Significance of Imidazole in Cancer Drug Discovery: Recent Advancements

Human health can be threatened by uncontrolled cell growth and division, such as in cancer [1]. There is no use of false hope for the patients who have cancer and who are in a situation where these cancerous cells have already started interfering with the proper functioning of normal organs. In the year of 2020, there were approximately 10 million deaths caused by cancer with 19.3 million new cases as per the report of the World Health Organization [2,3]. Even though there is quite a number of cancer treatment medications available, the need to create new and better treatment options is still very important. The last decade, of research has directed a lot of effort into the search for new and existing anticancer agents. In cancer therapies, every actor has a role and the microtubule cytoskeleton is however a well-established contributor to drug development [4,5].

Figure_1; chemical structure of Imidazole [6]

In the year 1858, German chemist Heinrich Debus made the first ever successful synthesize of imidazole ring through the reaction of glyoxal and ammonia to yield imidazole type compound. This was a significant development in organic, and then in further medicinal chemistry, because imidazole in which two nitrogens are present in the aromatic ring of five shows endless possibilities of reactivity and interactions [6,7]. Considering its ability to hit diverse biological targets, imidazole is therefore often used as a central scaffold for the development of antitumor compounds [8]. As a result of this structural property, imidazole is able to insert into DNA, bind to metals and to enzymes essential for cancer disposition as well as to the growth and development of cancerous cells. Ultimately, the two nitrogen atoms enhance drug affinity and selectivity towards the target sites in the treatment of cancer, thus more therapeutic outcomes with less adverse effects [9,10]. In order to manufacture new derivatives more complex than the earlier developed imidazole-based entities and which would be less toxic, the researchers propose to undertake the synthesis of new compounds. Modifications on the imidazole ring can serve to either limit or favour the ability of such compounds to interact with specific cancer-associated structures or enzymes within the biological system [11]. As a case, imidazole rings possessing donating substituents tend to exhibit higher anti-cancer activity because of the enhanced hydrophobic effect with the target. On the other hand, electron-withdrawing substituents tend to enhance the binding of such compounds to metalloproteins by facilitating charge transfer and therefore increase the ionic character of the compounds. Furthermore, the positioning of substituents also on the imidazole rings plays an important role in establishing its orientation in the active sites [12-14]. For example, substituents at the 2-position are known for strengthening interactions with structural metal ions, hence making it possible to specifically inhibit enzymes, for instance, carbonic anhydrase IX (CA IX) of hypoxic tumor cells. Research has further suggested that the change in substituents from a 1 position to a 3 position on the imidazole ring increases the selectivity towards certain types of cancer treatment such as that of HDAC or HIF. It has been found that some benzimidazole hybrid derivatives containing a benzimidazole moiety have been evaluated as potential inhibitors of HDAC. Such derivatives retain the important transition metal binding property of imidazole and include a benzimidazole ring to increase the binding and retention of the compound [15,16].

2. Mechanisms of Action of Imidazole Derivatives in Cancer Therapy
   1.  Inhibition of Enzymes

Anticancer treatments with imidazole derivatives are based to a greater extent on the inhibition of enzyme activity that is important for the proliferation and stimulated metabolism of the cancer cells. There are many imidazole derivatives that act as inhibitors of cytochrome enzymes or histone deacetylases (HDACs) and carbonic anhydrase (CA) whose expression is usually elevated in some tumours [17]. For instance:

1. 1. 1. Inhibition of Histone Deacetylase:

Imidazole-based HDAC inhibitors manipulate gene expression and result in apoptosis of cancerous cells and incarceration of espionage agents, among others, through epigenetic mechanisms. In the case of the imidazole core, the two nitrogen components are bound with a zinc ion, which is the same role played by many other well-known metallurgical HDAC inhibitors like hydroxamic acids [18]. The Triazolyl-imidazole derivatives showed extremely selective action toward HDAC isoenzymes, however specific to HDAC6 known to facilitate cancer cell motility and metastasis. Development of Imidazole derivatives That Selectively Inhibit HDAC6 may limit the degree of metastatic spread of cancer without harming normal tissues. There are also imidazolyl-pyrazole derivatives; these are hybrids of an imidazolyl group with other heterocycle systems like pyrazoles to enhance their binding affinities and selectivity for HDACs. It has been established that these types of agents inhibit HDACs but also work in conjunction with such agents to eradicate specific cancers such as breast and lung cancer [19].

1. 1. 2. The inhibition of carbonic anhydrase:

Imidazole derivatives displayed selective inhibition towards CA IX and CA XII isozymes which are active in the hypoxic tumor microenvironment and play a role in dysregulating the pH of tumor cell hence limiting their proliferation and metastasis. CAs of the hypoxia-inducible type, such as CA IX, are typically expressed in excess in poor perfusion tumors aiding the tumor in creating an acidic environment that is favorable for its growth. Compounds Furthermore, molecular approaches to directed tumor therapy based on such inhibitors with CA IX function are suggested CT activators that sensitize tumor cells to immunological or general therapeutic agents [20].

1. 2.  DNA Interaction and Intercalation

Some imidazole derivatives, including imidazo[4,5-b]pyridine, are DNA intercalators, they bind to the DNA between the base pairs interfering with the replication apparatus of cancerous cells [21]. In general, DNA intercalators insert between the base pair of DNA causing distortion. Imidazole derivatives dosed in the intercalation site of the base layers unmanaged the DNA double helical structure stiffening their position via van der waals and π-interactions. Molecules based on imidazole may also interact with DNA bases forming hydrogen bonds which act to stabilize the intercalative complex. These drugs block the transcriptional as well as the replicational machinery of the cell, causing cell death [22]. Drug discovery of imidazole-charged DNA binding agents focuses primarily on selectivity towards healthy tissues and utilization of characteristics of the cancer DNA structure or oncogenesis protein expression. Metronidazole and clotrimazole are two examples of methylimidazole derivatives possessing antimicrobial activity although they do not intercalate DNA in the orthodox way. Still, derivatives of these two drugs that were designed to allow DNA binding have been found to be intercalators in some studies [23].

