Synthesis and Antimicrobial Activity of Novel Substituted 4-[3-(1H-Benzimidazol-2-yl)-4-hydroxybenzyl]-2-(1H-benzimidazol-2-yl)phenol Derivatives

Article abstract of DOI:10.1134/S1070363217120477

A series of novel substituted bis-benzimidazole derivatives were synthesized by reaction of 5,5′-methylenebis(2-hydroxybenzaldehyde) with various substituted o-phenylenediamines in glacial acetic acid. The structure of the newly synthesized compounds was elucidated by ¹H and ¹³C NMR, FT-IR, and MS spectra, and their antimicrobial activity against gram positive and gram negative bacteria and antifungal activity were evaluated. The thienyl-substituted derivative showed significant activity against Bacillus licheniformis, Bacillus subtilis, Staphylococcus aureus, Klebsiella pneumonia (bacteria), and Fusarium solani (fungi). The activities of the fluoro-substituted substituted derivative against some bacterial strains and of the thienyl-substituted derivative against fungi were found to be similar to those of standard drugs.

Full text of DOI:10.1134/S1070363217120477

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 12, pp. 3017–3022. © Pleiades Publishing, Ltd., 2017.
Synthesis and Antimicrobial Activity of Novel Substituted
4
-[3-(1H-Benzimidazol-2-yl)-4-hydroxybenzyl]-
1
2
-(1H-benzimidazol-2-yl)phenol Derivatives
a
a
b
a
V. Anil , B. Shankar , G. Bharath , and P. Jalapathi *
a
Department of Chemistry, University College of Science, Osmania University,
Saifabad, Hyderabad, Telangana, 500004 India
*
e-mail: pochampalli.ou.chemi@gmail.com
b
Bioengineering and Environmental Sciences Division, Indian Institute of Chemical Technology,
Hyderabad, 500007 India
Received January 2, 2017
Abstract—A series of novel substituted bis-benzimidazole derivatives were synthesized by reaction of 5,5′-
methylenebis(2-hydroxybenzaldehyde) with various substituted o-phenylenediamines in glacial acetic acid. The
1
13
structure of the newly synthesized compounds was elucidated by H and C NMR, FT-IR, and MS spectra, and
their antimicrobial activity against gram positive and gram negative bacteria and antifungal activity were
evaluated. The thienyl-substituted derivative showed significant activity against Bacillus licheniformis, Bacillus
subtilis, Staphylococcus aureus, Klebsiella pneumonia (bacteria), and Fusarium solani (fungi). The activities of
the fluoro-substituted substituted derivative against some bacterial strains and of the thienyl-substituted
derivative against fungi were found to be similar to those of standard drugs.
Keywords: bis-benzimidazoles, acetic acid, antibacterial activity, antifungal activity
DOI: 10.1134/S1070363217120477
Benzimidazole is a privileged pharmacophore
encountered in a number of fundamental cellular
components and bioactive molecules. Indeed, a
number of important drugs used in different
therapeutic areas contain a benzimidazole moiety [1].
Examples are proton pump inhibitor omeprazole, anti-
hypertensive drugs candesartan and telmisartan,
antihelminthics albendazole and mebendazole, as well
as several other kinds of investigational therapeutic
agents including antitumor and anticancer [2, 3].
Literature survey revealed a number of interesting
biological activities such as antitubercular, anticancer,
antihelminthic, anti allergic [4], antifungal [5, 6],
antihistaminic (astemizole) [7], and antioxidant [8–13].
benzodiazepines, bis(alkylaminophenylfurans), and bis-
benzimidazoles. The basic moiety of telmisartan
(reported as cytotoxicity agent in prostate cancer cell
line) is also bis-benzimidazole scaffold. These
heterocyclic dimers with acyclic and cyclic spacers
target DNA to exhibit their anticancer activity by
intercalation and alkylation mechanism, which induces
DNA binding, interstrand cross-linking, and disruption
of cellular processes necessary for cell maintenance
and replication in cancer cells. In view of the above
stated, in continuation of our previous work on the
synthesis of bioactive benzimidazole derivatives
[15, 16] herein we report the synthesis of new substituted
4-[3-(1H-benzimidazol-2-yl)-4-hydroxybenzyl]-2-(1H-
benzimidazol-2-yl)phenol derivatives and evaluation
of their anti bacterial and antifungal activities.
