A SHORT REVIEW ON POTENTIAL ACTIVITIES OF BENZIMIDAZOLE DERIVATIVES

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ABOUT AUTHOR:
Balram Soni*
Psychiatric Centre, S.M.S. Medical College,
Jaipur, Rajasthan, India
brpharma@rediffmail.com

ABSTRACT
Benzimidazole derivatives have shown hopeful activity in the treatment of several diseases, for this reason, the synthesis of novel benzimidazole remains a main focus for researchers. This review article summarizes the chemistry of different derivatives of benzimidazole along with their biological activities. The review article also covers the most active benzimidazole derivatives that have shown considerable pharmacological actions.

REFERENCE ID: PHARMATUTOR-ART-2227

INTRODUCTION
Benzimidazoleis a heterocyclic aromatic organic compound. It is an important pharmacophore and a privileged structure in medicinal chemistry. 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]

The use of benzimidazole dates many years back for study of structural modifications and their pharmacological actions. Various benzimidazole derivatives were synthesized with the substitution of fluorine, propylene, tetrahydroquinoline which resulted in compounds with increased stability, bioavailability and significant biological activity.^[2-3] In light of the affinity they display towards a variety of enzymes and protein receptors, medicinal chemists would certainly classify them as privileged ‘sub-structures’ for drug designing. The incorporation of the nucleus is an important synthetic strategy in studies of drug discovery. In the past few decades, benzimidazole and its derivatives have received much attention due to their chemotherapeutic values.^[4]

Benzimidazole derivatives play very efficient role in the medical field with plenty of useful therapeutic activities like anti-inflammatory^[5], antimicrobial^[6], Diuretic^[7], antiviral^[8], anticancer^[9], Antiprotozoal^[10], Antiulcer^[11], anti-oxidant^[12], Anti-Asthmatic^[13], Anti-Diabetic^[14], Cysticidal^[15], Analgesic^[16], antihypertensive^[17], anthelmintics^[18], anti-HIV^[19], anti-convulsant^[20], and spasmolytic^[21] activity. Benzimidazole and its derivatives have been showing hopeful activity in the treatment of several diseases, for these reasons, they achieved much attention as important pharmacophore and privileged structure in medicinal chemistry.

In order to obtain more effective chemotherapeutic agents, a variety of reports have been presented on the synthesis and biological evaluation of novel benzimidazole derivatives. The literature survey revealed the importance of the substitutions at 1, 2 and 5 positions of the benzimidazole ring for their pharmacological activities.

This review summarizes to know about the different derivatives of benzimidazole with their pharmacological activities. The synthesis of novel benzimidazole derivatives remains a main focus of medicinal research.

Compounds Having Benzimidazole Nucleus
* As Oral Anticoagulants
Dabigatran is an oral anticoagulant drug that acts as a direct thrombin (factor IIa) inhibitor. It can be used for the prevention of stroke in patients with atrial fibrillation. The drug was developed as an alternative to warfarin, since it does not require maintenance of international normalized ratio or monitoring by frequent blood tests, while offering similar efficacy in preventing ischemic events. Dabigatran can also be used to prevent the formation of blood clots in the veins (deep venous thrombosis) in adults who have had an operation to replace a hip or knee.^[22]

Dabigatran

* As Oral Antidiabetic
Oral hypoglycemic drugs are used only in the treatment of type 2 diabetes which is a disorder involving resistance to secreted insulin. The oral antidiabetic containing benzimidazole includes Rivoglitazone.^[23]

Rivoglitazone

* As Oral Antiviral
Antiviral drugs are a class of medication used specifically for treating viral infections such as influenza, herpes virus, viral hepatitis, human cytomegalovirus(HCMV) and human immunodeficiency virus (HIV) etc. The  oral antiviral drug containing benzimidazole includes Maribavir which isused for the prevention and treatment of human cytomegalovirus (HCMV) disease in hematopoietic stem cell/bone marrow transplant patients. The oral antiviralcontaining benzimidazole includes Maribavir.^[24]

Maribavir

* Drugs in HSDD
HSDD (hypoactive sexual desire disorder) is the most commonly reported female sexual complaint and characterized by a decrease in sexual desire that causes marked personal distress and/or personal difficulties. The benzimidazole drug used in HSDD is Flibanserin which is a 5-HT₁A receptor agonist and 5-HT₂A receptor antagonist used as a non-hormonal treatment for pre-menopausal women with HSDD that had initially been investigated as an antidepressant. The drug containing benzimidazole used in HSDD includes Flibanserin.^[25-26]

Flibanserin

* As Anti-hypertensive
Antihypertensive are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. The anti-hypertensive containing benzimidazole is Candesartan and Telmisartan.

Candesartan is an angiotensin-II receptor antagonist used mainly for the treatment of hypertension. Candesartan is also available in a combination formulation with a low dose thiazide diuretic, invariably hydrochlorothiazide, to achieve an additive antihypertensive effect. Candesartan/hydrochlorothiazide combination preparations are marketed under various trade names.^[27]

Candesartan

Telmisartanis an angiotensin-II receptor antagonist used in the management of hypertension.

