Syntheses, in vitro evaluation and molecular docking studies of 5-bromo-2-aryl benzimidazoles as α-glucosidase inhibitors

Article abstract of DOI:10.1007/s00044-016-1614-y

Based on the previous reports on α-glucosidase inhibitory activity of benzimidazole class, we intend to evaluate further this class as potential inhibitors of α-glucosidase enzyme. Thus, in the current study synthesis of 5-bromo-2-aryl benzimidazole deriv

Full text of DOI:10.1007/s00044-016-1614-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1614-y
ORIGINAL RESEARCH
Syntheses, in vitro evaluation and molecular docking studies of 5-bromo-
-aryl benzimidazoles as α-glucosidase inhibitors
2
1 ●
2 ●
1 ●
2 ●
5 ●
Tanzila Arshad Khalid Mohammed Khan Najma Rasool Uzma Salar
2
,3 ●
5 ●
4 ●
4 ●
Shafqat Hussain
Tehreem Tahir Mohammed Ashraf Abdul Wadood
6 ●
7,8 ●
7,8
Muhammad Riaz Shahnaz Perveen Muhammad Taha
Nor Hadiani Ismail
Received: 23 February 2016 / Accepted: 14 June 2016
©
Springer Science+Business Media New York 2016
Abstract Based on the previous reports on α-glucosidase
inhibitory activity of benzimidazole class, we intend to
evaluate further this class as potential inhibitors of α-glu-
cosidase enzyme. Thus, in the current study synthesis of
twenty-five showed excellent to moderate activity in
the range of IC50 = 12.4–103.2 μM. Inhibitory results
were compared with the standard drug acarbose (IC50
=
38.25 ± 0.12 μM). Compounds 1 (IC50 = 37.82 ± 0.08 μM),
9 (IC50 = 37.76 ± 0.05 μM), 12 (IC50 = 24.96 ± 0.09 μM),
16 (IC50 = 21.15 ± 0.08 μM) and 17 (IC50 = 8.34 ± 0.02
μM) showed excellent inhibition as compared to standard
drug acarbose (IC50 = 38.25 ± 0.12 μM). Especially,
17 (IC50 = 8.34 ± 0.02 μM) was found to be five-fold more
active than the standard.
5
-bromo-2-aryl benzimidazole derivatives 1–25 was carried
out. All the synthetic compounds were characterized by
1
different spectroscopic techniques EIMS, HRMS, H-NMR,
1
3
and C-NMR. Molecular docking was also performed on
the selected compounds 1, 4, 7, and 17 having varying
substitution pattern in order to understand the molecular
interaction of molecules with the active site of the enzyme.
All compounds were evaluated for their in vitro α-gluco-
sidase inhibitory activities. Twenty-three compounds out of
●
Keywords Benzimidazole In vitro α-Glucosidase
●
●
inhibition Structure-activity relationship Diabetic
●
complications Obesity
*
Khalid Mohammed Khan
hassaan2@super.net.pk
khalid.khan@iccs.edu
Introduction
1
2
Jinnah University for Women, 5-C, Nazimabad, Karachi 74600,
Pakistan
Benzimidazole is a bicyclic and heterocyclic ring structure
consisting of a fused benzene and imidazole ring system (Brink
and Folkers, 1949). Some benzimidazole derivatives are abun-
dant in marine natural products, like in marine sponge (Calcul
et al., 2003). All seven positions are available for substitution in
benzimidazole, but the most biological active analogs are 1, 2,
H. E. J. Research Institute of Chemistry, International Center for
Chemical and Biological Sciences, University of Karachi, Karachi
7
5270, Pakistan
3
4
5
6
7
Deparment of Chemistry, Karakoram International University,
Gilgit, Pakistan
5, di- or tri-substituted analogs. Many drugs possess benzimi-
Department of Biochemistry and Biotechnology, The Islamia
University of Bahawalpur, Bahawalpur 63100, Pakistan
dazole moiety as the core part of their structures, for example,
omeprazole, mebendazole, albendazole, and astemizole. This
indicates the importance of benzimidazole as a privileged
pharmacophore (Dinparast et al., 2016; Castillo et al., 2016;
Song et al., 2015; Gao et al., 2015; Mariappan et al., 2015;
Mavrova et al., 2015; Błaszczak-Świątkiewicz et al., 2014;
Desai et al., 2014; Zhang et al., 2012; Guo et al., 2008; Sur
et al., 2005; Olbe et al., 2003).
Department of Biochemistry Abdul Wali Khan University,
Mardan, Khyber Pakhthunkhwa, Pakistan
PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr.
Salimuzzaman Siddiqui, Karachi 75280, Pakistan
Atta-ur-Rahman Institute for Natural Product Discovery,
Universiti Teknologi MARA (UiTM), Puncak Alam Campus,
4
2300 Bandar, Puncak Alam, Selangor D. E., Malaysia
8
Literature search shows that benzimidazole and its deriva-
tives possess a wide spectrum of biological activities such as
Faculty of Applied Science, Universiti Teknologi MARA, Shah
Alam 40450 Selangor D. E., Malaysia

