An efficient synthesis and cytotoxic activity of 2-(4-chlorophenyl)-1H–benzo[d]imidazole obtained using a magnetically recyclable Fe3O4 nanocatalyst-mediated white tea extract

Article abstract of DOI:10.1002/aoc.3934

A simple and efficient procedure has been developed for the synthesis of biologically relevant 2-substituted benzimidazoles through a one-pot condensation of o-phenylenediamines with aryl aldehydes catalysed by iron oxide magnetic nanoparticles (Fe_3<

Full text of DOI:10.1002/aoc.3934

Received: 15 February 2017
DOI: 10.1002/aoc.3934
Revised: 14 May 2017
Accepted: 20 May 2017
F U L L PA P E R
An efficient synthesis and cytotoxic activity of 2‐(4‐chlorophenyl)‐
H–benzo[d]imidazole obtained using a magnetically recyclable
Fe O nanocatalyst‐mediated white tea extract
1
3
4
Sara Shojaee | Mahnaz Mahdavi Shahri
Department of Chemistry, Shiraz Branch,
Islamic Azad University, Shiraz, Iran
A simple and efficient procedure has been developed for the synthesis of biologically
relevant 2‐substituted benzimidazoles through a one‐pot condensation of
o‐phenylenediamines with aryl aldehydes catalysed by iron oxide magnetic nanopar-
Correspondence
Mahnaz Mahdavi Shahri, Department of
Chemistry, Shiraz Branch, Islamic Azad
University, Shiraz, Iran.
ticles (Fe O MNPs) in short reaction times with excellent yields. In the present
3 4
study, Fe O MNPs synthesized in a green manner using aqueous extract of white
3
4
Email: mahnaz.chem@gmail.com
tea (Camelia sinensis) (Wt‐Fe O MNPs) were applied as a magnetically separable
3
4
heterogeneous nanocatalyst to synthesize 2‐(4‐chlorophenyl)‐1H–benzo[d]imidaz-
ole which has potential application in pharmacology and biological systems. Fourier
transform infrared and NMR spectroscopies were used to characterize the 2‐(4‐
chlorophenyl)‐1H–benzo[d]imidazole. In vitro cytotoxicity studies on MOLT‐4 cells
showed a dose‐dependent toxicity with non‐toxic effect of 2‐(4‐chlorophenyl)‐1H–
benzo[d]imidazole, up to a concentration of 0.147 µM. The green synthesized Wt‐
Fe O MNPs as recyclable nanocatalyst could be used for further research on the
3
4
synthesis of therapeutic materials, particularly in nanomedicine, to assist in the treat-
ment of cancer.
KEYWORDS
3 4
anticancer activity, benzimidazoles, Fe O magnetic nanocatalyst, green synthesis
1
| INTRODUCTION
simple separation of them using an external magnet, high
degree of chemical stability in various organic and inorganic
solvents, reusability and benign character in the context of
green chemistry. As a result, these features have enabled
researchers to apply nanocatalysts as green and sustainable
Nanotechnology refers to an emerging field of science that
includes synthesis and development of various nanomaterials.
Nanoscale materials have recently attracted increasing atten-
tion because they exhibit useful and unique properties com-
pared to conventional polycrystalline materials. Iron oxide
nanoparticles, due to their superparamagnetic behaviour and
surface modification properties, are considered to be suitable
candidates in cancer therapy. They have emerged as viable
alternatives to conventional materials, as robust, readily avail-
able, high‐surface‐area heterogeneous catalyst supports, being
magnetically separable, thereby eliminating the requirement
of catalyst filtration after completion of a reaction. Other
important features of these catalysts are high catalytic activity,
[
3]
options for organic transformations.
[1]
A unique method for the synthesis of iron oxide magnetic
nanoparticles (Fe O MNPs) is to fabricate nanoparticles
3
4
using natural products, such as plant extracts, which are
[2]
readily scalable and non‐toxic compared with physical and
[
4,5]
chemical methods.
White tea can be a good candidate
for synthesizing nanoparticles and applying the phenolic
[
6]
compounds as reducing and capping agents.
The development of greener procedures for the synthesis
of heterocyclic compounds is still a desirable goal in the field
Appl Organometal Chem. 2017;e3934.
wileyonlinelibrary.com/journal/aoc
Copyright © 2017 John Wiley & Sons, Ltd.
