MEDICINAL SIGNIFICANCE OF BENZIMIDAZOLE ANALOGUES: A REVIEW

MEDICINAL SIGNIFICANCE OF BENZIMIDAZOLE ANALOGUES: A REVIEW

Sharanabasappa B. Patil

Department of Chemistry, Ramaiah Institute of Technology, Bangalore - 560054, Karnataka, India.

ABSTRACT: Benzimidazoles are well known biologically active N-containing heterocycles, widely used as drugs such as antifungal, antibacterial, antiparasitic, and antihelmintic. In addition, N₁ and C₂-substituted benzimidazoles and their derivatives have been found to be potent biologically active compounds as well. Further, N₁-substituted benzimidazoles have exhibited anti-microbial, antihelmintic activities and also antiviral activity against human cytomegalovirus and herpes simplex virus type-1. Specifically, N₁-substituted benzimidazole like 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole is known for inhibition of transcription elongation by RNA polymerase II. Another N₁-substituted benzimidazole derivative called enviroxime [2-amino-1- (isopropyl-sulphonyl)-6-benzimidazole phenyl ketone oxime] was reported to be a potent inhibitor of rhinovirus replication in human embryonic nasal organ cultures. The biological activities of these compounds depend upon the substitution on the benzimidazole at the N-1 or C-2 position. Since the benzimidazole heterocyclic ring system mimics the purine bases like adenine and guanine of nucleic acids, the N₁-substituted benzimidazole may incorporate into viral nucleic acid by enzymatic process and subsequently can alter the structure and/ or function of viral growth.

Benzimidazole derivatives and Medicinal Significance

INTRODUCTION ON BENZIMIDAZOLES: Benzimidazole Fig. 1 is a heterocyclic aromatic organic compound. This bicyclic compound consists of the fusion of benzene with imidazole. Historically the first benzimidazole was prepared by hoebecker in 1872, who obtained 2,5 or (2,6) dimethyl benzimidazole. The benzimidazoles are also known as benzoglyoxalines. This tautomer is analog to that found in imidazole and amidines. The benzimidazole is, in fact, may be considered as a cyclic analog of amidine Fig. 2.

FIG. 1: BENZIMIDAZOLE

FIG. 2: CYCLIC ANALOG OF AMIDINE

Benzimidazoles are weakly, somewhat less basic than imidazoles. Benzimidazoles are also sufficiently acidic to be generally soluble in aqueous alkali and form N-metallic compounds. The acidic properties like those of imidazole seem to be stabilization due to resonance. The dipole moment of benzimidazole determined to be 3.93 D. Benzimidazole rings possess a high degree of stability. Benzimidazole, for example, not effected by concentrated sulphuric acid when heated under pressure at 270 °C_, nor by vigorous treatment with concentrated hydrochloric acid. Oxidation cleaves the benzene ring of benzimidazole only under vigorous conditions. Further, benzimidazole undergoes a variety of reactions such as alkylation, acylation, halogenation, nitration, etc. The compounds of benzimidazole analogs are mainly classified into the following two types, namely, N₁-substituted benzimidazole analogs and C₂-substituted benzimidazole analogs.

This part deals mainly with the study of biological and medicinal applications of N₁-substituted benzimidazole analogs and C₂-substituted benzimidazole analogs.

1.1. Medicinal Applications of Benzimidazole Analogues: Most of the benzimidazole analogs are also known for their clinical use. Some of them are as follows.

1.1.1. Benzimidazole Analogues as Antibacterial and Antifungal Agents: Most of the benzimidazole derivatives also exhibit antibacterial activity. For example, derivatives of pyrimido[1,6-a] benzimidazole represent a new class of DNA-gyrase inhibitors, which are effective antibacterial agents ¹. Antimicrobial and antifungal properties were reported for 3-alkylthiomethyl-l-ethyl-, 3-alkoxy-methyl-l-butyl-, and 3-alkylthiomethyl-l-butylben-zimidazolium chlorides, as well as for 2-chloromethyl-5H-methylbenzimidazoles ^{2, 3}.

