Review Benzimidazole
Review Benzimidazole
Review Benzimidazole
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Abstract: Benzimidazole is an important moiety from a medicinal chemistry perspective due to its
various biological activities such as antimicrobial, anti-cancer, anti-diabetic, anti-Alzheimers, and anti-
inflammatory, etc. 2-acetylbenzimidazole is exploited to obtain various heterocyclic compounds of
pharmacological interest. This review's main motive is to present the literature on 2-
acetylbenzimidazole chemistry and provide valuable and up-to-date information for its applications.
The present review is carried out by compiling literature from 1964 to 2020 concerning the synthesis
and biological aspects of various heterocyclic compounds derived from 2-acetylbenzimidazole.
Literature was collected from various online search engines viz. Google Scholar, PubMed, Science
Direct, Core, and Semantic scholar. 2-acetylbenzimidazole has been successfully employed as a
synthon to obtain heterocyclic system viz. oxirane, pyrazoline, thiazole, pyrazole, isoxazoline,
isoxazole, pyridine, pyrimidine, thiazine, diazepine, and other miscellaneous rings. 2-
acetylbenzimidazole has shown promise for the convenient synthesis of various heterocyclic
compounds. The reactions can be carried out on various reactive sites of 2-acetylbenzimidazole, which
are the carbonyl group and the amino group. This review will help to explore various heterocyclic
compounds and particularly in the synthesis of biologically useful compounds.
1. Introduction
2. Synthesis of 2-acetylbenzimidazole
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the pH of the solution exceeds 7.0, then the yield of 2-acetylbenzimidazole decreases
considerably [11].
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,
Scheme 7. Synthesis of benzimidazole derivatives 10,11,12-a & b.
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Two series of pyrazoline were prepared, starting from 2-acetyl benzimidazole. The
cyclo condensation of chalcones 45a-e with hydrazine hydrate and phenylhydrazine yielded
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different pyrazoline derivatives 46a-e and 47a-e (Scheme 18). The compounds were screened
against Mycobacterium tuberculosis. Compounds 45a and 45d were found to have MIC values
of 1.25 and 1.53μg/mL, respectively. Compounds 47c and 47e showed MIC values of 2.69 and
2.75, respectively [26].
A similar pyrazoline series was synthesized by Shaharyar and co-workers and screened
at a single dose (10-5 M) against NCI 60 cell panel. Derivativecontaining 3,4-dimethoxyphenyl
group at 5thposition of pyrazoline 47e was found to be the most active candidate [27].
Benzimidazole linked pyrazoline 55a-j were achieved through the cyclo condensation
of chalcone derivatives 53a-j with acid hydrazide 54 in acetic acid at 130oC (Scheme 21).
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Two series of pyrazoline derivatives linked to benzimidazole moiety 64a-e and 65a-e
were prepared in our laboratories by multistep reactions using 2-aceylimidazole as a starting
material (Scheme 24). The compounds were tested for their antimicrobial activity. Among the
compounds screened, 64d showed good activity (MIC = 64 μgmL-1) against S. aureus and E.
coli. Compounds were found to be inactive against C. albicans [33].
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A series of benzimidazole chalcones bearing indole ring system 72a-c were prepared
by Saundane et al. [35]. The chalcones 72a-c on treatment with hydrazine or phenylhydrazine
gave 73a-d (Scheme 27). Compounds were evaluated for their antimicrobial and antioxidant
activities. Few of the compounds showed good activity.
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Two series of Thiazole-2-amines 84a-d and 87a-i has been prepared by the cyclization
of 2-acetylbenzimidiazoles 83a-d & 85a-i and 2-bromo-1-(1-alkyl-1H-benzo[d]imidazol-2-
yl)-1-ethanone 86a-i with thiourea (Scheme 31) and evaluated for their antibacterial and
antifungal activity. Some of these compounds demonstrated antibacterial activity [39].
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A series of benzimidazoles linked with various heterocyclic systems 93, 94, 95, 97 and
98 have been synthesized from N-methyl-2-bromoacetylbenzimidazole 89 (Scheme 32). Some
benzimidazole derivatives were found as corrosion inhibitors [40].
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The pyrazoles 108a-e derivatives were prepared from chalcones 107a-e (Scheme 36).
The compounds were tested for anti-inflammatory activity and showed significant % inhibition
of edema, i.e., 63.63, and 62 % at a dose of 200 mg/mL [43].