2
-Phenylbenzimidazole was subjected to cell-based
assays for cyclotoxicity and antiviral activity against a
panel of RNA and DNA viruses [14]. During the past
three decades several classes of anticancer drugs have
been identified through both empirical screening and
rational design of new compounds. These include
several heterocyclic dimers such as bis-pyrrolo-
5,5′-Methylenebis(2-hydroxybenzaldehyde) (2) [17,
18] was prepared in good yield by electrophilic
substitution reaction of salicylaldehyde (1) with 1,3,5-
trioxane (formaldehyde trimer) in glacial acetic acid in
the presence of a catalytic amount of concentrated
sulfuric acid. Various bis-benzimidazoles 4a–4h were
synthesized in moderate to good yields by condensa-
1
The text was submitted by the authors in English.
3
017

3
018
ANIL et al.
Scheme 1.
NH2
R
NH2
1
H
,3,5-Trioxane,
HO
OH
OH
2
SO /AcOH,
4
3a–3h
AcOH, reflux, 3–4 h
reflux, 24 h, N2
N
NH
N
NH
CHO
HO
OH
CHO
CHO
R
R
1
2
4a–4h
R = H (a), Me (b), HO (c), F (d), Cl (e), Br (f), cyclopentyl (g), thiophen-2-yl (h).
tion of 2 with substituted o-phenylenediamines 3a–3h
in glacial acetic acid under nitrogen (Scheme 1).
o-Phenylenediamines 3g and 3h required for the
synthesis of 4g and 4h were prepared starting from
positive (Bacillus licheniformis, Bacillus subtilis,
Staphylococcus aureus) and three gram negative
bacteria (Escherichia coli, Klebsiella pneumonia, and
Pseudomonas aeruginosa) by the agar diffusion
method using ciprofloxacin as standard drug. The
inhibition zone diameters and MIC values (minimum
inhibitory concentration, µg/mL) are given in Table 1.
Compounds 4b–4d and 4h showed excellent inhibitory
activity against all bacterial strains, which may be
attributed to the presence of thiopene, methyl,
hydroxy, and highly electronegative fluoro sub-
stituents. Compounds 4e, 4f, and 4g showed a good
activity (inhibition zone ≥20 mm). It may be
concluded that the presence of fluorine, chlorine, or
bromine atom in the benzene ring enhances the
antibacterial activity. According to the MIC values,
compounds 4a, 4c, 4d, and 4f exhibit moderate to
good inhibitory activity (MIC 200–25 µg/mL) against
bacterial strains. Compound 4h exhibited broad spec-
trum of antibacterial activity and moderate MIC values
against all the tested strains. All other remaining
compounds showed slightly higher MIC values.
4
-bromo-2-nitroaniline which was protected with
Boc O at 0°C and brought into Suzuki coupling
2
reaction with cyclopentyl- or thiophen-2-ylboronic
acid in the presence of Pd catalyst and Na CO at 70°C.
2
3
The resulting compound was reduced with FeCl /N H ·
3
2
4
H O, followed by deprotection. Compounds 3g and 3h
2
were obtained in good yield, and their analytical data
matched the theoretical values. 4-Cyclopentylbenzene-
1
,2-diamine (3g) has not been reported previously. The
other o-phenylenediamines are commercially available.
The structures of all newly synthesized compounds
1
13
4
a–4h were confirmed by IR, H and C NMR, and
mass spectra. In the IR spectrum of 4a, the phenolic
OH and NH stretching bands appeared at 3498 and
–
1
3
2
144 cm , respectively. The absorption peak at
–
1
700 cm was attributed to the C=N bond of
1
benzimidazole. The H NMR spectrum of 4a contained
two broadened singlets at δ 13.14 and 12.96 ppm due
to OH and NH protons and a singlet at δ 3.98 due to
The antifungal activity of 4a–4h was evaluated
against four fungal strains, viz. Aspergilus niger,
Candida albicans, Fusarium oxysporum, and
Fusarium solani, in comparison with the standard
antifungal drug nystatin (Table 2). Bis-benzimidazole
derivatives 4a–4f turned out to be inactive against all
the tested fungal strains. Compounds 4h and 4g
showed a good activity against all fungal strains. The
MIC values of 4h and 4g ranged from 75 to 25 µg/mL,
which may be regarded as moderate to be good
activity.