1 of 8
https://doi.org/10.1002/aoc.3934

2
of 8
SHOJAEE AND MAHDAVI SHAHRI
of organic synthesis. Among heterocycles, benzimidazole
and its derivatives are an important class of nitrogen‐
containing heterocycles with a wide range of applications
and which play a basic role in remedial and medical chemis-
[7]
[8]
[9]
[10,11]
[15]
SCHEME
Chlorophenyl)‐1 H benzo [d] imidazole
1
Wt‐Fe O MNPs catalyzed synthesis of 2‐(4‐
3
4
try. Their antifungal, antimicrobial, anthelmintic,
[
12,13]
[14]
antiviral,
topoisomerase inhibition and anticancer
activities have been the subject of much consideration lately.
Consequently, their use is essential for improvement of new
therapeutic drugs, as demonstrated and supported by some
commercial benzimidazole products in Figure 1. So, various
methods have been studied for the fabrication of these com-
pounds. The most praised procedure is the condensation reac-
tion of o‐phenylenediamine and carboxylic acid or its
derivatives like aldehydes in the presence of a catalyst, at
acidic pH and high temperature and sometimes with volatile
(
(
FeCl ⋅6H O, 97%) and ferrous chloride tetrahydrate
3
2
FeCl ⋅4H O, 99%) were used as iron precursors, and were
2
2
provided by Merck (Darmstadt, Germany). o‐
Phenylenediamine, acetonitrile and 4‐chlorobenzaldehyde
were purchased from Merck and used without further
purification. All aqueous solutions were freshly prepared
using distilled deionized water.
[
16]
solvents. Another common method consists of dehydroge-
nation and then oxidation of aniline Schiff bases via oxidizers
[
17,18]
[19]
[20]
such as NaHSO3,
MnO2,
I /KI/K CO /H O,
etc.
2
2
3
2
2
.2 | Green synthesis of Wt‐Fe O MNPs as
3
4
In the present paper, we report an effective method for the
synthesis of 2‐(4‐chlorophenyl)‐1H–benzo[d]imidazole by
the condensation of o‐phenylenediamine with aryl aldehyde
using green‐synthesized Fe O MNPs (Wt‐Fe O MNPs) as
Nanocatalyst
White tea was washed to remove possible impurities, and
then dried in sunlight to completely remove moisture. After
that, it was ground into powder and kept at 4°C for further
analysis. The resultant ground white tea sample (about 4 g)
was boiled with distilled deionized water (100 ml) in an
Erlenmeyer flask while being continuously stirred for
30 min. After filtration with filter paper using a vacuum
pump, the residue was cooled to room temperature, and
stored at 4°C until used.
3
4
3 4
active and recyclable magnetic nanocatalyst, as shown in
Scheme 1. To the best of our knowledge, this is the first work
to synthesize benzimidazoles using green‐synthesized Fe O4
3
MNPs as a stable and heterogeneous reusable nanocatalyst. It
is of considerable advantage to use magnetically recoverable
and environmentally benign heterogeneous nanocatalysts in
the synthesis of pharmaceutically important heterocyclic
compounds. The anticancer activity of 2‐(4‐chlorophenyl)‐
Synthesis of Wt‐Fe O MNPs was based on our previous
3
4
[
21]
1H–benzo[d]imidazole was investigated and structural
study.
In a typical procedure, 2 mol of FeCl ⋅6H O and
3
2
characterization was conducted using Fourier transform
1 mol of FeCl ⋅4H O were dissolved in 100 ml of deionized
2
2
infrared (FT‐IR) and NMR spectroscopies.
water in a molar ratio of 2:1 under nitrogen atmosphere. After
that, 20 ml of a white tea aqueous extract was added to the iron
solution, and then the solution was subjected to vigorous mag-
netic stirring for 1 h at room temperature. At the beginning,
the pH value was observed to be 9.0 because of natural com-
pounds in the white tea extract. After complete bioreduction
of ions, the white tea extract was centrifuged at 7000 rpm
2
| EXPERIMENTAL
.1 | Materials
2
White tea (Camelia sinensis) plant was purchased from a
for 5 min to isolate the black powder of Wt‐Fe O MNPs from
local herb shop in Iran. Ferric chloride hexahydrate
3 4
the compounds present in the solution and washed several
times with ethanol and dried in an oven at 60°C for 12 h.
