Ajptr 93021 - 5950
Ajptr 93021 - 5950
Ajptr 93021 - 5950
Please cite this article as: Shivakumar et al., A Review On Substituted Benzimidazoles: Biologically
Active Compounds. American Journal of PharmTech Research. 2019.
Shivakumar et. al., Am. J. PharmTech Res. 2019; 9(03) ISSN: 2249-3387
INTRODUCTION
Benzimidazole is a heterocyclic aromatic organic compound. It is a very important pharmacophore
and a privileged structure in medicinal chemistry. This compound is bicyclic and consists of the
fusion of benzene and imidazole [1]. Benzimidazole is a benzo derivative of imidazole. Although
benzimidazole is the common name of the parent compound of the series, other names such as
benzimidazole and 1,3-benzodiazole (Figure 1) are often used.
H
N
Figure 1: 1H-Benzimidazole
The properties of benzimidazole and its analogs have been studied for over hundred years.
However a particular interest of researchers in benzimidazole derivatives was that 5, 6-dimethyl-1-
(α-Dribofuranosyl)benzimidazole is a fundamental component of the structure of vitamine B12 [2].
Monoacyl derivative of o-phenylenediamine is converted by heat alone into the corresponding
benzimidazole (Figure 2). These conversions are generally carried out at a temperature slightly
above the melting point of the starting compounds. This is a convenient method for the synthesis
of benzimidazoles when the monoacyl derivatives are readily obtained. The process can be
improved by heating the monoacyl derivative of diamine in a nitrogen atmosphere to prevent
oxidation. The diacyl derivatives of o-phenylenediamines are again converted into benzimidazoles,
however higher temperatures are needed.
H H
NH2 N R
O- N
C
C OH R + H2O
NH + R N N
H
H
N
C R + RCOOH
N
means of identifying fatty acid α-hydroxy acid. Phenylacetic acid and diphenylacetic acid are
converted to the corresponding benzimidazoles when heated with o-phenylenediamine. The
Phillips modification of the above procedure consists in refluxing with the o-phenylenediamine
and mono basic acid in 4N hydrochloric acid. The benzimidazole is then precipitated by
neutralizing the solution with ammoniumhydroxide. Benzoic acid gives only traces of 2-
phenylbenzimidazole (Figure 3). Apparently this method is not applicable to the aromatic
monobasic acid.
O OH
NH2
N
4NHCl
+
NH2 N
H
S
CH3
NH
N O
N
H
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Shivakumar et. al., Am. J. PharmTech Res. 2019;9(03) ISSN: 2249-3387
CH3
N CH3
N
N
N N
CH3
N O
N CH3
C N
CH3
NH CH3
HN N S
C S
R1
HN
N
R1 Thiadiazoles R2
R2
R3 R3
CH3
N
N
N CH3
N R3
CH3
N N
T riazoles R2
N
R1
SH
Antiulcer activity:
Nadeem H et al [8], reported that a series of six new benzimidazole-pyrazole hybrid molecule
(Figure 8, Table 2) were synthesized and characterized. In vivo anti ulcerogenic activity was
evaluated for all compounds synthesized. All six compounds synthesized showed higher anti-ulcer
activity as compared against standard omeprazole. The results clearly show that these new
benzimidazole-pyrazole hybrids may constitute a new category of potential anti ulcer compounds
and may be considered as new anti-ulcer drugs upon further investigation.
N
S O
N
H
N
N
1
R
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HO X
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Shivakumar et. al., Am. J. PharmTech Res. 2019;9(03) ISSN: 2249-3387
It has been found that some of synthesized benzimidazole derivatives have a potent virus-
inhibiting activity against pandemic influenza virus with fairly modest cytotoxicity.
O O
H
Cl N
NH
N N
Cl
NH
N O
Cl
OH
Ar = -2,3,4-(OCH3)3-C5H2
Figure 12: 2-((Benzimidazol-2-yl)thio)-1-arylethan-1-one derivatives
Kamal A et al [13], synthesized a new series of 2-aryl-1,2,4-oxadiazolo-benzimidazole conjugates
(Figure 13) and investigated their antiproliferative activity in the group of sixty cancer cell lines.