1
bridging methylene group. In the H NMR spectra of
all compounds 4a–4h, aromatic protons resonated in
1
3
the region δ 6.99–7.98 ppm. The C NMR spectra of
4
a–4h showed aromatic carbon signals in the region δC
1
15.3–156.9 ppm, and the CH signal was observed at
2
δ 42.4 ppm. The mass spectrum of 4a displayed a strong
C
+
molecular ion peak at m/z 433 [M] (C H N O ).
2
7
20
4
2
Thus, the spectral data for the synthesized compounds
were in agreement with their molecular structures
(
Scheme 1).
The antibacterial activity of newly synthesized
compounds 4a–4h was evaluated against three gram
In summary, have synthesized a series of novel bis-
benzimidazole derivatives and tested them for anti-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 12 2017

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF NOVEL SUBSTITUTED
3019
a
Table 1. Antibacterial activity of compounds 4a–4h
Inhibition zone diameter, mm (minimum inhibitory concentration, μg/mL)
gram-negative bacteria gram-positive bacteria
Comp. no.
Escherichia
Klebsiella
pneumonia
Pseudomonas
aeruginosa
Bacillus
licheniformis
Bacillus
subtilis
Staphylococ-
cus aureus
coli
4
4
4
4
4
4
4
4
a
b
c
d
e
f
22 (50)
24 (75)
23 (17)
21 (12)
21 (25)
25 (75)
25 (17)
23 (15)
28 (20)
24 (25)
No activity
26 (50)
21(50)
20 (200)
25 (100)
25 (25)
23 (50)
23 (125)
20 (75)
22 (50)
21 (125)
22 (125)
21 (25)
24 (150)
21 (100)
20 (25)
23 (100)
20 (100)
25 (25)
18 (25)
26 (75)
24 (100)
26 (175)
25 (175)
24 (175)
28 (25)
24 (50)
21 (50)
24 (75)
26 (200)
22 (175)
25 (200)
25 (25)
26 (200)
20 (175)
21 (200)
24 (25)
22 (125)
21 (150)
25 (175)
22 (25)
26 (125)
23 (125)
26 (200)
25 (25)
g
h
Ciprofloxacin
Control (1% DMSO)
No activity
No activity
No activity
No activity
No activity
a
Inhibition zone diameters were measured for stock solutions with a concentration of 100 μg/mL.
bacterial and antifungal activity in vitro. The
synthesized compounds showed a high activity against
all the bacterial strains used, whereas only two
compound, 4h and 4g were active against four fungal
strains. We will focus on these two compounds in
further research to improve their antimicrobial activity.
diameter of inhibition zone (in mm). Samples of the
tested compounds (50 μL, c = 1 mg/mL) were loaded
into the wells on the plates. All solutions were
prepared in DMSO, and pure DMSO was loaded as
control. The plates were incubated at 35°C for 1–
5 days and then were examined for the formation of
inhibition zone. Each inhibition zone was measured
three times for each bacterium culture [20, 21].
EXPERIMENTAL
Minimal inhibitory concentration (MIC) measure-
ment. The microorganism’s susceptibility tests in
nutrient and potato dextrose broths were used for the
determination of MIC. Stock 1000 μg/mL solutions of
the tested compounds, ciprofloxacin, and Nystatin
The melting points were determined in open
capillaries and are uncorrected. The IR spectra were
recorded in KBr on a Perkin Elmer Model 337
instrument. The H and C NMR spectra were
recorded on Bruker AV 300 and 400 MHz instruments
1
13
using DMSO-d as solvent and tetramethylsilane as
6
a
internal standard. Thin layer chromatography (TLC)
was carried out on aluminum plates coated with silica
gel 60 F254 (Merck; cat. no. 105 554); spots were
visualized with UV light at 254 nm or alternatively by
staining with aqueous basic potassium permanganate.
Column chromatography was performed using silica
gel (60 Å, 100–200 mesh; Merck). Commercially
available reagents were used as supplied, and all
solvents were distilled before use. All reactions were
performed in oven-dried glassware.
Table 2. Antifungal activity of compounds 4g and 4h
Inhibition zone diamter, mm (MIC, μg/mL)
Comp. no.
