PHARMACOLOGICAL ACTIVITIES OF BENZIMIDAZOLE- A REVIEW

About Authors:
Narinderpal Kaur*, Annapurna Negi, Jyotsna
Assistant Professor
School of Pharmacy and emerging Sciences
Baddi University of Emerging sciences and Technology
Baddi, Himachal Pradesh
*narinder.sonia@gmail.com

Abstract
In recent years the synthesis of benzimidazole and its derivatives has attracted the attention of many organic chemists because of the compounds' interesting biological activity and the crucial importance of the benzimidazole unit in the function of these biologically important molecules. Benzimidazole and its derivatives play an important role in medical field with large number of Pharmacological activities such as antimicrobial, antiviral, antidiabetic and anticancer activity. This review is summarized to know about the chemistry of different derivatives of benzimidazoles along with their biological actions such as antioxidant, antimicrobial, anthelmintic, analgesic, antiprotozoal, antiulcer, antiviral, anticancer, antihypertensive, antineoplastic, antiinflammatory, antifungal and anticonvulsant activity.

REFERENCE ID: PHARMATUTOR-ART-1946

INTRODUCTION
Benzimidazole is a heterocyclic aromatic organic compound. It is an important pharmacophore and a privileged structure in medicinal chemistry. This compound is bicyclic in nature which consists of the fusion of benzene and imidazole. Nowadays is a moiety of choice which possesses many pharmacological properties. The most prominent benzimidazole compound in nature is N-ribosyl-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12^.[1] Presence of benzimidazole nucleus in numerous categories of therapeutic agents such as antimicrobials, antivirals, antiparasites, anticancer, anti-inflammatory, antioxidants, proton pump inhibitors, antihypertensives, anticoagulants, immunomodulators, hormone modulators, CNS stimulants as well as depressants, lipid level modulators, antidiabetics, etc. has made it an indispensable anchor for development of new therapeutic agents. Varied substitutents around the benzimidazole nucleus have provided a wide spectrum of biological activities. Importance of this nucleus in some activities like, Angiotensin I (AT₁) receptor antagonism and proton-pump inhibition is reviewed separately in literature. Even some very short reviews on biological importance of this nucleus are also known in literature. However, owing to fast development of new drugs possessing benzimidazole nucleus many research reports are generated in short span of time. So, there is a need to couple the latest information with the earlier.

Benzimidazoles are a chemical class of compounds with broad anthelmintic activity that are vastly used on livestock and pets to control all kinds of parasitic worms (helminths). Some veterinary benzimidazoles are also used as anthelmintics in human medicines. Others benzimidazoles are also used in agriculture to control parasitic helminths of plants, or as fungicides. In fact, benzimidazoles were already used as plant fungicides before their development as veterinary anthelmintics. The first veterinary benzimidazoles introduced in the 1960's (e.g. thiabendazole,parbendazole, oxibendazole) were highly effective against adults and larvae of most gastrointestinal roundworms (nematodes) of livestock.

In the 1970's newer benzimidazoles such as albendazole, fenbendazole, mebendazoleandoxfendazole were introduced that are also effective against non-gastrointestinal roundworms (in the lungs, kidneys, skin, etc., depending on compound and dose) as well as against tapeworms (cestodes). Albendazole is also effective against adult liver flukes (Fasciola hepatica).Triclabendazole is a special case: it is not effective against roundworms and tapeworms, but controls all larval and adult stages of various parasitic liver flukes (trematodes).Closely related with the benzimidazoles are the so-called pro-benzimidazoles febantel, netobimin and thiophanate. These compounds are pro-drugs because once in the organism of the host they are transformed into the active benzimidazole, mainly in the liver. Febantel is transformed into fenbendazole, and netobimin into albendazole. Pro-benzimidazoles have the advantage of being more soluble in water. This makes it easier to formulate them and they are also better absorbed in the host's body.

Pharmacological actions

Antimicrobial & antibacterial effects:-
Literature survey shows that among the benzimidazole derivatives, 2-substituted ones are found to be pharmacologically more potent and hence the design and synthesis of 2-substituted benzimidazoles are the potential area of research Some widely used antibacterial drugs such as furacilin, furazolidone and ftivazide are known to contain this group^[25]. In past decades, hydrazones have received much attention and many studies ^[26-31] have been reported due to their chemotherapeutic value in the development of novel anti- microbial agents. A series of 1, 2-disubstituted-1Hbenzimidazole- N alkylated- 5-carboxamidine derivatives are very potent antibacterial activities against S. aureus and methicillin resistant S. aureus. The study revealed the best activity, with MIC values of 0.78 - 0.39 μg/mL against these species. Various Chloro and dichloro substituted benzimidazole also possess antibacterial activities. Isoxazolyl substituted compounds were screened for activity against Gram Negative species like E.coli and Proteus vulgaris,Gram positive like Bacillus mycoides and staphylococcus aureus^[44]. Some Benzimidazole compounds possessing hydrazone moiety were studied in order to investigate their possible antibacterial and antifungal activity. Most of the test compounds found to be significantly effective against Proteus vulgaris,Staphylococcus typhimurium, Klebsiella pneumoniae and Pseudomonas aeruginosa gram-negative bacterial strains6. Some fluroquinolones substituted Benzimidazole derivatives have been reported by microwave assisted method. The synthesized compounds are reported to be the derivatives of Ciprofloxacin & Norfloxacin.

