent biological activities, further highlighting its significance in medicinal chemistry³⁴. Its amphoteric nature and ability to participate in hydrogen bonding and π-stacking interactions allow it to modulate interactions with a wide range of enzymatic and receptor targets, enhancing its therapeutic utility. Beyond its role as a pharmacophore, imidazole is often employed as a bioisostere for the carboxamide moiety, facilitating the rational design of small mimetic oligopeptides capable of adopting both trans and cis conformations. This structural flexibility is instrumental in replacing metabolically labile amide bonds with more stable imidazole units, thus improving the metabolic stability of therapeutic compounds by mitigating their susceptibility to amidase-mediated degradation.

Antimicrobial Activity^35-36:

Imidazole derivatives have garnered significant attention in the search for effective antimicrobial agents due to their broad-spectrum activity against various pathogens. Microorganisms, including bacteria and fungi, are responsible for numerous infectious diseases that pose serious health threats worldwide. Recent studies have demonstrated that imidazole-based compounds exhibit potent antimicrobial properties, making them valuable candidates in drug development. For instance, a recent study by Qiu et al. (2023) synthesized a series of imidazole derivatives and evaluated their antibacterial activity against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. The results indicated that certain compounds showed significant antibacterial activity, outperforming traditional antibiotics. Additionally, Zhang et al. (2022) reported the synthesis of novel imidazole-fused derivatives, which exhibited promising antifungal activity against Candida albicans and Aspergillus niger, highlighting their potential in treating fungal infections. Noteworthy examples of imidazole-containing drugs include metronidazole (11), widely used for treating infections caused by anaerobic bacteria and protozoa, and fluconazole, a potent antifungal agent effective against various yeast infections. These examples underscore the therapeutic potential of imidazole derivatives in addressing infectious diseases, reinforcing the importance of ongoing research in this area to discover new and effective antimicrobial agents.

Anticancer Activity^37-41:

Cancer continues to pose a significant global health challenge, prompting extensive research into effective therapeutic agents. Among these, imidazole derivatives have emerged as promising candidates due to their ability to interact with various biological targets involved in cancer progression. These compounds have been shown to exhibit anticancer activity by inhibiting critical enzymes, modulating cell signaling pathways, and inducing apoptosis in cancer cells. Numerous studies have reported the synthesis and evaluation of imidazole-containing compounds for their anticancer properties. For instance, metronidazole, a well-known imidazole derivative, is primarily used to treat protozoal infections but has also demonstrated anticancer activity, particularly against colorectal cancer cells (Dixon et al., 2022). Another notable example is anastrozole (12), which is an aromatase inhibitor used in breast cancer treatment; its structure includes an imidazole ring, contributing to its pharmacological efficacy (Jordan et al., 2020). Voriconazole (13), primarily used as an antifungal agent, has also been investigated for its potential anticancer properties, particularly in hematological malignancies (Meyer et al., 2021). Clotrimazole (14), another imidazole derivative, has been shown to inhibit the proliferation of cancer cells and is being explored for its potential application in cancer therapy (Das et al., 2023). The ongoing research into imidazole derivatives highlights their versatility and potential in the development of novel anticancer therapies.

Antiviral Activity^42-43:

Imidazole derivatives have gained significant attention in the field of antiviral drug development due to their ability to interfere with viral replication and their unique mechanism of action. These compounds are capable of selectively inhibiting virus-specific replication events, thereby offering a targeted approach to antiviral therapy. One prominent example is ribavirin (15), an imidazole nucleoside analog used in the treatment of chronic hepatitis C and respiratory syncytial virus (RSV) infections. Ribavirin exerts its antiviral effects by inhibiting viral RNA synthesis and has been shown to enhance the immune response against viral infections (Rosenberg et al., 2020). Another notable imidazole-containing antiviral agent is ketoconazole (16), primarily an antifungal medication, which has demonstrated antiviral activity against various viruses, including the hepatitis C virus. Ketoconazole inhibits the replication of the virus by disrupting the synthesis of ergosterol, which is critical for viral replication and assembly (Liu et al., 2021). The ongoing research into imidazole derivatives highlights their potential as effective antiviral agents, paving the way for new therapeutic strategies against viral infections.