Some 5-nitrobenzimidazole derivatives also exhibit fungicidal activity ⁴. The certain antimicrobial and antifungal potential were observed in heterocyclic benzimidazole derivatives ⁵.

FIG. 3: BENOMYL

FIG. 4: CARBENDAZIM

Benzimidazole derivatives such as benomyl Fig. 3, carbendazim Fig. 4, fuberidazole Fig. 5 and thia-bendazole are developed as fungicides which have high activity against many opportunistic fungi.

FIG. 5: FUBERIDAZOLE

1. Kazimierczuk et al., ⁶ reported antimicrobial and antiprotozoal activities of 5,6-dinitro and 2-dialkylamino substituted benzimidazoles.
2. C. Kuhler et al., ⁷ reported novel structure derived from 2-{[(2-pyridyl) methyl]thio}-1H-benzimidazole and also many fluorine-containing benzimidazole analogs are known for their antibacterial activity ⁸.
3. A. Kilcigil et al., ⁹ have reported the synthesis and antifungal properties of some benzimidazole derivatives.

Recently Mashelkar et al., ¹⁰ reported syntheses, antibacterial, anti-asthmatic and anti-diabetic activities of novel N₁-substituted benzimidazoles.

1.1.2. Benzimidazole Analogues as Analgesic, Anti-inflammatory, and Antipyretic Agents: In recent years, much effort was devoted to studying the analgesic drug etonitazene, a benzimidazole analog selectively interacting with opiate receptors of the µ-subtype ^11-15. Etonitazene Fig. 6 is a highly potent analgesic drug, has approximately 1000-1500 times more potency than morphine. However, it has a strong dependency potential similar to that of morphine, and a strong tendency to produce respiratory depression and is therefore not used in humans. It is, however, useful in addiction studies on animals.

FIG. 6: ETONITAZENE

Further analgesic and anti-inflammatory activity were observed in some derivatives of 3-(benzimidazol-2-yl) propanoic acid ¹⁶ Fig. 7 and 2-aminobenzimidazole ¹⁷ Fig. 8. Some of the benzimidazole derivatives also possess selective anti-inflammatory and antipyretic activity^.18.

FIG. 7: BENZIMIDZOL-3-PROPIONIC ACID

FIG. 8: 2-AMINOBENZIMIDAZOLE

1.1.3. Benzimidazole Analogues as CNS Depressants: Some benzimidazole derivatives produce various, in type and strength, effects upon the central nervous system, including psycho-stimulant, neuroleptic, antidepressant, tranquilizer (anxiolytic), anticonvulsant, and hypnotic action. It was shown that dibazole and 5,6-dimethyl-benzimidazole (dimedazole, dimezole) Fig. 9 are capable of eliminating some neurological disorders accompanying experimental brain traumas and can be used for the prophylaxis of pain shock ¹⁹. A single administration of bemithyl, ethomerzole (5-ethoxy-2-ethylthiobenzimidazole hydrochloride), and 2-phenylthio-6-ethylbenzimidazole hydro-bromide Fig. 10 also produced an anxiolytic action not accompanied by sedative effects ²⁰.

FIG. 9: 2-PHENYLTHIO- 5,6-DIMETHYLBENZIMIDAZOLE

FIG. 10: 2-PHENYLTHIO-6- ETHYLBENZIMIDAZOL

FIG. 11: PIMOZIDE

Pimozide Fig. 11 is capable of inhibiting the release of dopamine-induced in-vitro by electric depolarization of membranes in the brain tissue ²¹ and enhances dopamine synthesis and circulation in the brain ^{22, 23}. The effect of pimozide on other catecholamines is less pronounced. In the human organism, pimozide reduces amphetamine-induced euphoria and arrests anxiety manifestations in schizophrenes and patients with psychic disorders of a neurotic type ^{24, 25}.

1.1.4. Benzimidazole Analogues as Antihypoxic and Antioxidant Agents: Some benzimidazole derivatives are capable of exhibiting antihypoxic and antioxidant activities. For example, ethomerzole exhibited a protective effect in tests on animals having different degrees of resistance with respect to hypoxic states and accelerated the restoration of behavioral, dynamometric, and locomotor characteristics in animals upon hypoxic trauma ²⁶.