Antifungal activity:-
Infectious diseases have been serious and growing threatens to human health during the past few decades. The decrease of sensibility to anti-microbial agents in current use has also been increasing for a great variety of pathogens and the resistance to multiple drugs is more and more prevalent for several microorganisms, especially for Gram-positive bacteria and some intractable fungi. Their inhibitory properties as regard representative fungi have been extensively exploited. Especially, it is worthy to note that Fluconazole, the first -line triazole-anti-fungal drug Recommended by World Health Organization (WHO) has established an exceptional therapeutic record for Candida infections, and become the first choice in the treatment of infections by Candida albicans and Cryptococcus neoformans due to its potent activity, excellent safety profile, and favorable pharmacokinetic characteristics. However, Fluconazole is not effective against invasive aspergillosis and is not fungicidal. In addition, extensive clinical use of Fluconazole has resulted in the increasing Fluconazole- resistant C. albicans isolates (Fang et al.,2010)^[120].

Antimalarial activity
Malaria caused 350-500 million clinical episodes annually and result in over one million deaths, most of which affect children under 5 years old in sub Saharan Africa. Malaria is the fifth cause of death from infectious diseases worldwide (after respiratory infections, HIV/AIDS, diarrhoeal diseases and tuberculosis). Recent estimates so that as many as 3.3 billion people live in areas at risk of malaria in 109 countries. In addition to its health toll, malaria puts a heavy economic burden on endemic countries and contributes to the cycle of poverty people face in many countries. Malaria mortality and morbidity began to increase in the 1980s due to a combination of factors such as increase in parasite and vector resistance to the current anti-malarial drugs and insecticides, the weakening of traditional malaria control programs, rapid decentralization and integration into deteriorating primary health service, and the development of humanitarian crisis situations in many malaria-endemic areas. This dramatic increase led to a compelling and urgent necessity for new malarial, with mechanisms of action different from the existing ones, and to identify new drug targets. Cloroquine has recently been shown to inhibit hemozoin formation within the parasite food vacuole. This process is also thought to be the molecular target of other quinoline anti-malarial. Hemozoin was originally considered to be formed by the polymerization of heme, but has now been demonstrated to be a crystalline cyclic dimmer of ferriprotoporphyrin IX. Thus, hemozoin synthesis, a process unique to the malaria parasite, offers a logical and valuable potential target for new anti-malarial drug development. New drugs that attack the same vital target of chloroquine but that are not subject to the same resistance mechanism would be highly desirable (Camacho et al., 2011),Ryckebusch et al. (2005) ^[115-127]

Antibacterial activity
The increase in bacterial resistance has attracted considerable interest in the discovery and development of new classes of anti-bacterial agents. The new agents should preferably consist of chemical characteristics that clearly differ from those of existing agents. Actinonin was first isolated from a Malayan strain of Actinomyces and found to show a weak inhibitory activity against Gram-positive and Gram-negative bacteria. However, recently actinonin has been proven to have anti-proliferative effects on human tumor cells. The action mechanism of actinonin is believed to be the inhibition of the peptide deformylase that is a new class of metal-loenzyme which is essential for bacterial survival. The hydroxamate group of actinonin, which can complex with the metal ion in the active pocket of the peptide deformylase, is necessary for its activity. Nevertheless, actinonin lacks in vivo efficacy, due to the poor bioavailability (Zhang et al., 2009). Second-generation macrolides such as clarithromycin (CAM) and azithromycin (AZM) have enjoyed widespread clinical use for the treatment of upper and lower respiratory tract infections as well as genital infections due to their superior anti-bacterial activity, pharmacokinetic properties and fewer gastrointestinal side (GI) effects compared with first-generation macrolides such as erythromy-cin (EMA) which is its acid instability, leading to consequential degradation products responsible for its poor pharmacokinetic profile and GI side effects . Their mechanism of action has been elucidated that the macrolides bind reversibly to the nucleotide A2058 in domain V of the 23S rRNA in the ribosom-al 50S subunit and block protein synthesis. However, the therapeutic Utility of the macrolides has been severely compromised by the emergence of widespread bacterial resistance which has become a serious medical problem worldwide.