Med Chem Res
antimicrobial, antiviral, antitumor, antioxidant, antiin-
flammatory, antihypertensive, anticoagulant, antidiabetic,
antiallergic, antihistaminic, antitubercular, anti-HIV, anti-
helmentic, antidepressant, and analgesic activity (Bansal and
Silakari, 2012; Nakano et al., 2000; Achar et al., 2010;
Kazimierczuk et al., 2002; Ozden et al., 2005; Walia et al.,
Saify et al., 1999; Zaidi et al., 2001; Zawawi et al., 2015;
Rahim et al., 2015; Taha et al., 2015) and also explored many
classes of compounds for their α-glucosidase inhibitory
activities (Niaz et al., 2015; Taha et al., 2015; Rahim et al.,
2015; Kashtoh et al., 2014; Khan et al., 2014).
There are only few reports available regarding the α-
glucosidase inhibitory activity of benzimidazole class
members such as benzimidazole pthalimide containing
amino acid (structure A) (Mobinikhaledi et al., 2015) and
aryl substituted benzimidazole (structures B and C) (Kumar
et al., 2010) (Fig. 1). Therefore, we decided to further
explore this class regarding α-glucosidase inhibitory activ-
ity in order to get the more potent inhibitor.
In the light of previous reports, we synthesized 5-bromo-
benzimidazole analogs 1–25 (general structure D) in order to
identify some more molecules having α-glucosidase inhibi-
tory potential with less or no cytotoxicity. To the best of our
knowledge, structures of compounds 1, 2, 4, 6, 9 (Dande-
gaonker and Shastri, 1965), 11, 12, 16, 17 (Cui et al., 2011),
18, 19, and 21 (Dandegaonker and Shastri, 1965) are pre-
viously known, whereas rest of the molecules are new.
2011).
Diabetes mellitus is responsible for about 5 % of the
deaths of the global population. Type 2 diabetes mellitus is
the most common type of disease, in which α-glucosidase
enzyme catalyzes the carbohydrates and converts it into
absorbable monosaccharide in the small intestine (Gao
et al., 2007). α-Glucosidase hydrolyzes the α-glucosidal
bond of linear and branched isomaltose oligosaccharides
and releases α-D-glucose, which is the main cause of
hyperglycemia (Van de Laar, 2008). Inhibition of this
enzyme is one of the simplest ways to treat type 2 diabetes
mellitus by delaying the intestinal glucose absorption pro-
cess (Rhabasa-Lhoret et al., 2004). Acarbose, miglitol, and
voglibose are inhibitors of α-glucosidase, which are being
clinically used for the treatment of type 2 diabetes mellitus
(
Meneilly et al., 2000; Lesley and Caroline, 2000) and
can be used as antidiabetic, anti-HIV, anti-obesity, and
anticancer agents (Gallienne et al., 2006; Groopman, 1990;
Zitzmann et al., 1999).
Results and discussion
Chemistry
However, these drugs are 50 % less effective than other
antidiabetic agents such as metformin and sulfonylurea, as
well as have some associated side effects such as diarrhea,
flatulence, and abdominal discomfort (Ag, 1994). There-
fore, it is a restrictive aspect to use the drug alone and thus it
is often used in combination with other antidiabetic drugs to
improve the efficacy. Hence it is an utmost important task to
develop safer medication for diabetes.
Benzimidazoles 1–25 were synthesized by treating commer-
cially available 4-bromo-1,2-benzenediamine with different
aromatic aldehydes in N,N-dimethylformamide in the presence
of a catalytic amount of sodium metabisulfite (Na S O )
(Scheme 1). 1,2-Diamino groups of 4-bromo-1,2-benzenedia-
mine undergo cyclization reaction with the aromatic aldehydes
to afford desired benzimidazole moieties. The reaction mixture
was refluxed for 4 h to afford the products in the form of
precipitates, which were collected via filtration and crystallized
in ethanol to get the pure products in high yields. Synthesized
derivatives were characterized by different spectroscopic
2
2 5
Our group has explored several classes of heterocyclic
compounds including benzimidazole for their potential ther-
apeutic effects (Khan et al., 1999, 2000, 2002, 2003, 2013;
1
13
techniques such as EIMS, HRMS, H-NMR, and C-NMR.
Biological activities
5
-Bromo-2-aryl benzimidazole derivatives 1–25 were
evaluated for their α-glucosidase inhibitory potential
Table 1). All compounds were found to be active and
(
Scheme 1 Syntheses of 5-bromo-2-aryl benzimidazole derivatives
1–25
Fig. 1 Rationale of the current study

