Abstract
Benzimidazole, one of the finest classes of heterocyclic aromatic compounds have the characteristic structure of benzene fused with a five-membered imidazole ring. Despite being made their first appearance in the late 1870s, they are considered as a ‘privileged molecule’. The applications of this wonder molecule range from medicinal chemistry to material science. Benzimidazole being a potent inhibitor for various enzymes has got therapeutic effects like anticancer, antimicrobial, anthelmintic, antioxidant, anticonvulsant, antifungal, anti-inflammatory, antiviral, antihistaminic, antipsychotic, etc. It has also made its existence in various branches of medical science viz ophthalmology, neurology, cardiology and more. The applications of benzimidazole are not only limited to the biological field but also expanded to the field of material chemistry as well. This chapter summarizes the pharmacological properties of benzimidazole, illustrated on numerous derivatives since 2016.
Keywords
- anti-cancer agent
- Benzimidazole
- biological activity
- N-heterocycle
- medicinal chemistry
- pharmacophore
1. Introduction
The benzimidazole nucleus is fairly unique among heterocyclic ring systems because of its outstanding structural similarity with various naturally occurring nucleotides [1]. In 1872, Hoebrecker synthesized the first benzimidazole molecule by the reduction of 2-nitro-4-methylacetanilide [2]. The biological significance is because its structure is similar to purines, and the importance of the applications depends on their abundance in most of the biologically active molecules. The discovery of the structure of vitamin B12 with 5, 6-dimethylbenzimidazole moiety in it, also elicited the search for benzimidazole - similar motifs for various pharmacological applications [3, 4, 5]. Following this, various research groups have outlined the synthesis and applications of benzimidazole [6, 7]. Benzene when fused with imidazole results in the formation of benzimidazole (
The greater reactivity of the 2nd position towards various electrophiles and nucleophiles is the outcome of tautomerization. Many drugs contain the benzimidazole nucleus as a core unit and have a widespread application in the pharmaceutical field [8, 9, 10, 11, 12, 13, 14]. The presence of benzimidazole pharmacophore in the various branches of medical science is inexplicable. The therapeutic uses of benzimidazole include anticancer [15, 16, 17, 18, 19, 20], antimicrobial [21, 22, 23, 24], antiparasitic [25, 26], anti-inflammatory and analgesics [27, 28, 29], antiviral [30, 31, 32], and antiulcerative [33] activities and in fields like ophthalmology, neurology, endocrinology, etc. The first example of a benzimidazole that was clinically available was thiabendazole (
In this chapter, a plethora of benzimidazole analogs with different pharmacological properties such as anticancer, antibacterial, antifungal, antiviral, anticoagulant, anti-inflammatory, antiparasitic, anthelmintic activity, etc. has been discussed.
2. Benzimidazole and its pharmacological significance
Benzimidazoles were initially used as a plant fungicide and veterinary anthelminthic. After the discovery and use of thiabendazole (
Various substituted derivatives of (
2.1 Anticancer activity
Cytotoxicity of benzimidazole derivatives is well known and, recently Noha et al. reported compounds of benzimidazole which are
The role of benzimidazole analogs as potential metal-based DNA-sensor is unanimous. Fluorogenic differential/sequential Schiff base chemosensors which solely consists of benzimidazole derivatives (
Drug repurposing of benzimidazole compounds is generally considered for the reason that, it has antitumor activities. Florio and coworkers screened anthelmintics which are derivatives of benzimidazole [37]. Certain drugs like albendazole (
Synthesis of
The stabilization of proteins in the cell is being coordinated by heat shock proteins (HSPs). HSP90 plays a major role in it. This can be reflected in cancer therapy. Neverdauskas et al. synthesized benzimidazole derivatives with resorcinol (
Benzimidazole is considered a privileged molecule in the medicinal world. Hernández-Romero et al. in 2021 synthesized first-row transition metal compounds which contain benzimidazole moieties (
Bistrović et al. synthesized monocationic benzimidazoles (
The 1, 3-disubstituted benzimidazoles (
Synthesis of imidazo[1,2-
Srour et al. in 2020 reported the formation of a novel class of 2-thiazol linked benzimidazoles (
Benzimidazole-tethered pyrazoles (
Mn(I) and benzimidazole co-ligands (
Prosser et al. synthesized a Cu(II) complex of benzimidazole (
Research works concentrating on the effective therapeutic agent possessing antiproliferative activity for human gastric cancer paved the way to the discovery of yet another benzimidazole derivative (
Aromatase inhibitors (AIs) are compounds that control estrogen-related diseases and hence breast cancer, as its concentration was found to be higher in such cases. Çevik et al. in 2020 synthesized some novel benzimidazole- triazolothiadiazine libraries and examined its aromatase inhibition activities [49]. Initial screening of these compounds towards anticancer properties against breast cancer cell line (MCF-7) in humans, resulted in getting good results. Upon further subjecting it to
among them was found to be almost equal in activity when compared with a reference drug letrozole (Figure 10).