Aspergilus Candida Fusarium Fusarium
niger
albicans Oxysporum
Solani
4
4
g
19 (50)
23 (25)
24 (50)
25 (25)
21 (75)
20 (50)
23 (25)
24 (25)
h
21 (25)
20 (25)
25 (75)
25 (25)
Nystatin
Control
No
No
activity
No
No
(1%
activity
activity
activity
In vitro antimicrobial assay. The antimicrobial
activity was evaluated by the agar well diffusion
method. The activity was determined by measuring the
DMSO)
a
Inhibition zone diameters were measured for stock solutions with
a concentration of 100 μg/mL.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 12 2017

3
020
ANIL et al.
were prepared in DMSO, followed by dilutions to
concentrations of 250–25 μg/mL. Inoculated micro-
organism suspensions were incubated at 37°C for 1–
(2 × 25 mL), dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography
using 5% ethyl acetate in pet ether as eluent. Yield
5
days for MIC determination [22, 23].
-Cyclopentylbenzene-1,2-diamine (3g). tert-
Butyl (4-bromo-2-nitrophenyl)carbamate, 100 mg
6
7%, white solid, mp 264–266°C, R 0.66 (EtOAc–
f
4
–
1
n-hexane, 1 : 2, v/v). IR spectrum, ν, cm : 3498, 3144,
1
2
700, 1630, 1547. H NMR spectrum, δ, ppm: 13.14 s
2H, OH), 12.96 s (2H, NH), 7.98 d (2H, Harom, J =
.3 Hz), 7.70 d (2H, Harom, J = 7.4 Hz), 7.58 d (2H,
Harom, J = 7.3 Hz), 7.29–7.23 m (6H, Harom), 7.00 d
(
(
0.315 mol, 1.0 equiv), was dissolved in THF/H O
2
(
7
82.5 mL), and Pd(PPh ) (3 mol %), cyclopentyl-
3
4
boronic acid (53 mg, 0.472 mol, 1.5 equiv), and
Na CO (49 mg, 0.472 mmol, 1.5 equiv) were added at
2
3
1
3
(
2H, Harom, J = 7.4 Hz), 3.98 s (2H, CH2). C NMR
room temperature. The mixture was refluxed with
stirring for 12 h. When the reaction was complete, the
mixture was filtered through a celite bed, the sorbent
was washed with ethyl acetate, and the organic layer
was separated, washed with water and brine, dried over
spectrum, δ , ppm: 156.9 (2C), 152.8 (2C), 140.9 (4C),
C
1
34.7(2C), 130.9 (2C), 128.7 (2C), 125.7 (4C), 119.0
(
2C), 116 (2C), 116.6 (2C), 115.3 (2C), 42.4 (CH ).
2
+
Mass spectrum: m/z 433.1 [M] .
Na SO , filtered, and concentrated under reduced
2
4
Compounds 4b–4h were synthesized in a similar
pressure. The crude residue was purified by column
chromatography with 20% ethyl acetate in hexane as
eluent. tert-Butyl (4-cyclopentyl-2-nitrophenyl)carbamate
was isolated as a light brick red solid. The product was
reduced with FeCl /N H · H O in methanol to obtain
way.
4
-[4-Hydroxy-3-(5-methyl-1H-benzimidazol-2-yl)-
benzyl]-2-(6-methyl-1H-benzimidazol-2-yl)phenol
4b). Reaction time 3.5 h. Yield 65%, brick red solid,
mp 275–277°C, R 0.60 (EtOAc–n-hexane, 1 : 2, v/v).
(
3
2
4
2
f
tert-butyl (2-amino-4-cyclopentylphenyl)carbamate which
was deprotected by treatment with dilute HCl to afford
–
1
1
IR spectrum, ν, cm : 2780, 1635, 1577. H NMR
spectrum, δ, ppm: 13.02 br.s (2H, OH), 12.03 br.s (2H,
NH), 7.93 s (2H, Harom), 7.56 d (2H, Harom, J = 7.4 Hz),
7.41 t (2H, Harom, J = 6.8 Hz), 7.23 d (2H, Harom, J =
4
-cyclopentylbenzene-1,2-diamine (3g). Yield 86%,
brown solid, mp 151–163°C, Rf 0.32 (EtOAc–
1
n-hexane, 1 : 2 by volume). H NMR spectrum, δ,
7
.4 Hz), 7.07 d.d (2H, Harom, J = 1.2, 4.4 Hz), 6.97 d
ppm: 6.80 s (1H, Harom), 6.50–6.41 m (1H, Harom, 6.14–
(
2H, H , J = 7.4 Hz), 3.96 s (2H, CH ), 2.42 s (6H,
arom
2
6
2
1
.01 m (1H, Harom, J = 2.68 Hz), 4.73 br.s (4H, NH2);
.81 m (1H), 1.92–1.90 m (2H), 1.82–1.80 m (2H),
1
3
CH ). C NMR spectrum, δ , ppm: 156.3 (2C), 151.8
3
C
(
2C), 138.8 (2C), 134.4 (2C), 132.7 (2C), 131.7 (2C),
131.0 (2C), 128.7 (2C), 125.1 (2C), 119.0 (2C), 116.9
2C), 115.1 (2C), 115.0 (2C), 42.6 (CH ), 20.9 (2C,
.43–1.41 m (2H), 1.40–1.39 m (2H) (cyclopentyl).