Med Chem Res
Table 1 In vitro α-glucosidase inhibitory activity of 5-bromo-2-aryl
benzimidazole derivatives 1–25
Table 1 continued
S. No.
8
R
(IC50 ± SEM)
96.87 ± 0.11
S. No.
1
R
(IC50 ± SEM)
37.82 ± 0.08
9
37.76 ± 0.05
97.35 ± 0.14
2
3
4
145.21 ± 0.16
54.62 ± 0.07
131.95 ± 0.12
1
0
1
1
1
2
92.63 ± 0.05
24.96 ± 0.09
5
6
61.34 ± 0.08
102.26 ± 0.17
1
1
3
4
97.31 ± 0.12
119.78 ± 0.12
7
158.23 ± 0.12
1
5
174.62 ± 0.19

Med Chem Res
Table 1 continued
S. No.
Table 1 continued
R
(IC50 ± SEM)
21.15 ± 0.08
S. No.
24
R
(IC50 ± SEM)
1
6
NA
1
7
8.34 ± 0.02
2
5
NA
1
8
102.82 ± 0.06
Standard = Acarbose
38.25 ± 0.12
SEM standard error of mean, NA not active, Std standard inhibitor
for α-glucosidase
showed their potential in terms of IC50 values within the
range of 8.34–174.62 μM when compared with the standard
drug acarbose (IC50 = 38.25 ± 0.12 μM), only two mole-
1
2
9
0
119.78 ± 0.11
114.27 ± 0.12
cules 24 and 25 showed no activity. Compounds 1 (IC50
=
=
=
3
2
8
7.82 ± 0.08 μM), 9 (IC50 = 37.76 ± 0.05 μM), 12 (IC50
4.96 ± 0.09 μM), 16 (IC50 = 21.15 ± 0.08 μM), 17 (IC50
.34 ± 0.02 μM) showed excellent and compounds 3 (IC50
54.62 ± 0.07 μM) and (IC50 = 61.34 ± 0.08 μM)
=
5
showed good inhibitory potential as compared to standard
acarbose (Table 1). However, other analogs exhibited
moderate inhibitory potential.
Limited structure-activity relationship studies revealed
that the activity of this series of compound mainly depends
upon the substitutions on the phenyl part of benzimidazole
moiety at position 2, their nature and respective positions of
substituents. Compound 17 (IC50 = 8.34 ± 0.02 μM) having
2
1
117.76 ± 0.13
4
-hydroxyl substitution was found to be five-fold more
active than the standard (IC50 = 38.25 ± 0.12 μM), analog
6 having 3-bromo substitution, residue 12 having 4-butoxy
1
substitution, molecule 9 having 2-hydroxyl substitution and
moiety 1 having 2-hydroxy, and 4-methoxy substitution on
the phenyl part at position 2 of benzimidazole showed
excellent inhibitory potential as compared to standard
acarbose. In order to understand the mechanism of
α-glucosidase inhibition, mode of binding inside the bind-
ing pocket of enzyme of these benzimidazoles and to con-
firm the assay results, molecular docking studies were
carried out.
2
2
3
92.47 ± 0.16
86.36 ± 0.11
2
Molecular docking
Docking studies were carried out using MOE-Dock as
docking software implemented in molecular operating