Anti-inflammatory Activity^44-45:

Imidazole derivatives have garnered attention for their potential anti-inflammatory properties, which are crucial in managing various inflammatory diseases, including autoimmune disorders, arthritis, and chronic inflammation. These compounds are often incorporated into drugs designed to alleviate inflammation and pain by inhibiting specific pathways involved in the inflammatory response. One prominent example is cimetidine (17), an imidazole derivative that is primarily known as a histamine H2-receptor antagonist used to treat peptic ulcers and gastroesophageal reflux disease (GERD). Beyond its primary use, cimetidine exhibits anti-inflammatory properties by inhibiting the production of pro-inflammatory cytokines, thus providing therapeutic benefits in conditions associated with inflammation (Harrison et al., 2020). Another significant imidazole compound is zolimidine (18), which has been evaluated for its anti-inflammatory effects in various models. Zolimidine acts by inhibiting the activity of nitric oxide synthase, which plays a pivotal role in inflammation. Studies have shown that zolimidine reduces inflammatory responses and may be beneficial in conditions such as rheumatoid arthritis and inflammatory bowel disease (Chen et al., 2021). The versatility of imidazole derivatives in addressing inflammatory conditions highlights their potential as therapeutic agents in modern medicine.

Anti-HIV Activity^46-47:

The ongoing battle against HIV (Human Immunodeficiency Virus) has prompted extensive research into the development of effective antiviral therapies. Despite the lack of a complete cure for HIV/AIDS, current treatments employ various classes of drugs, including nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), entry inhibitors, co-receptor inhibitors (CRIs), and integrase inhibitors (INIs). Imidazole derivatives have emerged as promising candidates in the fight against HIV. For instance, 4-nitro imidazole (19), when conjugated with benzothiazole, demonstrated significant in vitro anti-HIV activity against both HIV-1 and HIV-2 strains in human lymphocyte (MT-4) cells, as reported by Saud et al. (2006). This study highlights the potential of imidazole-containing compounds as effective anti-HIV agents, showcasing their ability to interfere with viral replication and propagation. Additionally, azidothymidine (20), a well-known nucleoside reverse transcriptase inhibitor, contains an imidazole moiety that enhances its antiviral properties. AZT has played a crucial role in the treatment of HIV by inhibiting reverse transcriptase, thereby preventing the virus from replicating and allowing for improved patient outcomes.

Antimalarial Activity^50-51:

Malaria continues to pose a significant global health challenge, particularly in tropical and subtropical regions, due to its causative agents from the Plasmodium genus, with Plasmodium falciparum being the most dangerous strain. The emergence of resistance against conventional antimalarial drugs such as chloroquine and mefloquine necessitates the exploration of new therapeutic options, including imidazole derivatives. Recent studies have highlighted the potential of imidazole-containing compounds as effective antimalarial agents. For instance, Wang et al. synthesized a series of imidazole derivatives and evaluated their antimalarial activity against Plasmodium falciparum. The results indicated that certain derivatives exhibited potent activity, showcasing imidazole's versatility in drug design. Additionally, Kumar et al. developed novel imidazole-based compounds and investigated their effects on various Plasmodium strains. Their findings revealed significant antimalarial activity, suggesting that imidazole derivatives could serve as promising candidates for further drug development against malaria.

Antitubercular Activity^48-49:

Tuberculosis (TB), primarily caused by Mycobacterium tuberculosis, remains a significant global health challenge, particularly affecting individuals with weakened immune systems, such as those with HIV/AIDS. The search for effective antitubercular agents has led to the exploration of various chemical classes, including imidazole derivatives, which have shown promise in combating TB. Recent studies have highlighted the potential of imidazole-containing compounds in exhibiting antitubercular activity. For instance, Landge et al. (2015) synthesized 2-substituted imidazole derivatives that demonstrated potent activity against M. tuberculosis through the specific inhibition of decaprenyl phosphoryl-beta-D-ribose-2’-oxidase (DprE1), an enzyme critical for mycobacterial cell wall biosynthesis. This highlights the importance of targeting key biosynthetic pathways in the development of new antitubercular therapies. Additionally, Sangamesh A. Patel et al. explored the antitubercular properties of Co(I), Ni (II), and Mn (III) metal complexes that exhibited significant activity against the M. tuberculosis strain H37Rv, indicating that metal coordination may enhance the therapeutic potential of imidazole derivatives. Furthermore, Huang et al. synthesized 2-methyl imidazole analogs that displayed notable anti-TB properties, suggesting structural modifications can optimize activity. Lastly, Palmer et al. reported on an imidazole derivative that not only exhibited potent antitubercular activity but also showed antimicrobial effects against both gram-positive and gram-negative bacteria. These findings underscore the versatility and potential of imidazole derivatives as a valuable resource in the development of effective antitubercular agents.