1. 3. Targeting Hypoxia-Inducible Factor (HIF)

Hypoxia in tumors is an ever-present feature that enhances the development of cancer and its treatment resistance properties. The activity of the HIF protein is dependent on the availability of oxygen in the cell [24]. In normoxic conditions, HIF-1α is marked for destruction by prolyl hydroxylase (PHD) enzymes that hydroxylate this transcription factor. In contrast, under hypoxic conditions, PHDs are inhibited, resulting in the stabilization of HIF-1α and the activation of HIF-dependent gene expression [25]. HIF-1α antagonists targeting Imidazole derivatives have been successful in blocking hypoxia-inducible factor signaling, which helps prevent cancer cells from proliferating in low-oxygen environments. HIF-1α blocking prevents neovascularization and modification to low-oxygen conditions, effectively limiting cancer growth and invasion [26].

3. Advancement in Imidazole-Based Anticancer Agents

Recent advancements in imidazole-containing compounds as anticancer drugs have focused on enhancing selectivity, potency, and minimizing side effects.

3. 1. Alkylation: Novel imidazole derivatives have recently been synthesized and used as an adjunct to alkylating agents for increased targeting of DNA. This approach vaccine targets cancer cells and minimizes the effects of the drug on healthy cells [27].
   2. Kinase Inhibition: Imidazole-based compounds have recently been developed, targeting internal tyrosine kinases and additional key enzymes within the cancer signalling pathway. These kinase inhibitors can protect against the proliferation of tumor cells and their metastasis. Such inhibitors are currently being refined for further cancer-specific kinases for decreased side effects due to inhibition of the pernicious kinase in normal healthy cells [28,29].
   3. Apoptosis Induction via Reactive Oxygen Species (ROS): Some derivatives of imidazole enhance the intracellular levels of ROS in cancer cells causing apoptosis in those cells [30]. ROS induction perturbation of cellular homeostasis occurs mostly in the cancer cells which have a higher rate of metabolism and are vulnerable to oxidative stress. The details of the research done currently entail increasing the potency of the activity of these compounds which selectively target cancer tissue to promote the generation of ROS [31].
   4. Dual Action Compounds: Other more recent imidazole-based drugs have been devised with two opposing characteristics, for example, DNA intercalation and inhibition of kinase activity or modulation of HIF while inducing ROS levels [32]. Such drugs are referred to as multifactorial agents and are intended to deal with drug resistance by attacking the cancer cells in several ways. The advantage of dual-action compounds is that they are useful in the treatment of highly aggressive and highly mutated and adaptive tumors [33].
4. Clinical Status and Challenges

Despite significant advances in preclinical studies, the clinical translation of imidazole-based drugs faces several challenges:

1. 1. Drug Resistance: Cancer cells frequently develop resistance to imidazoles and similar drugs by methods such as drug efflux and alteration of the drug target proteins. Resistance to HDAC inhibitors is also acquired by tumor cells through mutations in genes or by engaging circumvention pathways which ultimately diminishes the effectiveness of these agents over time [35].
   2. Pharmacokinetics and Bioavailability: The majority of imidazole compounds have restricted bioavailability and a short elimination half-life which calls for either extensive chemical modifications or careful formulation strategies to optimize their bio-pharmacokinetics. Adjunct therapy with Clotrimazole and Miconazole in Brain Tumors and Gliomas [36]. These drugs have been mainly evaluated in preclinical studies but there is also some clinical exploration of using them although the focus is largely on more advanced cancers like brain tumors and gliomas. The compounds have been effective against cultured cells; however, several studies have shown that these effects are impossible to achieve in the living organism because of insufficient distribution, especially through the blood-brain barrier [37].
   3. Selectivity and Off-Target Effects: Imidazole formulations are usually more specific than many drugs that belong to other heterocyclic classes, the issue of obtaining a therapeutic window that is both effective and devoid of toxic effects is still a concern [38]. In several clinical trials Mitoguazone has been evaluated, in particular for hematologic malignancies such as acute and chronic leukaemias and lymphomas. It did show some degree of tolerability and efficacy, however its development was halted because of unsatisfactory activity and toxicities [39].
   4. Drug Delivery: The bioavailability, solubility, or metabolism of many imidazole derivatives limit the concentration of the drug within the tumor. Prodrugs, targeted delivery or formulation into nanoparticles are the strategies being devised to mitigate these challenges. Imexon has reached Phase I and Phase II clinical trials for different cancers like multiple myeloma and non-small cell lung cancer - the major hurdle however its toxicity profile especially vascular toxicity which has restricted its dosage and combinations with other chemotherapeutics [40,41].

CONCLUSION

Compounds containing imidazole rings are a class of chemical compounds that are promising in terms of their potential for developing novel anticancer agents based on their multiple mode of actions, ease of chemical modifications, and relatively-safety. With the advancement of the research, new imidazole derivatives will be developed which will be more selective and potent with lower side effects and will thus be very useful in the fight against cancer. However, there will still be a need to further research their uses in clinics and how to address the pharmacokinetics and resistance issues for relief of this active class of drugs to goodwill, into the treatment of cancer.

Conflict of interest: The authors have no competing interests to declare that are relevant to the content of this article.

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