Med Chem Res
Fig. 2 Predicted binding mode of a compound 17, b compound 1, c compound 7, and d compound 4 in the active site of α-glucosidase
environment (MOE) (www.chemchomp.com). The docking
scores demonstrated that these compounds showed inter-
actions with active site residues of the enzyme. Docking
score is the binding free energy calculated by the GBVI/
WSA scoring function, which is the score of the last stage
showing the overall fitness of compound in the pocket. For
all scoring functions, lower scores indicate more favorable
poses. The unit for all scoring functions is kcal/mol. The
docking conformation of the most active compound 17 in
the series showed six interactions with important active site
residues (Fig. 2a). The hydroxyl group at the phenyl ring
established two hydrogen bonds with His111 and Gln181,
respectively. The phenyl ring of the compound formed
arene–arene and arene–cation interactions with active site
residues Phe177 and Arg439, respectively. Furthermore, the
imidazole ring of the compound formed arene–arene and
arene–cation interactions with Phe300 and Arg439,
respectively. The presence of electron donating group OH at
position 4 of the phenyl ring increases the electron density;
as a result more interactions were observed for this com-
pound. This strong bonding network might be one of the
reasons for compound 17 to be the most active in the series.
Like compound 17, good interactions were observed for
compounds 1, 3, 5, 9, 12, and 16. All these compounds have
electron donating moiety at phenyl ring and thus have
increased electron density that might be responsible for the
good interactions between these compounds and active site
residues. The lower activities of compounds 1, 3, 5, and 12
as compare to compound 17 might be due to the presence of
methoxy or chlorine moieties at the phenyl ring that pro-
duce steric hindrance between these compounds and active
site residues of the enzyme as indicated by the lower
docking scores of these compound. For example, in case of
compound 1, only four interactions were observed between
the compound and active site residues of the enzyme
(Fig. 2b). The oxygen atom of the methoxy group of com-
pound 1 forms a hydrogen bond with His239, the phenyl
ring of the compound forms arene–arene interaction with
Phe157, whereas the imidazole ring of the compound
establishes two arene–cation interactions with Arg312. In
the case of least-active compounds 15, 7, 2, and 4 mild
interactions were observed. The mild interactions observed
in case of these compounds might be due to the presence of
more steric hindrance on the phenyl ring of these com-
pounds as compared to compound 17. For example, in the
case of compound 7, only two interactions were observed.

Med Chem Res
Fig. 3 Binding interaction of
acarbose in the binding pocket
of α-glucosidase
The oxygen atom of methoxy group of compound 7 estab-
lished hydrogen bond with active site residue Arg312, while
the imidazole ring of the compound formed arene–arene
interaction with active site residue Phe177 (Fig. 2c). Simi-
larly, the docking conformation of compound 4 showed that
oxygen atom of the methoxy moiety of the compound
formed hydrogen bond with active site residue His348,
whereas the phenyl and imidazole rings of the compound
established arene–cation interactions with Arg439 and
Arg312, respectively (Fig. 2d). Overall the docking results
showed that the electron donating moieties on the phenyl ring
of these compounds promote the interaction with the active
site residues and thus increase the activity. However,
increasing the number of different moieties on the phenyl
ring increases the steric hindrance and thus decreases the
number of interactions, resulting in lowering the activity. To
test the adopted protocols and to compare the molecular
docking study of the synthetic compounds, the standard
inhibitor acarbose was docked into the active site of our
developed α-glucosidase model. The acarbose fitness in the
binding pocket and interaction with the important active site
residues is shown in Fig. 3, which reflects a good correlation.
further chemical modifications on these molecules could
have resulted in lead molecules with high degree of inhibi-
tory activity and selectivity towards α-glucosidase enzyme.
Materials and methods
Reagents were purchased from Sigma-Aldrich, USA. All
reagents and solvents were of analytical grade and used as
received. Thin layer chromatography was performed on pre-
coated silica gel, GF-254. Spots were visualized under
ultraviolet light at 254 and 366 nm. Mass spectra were
recorded under electron impact (EI) on MAT 312 and MAT
1
113D mass spectrometers. The H-NMR were recorded on a
Bruker AM spectrometer, operating at 300, 400, and 500
MHz. The chemical shift values are presented in ppm (δ)
relative to tetramethylsilane (TMS) as an internal standard
and the coupling constants (J ) are in Hz.
In vitro α-glucosidase inhibition assay
α-Glucosidase inhibitory potential of all the synthetic ben-
zimidazoles was measured by the reported method (Rahim
et al., 2015). Typically, α-glucosidase activity was mea-
sured in phosphate buffer 50 mM of pH 6.8 that contains
Conclusion
5
% v/v dimethylsulfoxide, and PNP glycoside was used as
5
-Bromo-2-aryl benzimidazole derivatives 1–25 were
a substrate. The inhibitors were pre-incubated with enzyme
for half an hour at 37 °C. Then substrate was added and the
enzymatic reaction was performed for 60 min at 37 °C.
Absorbance was measured spectrophotometrically at 400
nm. The assay was carried in triplicate at five different
concentrations around the IC50 values that were roughly
calculated in the first turn of the experiments, and the mean
values were adopted.
screened for α-glucosidase inhibitory potential. Compounds
1
1
and 17 (IC = 8.34 ± 0.02 μM) showed potent α-glucosidase
inhibitory activity as compared to standard acarbose (IC =
(IC = 37.82 ± 0.08 μM), 9 (IC = 37.76 ± 0.05 μM),
5
0
50
2 (IC = 24.96 ± 0.09 μM), 16 (IC = 21.15 ± 0.08 μM),
5
0
50
5
0
5
0
3
8.25 ± 0.12 μM). Molecular docking studies were carried
out to identify their mode of binding, which revealed that

