A Current Study on Benzimidazole Derivatives

 

Y. Dattatri , R. Harika, Chaitanya Prasad Meher*, P. Divyajyothi, R. Sangeetha, P. Santosh

Maheshwara Institute of Pharmacy, Chitkul, Isnapur, Patancheru, Hyderabad-502 307 (Andhra Pradesh)

*Corresponding Author E-mail: chaitanyameher84@gmail.com

 

Benzimidazoles are regarded as a promising class of bioactive heterocyclic compounds that exhibit a wide range of biological activities. Their nucleus is a constituent of vitamin B12 and is present in numerous compounds possessing antioxidant, antiparasitic, anthelmintic, antiproliferative, anti-HIV, anti-allergy, anti-inflammatory, antihypertensive, antineoplastic  and antiulcer activity .The present review article is concerned about the heterocyclic chemistry of benzimidazole. Basically it gives emphasis on potential biological activities of benzimidazole derivatives. Benzimidazole is an important lead compound, on modification of the nucleus owing to gives inherent properties and therapeutic action. The present review focuses on the biological activities of the benzimidazoles derivatives reported from 2000 to 2012.

 

 

INTRODUCTION:

Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound consists of the fusion of benzene and imidazole. The most prominent benzimidazole compound in nature is N-ribosyl-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B₁₂.

 

Benzimidazole, in an extension of the well-elaborated imidazole system, has been used as carbon skeletons for N-heterocyclic carbenes. The NHCs are usually used as ligands for transition metal complexes. They are often prepared by deprotonating an N,N'-disubstituted benzimidazolium salt at the 2-position with a base. Because most benzimidazoles are sparingly soluble in water, they are given PO as a suspension, paste, or bolus. Differences in the rate and extent of absorption from the GI tract depend on such factors as species, dosage, formulation, solubility, and operation of the esophageal groove reflex.

 

1H-BENZIMIDAZOLE

Molecular Formula = C7H6N2 Formula Weight    = 118.13594 Composition          =  C(71.17%) H(5.12%) N(23.71%) Molar Refractivity = 36.61 ± 0.3 cm3 Molar Volume       = 95.0 ± 3.0 cm3 Parachor                = 264.8 ± 4.0 cm3 Index of Refraction= 1.696 ± 0.02 Surface Tension    = 60.1 ± 3.0 dyne/cm Density                  = 1.242 ± 0.06 g/cm3 Polarizability         = 14.51 ± 0.5 10-24cm3 Monoisotopic Mass = 118.053098 Da Nominal Mass       = 118 Da Average Mass       = 118.1359 Da

 

Synthesis of benzimidazole

Benzimidazoles have most commonly been prepared from the reaction of 1, 2-diaminobenzenes with carbonyl-containing compounds (Carboxylic acids, Aldehyde, etc.) under harsh dehydrating reaction conditions, utilizing strong acids such as polyphosphoric acid, hydrochloric acid, boric acid, or p-toluenesulfonic acid. The use of milder reagents, particularly Lewis acids, inorganic clays, or mineral acids, has improved both the yield and purity of this reaction.

 

From Amidines and Related Compounds

The formation of benzimidazoles from N-aryl amidines is obtained by reacting it with benzenesulfonyl chloride in triethylamine under anhydrous condition.

 

From Five-Membered Ring Heterocycles

Benzimidazole is formed in good yield by photolysis of indazoles.

 

From Six-Membered Ring Heterocycles

Benzimidazole and its 1-methyl derivative are obtained in 100 and 50% yields, respectively. By allowing O-phenylene diamine or N-methyl-O-phenylene diamine to react with S-triazine at temperature just over the melting point of diamine.

 

Reactions of benzimidazole

Nucleophilic substitution in the imidazole ring :

The chichibabin reaction is used for the synthesis of a number of 2-aminobenzimidazole derivatives. For unsubstituted 2-halobenzimidazole a competition exist between proton abstraction by the nucleophile at the 1 position with concomitant retardation of 2-substitution. Accordingly chloride ion is not displaced from 2-Chlorobenzimidazole by powerful nucleophiles. Whereas, 2-Chloro-1-mehtyl benzimidazole reacts readily with sodium methoxide or ethoxide.

 

Reaction involving Aryens and Free radicals

Benzimidazole reacts as a nucleophile with benzyne to give 2-phenyl benzimidazole.

 

Benzimidazole reacts with free radicals by thermal or photochemical methods.

 

Reduction

The standard method for reduction of benzimidazole involves hydrogenation in the presence of a platinum catalyst in acetic acid, palladium used.

 

Oxidation

Oxidation is carried out in hydrogen peroxide, lead oxide, lead tetra acetate and chromic acid.

 

The various pharmacological actvities of benzimidazole derivative are listed below in table-1.