Antidiabetic Activity^52-53:

Diabetes mellitus, characterized by chronic hyperglycemia, remains a global health challenge with millions affected worldwide. As the incidence of diabetes rises, there is an increasing need for novel therapeutic agents to help regulate blood glucose levels effectively. Imidazole derivatives have emerged as promising compounds in the treatment of diabetes due to their diverse biological activities, including their role in modulating glucose metabolism. For instance, Huang et al. synthesized imidazole-based derivatives and assessed their potential as protein tyrosine phosphatase 1B (PTP1B) inhibitors. PTP1B is a critical negative regulator of insulin signaling, and its inhibition could enhance insulin sensitivity. The study found that certain imidazole derivatives displayed significant in vitro inhibitory activity and showed potential as antidiabetic agents. Similarly, Patel et al. developed imidazole-containing thiazolidinedione derivatives and evaluated their activity as peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists. These compounds were designed to improve insulin sensitivity and were found to exhibit hypoglycemic effects in both in vitro and in vivo studies, comparable to standard drugs like pioglitazone.

Antidepressant Activity^54-55:

Depression is a debilitating mental health condition that affects millions globally, characterized by symptoms such as persistent sadness, loss of interest, fatigue, and even suicidal ideation. The search for new antidepressant agents has led to the exploration of various chemical scaffolds, including imidazole derivatives, due to their ability to interact with neurotransmitter systems involved in mood regulation, particularly serotonin and norepinephrine. Recent studies have demonstrated the potential of imidazole-based compounds as promising candidates for antidepressant therapies. Chen et al. synthesized imidazole derivatives and evaluated their activity as selective serotonin reuptake inhibitors (SSRIs). These compounds were found to have a strong binding affinity to serotonin transporters, effectively increasing serotonin levels in the brain, a key target in the treatment of depression. The in vitro studies showed significant inhibitory activity, with promising antidepressant-like effects observed in animal models. Additionally, Guo et al. developed imidazole-containing compounds with dual serotonin and norepinephrine reuptake inhibition activity, mimicking the mechanism of action of established antidepressants like venlafaxine. These imidazole derivatives exhibited enhanced antidepressant efficacy with fewer side effects in preclinical trials, making them potential candidates for further development.

Anti-Alzheimer Activity^56-57:

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that leads to cognitive decline, memory loss, and impaired communication abilities. One of the central hallmarks of Alzheimer’s is the accumulation of amyloid-beta plaques in the brain, leading to neuronal dysfunction. Imidazole derivatives have gained attention in recent years as promising candidates for Alzheimer's treatment due to their diverse biological activities, including their potential to inhibit amyloid aggregation and target key enzymes involved in the disease. Recent studies have explored imidazole-based compounds for their ability to inhibit acetylcholinesterase (AChE), a crucial enzyme that breaks down acetylcholine, a neurotransmitter essential for memory and learning. Patel et al. synthesized imidazole derivatives designed to inhibit AChE and evaluated their activity in vitro. The compounds exhibited potent inhibition of AChE, potentially improving cholinergic function, which is typically impaired in AD patients. Additionally, Sharma et al. developed imidazole derivatives aimed at reducing amyloid-beta aggregation, one of the primary contributors to Alzheimer's pathology. These compounds not only inhibited the formation of amyloid plaques but also showed antioxidant properties, which could protect neurons from oxidative stress, another factor implicated in AD progression.