Telmisartan

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* As Anthelmintics
These are the drugs used for the treatment of a variety of parasitic worm infestations. The drugs containing benzimidazole are albendazole, mebendazole, thiabendazole which are broad spectrum anthelmintics, effective against nematode infestations, including round worms, tapeworms, whipworm, hookworm and flukes of domestic animals and humans.^[28-29]

* As Fungicidal
Examples of benzimidazole class fungicides include benomyl, carbendazim, chlorfenazole, cypendazole, debacarb, fuberidazole, furophanate, mecarbinzid, rabenzazole, thiabendazole, thiophanate.

Carbendazim is a systemic fungicide with protective and curative action. It is absorbed through the roots and green tissues. It acts by inhibiting beta-tubulin synthesis, inhibiting development of germ tubes and the growth of mycelia. It is compatible with most of the insecticides. It is used for the control of blast, sheath blight, brown spot, powdery mildew, scab, anthracnose & leaf spot diseases in various crops.^[30]

Carbendazim

* Drugs in GIT
Domperidoneis the example of drug containing benzimidazole, is a peripheral, specific dopamine receptor blocker. Domperidone is given in order to relieve nausea and vomiting; to increase the transit of food through the stomach(as a prokinetic agent through increase in gastrointestinal peristalsis); and useful in gastroparesis to increase lactation (breast milk production) by release of prolactin. It is also used in the scientific study of the way dopamine (an important neurotransmitter) acts in the body. ^[31]

Domperidone

* Drugs in Allergic conjunctivitis

The drugs containing benzimidazole areEmedastine, Mizolastine, Clemizole, and Astemizole.^[32]

Emedastineis a second generation antihistamine used in eye drops to treat allergic conjunctivitis. It acts as a H₁ receptor antagonist. It works by blocking certain natural substances, histamines that cause allergic symptoms.

Emedastine

Mizolastine is a once daily, non-sedating antihistamine. It blocks H₁ receptors and is commonly fast-acting. It does not prevent the actual release of histamine from mast cells, just prevents it binding to receptors.

Mizolastine

Clemizole: Clemizole is an H₁-antihistamine, i.e. a drug that is used to treat allergic reactions.

Clemizole

Astemizole: Astemizole is a long-acting, highly selective H₁-antihistamine with minimal central and anticholinergic effects. Astemizole is used in the treatment of Conjunctivitis, Allergic Rhinitis, and Urticaria.

Astemizole

* As Antipsychotic
In psychosis, thinking of patient becomes illogical, bizarre and loosely organized. Patient has difficulty in understanding reality and their own conditions. These drugs are used in schizophrenia and chronic psychosis. Some drugs containing benzimidazole nucleus are droperidol, pimozide, and benperidol.^[33-35]

Pimozide

Droperidol: is an antidopaminergic drug used as an antiemetic and antipsychotic. Droperidol is also often used for neuroleptanalgesic anesthesia and sedation in intensive-care treatment.

Droperidol

Benperidol: It is an antipsychotic, which can be used for the treatment of schizophrenia,but it is primarily used to control antisocial hypersexual behaviour, and is sometimes prescribed to sex offendersas a condition of their parole, as an alternative to anti-androgen drugs such as cyproterone.

Benperidol

* As Analgesic
Bezitramide: Itis a narcotic analgesic. Bezitramide itself is a prodrug which is readily hydrolyzed in the gastrointestinal tract to its main metabolite, despropionyl-bezitramide.

Bezitramide

* As Antimicrobial
Ciprofloxacin: Ciprofloxacin is an antibiotic that belongs to the family of medications known as quinolones. It is used to treat infections caused by certain bacteria. It is most commonly used to treat infections of the skin, sinuses, bone, lung, ear, abdomen, kidney, prostate, and bladder.

Ciprofloxacin

* As Anti-diarrheal
Rifaximin: Itis a semisynthetic antibiotic based on rifamycin. It is used in the treatment of traveler's diarrhea and hepatic encephalopathy.^[36]

Rifaximin

* As Anti-neoplastic
Nocodazole: It is an anti-neoplastic agent which exerts its effect in cells by interfering with the polymerization of microtubules.

Nocodazole

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* As Antiulcer drug
These are the drugs used as a short-term treatment in healing and symptomatic relief of duodenal ulcers and erosive or ulcerative gastroesophageal reflux disease (GERD); Gastric ulcer (GU), Peptic ulcer disease (PUD), (Zollinger-Ellison syndrome), Helicobacter pylori eradication to reduce risk of duodenal ulcer recurrence. Some drugs containing benzimidazole nucleus are Rabeprazole, Omeprazole, Lansoprazole, Pantoprazole, etc. These drugs belong to class of proton pump inhibitor.^[37-39]

Rabeprazole

Omeprazole: Itis a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease, laryngopharyngeal reflux, and Zollinger–Ellison syndrome.

Omeprazole

* As Calcium Sensitizer
Pimobendan: It is a calcium sensitizer with positive inotropic and vasodilator effects. It is also a selective inhibitor of phosphodiesterase III (PDE3). Pimobendan is used in the management of heart failure in dogs, most commonly caused by myxomatous mitral valve disease (also known as endocardiosis), or dilated cardiomyopathy.^[40]

Pimobendan

CONCLUSION
Benzimidazoles find several applications in different areas of chemistry. The position and type of substituents on the benzimidazole ring are responsible for a variety of biological activity. It will be interesting to observe that these modifications can be utilized as potent therapeutic agents in future. This comprehensive overview summarizes the chemistry of different derivatives of substituted benzimidazole along with their biological activity.

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