BENZIMIDAZOLE (C7H6N2): HISTORY, STRUCTURE, ADVANTAGES, DISADVANTAGES - CHEMISTRY - 2025

The benzimidazole is an aromatic hydrocarbon, whose chemical name is 1- H-benzimidazole and its chemical formula C ₇ H ₆ N ₂. Its structure comprises the union of a benzene ring plus a nitrogenous pentagonal ring called imidazole.

Benzimidazole is said to be a heterocyclic compound, because it has two atoms in its rings that belong to different groups. Many drugs are derived from benzimidazole aimed at treating parasites (anthelmintic), bacteria (bactericide) and fungi (fungicide), which can be used on animals, plants and humans.

Chemical structure of benzimidazole. Source: The original uploader was Cacycle at English Wikipedia.

Benzimidazole has also been discovered other properties such as its photodetector and proton conducting capacity in solar cells, being compared with 2,2'-bipyridine due to its optoelectronic properties.

The benzimidazole derivatives are classified into methyl carbamates, triazoles, halogenated triazoles, and probenzimidazoles.

In agriculture, some substances derived from benzimidazole are widely used to prevent the deterioration of fruits during transport. These include Carbendazole, Bavistin and Thiabendazole.

On the other hand, in addition to anthelmintics, antimicrobials, antifungals and herbicides, there are currently a myriad of drugs that contain the benzimidazole nucleus in their structure.

Among the drugs, the following stand out: anticancer, proton pump inhibitors, antioxidants, antivirals, anti-inflammatories, anticoagulants, immunomodulators, antihypertensives, antidiabetics, hormonal modulators, CNS stimulants, lipid level depressants or modulators, among others.

History of benzimidazole

Benzimidazole was first synthesized between the years 1872 to 1878, first by Hoebrecker and then by Ladenberg and Wundt. Eighty years later its potential value as an anthelmintic was discovered.

Thiabendazole was the first benzimidazole-derived antiparasitic discovered, which was synthesized and marketed in 1961 by Merck Sharp and Dohme laboratories.

They quickly realized that this compound had a very short half-life and, therefore, its structure was modified creating 5-amino Thiabendazole and Cambendazole, which showed a slightly longer half-life.

Subsequently, the Smith Kline and French laboratories promoted the development of new benzimidazole derivatives, improving the anthelmintic properties of their predecessors. To do this, they eliminated the thiazole ring located in position 2 and incorporated a thiocarbamate or carbamate group.

From there are born albendazole, mebendazole, flubendazole and many others.

Structure

It is made up of a benzene ring plus an imidazole ring. The latter is a nitrogenous pentagonal ring.

The atoms of the benzimidazole structure are listed counterclockwise, starting at the nitrogen of the imidazole molecule and ending at the last carbon of the benzene ring. (See image at the beginning of the article).

Benzimidazole is characterized by being a crystalline or whitish powder that is poorly soluble in water.

Classification of benzimidazole derivatives

Methyl carbamates

It includes the following compounds: albendazole, mebendazole, oxfendazole, flubendazole, ricobendazole, oxibendazole, febendazole, parbendazole, cyclobendazole, and lobendazole.

Triazoles

Among the thiazoles are: thiabendazole and cambendazole.

Halogenated triazoles

As a representative of this category, triclabendazole can be mentioned.

Probenzimidazoles

In this group there are: Netobimin, Thiophanate, Febantel.

Associations

Binding of benzimidazole with other substances can improve the spectrum of action. Example:

Diethylcarbamazine plus benzimidazole: improves its function against filarial larvae.

Praziquantel plus pyrantel pamoate plus benzimidazole: broadens the spectrum against cestodes.

Niclosamide plus benzimidazole: (benzimidazole plus closantel) improves the effect against trematodes.

Triclabendazole plus levamisole: improves the effect against flukes and nematodes.

There are other combinations such as the union of the benzimidazole nucleus with triazine to form anticancer and antimalarial compounds. Example 1,3,5-triazino benzimidazol-2-amine.

Various drugs that contain the structure of benzimidazole. Source: Ibrahim Alaqeel S. Synthetic approaches to benzimidazoles from o-phenylenediamine: A literature review, Journal of Saudi Chemical Society 2017; 20 (1): 229-237. Available in: reader.elsevier.com/

Properties of benzimidazole derivatives

Antibacterial property

This is not one of the most prominent functions of this compound, however, it is said that some of its derivatives can affect a small group of bacteria, among them is Mycobacterium tuberculosis.

In this particular, more than 139 compounds have been synthesized with this base, where 8 have shown strong activity against the causative agent of tuberculosis, such as benzimidazoles N-oxides (2,5,7-benzimidazole).

Anthelmintic property

In this sense, one of the most frequent parasitosis is that produced by Ascaris lumbricoides. This intestinal parasite can be treated with albendazole, a derivative of benzimidazole that works by minimizing the ATP of the helminth, causing immobility and death of the parasite.