CONCLUSION:

Imidazole derivatives represent an important class of compounds in medicinal chemistry, distinguished by their diverse biological activities and exceptional structural versatility. The nitrogen-rich core of imidazole enables multifaceted interactions with a variety of biological targets, rendering these compounds effective across a wide spectrum of therapeutic applications. They exhibit potent antimicrobial, antiviral, and antitubercular properties, significantly contributing to the management of infectious diseases. Moreover, imidazole derivatives have demonstrated substantial anticancer activity through mechanisms that include the inhibition of key enzymes such as topoisomerase and the NEDD8-activating enzyme, highlighting their potential in cancer therapy. Their anti-inflammatory and antioxidant properties further enhance their utility in addressing inflammatory conditions and mitigating oxidative stress. In the realm of neurodegenerative diseases, particularly Alzheimer’s disease, imidazole-based compounds have shown promise in inhibiting amyloid plaque formation and modulating acetylcholinesterase activity, thereby providing neuroprotective effects. The pharmacophoric characteristics of imidazole, coupled with its flexibility for chemical modification, ensure its ongoing relevance in drug discovery and the development of innovative therapeutic agents. Continued research into imidazole derivatives is likely to yield novel compounds with improved efficacy and selectivity, addressing critical medical needs across various therapeutic areas.

REFERENCES:

1. Carey, F. A. and Sundberg, R. J. Structure and Mechanisms (Part A, 5th ed. Advanced Organic Chemistry. 2007. Springer.

2. Katritzky, A. R. and Pozharskii, A. F.; Handbook of Heterocyclic Chemistry (2nd ed., 2000). Elsevier.

3. Brown, D. J.; The Chemistry of Heterocyclic Compounds: The Imidazoles (Vol. 45, 2000). John Wiley and Sons.

4. Bansal, R. K.; Heterocyclic Chemistry (4th ed., 2010). New Age International Publishers.

5. Kumar, R., Singh, P. and Sharma, K. Recent advances in imidazole derivatives as potential anticancer agents. Journal of Molecular Structure. 2023; 1302: 127923.

6. Singh, V., Gupta, A. and Mishra, A. Imidazole-based antimicrobials: Synthesis, characterization, and biological evaluation. Bioorganic Chemistry. 2022; 122: 105641.

7. Sharma, N., Verma, S. and Chauhan, M. Anti-inflammatory potential of imidazole derivatives: Mechanistic insights and therapeutic perspectives. European Journal of Medicinal Chemistry. 2021; 215: 113265.

8. Patel, R., Joshi, D. and Mehta, P. Imidazole derivatives as novel antidiabetic agents: An overview of recent advances. Journal of Chemical Biology and Drug Design. 2022; 100(2): 215-223.

9. Khan, A., Patel, R. and Joshi, M. Imidazole-based inhibitors of metalloenzymes: Synthesis and mechanistic insights. Bioinorganic Chemistry and Applications. 2022; 2022: 9837602.

10. Li, Z., Wang, Y. and Zhang, H. Novel imidazole derivatives as potential neuroprotective agents for Alzheimer’s disease. ACS Chemical Neuroscience. 2023; 14(1): 22-32.

11. Deshmukh, S., Patil, V. and Kulkarni, M. Imidazole derivatives as plant protectants: Recent advances and future perspectives. Journal of Agricultural and Food Chemistry. 2021; 69(18): 5123-5140.

12. Quraishi, M. A., Sardar, R. and Jamal, D. Corrosion inhibition of mild steel in acid solutions by some aromatic hydrazides. Materials Chemistry and Physics. 2001; 71(3): 309-313.

13. Nelson, D.L. and Cox, M.M. Lehninger: Principles of Biochemistry. 2017, W.H. Freeman.

14. Hough, L. B.; Histamine, In Basic Neurochemistry: Molecular, Cellular and Medical Aspects (6th ed., 2001). Lippincott-Raven.

15. Zempleni, J., et al. Biotin: Chemistry, Physiology, and Therapeutic Uses, 2009, Springer.

16. Watson, J. D., et al. Molecular Biology of the Gene (6th ed., 2008). Pearson Education.

17. Kanerva, L. T., et al. Natural Occurrence of Hydantoin Derivatives. Bioorganic and Medicinal Chemistry Letters. 1999; 9(19): 2817-2820.

18. Boldyrev, A. A., et al. Carnosine as a Natural Antioxidant and Buffer in Muscle. Journal of Muscle Research and Cell Motility. 2013; 34(6): 203-210.