The phase purity of samples was determined using X‐ray
diffraction (XRD) analysis conducted with a diffractometer
0
(
X Pert PRO). FT‐IR analysis was done to determine the
functional groups present in white tea extract and their possi-
ble involvement in the synthesis of Fe O MNPs. FT‐IR
3
4
spectra were recorded with a Shimadzu FTIR 8400 spectro-
photometer in KBr discs. The morphology and size of sam-
ples were characterized using scanning electron microscopy
(KYKY‐EM 3200 digital scanning electron microscope).
Further, the elemental composition was determined using
FIGURE 1 Important benzimidazole‐containing commercial drugs
energy‐dispersive X‐ray (EDX) analysis.

SHOJAEE AND MAHDAVI SHAHRI
3 of 8
2
.3 | General procedure for synthesis of 2‐(4‐
curves. Dimethylsulfoxide (0.1%) was used as the negative
control.
Chlorophenyl)‐1H–benzo[d]imidazole
The product was synthesized by the reaction between
o‐phenylenediamine (1.0 mmol), acetonitrile (3 ml) as sol-
3
3
| RESULTS AND DISCUSSION
vent, 4‐chlorobenzaldehyde (2.2 mmol) and Wt‐Fe O4
3
.1 | Mechanism of formation of Wt‐Fe O
(6%) as a green and recyclable magnetic nanocatalyst under
3
4
MNPs as Nanocatalyst
reflux condition at 80°C and the reaction progress was
monitored by TLC. After the completion of the reaction,
Wt‐Fe O nanocatalyst was collected using a magnet and
The addition of ferric chloride solution as iron precursor to
the white tea extract containing flavones and many polyphe-
nols as reducing agent causes the reduction of Fe and stabi-
lization of the nanoparticles. Therefore, after adding iron
solution, the colour of the Fe /white tea extract solution
quickly changed from light brown to black, demonstrating
the formation of Fe O MNPs in the white tea extract (Wt‐
Fe O MNPs) as shown in Figure 2. A decrease in pH during
the formation of Fe O MNPs indicates that hydroxyl group
3
4
the sediment was purified by recrystallization. It was dis-
solved in EtOH (15 ml) and then poured into ice–water
3+
(30 ml). The pure solid product was filtered, washed with
3+
ice–water and dried.
The Fe O magnetic nanocatalyst after being recovered
3
4
3
4
by magnet separation was washed with EtOH and dried.
The recovered nanocatalyst was reused for a further four
times giving a yield of up to 95%. The structure was charac-
terized using NMR and FTIR spectroscopies and melting
3
4
3
4
was involved in the reduction process. The following equa-
tions represent the formation of Wt‐Fe O MNPs:
3
4
1
13
point measurement. H NMR and C NMR spectra were
recorded with a Bruker Avance‐DPX‐250/400 spectrometer
operating at 250 and 62.5 MHz, respectively.
Fe3 þ H O → FeðOHÞ þ 3H
þ
þ
2
3
FeðOHÞ →FeOOH þ H2O
3
Melting points were determined using Electrothermal IA
2
FeOOH þ FeðOHÞ þ flavones and other polyphenols
2
9000 melting point apparatus in open capillary tubes and are
→
Wt‐ Fe O MNP ↓ þ 2H O
3
4
s
2
uncorrected. TLC was performed using aluminium sheets
coated with silica gel 60 (Merck) containing fluorescent indi-
cators (F254).
3
.2 | Characterization of Wt‐Fe O MNPs as
3
4
Nanocatalyst
The FT‐IR spectra of the synthesized Wt‐Fe O MNPs and
3
4
2
.4 | Cytotoxicity assay
the white tea extract are shown in Figure 3. The FT‐IR spec-
trum of white tea extract shows an intense broad peak at
3399 cm− characteristic of the hydroxyl functional group
The cytotoxicity effect of 2‐(4‐chlorophenyl)‐1H–benzo[d]
imidazole on MOLT‐4 cell line and a normal blood cell
line was quantified using a 3‐(4,5‐dimethylthiazol‐2‐yl)‐
1
3+
in polyphenols. After reduction of Fe , the decreases in
band intensity imply the involvement of the OH groups in
2,5‐diphenyltetrazolium bromide (MTT) kit (Sigma‐
−
1
Aldrich) according to the standard method. The cells were
allowed to grow in a 75 cm cell culture flask (TPP
Techno Plastic Products, Trasadingen, Switzerland) until
the reduction process. The bands at 1618 and 1639 cm
are due to C═C aromatic bonds from natural compounds.