+
Mass spectrum: m/z 177.4 [M] .
(
2
4
-(Thiophen-2-yl)benzene-1,2-diamine (3h) was
+
CH ). Mass spectrum: m/z: 461.3 [M] .
3
synthesized in a similar way from 5-bromo-2-nitro-
aniline and thiophen-2-ylboronic acid. Yield 89%,
2
-{2-Hydroxy-5-[4-hydroxy-3-(6-hydroxy-1H-
benzimidazol-2-yl)benzyl]phenyl}-1H-benzimidazol-
-ol (4c). Reaction time 4 h. Yield 68%, white solid,
mp 197–199°C, R 0.61 (EtOAc–n-hexane, 1 : 2, v/v).
white solid, mp 143–149°C, R 0.43 (EtOAc–n-hexane,
f
1
5
1
: 2 by volume). H NMR spectrum, δ, ppm: 7.35 d
(
1H, H , J = 2.68 Hz), 7.20 s (1H, Harom), 7.00 m (1H,
f
Th
–
1
1
IR spectrum, ν, cm : 3422, 2725, 1624, 1574. H
NMR spectrum, δ, ppm: 12.80 br.s (2H, OH), 12.50
br.s (2H, NH), 9.35 br.s (2H, OH), 7.87 s (2H, Harom),
Harom), 6.82 d (1H, H , J = 2.38 Hz), 6.74–6.72 m
Th
(
2H, Harom), 6.52 d (1H, H , J = 2.4 6 Hz), 4.53 s (4H,
Th
+
NH ). Mass spectrum: m/z 191.4 [M] .
2
7
1
.44 d (2H, Harom, J = 7.4 Hz), 7.20 d.d (2H, Harom, J =
.4, 7.3 Hz), 7.01–6.93 m (4H, Harom), 6.74 d (2H,
4
-[3-(1H-Benzimidazole-2-yl)-4-hydroxybenzyl]-
2
-(1H-benzimidazole-2-yl)phenol (4a). o-Phenylene-
13
Harom, J = 7.4 Hz), 3.95 s (2H, CH ). C NMR spectrum,
δC, ppm: 156.3 (2C), 153.6 (2C), 140.9 (2C), 132.1
2
diamine (3a), 130 mg (1.171 mmol), was slowly added
to a solution of 200 mg (0.781 mmol) of 5,5′-meth-
ylenebis(2-hydroxybenzaldehyde) (2) in glacial acetic
acid, and the mixture was refluxed for 3 h, the progress
of the reaction being monitored by TLC. The mixture
was cooled to room temperature, diluted with water
(
1
2C), 131.9 (2C), 126.2 (2C), 123.1 (2C), 117.2 (2C),
15.2 (2C), 115.1 (2C), 111.5 (2C), 42.5 (CH .). Mass
2
+
spectrum: m/z: 465.4 [M] .
4-[3-(5-Fluoro-1H-benzimidazol-2-yl)-4-hydroxy-
benzyl]-2-(6-fluoro-1H-benzimidazol-2-yl)phenol (4d).
Reaction time 3 h. Yield 85%, white solid, mp 240–
(
50 mL), and extracted with ethyl acetate (3 × 50 mL).
The combined organic layers were washed with brine
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 12 2017

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF NOVEL SUBSTITUTED
42°C, R 0.68 (EtOAc–n-hexane, 1 : 2, v/v). IR cyclopentyl), 1.70–1.52 m (8H, cyclopentyl).