The compounds (NSC: 761109/1) and (NSC: 761814/1) showed remarkable cytotoxic activity
against most of the cancer cell lines in the one dose assay and were administered at five dose levels
(0.01, 0.1, 1, 10 and 100 μM) with GI50 values in the range of 0.79–28.2 μM. The flow cytometric
results of these compounds showed increased cells in the G2/M phase, indicating a G2/M cell
cycle arrest. Furthermore, these compounds showed inhibition of tubulin polymerization and
disruption of microtubule formation.
F N N
O H 3 CO N N
O
N N OCH 3
H N N OCH 3
H
OCH 3 OCH 3
H 3CO H 3 CO
Antihypertensive activity:
Han XF et al [14], reported that novel angiotensin II receptor type 1 (AT1) blockers bearing 6-
substituted carbamoyl benzimidazoles with a chiral center were developed and synthesized as the
first step in the development of new antihypertensive agents. The newly synthesized compounds
were tested for their potential ability to displace [125I] Sar1 Ile8-Ang II, which was specifically
bound to human AT1 receptor. The candidate (Figure 14) was identified on the basis of plasma
analyses, toxicology studies, and chronic oral tests for its excellent efficacy in antihypertension
and relatively low toxicity.
CH3
N CH3
O
N
NH
H3C
N
N
N NH
HIV Inhibitors:
MariaMonforte A et al [16], reported some N1-aryl-2-arylthioacetamido-benzimidazoles (Figure
16) as a novel class of Non-nucleoside reverse transcriptase inhibitors (NNRTIs). Most of the new
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Shivakumar et. al., Am. J. PharmTech Res. 2019;9(03) ISSN: 2249-3387
compounds well tried to be very much effective in inhibiting every RT enzyme protein at
nanomolar concentrations and HIV-1 replication in MT4 cells with low toxicity.
CH3
X CH3 R'
R N
S NH
N
O R"
X = -CH2, -SO2
R = -H, -Cl
R’ = -Br, -Cl, -NO2; R”= -H, -CH3, -COOCH3, -SO2CH3, -SO2NH2
Figure 16: N1-aryl-2-arylthioacetamido-benzimidazole derivatives
Ferro SF et al [17], reported that non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an
integral part of the currently available combination antiretroviral therapy (cART) which helps to
reduce the AIDS-mortality and turned the disease from fatal to chronic. In this context, they
recently reported a series of 6-chloro-1-(3-methylphenylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-
ones (Figure 17) as potent non-nucleoside HIV-1 reverse transcriptase inhibitors. All the newly
obtained compounds were evaluated as RT inhibitors and were co tested against RTs containing
single amino acid mutations. Finally, molecular docking studies were conducted to rationalize the
identified activity of the most promising compound.
R
O n
S
O
Cl N
O
N
H
evaluated against the protozoan parasite Trypanosoma brucei rhodesiense by in vitro method. The
thiophene analogue and the N-methyl compound showed superior antitrypanosomal activity
compared to that of the parent I.
NH2
N N NH2
HN
HN NH
N X N NH
H
NH2 H2N R
X= -O, -S R= -CH 3, -C2H5, -C3H7, -Cyclohexyl
1
R N
CF 3
2 N
R
3
R
Figure 18: Benzimidazole diamidine analogues
Karaaslan C et al [19], synthesized a number of mono and dicationic new 2-anilinobenzimidazole
carboxamidines (Figure 19) starting from 4-amino-3-nitrobenzonitrile and corresponding o-
phenylenediamines. Their antiparasitic activity against Plasmodium falciparum and Trypanosoma
brucei rhodesiense was investigated in vitro. Some of the dicationic compounds showed equal or
very close activity against T.b. rhodesiense with melarsoprol and co-exhibited a promising activity
against P. falciparum compared to chloroquine.