TABLE-1

BENZIMIDAZOLE DERIVATIVE	PHARMACOLOGICAL USES	REFERENCES
Adimolol	Antihypertensive agent	Palluk R.et.al1
3-[3-[[2-hydroxy-3-(1-naphthyloxy)propyl]amino]-3-methyl-butyl]-1H-benzimidazol-2-one
Afobazole
5-ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole	Anxiolytic drug	Neznamov.et.al2
Ageliferin
N-[[(5S,6R,7R)-2-amino-7-(2-amino-1H-imidazol-5-yl)-5-[[[(4-bromo-1H-pyrrol-2-yl)carbonyl]amino]methyl]-4,5,6,7-tetrahydro-1H-benzimidazol-6-yl]methyl]-4-bromo-1H-pyrrole-2-carboxamide	Antibacterial	Kenneth L. et al3
Albendazole	It is a broad spectrum anthelmintic	Horton .et.al4
Methyl [6-(propylthio)-1H-benzoimidazol-2-yl]carbamate
Astemizole	Antihistamine drug.	Matsumoto S.et.al5
1-[(4-fluorophenyl)methyl]- N-[1-[2-(4-methoxyphenyl)ethyl]- 4-piperidyl]benzoimidazol-2-amine
Bendamustine	Used  in the treatment of chronic lymphocytic leukemias	Kath R.et.al6
4-[5-[Bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid
Benomyl
Methyl [1-[(butylamino)carbonyl]-1H-benzimidazol-2-yl]carbamate	Fungicide	Ashton.et.al7
Benperidol
1-{1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one	It is an antipsychotic, which can be used for the treatment of schizophrenia	Bobon J.et.al8
Bezitramide
4-[4-(2-oxo-3-propanoyl-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-2,2-diphenylbutanenitrile	Narcotic analgesic	Janssen.et.al9
Bilastine
2-[4-(2-{4-[1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl}ethyl)phenyl]-2-methylpropanoic acid	Used for the treatment of allergic rhino conjunctivitis and urticaria (hives)	Corcóstegui.et.al10
Candesartan
2-ethoxy-1-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1H-1,3-benzodiazole-6-carboxylic acid	Used mainly for the treatment of hypertension	Pfeffer M.et.al11
Carbendazim
Methyl 1H-benzimidazol-2-ylcarbamate	Broad-spectrum benzimidazole fungicide	Merck .et.al12
Chlormidazole
1-[(4-chlorophenyl)methyl]-2-methyl-1H-1,3-benzodiazole	Antifungal drug	Merck .et.al12
Clopimozide
3-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidyl]-6-chloro-1H-benzimidazol-2-one	Typical antipsychotic drug	De Cuyper HJ.et.al13
Crenolanib
1-(2-{5-[(3-Methyloxetan-3-yl)methoxy]-1H-benzimidazol-1-yl}quinolin-8-yl)piperidin-4-amine	Investigational new drug for the treatment of certain types of cancer	Lemmon.et.al14
Dabigatran
Ethyl 3-{[(2-{[(4-{N'-hexyloxycarbonyl carbamimidoyl}phenyl)amino]methyl}-1- methyl-1H-benzimidazol-5-yl)carbonyl] (pyridin-2-yl-amino)propanoate	Oral anticoagulant	Eerenberg.et.al15
Dexlansoprazole
(R)-(+)2-([3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl)-1H-benzo[d]imidazole	Use  in the treatment and maintenance of patients with erosive oesophagitis and non-erosive gastro-oesophageal reflux disease (GERD or GORD)	Metz.et.al16
Domperidone
5-chloro-1-(1-[3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl]piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one	Antidopaminergic drug	Swann IL.et.al17
Droperidol
1-{1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,5,6-tetrahydropyridin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one	Antidopaminergic drug used as an antiemetic and antipsychotic.	Peroutka SJ.et.al18
Esomeprazole
(S)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl]-3H-benzoimidazole	Used in the treatment of dyspepsia, peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD/GERD) and Zollinger-Ellison syndrome.	Somogyi.et.al19
Flibanserin
1-(2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)-1,3-dihydro-2H-benzimidazol-2-one	Used for the treatment for pre-menopausal women with Hypoactive Sexual Desire Disorder (HSDD)	Borsini F.et.al20
J-113,397
1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-2H-benzimidazol-2-one	Opioid analgesic	Kawamoto.et.al21
Lansoprazole
(RS)-2-([3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl)-1H-benzo[d]imidazole	Proton-pump inhibitor (PPI) which inhibits the stomach's production of gastric acids	Sterry W.et.al22
Lerisetron
1-benzyl-2-piperazin-1-yl-1H-benzimidazole	Currently in clinical trials for the treatment of nausea associated with cancer chemotherapy.	Huckle R.et.al23
Mebendazole
methyl (5-benzoyl-1H-benzimidazol-2-yl)carbamate	It is used to treat infestations by worms including pinworms, roundworms, tapeworms, hookworms, and whipworms.	Luder PJ.et.al24
Mibefradil
(1S,2S)-2-(2-((3-(1H-benzo[d]imidazol-2-yl)propyl) (methyl)amino)ethyl)-6-fluoro-1-isopropyl- 1,2,3,4-tetrahydronaphthalen-2-yl 2-methoxyacetate	Drug for the treatment of hypertension and chronic angina pectoris	Bezprozvanny.et.al25
NS-2664
5-furan-3-yl-1-(3-imidazol-1-yl-phenyl)-1H-benzoimidazole	Anxiolytic drug	Mirza NR.et.al26
NS-2710
1-[1-[3-(3-pyridyl)phenyl]benzimidazol-5-yl]ethanone O-ethyloxime	Anxiolytic drug	Evenden J.et.al27
Omeprazole
(RS)-5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl)-1H-benzo[d]imidazole	Used in the treatment of dyspepsia, peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD/GERD), laryngopharyngeal reflux (LPR) and Zollinger–Ellison syndrome	Yang.et.al28
Oxatomide
1-{3-[4-(diphenylmethyl)piperazin-1-yl]propyl}-1,3-dihydro-2H-benzimidazol-2-one	first-generation antihistamine	Ohmori K.et.al29
Pantoprazole
(RS)-6-(Difluoromethoxy)-2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzo[d]imidazole	Proton pump inhibitor drug that inhibits gastric acid secretion.	Pali.et.al30
Pimobendan
(RS)-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazin-3(2H)-one	Used in the management of heart failure in dogs, most commonly caused by myxomatous mitral valve disease (also known as endocardiosis), or dilated cardiomyopathy.	Gordon.et.al31
Rabeprazole
(RS)-2-([4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl)-1H-benzo[d]imidazole	Antiulcer drug	Morii M.et.al32
Ramosetron
(1-methyl-1H-indol-3-yl)[(5R)-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl]methanone	Used for the treatment of nausea and vomiting.	Fujii Y.et.al33
Rivoglitazone
(RS)-5-{4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy]benzyl}-1,3-thiazolidine-2,4-dione	Undergoing research for use in the treatment of type 2 diabetes	Schimke K.et.al34
RWJ-51204
5-ethoxymethyl-7-fluoro-3-oxo-1,2,3,5-tetrahydrobenzo[4,5] imidazo[1,2a]pyridine-4-N-(2-fluorophenyl)carboxamide	Anxiolytic drug used in scientific research	Atack JR.et.al35
Telmisartan
2-(4-{[4-methyl-6-(1-methyl-1H-1,3-benzodiazol-2-yl)-2-propyl-1H-1,3-benzodiazol-1-yl]methyl}phenyl)benzoic acid	Used in the management of hypertension	Benson.et.al36
Tiabendazole
4-(1H-1,3-benzodiazol-2-yl)-1,3-thiazole	Fungicide and parasiticide.	Upadhyay MP.et.al37
VUF-6002
5-Chloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1H-benzimidazole	It has antiinflammatory and analgesic effects in animal studies of acute inflammation	Zhang.et.al38