3021
1
3
2
C
f
–
1
1
spectrum, ν, cm : 2700, 1635, 1579, 807. H NMR
spectrum, δ, ppm: 13.18 br.s (2H, OH), 12.61 s (2H,
NH), 7.97 s (2H, Harom), 7.55 d (2H, Harom, J = 7.4 Hz),
NMR spectrum, δ , ppm: 156.2 (2C), 152.8 (2C),
C
140.7 (2C), 137.5 (2C), 136.0 (2C), 134.7 (2C), 131.0
(2C), 129.7(2C), 123.6 (2C), 120.0 (2C), 116.2 (2C),
114.9 (2C), 114.2 (2C), 48.7 (2C, cyclopentyl), 42.1
7
.39 s (2H, Harom), 7.27 d (2H, Harom, J = 7.4 Hz), 7.12
s (2H, Harom), 7.00 d (2H, Harom, J = 7.3 Hz), 3.97 s
(CH ), 35.2 (2C, cyclopentyl), 25.8 (2C, cyclopentyl).
Mass spectrum: m/z 569.5 [M] .
2
1
3
+
(
2H, CH2). C NMR spectrum, δ , ppm: 156.5 (2C),
C
1
(
1
52.9 (2C), 152.8 (2C), 145.5 (2C), 138.5 (2C), 134.7
2C), 130.8 (2C), 128.7 (2C), 119.0 (2C), 116.7 (2C),
16.0 (2C), 111.9 (2C), 105.4 (2C), 42.0 (CH ). mass
4
-[4-Hydroxy-3-(5-(thiophen-2-yl)-1H-benzimi-
dazol-2-yl)benzyl]-2-(6-(thiophen-2-yl)-1H-benzimi-
dazol-2-yl)phenol (4h). Reaction time 4 h. Yield 83%,
white solid, mp 282–284°C, R 0.63 (EtOAc–n-hexane,
2
+
spectrum: m/z: 469.3 [M] .
f
–
1
1
4-[3-(5-Chloro-1H-benzimidazol-2-yl)-4-hydroxy-
1 : 2, v/v). IR spectrum, ν, cm : 2746, 1688, 1520. H
NMR spectrum, δ, ppm: 13.19 br.s (2H, NH), 13.14
br.s (2H, OH), 12.76 t (2H, thiophene, J = 6.8 Hz),
7.98 s (2H, Harom), 7.74 t (2H, Harom, J = 6.8 Hz), 7.60–
7.49 m (8H, Harom), 7.28 d (2H, Harom, J = 7.4 Hz), 7.15
d (2H, Harom, J = 7.4 Hz), 7.02 d (2H, Harom, J =
7.4 Hz), 4.00 s (2H, CH2). C NMR spectrum, δC,
ppm: 155.9 (2C), 152.0 (2C), 142.4 (2C), 140.9 (2C),
138.9 (2C), 138.3 (2C), 134.7 (2C), 131.0 (2C), 131.9
(2C), 128.7 (2C), 127.9 (2C), 125.6 (2C), 125.5 (2C),
benzyl]-2-(6-chloro-1H-benzimidazol-2-yl)phenol (4e).
Reaction time 4 h. Yield 69%, white solid, mp 270–
2
trum, ν, cm : 2730, 1560, 1598, 835. H NMR spec-
trum, δ, ppm: 13.18 br.s (2H, OH), 12.50 br.s (2H,
NH), 7.98 d (2H, Harom, J = 7.4 Hz), 7.77–7.61 m (4H,
Harom), 7.28 d.d (4H, Harom, J = 1.4, 7.4 Hz), 7.01 d
72°C. R 0.66 (EtOAc–n-hexane, 1 : 2, v/v). IR spec-
f
–
1
1
13
1
3
(
2H, Harom, J = 7.4 Hz), 3.97 s (2H, CH2). C NMR
spectrum, δ , ppm: 153.2 (2C), 152.8 (2C), 142.3 (2C),
C
1
37.0 (2C), 132.2 (2C), 130.1 (2C), 129.8 (2C), 129.3
120.0 (2C), 117.9 (2C), 115.1 (2C), 114.2 (2C), 42.1
+
(
2C), 125.3 (2C), 119.0 (2C), 116.8 (2C), 116.2 (2C),
(CH ). Mass spectrum: m/z 597.3 [M] .