2
−
1
The peaks located at around 1230 and 1047 cm can be
assigned to ─C─N stretching vibrations of amine and
amides, and ─C─O─C or ─C─O groups, respectively. In
95% confluent. The cells were then seeded into each well
of a 96‐well microculture plate (TPP Techno Plastic Prod-
5
−1
−1
ucts) at a concentration of 1 × 10 cells ml and treated
with 2‐(4‐chlorophenyl)‐1H–benzo[d]imidazole at various
concentrations. After incubation for 72 h at 37°C in a 5%
addition, the bands at 587 and 479 cm are attributed to
[
22]
stretching vibration of the Fe─O bond in magnetite.
Consequently, the white tea extract contains phenolic
compounds, alkaloids, flavonoids and caffeine, acting as
capping and reducing ligands for the green synthesis of
Fe O MNPs as nanocatalyst.
−
1
CO incubator (Binder GmbH), 25 μl of a 5.5 mg ml
2
MTT solution was added to each well, covered with alumin-
ium foil and incubated for a further 3 h in the dark. Immedi-
ately afterwards, the medium was aspirated and the
remaining purple formazan was lysed with MTT solution.
The assay was performed in triplicate. The optical density
was then measured at 570 nm using an enzyme‐linked immu-
nosorbent assay universal microplate reader (Bio Tek Instru-
ments Inc., VT, USA). The inhibitory concentration (IC )
3
4
Figure 4 shows the XRD pattern of Wt‐Fe O MNPs syn-
3
4
thesized using white tea extract. A broad diffraction peak at 2θ
of 10.0° is observed, which may be assigned to the structure of
natural compounds in white tea extract. Five strong peaks are
observed at 2θ of 30.1°, 35.5°, 43°, 57° and 63°, correspond-
ing to the crystal planes of (200), (311), (400), (422) and
50
[
23]
value was determined from absorbance versus concentration
(511), respectively, of crystalline Wt‐Fe O MNPs.
3
4

4
of 8
SHOJAEE AND MAHDAVI SHAHRI
3 4
FIGURE 2 Schematic of synthesis of Wt‐Fe O MNPs using white tea (Camelia sinensis) extract
3
.3 | Characterization of 2‐(4‐Chlorophenyl)‐
H–benzo[d]imidazole
1
In the FT‐IR spectrum (Figure 6), vibration bands at
1
−1
3
471 cm− are assigned to N─H stretching, 3057 cm to
−
1
C─H aromatic stretching, 1588 cm to C─C aromatic
stretching, 1430 cm− to aromatic ring and 1271 cm to
1
−1
−1
C─N stretching. Also, the band at 1091 cm corresponds
to C─H bending and 962 cm− to out‐of‐plane bending of
aromatic C─H, and finally strong absorptions at 543, 739
and 828 cm− correspond to C─Cl bond.
1
1
1
Figure 7 shows the H NMR analysis (500 MHz,
FIGURE 3 FT‐IR spectra of (a) white tea plant extract and (b) green‐
synthesized Wt‐Fe MNPs
DMSO‐d , δ, ppm): 13.00 (s, 1H), 8.13–8.16 (m, 2H),
6
13
3
O
4
7.62 (2H), 7.52 (1H), 7.19 (2H). Figure 8 shows the
C
NMR analysis (500 MHz, DMSO‐d , δ, ppm): 150.61,
6
1
43.8, 134.99, 129.52, 111.30. The melting point is deter-
mined as 292–294°C.