Antiviral activity
Chronic infection with the hepatitis C virus (HCV) is a major risk factor for developing cirrhosis and hepatocellular carcinoma. Approximately 3% of the worldwide population is chronically infected with HCV (Alter and Seeff, 2000; Bialek and Terrault, 2006). A preventive vaccine has not been developed and limits of current therapeutics include serious side effects and therapy usually lasting 48 weeks with only a 50% sustained virological response rate (Bowen and Walker, 2005; De Francesco and Migliaccio, 2005; Fried et al., 2002; Houghton and Abrignani, 2005). A recent major advance was the development of an infectious virus system based on the transfection of human hepatoma cells with genomic HCV RNA (JFH1) isolated from a patient with fulminant hepatitis (Kato et al., 2001; Linden-bach et al., 2005; Wakita et al., 2005; Zhong et al., 2005). This cell culture model allows all stages of the HCV life cycle to be studied (Liu et al., 2011). Antiviral properties of various benzimidazole derivatives have been reported in a variety of studies using different virus strains, such as human cytomegalovirus (HCMV), human immunodeficien-cy virus, and hepatitis B and C virus. Also, amidino-substituted benzimidazoles, such as bis(5-amidino-2-benzimidazolyl) methane (BABIM), showed ability to block respiratory syncytial virus induced cell fusion. In addition, introducing amidino moiety to benzimidazole ring was shown to possess potent antimicrobial and anti-protozoal activity.

Anti hypertensive Agents
The biphenyl benzimidazoles have potent antihypertensive action as compared to the previous related drugs due to better availability upon the oral administration, 2- position of biphenyl is essential for the activity^.[41] Substituted aryl or alkyl caboxamido derivatives have reported to possess Angiotensin-II AT1 receptor antagonistic activity so are good antihypertensives agents^.[42] The renin-angiotensin system (RAS) plays a key role in regulating cardiovascular homeostasis and electrolyte/ fluid balance in normotensive and hypertensive subjects. Activation of the renin-angiotensin cascade begins with renin secretion from the juxtaglomerular apparatus of the kidney and culminates in the formation of the octapeptide angiotensin II (AII), which then interacts with specific receptors present in different tissues.Two basic types of receptors, both having a broad distribution, have been characterized so far: the AT1 receptor, responsible for the majority of effects attributed to this peptide, and the AT2 receptor, with a functional role yet uncertain. The main effects of AII are the regulation of blood pressure through vasoconstriction, thereby effecting an increase in vascular resistance, the regulation of volemia through the stimulated release of vasopressin and aldosterone, which induces saline retention, and the regulation of the adrenocorticotropic hormone (ACTH). Thus, reducing the levels of AII by inhibition of one of the RAS enzymes or directly blocking the AII receptors is in theory a good approach for treating hypertension, confirmed by the success of angiotensin-converting enzyme (ACE) inhibitors as antihypertensive. It also stimulates the release of vasopressin luteinizing hormone oxytocin and corticotropin. ANG II further induces vagus suppression and α-adrenergic potentiation and increases inotropy and chronotropy.

Antitumor activity
Several new nitrobenzimidazoles have been reported to possess cytotoxic activity against breast cancer. In the reported research it was also found out that the compounds like thiadiazole, tetrazole, triazines and imidazolesalso possess the activity ^.[50]

Anti prozoal Activity
Benzimidazole derivatives reported are 5, 6 dinitro and thioalkyl or thioaryl substituted compounds .These active compounds reported to possess activity against Stenotrophomonas malthophilia. These compounds have activity related to metronidazole against gram positive and gram negative bacteria. Substituted 2- trifluorobenzimidazoles have been reported^{.[56, 57]} Earlier it have reported anti-giardial activity^{.[58, 59]} One of another research involves the synthesis of series of 2-(trifluoromethyl)- 1H- Benzimidazole derivatives by using Phillips cyclocondensation of a substituted 1,2-phenylenediamine and trifluoroacetic acid.