The role of benzimidazole compounds in the treatment of breast cancer is exemplary. Gangrade et al. demonstrated the use of benzimidazole derivatives in the inhibition of Wnt/β-catenin signaling [50]. The upregulation of Wnt/β-catenin signaling in triple-negative breast cancer (TNBC), when compared to normal and other breast cancer subtypes, is inevitable. Benzimidazole compounds like SRI33576 (
Cheong and co-workers designed and synthesized benzimidazole methylcarbamate analogue (
Liang and co-workers synthesized selenium-containing benzimidazole derivatives through condensation of peptide coupling reagents and irradiation of microwaves [52]. These selenediazole derivatives were recognized as potent anticancer agents against MDA-MB-231 and MCF-7 breast cancer cell lines. Compounds (
Husain et al. prepared various derivatives of furanone appended benzimidazoles, which effectively contribute to cancer therapy [53]. Compound (
Compounds (
Molinspiration software and they possess high bioactivity scores. It was also found that they obey Lipinski’s rule and could be emerged as a lead anticancer drug (Figure 11).
Shinde and co-workers used D-glucose as the precursor for the synthesis of ribofuranosyl nucleosides (
Sireesha et al. designed and synthesized benzimidazole/benzoxazole-linked
Benzimidazole derivatives (
Synthesis of organoruthenium(II) complexes of benzimidazoles (
2.2 Antibacterial and antifungal activity
Heterocyclic appended benzimidazoles were synthesized and their antibacterial and antifungal activities were tested [59]. The mechanism of action of these molecules was also examined by using docking studies with bacterial proteins such as DNA gyrase subunit B (DNAG) and penicillin-binding protein 1a (PBP1a). The compounds with thiazole and thiadiazole moieties (
Ajani et al. synthesized various
Benzene-1,2- diamine undergoes condensation reactions with anthranilic acid, 3, 5-dinitrophenylbenzoic acid, and phenylacetic acid, catalyzed by NH4Cl yielded the precursor molecules, which on reaction with electrophile-releasing agents produced the corresponding
1-aryl-substituted 1, 2, 3-triazole appended amidinobenzimidazoles linked
A microwave-assisted, Ni(II) catalyzed novel preparation of 2,6-disubstituted and 1,2,6-trisubstituted benzimidazoles were achieved by Patel and his group (Figure 15) [62]. The
A comparative antimycobacterial activity study of 2,5-disubstituted and 1,2,5-trisubstituted benzimidazoles was reported in 2020 [63]. The
A library of mono and disubstituted benzimidazoles were synthesized by applying different methodologies, i.e., by using the microwave, ultrasound (US), infrared (IR), simultaneous application of US and IR, and by conventional heating [64]. The antimicrobial and antifungal activities of these benzimidazole derivatives were then evaluated. It was found that some compounds such as (
Very recently, Khan et al. designed and synthesized pyrimidine-benzimidazole hybrids (
Zha et al. demonstrated benzimidazole derivatives (
Claisen-Schmidt condensation of 2-acetylbenzimidazole and aldehydes followed by a series of steps resulted in the synthesis of benzimidazole derivative (
Karaburun et al. described the multi-step synthesis of a series of benzimidazole-1,3,4-oxadiazole derivatives (
Recently, Aroso and co-workers computationally designed benzimidazole derivatives through palladium-catalyzed reactions [69]. The reaction between 4-bromo-1,2-diaminobenzene and 2-nitrobenzaldehyde, followed by a couple of palladium-catalyzed Suzuki–Miyaura and Buchwald-Hartwig amination cross-coupling reactions resulted in the formation of (
Chen et al. designed flavonoid analogs (
Compound (
Synthesis of benzimidazole derivatives like triazinane (
Wang et al. reported the synthesis of a series of benzimidazole moieties (
A novel, one-pot synthesis of 2-substituted benzimidazoles and Mannich bases (
Qualitative and quantitative antimicrobial bioassay of these benzimidazole derivatives showed activity against a broad spectrum of gram-positive and negative bacterial strains both in planktonic and adherent states. The presence of nucleophilic groups like -OH or -CH3 accounts for the microbicidal activity (Figure 20).