3
.4 | Possible mechanism for Wt‐Fe O
3
4
MNPs‐catalyzed synthesis of 2‐(4‐
Chlorophenyl)‐1H–benzo[d]imidazole
The synthesized Fe O MNPs were applied as a reusable
3
4
catalyst in a condensation reaction which in turn will produce
biologically important heterocyclic compounds such as
benzimidazole and derivatives. The possible mechanism for
the formation of benzimidazole compounds from the conden-
sation reaction between o‐phenylenediamine and benzalde-
3 4
FIGURE 4 XRD pattern of Wt‐Fe O MNPs
Figure 5(a) presents the cubic morphology with a mean
hyde in the presence of a catalytic amount of Wt‐Fe O4
3
diameter of 37 nm of the Wt‐Fe O MNPs. From the EDX
spectrum, shown in Figure 5(b), the peaks around 0.7 and
MNPs is shown in Scheme 2. In the first step of the synthesis
of 2‐substituted benzimidazoles, iron oxide forms hydrogen
bonds with aldehyde of which the carbonyl carbon is
activated and then diamine attacks the aldehyde which
generates 2‐substituted benzimidazoles.
Reusability is one of the most significant properties of
a good catalyst. One of the advantages of this work is the
3
4
6.2 keV are related to the binding energies of Fe and the other
signals in the range 0.0–0.5 keV represent the typical absorp-
tion of carbon and oxygen and thus indicate the presence of
the plant extract (as a capping ligand) on the surfaces of the
MNPs.
[
24]

SHOJAEE AND MAHDAVI SHAHRI
5 of 8
3 4
FIGURE 5 (a) scanning electron microscopy image and (b) EDX spectrum of Wt‐Fe O MNPs
room temperature. The reaction proceeded smoothly at 50°
C, and an increase in temperature to 70, 80 and 90°C
increased the rate of reaction. Consequently, the reaction time
was short and high yield was obtained at 80°C.
It was observed that an increase in temperature causes a
rise in the energy levels of the molecules involved in the reac-
tion, so the rate of the reaction increases. The minimum
energy needed for a reaction to precede, known as the activa-
tion energy, stays the same with increasing temperature.
However, the average increase in particle kinetic energy
caused by the absorbed heat means that a greater proportion
of the reactant molecules now have the minimum energy nec-
essary to collide and react. Also, the rate of reaction will
decrease with a decrease in temperature.
FIGURE 6 FT‐IR analysis of 2‐(4‐chlorophenyl)‐1H–benzo[d]
imidazole
production of a non‐toxic, environmentally benign, hetero-
geneous catalyst, and its ability to act as a recyclable cat-
3.6 | Effect of catalyst
alyst. After the completion of the reaction, the Wt‐Fe O4
Catalysts are substances that increase reaction rate by lower-
ing the activation energy needed for the reaction to occur.
The effect of the Wt‐Fe O MNPs catalyst on the rate of reac-
3
MNPs could be recovered using an external magnetic field;
the separated nanocatalyst was then dried and reused
several times in subsequent runs using the same recovered
catalyst without considerable loss of catalytic activity
3
4
tion was evaluated and the results are summarized in Table 2.
At first, a controlled reaction was carried out in the absence
of catalyst. Very little yield of products even after 6 h was
observed (20%). The reaction was then studied with various
amounts of nanocatalyst (4–10%) at 80°C. The results indi-
cated that the product yield increased with catalyst concentra-
tion. Maximum yield was obtained by using 6 mol% loading
of catalyst within a short reaction period of 2 h only. With a
further increase in the catalyst concentration (8 and 10 mol
%), the yield of the product did not improve.
(Figure 9).
3
.5 | Effect of temperature
The effect of temperature on the rate of reaction was evalu-
ated at different temperatures for the synthesis of benzimid-
azoles in the presence of Wt‐Fe O MNPs as nanocatalyst
3
4
(Table 1). It was observed that the reaction was very slow at

6
of 8
SHOJAEE AND MAHDAVI SHAHRI
1
FIGURE 7 H NMR analysis of 2‐(4‐chlorophenyl)‐1H–benzo[d]imidazole
1
3
FIGURE 8
C NMR analysis of 2‐(4‐chlorophenyl)‐1H–benzo[d]imidazole
The results show that the catalyst has an effect but only
up to a certain amount, and there is no effect on further
increasing the amount of catalyst. Although the catalyst is
not used up in the reaction, it is in use during the reaction,
so when there is only very little of the catalyst, all the catalyst
can be involved, and a lot of reactants still remain to be
catalysed in the next catalysis cycles, and they can react
sooner if more catalyst is added. But if enough catalyst is
added such that not all of it is involved, any more added
catalyst will not be operative and the reaction rate will not

SHOJAEE AND MAHDAVI SHAHRI
7 of 8
3 4
SCHEME 2 Possible mechanism for Wt‐Fe O MNPs catalyzed synthesis of 2‐substituted benzimidazoles
TABLE 3 Anticancer activity of 2‐(4‐chlorophenyl)‐1H–benzo[d]
imidazole and reference drugs against MOLT‐4 cell line
Drug
IC50 (μg ml−
Cisplatin Doxorubicin 2‐aryl benzimidazoles
2.133 0.013 42 ± 0.2
1
)
further increase. As a result, the Wt‐Fe O4 magnetic
3
nanocatalyst acts as a considerable function of an accelerator
promoting the time‐ and cost‐effective formation of product.