The compounds were evaluated in vitro against various protozoan parasites naming Giardia intestinalis, Entamoeba histolytica, Trichomonas vaginalis and Leishmania mexicana,and they showed nanomolar activities against some of the above mentioned protozoa. The compounds were also tested in vitro and in vivo against the nematode Trichinella spiralis^.[60]

Antiparasitic Activity
2-(Trifluoromethyl)-1Hbenzimidazole derivatives showed the most desirable in vitro antiparasitic profile against Giardia intestinalis, Entamoeba histolytica, Trichomonas vaginalis and Trichinella spiralisThe anthelmintic drugs derived from benzimidazole 2-carbamates, such as albendazole (ABZ) and mebendazole (MBZ), are used mainly to treat endoparasitic diseases in domestic animals and humans. These types of compounds are characterized by a high therapeutic index and low toxicity; however, they find little use in tissue-dwelling parasites mainly due to poor solubility and absorption problems.

Antiulcer activity
Substituted Benzimidazoles are potent inhibitors of Parietal cell proton pump, the H+/K+ ATPase, the substituted benzimidazoles are capable of blocking gastric acid secretion in response to some stimuli. For the activity sulfoxide group, methylene group with hetercycles is important for activity^.[43]

Anti-inflammatory activity
Benzimidazole is one of the most promising heteroaryl moiety that yielded many successful drugs like omeprazole and mebendazole. Benzimidazole moiety with carboxylic acid substitution at 2 position, fulfills the minimum and desirable structural requirements that are common in most of the marketed anti-inflammatory drugs and so some benzimidazole-2-carboxylic acid Derivatives were synthesized. They were tested for acute anti-inflammatory activity against carrageenan induced rat paw edema model. The test compounds were found to be safe 2000 mg/kg, p.o. doses and exhibited good anti-inflammatory activity at 100 mg/kg p.o. and higher doses. The anti-inflammatory effect against carrageenan edema suggests inhibition of prostaglandin synthesis as their probable mechanism of action.

Non steroidal anti-inflammatory drugs (NSAIDs) are one of the most widely used drug category against inflammation, mild to moderate pain, and fever. Specific uses also include the treatment of headaches, arthritis, sports injuries, and menstrual cramps. Their use is mainly restricted by their well known and serious adverse gastrointestinal side effects^[66-70] such as gastroduodenal erosions and ulceration. Therefore, search for better and safer anti-inflammatory agents is always going on at a rapid pace.

A series of 2- methylaminobenzimidazole derivatives were synthesized and reported ^[51] by the reaction of 2-(chloromethyl)-1H-benzimidazole derivatives with primary aromatic amines The new synthesized compounds were screened for analgesic and anti-inflammatory activities by the author on acetic acid induced writhing in mice and carrageenan induced paw oedema in rats. Some Compounds showed a potent analgesic (89% at 100 mg/kg b.w) and anti-inflammatory (100% at 100 mg/kg b.w) activities compared with standard drug Nimesulide (100% at 50 mg/kg b.w) respectively. Another research was carried out indicating that benzimidazole on combination with iodole Skelton give potent anti inflammatory action similar to indomethacin^.[52] A series of benzamides has been synthesized with N – acridin -9-yl substituent^.[53]

Anti-Oxidant activity
Some compounds possessing dihydrochlorides have also been reported possessing antioxidant activity, these salts also possess mild platelet and erythrocyte antiaggregant activity^.[54] In another approach it was found out that using trimethyl group with benzimidazole also adds antioxidative property by 5-lipoxygenase inhibitory action^.[55]

HIV Inhibtors:-
Tetrahydro-imidazo[1,4]-benzodiazepin-2(1H)one(TIBO) is a noncompetitive non nucleotide antiretroviraldrug with a specific allosteric binding site of HIV-1 RT. TIBO derivatives have proved to be potent, highly selective and specific inhibitors of HIV-1 replication in vitro. The reverse transcriptase (RT) of HIV-1, but not HIV-2, is inhibited by the TIBO compounds. Several compounds other than TIBO have recently been reported to specifically inhibit HIV-1 replication. In a research it was investigated that some novel benzimidazole derivatives, bearing analogy to TIBO, have been synthesized, and were evaluated for inhibition of HIV-1 infectivity. The most active and selective compounds are a series of N-alkoxy- 2-alkyl-benzimidazoles, several having EC50 < 10Μm (one sub-micromolar at 600nM), and selectivity ratios of 10–167. The selective benzimidazoles, show modest RT inhibition^.[33]

CONCLUSION
Benzimidazole is an important heterocyclic moiety for the discovery of new drugs. This has been noticed so far, that modifications on benzimidazole moiety displayed valuable biological activities. It will be interesting to observe that these modifications can be utilized as potent therapeutic agents in future. The knowledge gained by various researches has suggested that substituted benzimidazoles and heterocycles, which are the structural isosteres of nucleotides allow them to interact easily with the biopolymers, possess pharmacological activity with lower toxicities. Since now, researchers have been attracted toward designing more potent Benzimidazole derivatives having wide diverse of biological activity

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