Benzimidazoles moieties linked with
Antoci and co-workers synthesized
The synthesis of naphthyl-substituted benzimidazole derivatives (
Sirim et al. designed and synthesized benzimidazole-acrylonitrile hybrid derivatives from benzene-1, 2-phenyleneamine and ethyl cyanoacetate followed by reaction with piperazines [78]. All the derived compounds exhibited anti-mycobacterial activity against
2.3 Antiparasitic activity
Taman et al. evaluated the antischistosomal activity of newly synthesized benzimidazole-related compounds like NBTP-OH (
Synthesis of 1, 3-disubstituted benzimidazol-2-ones (
Molecular docking studies and quantitative structure–activity relationship (QSAR) delivered that benzimidazole derivatives (
Tonelli et al. designed and synthesized benzimidazole derivatives from benzene-1, 2-diamine and various acids followed by suitable functionalization and used it as a potent antileishmanial agent [82]. Benzimidazole derivatives were tested against
Exploration of the inhibitory activity of certain benzimidazole compounds like albendazole (
2.4 Antiviral activity
Compound (
Ibba et al. demonstrated the role of benzimidazole derivatives (
Research for the inhibitory action of
2.5 Other properties like antipsychotic, antidiabetic, anticoagulant activities, etc.
Imran et al. in 2021 [87]. The derivatives lowered the neurodegeneration and inflammation of neurons by down-regulating inflammatory cascades caused by oxidative stress (Figure 27).
The prominence of benzimidazole in the field of medicine is exceptional. Etazene (
Tantray and co-workers studied psychiatric disorders like depression and acknowledged the fact that glycogen synthase kinase-3
Hussain et al. synthesized certain benzimidazole analogs (
Dabigatran is an effective drug having a benzimidazole core as the activity center and is used for the treatment of cardiovascular diseases because of its antithrombin as well as anticoagulant activities. Zhang et al. in 2020 enhanced the activity and bioavailability of dabigatran by adding methyl and methoxy groups into the benzene ring [91]. By studying the anticoagulant action and thrombin inhibition properties of compounds (
3. Conclusions
To sum up, benzimidazole is a chemical compound that belongs to the family of heterocyclic aromatic organic compounds. It is a potent biologically important molecule with a noticeable therapeutic activity. Applications of benzimidazole extend to medicinal chemistry. Several advanced research in this area also found out that the aforementioned compound has significant antimicrobial activities especially against many strains of viruses, fungus, bacteria, etc. It is also widely used in medicinal chemistry as an accepted drug against parasites and their allied infections. Benzimidazole is also used as an analgesic and anti-inflammatory agent. Recent studies have also created a lot of attention for the compound since it has an anti-carcinogenic activity like cytotoxicity and hence may become a viable cure for cancer in the future. The applications of benzimidazole cannot be marginalized. It has got a whole spectrum of medicinal agents. Benzimidazole has gained popularity in material science.
Apart from this, the multi-target capability of benzimidazole scaffolds has not been explored extensively. Being a versatile motif, benzimidazole could provide a plethora of novel multi-target ligands against various debilitated pathological conditions. The lack of comprehensive compilation about the SAR of many compounds and the various research reports stemmed the reason for less number of active benzimidazole compounds reaching the market. The existing design of benzimidazole derivatives can be further revised to accommodate potential multitargeting agents, thus enhancing and treating multifactorial disorders. This can be a breakthrough establishment in benzimidazole history.
In short, the importance of this imidazoline compound has been proved by the number of research papers getting published in a short period. This chapter is trying to narrate the formulation as well as execution of benzimidazoles in different fields of medicinal chemistry.
Acknowledgments
The authors would like to acknowledge the support given by the Department of Chemistry, Amrita Vishwa Vidyapeetham, Amritapuri campus for providing the necessary facilities to carry out research work.
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