Mebendazole can also be mentioned, another derivative of this compound that significantly paralyzes the absorption of glucose and other nutrients in the intestine of the parasite, creating a biochemical imbalance.

This drug irreversibly binds to the ß subunit of tubulin, affecting microtubules and microfilaments, which causes parasite immobility and death.

Most benzimidazole-derived anthelmintics are active against helminths, cestodes, and trematodes.

Fungicidal property on plants (herbicide)

1- H-Benzimidazole, 4,5 dichloro 2- (trifluoromethyl) is a herbicide commonly used for the treatment of diseases at the plant level.

Plant-level disease is almost always caused by fungi, which is why the antifungal property is very important when it comes to herbicides. An example is benomyl or benlate which, in addition to having an antifungal action on fungi that attack certain plants, also has an acaricidal and nematicidal action.

Herbicides are absorbed by the leaves and roots of plants and reduce the fungal infections that commonly attack large crops of cereals, vegetables, fruit and ornamental plants.

These products can act preventively (prevent plants from getting sick) or curative (eliminate the already installed fungus).

Among the herbicides derived from benzimidazole that can be mentioned are: thiabendazole, parbendazole, helmthiophane and carbendazim.

Optoelectronic Properties

In this sense, some researchers have described that benzimidazole has optoelectronic properties very similar to that of the compound called 2,2′-bipyridine.

Other properties

In addition to the properties already described, it has been discovered that benzimidazole has the property of inhibiting the enzyme topoisomerase I. This enzyme is essential in the processes of DNA replication, transcription and recombination, since it is responsible for winding, unwinding or supercoiling the DNA helix.

Therefore, some antibacterials work by inhibiting this enzyme. Also some anticancer agents act at this level, inducing an apoptotic response (cell death).

On the other hand, some researchers have created a new glass using organic substances, such as benzimidazole, imidazole plus a metal (zinc). This glass is more flexible than glass made of silica.

Advantages and disadvantages of benzimidazole derivatives

Advantage

These drugs have the advantage that they are inexpensive, broad spectrum, and most are effective in killing larvae, eggs, and adult worms. This means that they act in all phases of the parasite's life. They are not mutagenic, nor are they carcinogenic. They have low toxicity to the host.

Some of its derivatives are not only used to treat companion or breeding animals or to treat plants, but are also useful for deworming humans, such as: albendazole, triclabendazole, mebendazole and thiabendazole.

Disadvantages

Among its disadvantages are its low water solubility, which makes good absorption at the gastrointestinal level of the host impossible.

As adverse effects in the host, it is known that they can produce mild hepatotoxicity, alteration in the thymus and spleen. In dogs it can lower the concentration of red blood cells and hematocrit.

On the other hand, there is the ability of parasites to create resistance.

Increased resistance has been seen from parasites that affect ruminants and Strongyloides that affect horses.

The mechanism of resistance seems to be involved in the mutation of the tubulin gene in which there is a change from one amino acid to another (phenylalanine for tyrosine at position 167 0 200 of the ß subunit of tubulin), changing the affinity of the compound for this structure.

Another disadvantage that occurs in a small group of benzimidazole derivatives is the teratogenic property, causing bone, ocular and visceral malformations in the host.

That is why some of them are contraindicated in pregnant women and in children under 1 year of age.

At the ecosystem level it acts not only against fungi and parasites, it also has action on diptera, aquatic organisms and annelids.

References

1. "Benzimidazole." Wikipedia, The Free Encyclopedia. 30 Aug 2019, 07:09 UTC. 2 Dec 2019, 21:31
2. Nj Health New Jersey Department of Health. Fact Sheet on Hazardous Substances (Benzimidazole). Available at: nj.gov/health
3. Ninán, Oscar, Chareyron, Robert, Figuereido, Oscar, & Santiago, Julio. (2006). Benzimidazole derivatives liquid crystals. Journal of the Peruvian Chemical Society, 72 (4), 178-186. Available at: scielo.org.
4. Márquez A. Anthelmintic activity of benzimidazole derivatives on Hymenolepis nana and Toxocara canis. Undergraduate work to qualify for the degree of Doctor of Chemobiological Sciences. National Polytechnic Institute. National School of Biological Sciences. Mexico. 2008. Available at: thesis.ipn.mx/bitstream
5. Bansal Y, Silakari O. The therapeutic journey of benzimidazoles: a review. Bioorg Med Chem. 2012; 20 (21): 6208-36. Available at: ncbi.nlm.nih.gov/
6. Ibrahim Alaqeel S. Synthetic approaches to benzimidazoles from o -phenylenediamine: A literature review, Journal of Saudi Chemical Society 2017; 20 (1): 229-237. Available in: reader.elsevier.com/