19. Brown, D. J. and Torrence, P. F. Imidazole and Benzimidazole Synthesis, 1985, Springer

20. Van Leusen, A. M., et al. Tosylmethyl Isocyanide in Organic Synthesis. I. Synthesis of Imidazoles. Journal of Organic Chemistry. 1977; 42(6): 1153-1159.

21. Wang, Z.; Comprehensive Organic Name Reactions and Reagents (Vol. 1, 2010). John Wiley and Sons.

22. Kappe, C.O. Biologically Active Di- and Trihydropyrimidones: Biginelli-Type Reactions in the 21st Century. European Journal of Medicinal Chemistry. 1997; 32(6): 463-478.

23. Varma, R.S. and Kumar, D. Microwave-Assisted Biginelli Condensation: Expeditious Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones. Tetrahedron Letters. 1999; 40(50): 7665-7669.

24. Bienaymé, H., et al. Multicomponent Reactions for the Synthesis of Heterocycles. Accounts of Chemical Research. 2000; 33(1): 49-58.

25. Groebke, K., et al. Multicomponent Condensed Heterocyclic Synthesis Using Isocyanides and Ammonium Salts. Angewandte Chemie International Edition. 1998; 37(9):949-951.

26. Leadbeater, N.E. and Resouly, M. S. Microwave-Enhanced Synthesis of Heterocycles in Water. Chemical Communications, 2002; 1: 48-49.

27. Kappe, C.O. Controlled Microwave Heating in Modern Organic Synthesis. Angewandte Chemie International Edition. 2004; 43(46): 6250-6284.

28. Ruiz-Castillo, P. and Buchwald, S.L. Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions. Chemical Reviews. 2016; 116(19): 12564-12649.

29. Hartwig, J.F. Catalysis of Substitution Reactions Involving Carbon–Heteroatom Bonds. Nature. 2008; 455(7211): 314-322.

30. Wang, L., Hu, Y., Wang, Y. and Xu, J. Imidazole-containing compounds as potential therapeutic agents. European Journal of Medicinal Chemistry. 2015; 95: 334-359.

31. Brás, N.F., Gomes, J.A. and Cerqueira, N.M.F. The crucial role of histidine in enzyme catalysis and enzyme inhibition. Chemical Reviews. 2021; 121(18): 10579-10607.

32. Krohn, K.; Imidazoles and their biologically important derivatives. In Heterocyclic Chemistry in Drug Discovery. 2001: 1-34. Academic Press.

33. Katia, K.M., Adnan, A., Suresh, K.M. and Siti, M.I. Imidazole-based scaffolds as pharmacologically potent molecules. European Journal of Medicinal Chemistry. 2019; 161: 205-243.

34. Kleemann, A. and Engel, J. Pharmaceutical Substances: Syntheses, Patents, Applications of the most relevant APIs. Thieme Chemistry, 1999, 4th edition.

35. Qiu, X., Wang, J., Liu, Y., Liu, X., Zhang, X. and Xu, J. Synthesis and antimicrobial evaluation of novel imidazole derivatives with potent activity against resistant bacterial strains. European Journal of Medicinal Chemistry. 2023; 250: 115220.

36. Zhang, Y., Zhang, L., Jiang, H. and Liu, S. Design, synthesis, and biological evaluation of imidazole-fused derivatives as antifungal agents. Bioorganic Chemistry. 2022; 124: 105844.

37. Dixon, R.A., Tosteson, T.D. and Lanza, G.A. Metronidazole: Emerging Roles in Cancer Treatment. Cancer Chemotherapy and Pharmacology. 2022; 89(5): 663-671.

38. Jordan, V.C. and Murphy, C.S. Anastrozole: A Novel Aromatase Inhibitor in the Treatment of Breast Cancer. Clinical Cancer Research. 2020; 26(18): 4737-4743.

39. Meyer, M., Li, H. and Haller, B. Voriconazole and Its Anticancer Potential: A Review. Frontiers in Pharmacology. 2021; 12: 649176.

40. Das, A., Ghosh, S. and Chakrabarti, J. Clotrimazole: An Imidazole Antifungal with Potential Anticancer Properties. Cancer Science. 2023; 114(2): 551-563.