2
+
114.8 (2C), 42.0 (CH ). Mass spectrum: m/z 501.0 [M] .
2
1
13
Supplementary data including H and C NMR and
mass spectra of some compounds are available from
the authors.
4-[3-(5-Bromo-1H-benzimidazol-2-yl)-4-hydroxy-
benzyl]-2-(6-bromo-1H-benzimidazol-2-yl)phenol (4f).
Reaction time 3.5 h. Yield 75%, brick red solid, mp
2
53–255°C, R 0.65 (EtOAc–n-hexane, 1 : 2, v/v). IR
ACKNOWLEDGMENTS
f
–
1
1
spectrum, ν, cm : 2724, 1638, 1579, 560. H NMR
spectrum, δ, ppm: 13.20 br.s (2H, OH), 12.50 br.s (2H,
NH), 7.98 d (2H, Harom, J = 7.4 Hz), 7.86 s (2H, Harom),
7
7
B. Shankar thanks to UGC-BSR (RFSMS-Award
no. 805/chem/ou/2013), New Delhi, India for financial
support in the form of senior research fellowship
(SRF). V. Anil thanks to the Head of the Department
of Chemistry, University College of Science, Osmania
University, Saifabad, Hyderabad, for providing the
facilities for the research work.
.59 s (2H, Harom), 7.38 d.d (2H, Harom, J = 1.4, 7.4 Hz),
.28 d.d (2H, Harom, J = 1.3, 7.4 Hz), 7.00 d (2H, Harom,
1
3
J = 7.4 Hz), 3.97 s (2H, CH ). C NMR spectrum, δ ,
2
C
ppm: 156.0 (2C), 152.5 (2C), 132.5 (2C), 132.0 (2C),
26.6 (2C), 125.6 (2C), 125.2 (2C), 114.1 (2C), 113.3
2C), 112.5 (2C), 42.5 (CH ). Mass spectrum: m/z:
1
(
5
2
+
91.2 [M] .
REFERENCES
4
-[3-(5-Cyclopentyl-1H-benzimidazol-2-yl)-4-hyd-
1
. Shadia, A.G., Ahmed, S.A., Mireya, L.R., Sean, M., and
HodaI, E.D., Eur. J. Chem., 2010, vol. 1, p. 67. doi
roxybenzyl]-2-(6-cyclopentyl-1H-benzimidazol-2-yl)-
phenol (4g). Reaction time 3.8 h. Yield 67%, brown
solid, mp 198–200°C, R 0.65 (EtOAc–n-hexane, 1 : 2,
v/v). IR spectrum, ν, cm : 2700, 1620, 1579, 2950. H
NMR spectrum, δ, ppm: 13.00 s (2H, OH), 11.09 br.s
1
0.5155/eurjchem.1.2.67-72.1
f
2
. Hayakawa, I., Shioya, R., Agatsuma, T., Furukawa, H.,
Naruto, S., and Sugano, Y., Bioorg. Med. Chem. Lett.,
–
1
1
2
004, vol. 14, p. 455. doi 10.1016/j.bmcl.2003.10.039
(
7
7
2H, NH), 7.92 s (2H, Harom), 7.60–7.51 m (2H, Harom),
3. Galal, S.A., Abd, E.A., Abdullah, M.M., and Diwani, H.I.,
Bioorg. Med. Chem. Lett., 2009, vol. 19, p. 2420. doi
10.1016/j.bmcl.2009.03.069
.49–7.39 m (2H, Harom), 7.40 d (2H, Harom, J =
.4 Hz), 7.24–7.13 m (2H, Harom), 6.98 d (2H, Harom
,
J = 7.4 Hz), 4.00 s (2H, CH ), 3.19 m (2H,
cyclopentyl), 2.12 m (4H, cyclopentyl), 1.79 m (4H,
4. Jabali, J.V., Keyur, P.T, and Rahul, S.K., Adv. Appl. Sci.
Res., 2011, vol. 2, no. 3, p. 89.
2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 12 2017

3
022
ANIL et al.