 

CONCLUSION:

The benzimidazoles are a large chemical family used to treat nematode and trematode infections in domestic animals. However, with the widespread development of resistance and the availability of more efficient and easier to administer compounds, their use is rapidly decreasing. They are characterized by a broad spectrum of activity against roundworms (nematodes), an ovicidal effect, and a wide safety margin. Those of interest are mebendazole, flubendazole, fenbendazole, oxfendazole, oxibendazole, albendazole, albendazole sulfoxide, thiabendazole, thiophanate, febantel, netobimin, and triclabendazole. Netobimin, albendazole, and triclabendazole are also active against liver flukes; however, unlike all the other benzimidazoles, triclabendazole has no activity against roundworms.

 

The most effective of the group are those with the longest half-life, such as oxfendazole, fenbendazole, albendazole, and their prodrugs, because they are not rapidly metabolized to inactive products. Effective concentrations are maintained for an extended period in the plasma and gut, which increases efficacy against immature and arrested larvae and adult nematodes, including lungworms.

 

They are more effective in ruminants and horses, in which their rate of passage is slowed by the rumen or cecum. Because the nature of their antiparasitic action depends on prolongation of contact time, repeated (2-3 times) PO administration of a full dose at 12-hr intervals increases their efficacy, even against benzimidazole-resistant worms. In addition, a reduced feed intake, which reduces the flow rate of digesta, increases the availability of benzimidazoles.

 

In the case of oxfendazole, and probably other benzimidazoles, the major route of exposure is biliary metabolites, followed by enterohepatic recycling of the drug after absorption from the small and large intestine. Worms in the mucosa of the small intestine may be exposed to more recycled anthelmintic than to drug contained in the passing ingesta in the GI tract.

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Received on 28.04.2013       Modified on 20.05.2013

Accepted on 25.05.2013      © AJRC All right reserved