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compounds were tested for their antibacterial activity against Gram +ve bacteria viz., B.
subtilis, S. aureus, and two Gram-ve bacteria viz. E. coli and K. pneumonia and found to be
active [44].
The chalcone 113 was cyclized with hydroxylamine hydrochloride using a catalytic
amount of sodium acetate in a mixture of acetic acid and ethanol under reflux conditions. The
isoxazoline 114 so obtained were condensed with ω-bromoalkoxy-phthalimide 115 in a
mixture of pyridine and ethanol to obtain 2-(5-aryl-4,5-dihydroisoxazol-3-yl)-1-N-
alkoxyphthalimido benzimidazoles 116a-h (Scheme 39) [36].
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compounds were evaluated for their anti-cancer activity against MCF-7 and NCI-H460 cell
line [45].
Compounds 125a-f were treated with malononitrile and ammonium acetate to achieve
derivatives 126a-f, via Knoevenagel condensation reaction. Compounds 126a-f on simple
condensation reaction with 3-nitrobenzaldehyde provided Schiff bases 127a-f that in
anhydrous 1,4-dioxane was refluxed with 2-mercaptoacetic acid 128 for 12 hrs to obtain 129a-
f (Scheme 43). These compounds were tested for antibacterial, antifungal, and cytotoxic
activity [48].
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Zoorob et al. [53] have prepared various pyrimidine derivatives 142a-e & 143a-e from
the chalcones 141a-e (Scheme 48). Chalcones were reacted with thiourea in boiling alcoholic
potassium hydroxide to give the pyrimidinethiones 142a-e. The analogous pyrimidines 143a-
e were prepared by the reaction of 141a-e with urea.
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A series of benzimidazole chalcone and its 1-methyl analogs 144a-d were cyclized
(Scheme 49) with different reagents such as thiourea guanidinium sulfate in different reactions
to produce pyrimidinethione 145a-d and aminopyrimidine 146a-d, respectively [51].
The chalcones 72a-b on condensation with thiourea and urea in separate reactions yielded
pyrimidine-2-thiol derivatives 147a-b and pyrimidin-2-ol derivatives 148a-b (Scheme 50),
respectively. These compounds were screened for their antioxidant and antimicrobial activities
and were found to possess good antioxidant and antimicrobial activity [35].
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Scheme 52. Synthesis of benzimidazole linked pyrimidine 153a-p, 154a-p & 155a-p.
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A new series of pyrimidines 162a-j have been synthesized by the reaction of chalcone
derivatives 161a-j with guanidine nitrate in ethanol and an aqueous solution of sodium
hydroxide (Scheme 54) for testing their antimicrobial activity. Results reveal that compounds
exhibited significant antibacterial and antifungal activities [57].
The chalcones 177a-g on treatment with bromine in acetic acid gave dibromo
derivatives 178a-g which reacted with an o-phenylene diamine in sulphuric acid to furnish 2-
(benzimidazol-2-yl-methyl)-3-arylquinoxazolines 179a-g (Scheme 60) [46].
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The chalcones 188a-d were reacted with bromine in carbon tetrachloride to yield
dibromo adduct 189a-d. During recrystallization from methanol or acetic acid, the dibromo
derivatives cyclized to give the pyrrolo[l,2-a]benzimidazoles 190a-d (Scheme 63) [53].
A series of some novel imines 196a-e were prepared (Scheme 65) by an acid-catalyzed
nucleophilic addition reaction between 5-amino-1,3,4-thiadiazole-2-thiol 195 and heteroaryl
chalcones 194a-e (Scheme 65). The compounds were screened for their antiulcer activity in
the pylorus-ligated rats. Antioxidant activities of the derivatives were determined by DPPH
method. Compounds showed a percentage of 70.43-73.47% protection at a dose of 10 mg/kg
body weight [67].
All the derivatives 196a-e were further screened for their hypnotic activity at a dose
level of 10 mg/kg body weight. The compounds showed a significant percentage of an increase
in sleeping time [68].
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4. Conclusions
Funding
The authors prepared the review article without any external funding.
Acknowledgments
Dr. Gopal Krishna Padhy would like to express his thanks to Dr. Chandra Sekhar Patro,
Principal, School of Pharmacy, Centurion University of Technology and Management,
Rayagada, Odisha, for his constant moral support during this work.
Conflicts of Interest
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