3.7 | Cytotoxicity effect
3 4
FIGURE 9 Recycling (left) of Wt‐Fe O MNPs as nanocatalyst and
The synthesized benzimidazole was tested for anticancer
activity against MOLT‐4 (human leukaemia) cancer cell line
by MTT colorimetric assay using cisplatin and doxorubicin
as standard anticancer drugs. Observation of morphological
changes in cells indicated that benzimidazole inhibited prolif-
eration of the MOLT‐4 cancer cell line. No toxicity was seen
in the normal blood cell line. The compounds were evaluated
in vitro at a concentration range of 10 to 100 μM. MTT col-
orimetric assay was used to determine growth inhibition. Cell
viability was decreased with an increase in concentration of
the test samples. The results are expressed as IC50 values in
Table 3. The IC value calculated for benzimidazole was
magnetic separation using an external magnet (right)
TABLE 1 Effect of temperature on synthesis of 2‐(4‐chlorophenyl)‐
1
H–benzo[d]imidazole
Entry
Temperature (°C)
Time (min)
300
Yield (%)
1
2
3
4
5
r.t.
50
70
80
90
50
75
89
96
96
180
180
120
120
5
0
2 ± 0.2 μg ml− in comparison to 0.013 and 2.133 μg ml
1
−1
4
for cisplatin and doxorubicin.
TABLE 2 Effect of catalyst on synthesis of 2‐(4‐chlorophenyl)‐1H–
benzo[d]imidazole
4 | CONCLUSIONS
Entry
Catalyst (mol%)
Time (min)
360
Yield (%)
In this research, 2‐(4‐chlorophenyl)‐1H–benzo[d]imidazole
was successfully synthesized using Wt‐Fe O MNPs as a
magnetically recyclable nanocatalyst. Temperature and
nanocatalyst concentration parameters involved in the synthe-
sis were analysed for the better yield of imidazole, and the
synthesized imidazole was found to be biocompatible.
1
2
3
4
5
None
35
78
95
96
95
3
4
4
6
180
120
8
120
10
120

8
of 8
SHOJAEE AND MAHDAVI SHAHRI
Anticancer activity was detected against MOLT‐4 cell line for
[12] Y. F. Li, G. F. Wang, P. L. He, W. G. Huang, F. H. Zhu, H. Y. Gao,
W. Tang, Y. Luo, C. L. Feng, L. P. Shi, Y. D. Ren, W. Lu, J. P.
Zuom, J. Med. Chem. 2006, 49, 4790.
−1
blood cancer and resulting in an IC value of 42 ± 0.2 μg ml
5
0
for MOLT‐4 cells. The present study successfully
demonstrated a simple, eco‐friendly method for the synthesis
of benzimidaozole with significant potential anticancer
properties.
[13] H. Banie, A. Sinha, R. J. Thomas, J. C. Sircar, M. L. Richards,
J. Med. Chem. 2007, 50, 5984.
[
14] P. S. Charifson, A.‐L. Grillot, T. H. Grossman, J. D. Parsons, M.
Badia, S. Bellon, D. D. Deininger, J. E. Drumm, C. H. Gross, A.
LeTiran, Y. Liao, N. Mani, D. P. Nicolau, E. Perola, S. Ronkin,
D. Shannon, L. L. Swenson, Q. Tang, P. R. Tessier, S.‐K. Tian,
M. Trudeau, T. Wang, Y. Wei, H. Zhang, D. Stamos, J. Med. Chem.
ACKNOWLEDGEMENT
The authors are grateful to the staff of the Department of
Chemistry, Shiraz Branch, Islamic Azad University for their
help with this research.