5
. Can-Eke, B., Puskullu, M.O., Buyukbingol, E., and
Iscan, M., Chem.-Biol. Interact., 1998, vol. 113, p. 65.
doi 10.1016/S0009-2797(98)00020-9
. Kus, C., Ayhan-Kilcigil, G., Can-Eke, B., and iŞcan, M.,
Arch. Pharm. Res., 2004, vol. 27, p. 156. doi 10.1007/
BF02980099
. Ayhan-Kilcigil, G., Kus, C., Çoban, T., Can-Eke, B.,
and Iscan, M., J. Enzyme Inhib. Med. Chem., 2004,
vol. 19, p. 129. doi 10.1080/1475636042000202017
. Göker, H., Ayhan-Kilcigil, G., Tunçbilek, M., Kus, C.,
Ertan, R., Kendi, E., Özbey, S., Fort, M., Garcia, C., and
Farré, A.J., Heterocycles, 1999, vol. 51, p. 2561. doi
Chem., 2008, vol. 16, p. 6965. doi 10.1016/j.Bmc.2008.
05.044
1
1
5. Devender, M., Anil, V., Jalapathi, P., Srinivasrao, V.,
Parthasarathy, T., and Rajakomuraiah, T., Med. Chem.
Res., 2013, vol. 22, p. 5481. doi 10.1007/s00044-013-
0543-2
6
7
8
6. Jalapathi, P., Devender, M., Umapathi Reddy, N., and
Rajakomuraiah, T., Lett. Drug Des. Discovery, 2012,
vol. 9, p. 471. doi 10.2174/157018012800389304
1
1
1
7. Marvel, C. and Sand Turkey, N., J. Am. Chem. Soc.,
1
957, vol. 79, p. 6000.
8. Shankar, B., Jalapathi, P., Sunitha, V., and Karunakar
1
0.3987/COM-99-8585
Rao, K., Pharma Chem., 2016, vol. 8, p. 192.
9
. Abdel Rahman, A.E., Mahmoud, A.M., El Naggar, G.M.,
and El Sherief, H.A., Pharmazie, 1983, vol. 38, p. 589.
9. Davood, A., Mojgan, P., Behrooz, M., Mehrangiz, S.,
and Razieh Nejat, Y., J. Serb. Chem. Soc., 2010,
vol. 75, p. 1181.
1
0. Soliman, F.S.G., Rida, S.M., Badawey, E.A.M., and
Kappe, T., Arch. Pharm., 1984, vol. 317, p. 951. doi
2
2
0. Keche, A.P., Hatnapure, G.D., Tale, R.T., Rodge, A.H.,
1
0.1002/ardp.19843171110
Birajdar, S.S., and Kamble, V.M., Med. Chem. Res.,
1
1
1
1. Coburn, R.A., Clark, M.T., Evans, R.T., and Genco, R.J.,
2
013, vol. 22, p. 1480. doi 10.1007/s00044-012-0144-5
J. Med. Chem., 1987, vol. 30, p. 205.
1. Shankar, B., Jalapathi, P., Ramesh, M., Kishore Kumar, A.,
2. Habib, N.S., Abdel Hamid, S., and El Hawash, M.,
Ragavender, M., and Bharath G., Russ. J. Gen. Chem.,
Farmaco, 1989, vol. 44, p. 1225.
2
7
016, vol. 86, p. 1711. doi 10.1134/S10703632160
029X
3. Göker, H., Kuş, C., Boykin, D.W., Yildiz, S., and
Altanlar, N., Bioorg. Med. Chem., 2002, vol. 10,
p. 2589. doi 10.1016/S0968-0896(02)00103-7
2
2. Shankar, B., Jalapathi, P., Nagamani, M., Bharath, G.,
and Karunakar Rao, K., Monatsh Chem., 2017, vol. 148,
p. 999. doi 10.1007/s00706-016-1838-z
1
4. Penning, T.D., Zhu, G.-D., Gandhi, V.B., Gong, J.,
Thomas, S., Lubisch, W., Grandel, R., Wernet, W.,
Park, Ch.H., Fry, E.H., Liu, X.-S., Shi, Y., Klinghofer, V.,
Johnson, E.F., Donawho, Ch.K., Frost, D.J., Bontcheva-
Diaz, V., Bouska, J.J., Olson, A.M., Marsh, K.C., Luo, Y.,
Rosenberg, S.H., and Giranda, V.L., Bioorg. Med.
23. Bhavanarushi, S., Kanakaiah, V., Gandu, B.,
Gangagnirao, A., and Vatsala, R., Med. Chem. Res.,
2
014, vol. 23, no. 1, p. 158. doi 10.1007/s00044-013-
0623-3
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