1.1.5. Benzimidazole Analogues as Antiaggregant Agents: Diabenol is capable of inhibiting platelet aggregation induced by ADP, adrenalin, collagen, PAF, and arachidonic acid, which is explained by suppression of the synthesis of thromboxane A₂. It was reported that diabenol not only influences the aggregation process but produces a certain disaggregating effect as well ²⁷.

FIG. 12: ETHOMERZOLE

The antiaggregant properties were also observed for dibazole ²⁸ and ethomerzole ²⁹ (5-ethoxy-2-ethylthiobenzimidazole) Fig. 12.

1.1.6. Benzimidazole Analogues as Hypo-glycemic Agents: The condensed benzimidazole derivative 9-(2-diethylaminoethyl)-2,3-dihydroimi-dazo[1,2-a]benzimidazole dihydrochloride (diabenol) Fig. 13 was reported to possess hypoglycemic and antiaggregant properties ²⁷.

FIG. 13: DIABENOL

1.1.7. Benzimidazoles Analogues as Antiallergic Agents: The group of effective long-action blockers of the histamine receptors includes astemizole ³⁰ Fig. 14 and mizolastine ³¹ Fig. 15_.

FIG. 14: ASTEMIZOLE

FIG. 15: MIZOLASTINE

1. Satoh et al., ³² mentioned the synthesis of benzimidazole derivatives as antiallergic agents with 5-lipoxygenase inhibiting action.
2. A. Kilcgil et al., ³³ studied synthesis and antioxidant properties of some novel benzimidazole derivatives on lipid peroxidation in the rat liver.
3. Sakai et al., ³⁴ reported pharmacokinetics properties of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-1H-benzimidazole.
4. F. Caselli et al., ³⁵ studied antihistaminic/ antiallergic activity of 2- dialkylaminoalkyl-thio(oxy)-1-substituted benzimidazoles.
5. L. Richards et al., ³⁶ reported substituted 2-phenyl benzimidazole derivatives novel compounds that suppress key markers of allergy.

1.1.8. Benzimidazole Analogues as Cardio-vascular Agents: In the 1940s, a group of researchers including Porai-Koshits, Ginzburg, and Efros synthesized 2-benzylbenzimidazole ³⁷ (dibazole) Fig. 16, which was capable of decreasing the tone of smooth muscles of the blood vessels and internal organs. This compound is widely used as a spasmolytic and hypotensive remedy ³⁸. Further pronounced antihypertensive activity is characteristic of most of benzimidazole derivatives which are capable of blocking calcium channels ^39-43.

FIG. 16: DIBAZOLE

Another benzimidazole analog, pimobendan ⁴⁴ Fig. 17 is a phosphodiesterase inhibitor with calcium sensitizing properties.

FIG. 17: PIMOBENDEN      

1.1.9. Benzimidazole Analogues As Antitumor Agents: Bendamustine Fig. 18, benzimidazole analog, which is available in the market and used for the treatment of leukemia. It belongs to the family of drugs called alkylating agents. It is also being studied for the treatment of sarcoma. Another promising group of antitumor compounds is represented by benzimidazo[t, 2-c]quinazolines and thiazolo[3,4-a]benzimidazoles ^{45, 46}.

FIG. 18: BENDAMUSTINE

E. B. Skibo et al., ⁴⁷ have reported structure-activity studies of antitumor agents based on pyrrolo[1,2-a]benzimidazoles.

A. Da Settimo et al., ⁴⁸ have reported synthesis and antitumor activity of pyridopyrimidobenzimidazole.

CONCLUSION: Nil

ACKNOWLEDGEMENT: Nil

CONFLICTS OF INTEREST: Nil

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    How to cite this article:

    Patil SB: Medicinal significance of benzimidazole analogues: a review. Int J Pharm Sci & Res 2020; 11(6): 2649-54. doi: 10.13040/ IJPSR.0975-8232.11(6).2649-54.

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