2
008, 51, 5243.
[
[
15] J. Chen, Z. Wang, C. M. Li, Y. Lu, P. K. Vaddady, B. Meibohm,
J. T. Dalton, D. D. Miller, W. Ji, J. Med. Chem. 2010, 53, 7414.
16] K. Bourgrin, A. Loupy, M. Soufiaoui, Tetrahedron 1998, 54, 8055.
REFERENCES
[17] M. A. Weidner‐Wells, K. A. Ohemeng, V. N. Nguyen, S. Fraga‐
Spano, M. J. Macielag, H. M. Werblood, B. D. Foleno, G. C. Webb,
J. F. Barrett, D. J. Hlasta, Bioorg. Med. Chem. Lett. 2001, 11, 1545.
[
1] D. A. Bazylinski, R. B. Frankel, K. O. Konhauser, Geomicrobiol. J.
007, 24, 465.
2
[18] S. E. López, J. Restrepo, B. Pérez, S. Ortiz, J. Salazar, Bull. Korean
[2] L. Ge, Q. Li, M. Wang, J. Ouyang, X. Li, M. M. Q. Xing, Int. J.
Nanomedicine 2014, 9, 2399.
Chem. Soc. 2009, 30, 1628.
[
[
[
19] I. Bhatnagar, M. V. George, Tetrahedron 1968, 24, 1293.
20] P. Gogoi, D. Konwar, Tetrahedron Lett. 2006, 47, 79.
21] S. Shojaee, M. Mahdavi Shahri, J. Chem. Pharm. Res. 2016, 8,
[
3] M. Maleki, N. Ghamari, M. Kamalzare, RSC Adv. 2014, 4, 9416.
[
4] F. Namvar, R. Mohammad, J. Baharara, M. Mahdavi, E. Amini,
M. S. Chartrand, Int. J. Nanomedicine 2014, 4, 3245.
1
38.
22] M. Mahdavi, F. Namvar, M. B. Ahmad, R. Mohamad, Molecules
013, 18, 5954.
[
5] M. Mahdavi, F. Namvar, M. B. Ahmad, R. Mohamad, Molecules
[
[
[
2
013, 18, 5954.
2
[
6] E. Damiani, T. Bacchetti, L. Padella, L. Tiano, J. Food, Compos.
Anal. 2014, 33, 59.
23] M. Mahdavi, M. B. Ahmad, M. J. Haron, Y. Gharayebi, K. Shameli,
B. Nadi, J. Inorg. Organometal. Polym. Mater. 2013, 23, 599.
[
[
7] S. Arora, Eur. J. Biomed. Pharm. Sci. 2016, 3, 276.
24] N. V. Mahire, P. P. Mahulikar, Chin. Chem. Lett. 2015, 26, 983.
8] S. Khabnadideh, Z. Rezaei, K. Pakshir, K. Zomorodian, N. Ghafari,
Res. Pharm. Sci. 2012, 7, 65.
[
9] D. Sharma, B. Narasimhan, P. Kumar, A. Jalbout, Eur. J. Med.
Chem. 2009, 44, 1119.
How to cite this article: Shojaee S, Mahdavi Shahri
M. An efficient synthesis and cytotoxic activity of 2‐
(4‐chlorophenyl)‐1H–benzo[d]imidazole obtained
using a magnetically recyclable Fe O nanocatalyst‐
[
[
10] A. A. Farahat, E. Paliakov, A. Kumar, A. M. Barghash, F. E. Goda,
H. M. Eisa, T. Wenzler, R. Brun, Y. Liu, W. D. Wilson, D. W.
Boykin, Bioorg. Med. Chem. 2011, 19, 2156.
3
4
mediated white tea extract. Appl Organometal Chem.
11] D. Valdez‐Padilla, S. Rodríguez‐Morales, A. Hernández‐Campos,
F. Hernández‐Luis, L. Yépez‐Mulia, A. Tapia‐Contreras, R.
Castillo, Bioorg. Med. Chem. 2009, 17, 1724.
2
017;e3934. https://doi.org/10.1002/aoc.3934