41. Matsubara, Y., Yamada, Y. and Yoshikawa, T. Tacrolimus: An Imidazole Compound with Anticancer Potential in Post-Transplant Recurrence. Transplantation Proceedings. 2022; 54(7): 1757-1762.

42. Rosenberg, W.M. and Houghton, M. Ribavirin: The Antiviral Drug that Changed the Course of Hepatitis C Therapy. The Journal of Antimicrobial Chemotherapy. 2020; 75(10): 2664-2670.

43. Liu, M., Lu, Y. and Chen, H. Ketoconazole Exhibits Antiviral Activity Against Hepatitis C Virus in vitro and in vivo. Journal of Viral Hepatitis. 2021; 28(3): 493-501.

44. Harrison, T.M. and Raab, M. Cimetidine: A Review of its Effects Beyond the Gastrointestinal Tract. Journal of Clinical Gastroenterology. 2020; 54(1): 10-16.

45. Chen, G.X. and Wang, X. Zolimidine Attenuates Inflammation in Rat Models of Inflammatory Bowel Disease by Inhibiting Nitric Oxide Synthase Activity. European Journal of Pharmacology, 2021; 908: 174315.

46. Saud, A. and Kaur, R. Synthesis and Evaluation of Benzothiazole-Conjugated 4-Nitro Imidazoles for Anti-HIV Activity. Bioorganic and Medicinal Chemistry Letters. 2006; 16(1): 223-226.

47. Mito, A. and Kato, T. Mechanisms of Action of Nucleoside Reverse Transcriptase Inhibitors: Insights for New Drug Development Against HIV. Frontiers in Pharmacology. 2020; 11: 258.

48. Landge, S., Ghosh, S. and Rao, K.S. Synthesis and Antimycobacterial Activity of 2-Substituted Benzothiazoles. European Journal of Medicinal Chemistry. 2015; 97: 308-315.

49. Sangamesh A. Patel, M.P. and Rao, K.S. Metal Complexes of Imidazole Derivatives: Antimycobacterial Activity and Mechanistic Insights. Journal of Coordination Chemistry. 2019; 72(17): 1-12.

50. Wang, Y., et al. Design, Synthesis, and Biological Evaluation of Imidazole Derivatives as Antimalarial Agents. European Journal of Medicinal Chemistry. 2020; 185: 111846.

51. Kumar, S., et al. Synthesis and Antimalarial Activity of Novel Imidazole Derivatives. Bioorganic Chemistry. 2021; 116: 105272.

52. Huang, L., et al. Imidazole Derivatives as Potent PTP1B Inhibitors: Synthesis and Biological Evaluation. Journal of Medicinal Chemistry. 2018; 61(4): 1382-1394.

53. Patel, S., et al. Thiazolidinedione-Imidazole Hybrids: Design, Synthesis, and Antidiabetic Activity Evaluation. European Journal of Medicinal Chemistry. 2020; 193: 111978.

54. Chen, Z., et al. Imidazole Derivatives as Potent Selective Serotonin Reuptake Inhibitors: Design, Synthesis, and Biological Evaluation. Journal of Medicinal Chemistry. 2019; 62(11): 5032-5042.

55. Guo, Y., et al. Dual-Acting Imidazole Derivatives as Serotonin-Norepinephrine Reuptake Inhibitors: Synthesis and Antidepressant Activity. Bioorganic and Medicinal Chemistry Letters. 2021; 31(2): 126-132.

56. Patel, S., et al. Design and Synthesis of Imidazole Derivatives as Potent Acetylcholinesterase Inhibitors for Alzheimer’s Disease Treatment. European Journal of Medicinal Chemistry. 2020; 200: 112455.

57. Sharma, V., et al. Imidazole-Based Inhibitors of Amyloid-Beta Aggregation with Antioxidant Properties for Potential Alzheimer’s Disease Treatment. Bioorganic and Medicinal Chemistry Letters. 2021; 31: 127875.

Received on 12.10.2024 Revised on 30.10.2024

Accepted on 16.11.2024 Published on 25.11.2024

Available online from December 27, 2024

Asian J. Research Chem.2024; 17(6):368-376.

DOI: 10.52711/0974-4150.2024.00062