NHR
N
HN
NH
N
H
R= -H
NH
NHR
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Br Br
N HO N HO
CH3 N CH3 N
N N
CH3 H F CH3 H CH3
COOCH 3 COOCH 3
+ N
- N
O O H
-
O
O
+
N N S
O
N
H R
R= a) -Cl; b) –Br
Figure 21: Some new benzimidazole analogs
Analgesic and Anti-inflammatory activity:
Gote SA et al [22], reported that a series of 7-chloro-2-[3-(1H-benzimidazol-2-yl)-5-aryl-4,5-
dihydro-1H-pyrazol-1-yl]-6-fluoro-1,3-benzothiazole (Figure 22) was synthesized by the action of
7-chloro-6-fluoro-2-hydrazino-1,3-benzothiazole on chalcones in the presence of catalytic amount
of glacial acetic acid and ethanol. The synthesized compounds were tested for their anti-
inflammatory and analgesic activity.
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Shivakumar et. al., Am. J. PharmTech Res. 2019; 9(03) ISSN: 2249-3387
N N N
CHO N H
F S
Cl Ar
Ar= ,
CHO
CHO CHO CHO CHO
CHO CHO
Cl
N
CH 3 OCH 3 OCH 3 H 3C CH3
, , , , OH , Br , Cl
N NH
R H
1
R
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NO2
NO 2
N
NO2 N
N
N N
O
O
N
NH
NH
HN
O N
NH
HS N S
N R1 R
NO 2 NO 2
N N
N
N
N
N
N S
R N N
NH
HS R
OH OH OH
CH3 CH3 CH3
Taha M et al [25], reported that novel 4-Methylbenzimidazole derivatives (Figure 25) were
synthesized and evaluated for their antioxidant activity. All synthesized compounds were
evaluated for DPPH activity. Some of the compounds showed excellent activities, ranging 12-29
μM, better than the standard drug n-Propylgallate (IC50 ¼ 30.30 ± 0.40 μM). For superoxide anion
scavenging activity, many of the compounds showed better activity than standard n-Propylgallate
(IC50 ¼ 106.34 ± 1.6 μM) and ranged from 82-104 μM.
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Shivakumar et. al., Am. J. PharmTech Res. 2019; 9(03) ISSN: 2249-3387
CH3
N O
N NH N
H
R
CH3 CH3
CH3 CH3 CH3 OH
OH OH
OH
R= OH , HO , OH , HO OH , OH
OCH3 Br
OH , OH , OH , OH
N
Cl
N
H
O
H
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2
R
N
1
R N S
N
N
H
Cl N OH
H
Figure 28: 5,6-dichloro-benzimidazole derivative
Vasorelaxant activity:
Navarrete-Vazquez G et al [29], reported that a series of 1H-benzo[d]imidazole analogues (Figure
29) of Pimobendan, substituted at position 5 with either –CF3 or –NO2, were synthesized using a
short synthetic route. All the nitro derivatives were potent, and showed a partial endothelium-
dependent vasorelaxant effects, with EC50s <5 μM. 2-Methoxy-4-[5-nitro-1H-benzo[d]imidazol-2-
yl]phenol was the most potent derivative in the series, showed an EC50 value of 1.81 μM and Emax
of 91.7% for ex vivo relaxant response in intact aortic rings, resulting in a 2.5-fold higher activity
compared to Pimobendan. The closely related 5-CF3 analogue was 19 times less potent than –NO2
substituted compound.
R1 N
R4
N
H
R2 R3
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27. Shao KP, Zhang XY, Chen PJ, Xue DQ, He P, Ma LY et al. Synthesis and biological
evaluation of novel pyrimidine–benzimidazol hybrids as potential anticancer agents.
Bioorganic and Medicinal Chemistry Letters. 2014; 24 (16): 3877-3881.
28. Ng RA, Guan J, Alford Jr VC, Lanter JC, Allan GF, Sbriscia T et al. Synthesis and SAR of
potent and selective androgen receptor antagonists: 5,6-Dichloro-benzimidazole
derivatives. Bioorganic and Medicinal Chemistry Letters. 2007; 17 (3): 784-788.
29. Navarrete-Vazquez G, Hidalgo-Figueroa S, Torres-Piedra M, Vergara-Galicia J, Rivera-
Leyva JC, Estrada-Soto S et al. Synthesis, vasorelaxant activity and antihypertensive effect
of benzo[d]imidazole derivatives. Bioorganic and Medicinal Chemistry. 2010; 18: 3985–
3991.
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