Med Chem Res
General experimental procedure for the syntheses of
141.3 (C, C-8), 140.6 (C, C-9), 130.8 (C, C-1′), 130.6 (CH,
C-6′), 126.1 (CH, C-6), 121.3 (C, C-2′), 118.8 (CH, C-4),
5
-bromo-2-aryl benzimidazole derivatives 1–25
1
18.3 (CH, C-3′), 117.7 (C, C-5), 117.4 (CH, C-7), 113.7
4
-Bromo-1,2-diaminobenzene (1 mmol) and different sub-
(CH, C-5′), 55.7 (CH , OCH ); EIMS: m/z (rel. abund. %),
3
3
+
stituted aromatic aldehydes (1 mmol) in N,N-dimethylfor-
mamide (10 mL) were taken into a 100 mL round-bottomed
flask. Catalytic amount of sodium metabisulfite (Na S O )
380 (M , 51), 382 (M+2, 100), 383 (M+4, 45), 367 (16),
352 (49), 339 (40), 303 (11), 288 (20); HRMS (EI) calcd.
for C H Br N O: m/z = 379.9160, found 379.9166.
2
2
5
14 10
2 2
was added into the reaction mixture and refluxed for 4 h.
Reaction progress was carefully monitored by thin layer
chromatography. After completion of reaction, it was added
into chilled distilled water (100 mL). Precipitates were
formed and filtered to afford products. Crude products were
crystallized from ethanol to get pure products in high yields.
5-Bromo-2-(4-ethoxy-3-methoxyphenyl)-1H-benzo[d]
imidazole (4)
1
Yield: 76 %; H-NMR: (400 MHz, DMSO-d ): δ 7.80
6
(d, 1H, J4,6 = 2 Hz, H-4), 7.74 (dd, 1H, J6′,2′ = 2, J6′,5′
=
8
.8 Hz, H-6′), 7.72 (d, 1H, J2′,6′ = 1.6 Hz, H-2′), 7.51 (d,
2
-(5-Bromo-1H-benzo[d]imidazol-2-yl)-5-methoxyphenol (1)
1H, J7,6 = 8.4 Hz, H-7), 7.32 (dd, 1H, J6,4 = 1.6, J6,7 = 8.4
Hz, H-6), 7.09 (d, 1H, J5′,6′ = 8 Hz, H-5′), 4.16 (m, 2H,
1
13
Yield: 82 %; H-NMR (300 MHz, DMSO-d ): δ 7.88
CH ), 3.92 (s, 3H, OCH ), 1.42 (t, 3H, CH ); C-NMR
6
2
3
3
(
d, 1H, J6′,5′ = 9.3 Hz, H-6′), 7.79 (d, 1H, J4,6 = 1.8 Hz,
(75 MHz, DMSO-d ): δ 152.8 (C, C-2), 150.5 (C, C-4′),
6
H-4), 7.56 (d, 1H, J7,6 = 8.7 Hz, H-7), 7.4 (dd, 1H, J6,4
=
150.3 (C, C-3′), 141.0 (C, C-8), 140.6 (C, C-9), 126.3
(CH, C-6), 123.1 (C, C-1′), 122.0 (CH, C-6′), 118.8 (CH,
C-4), 117.6 (C, C-5), 117.3 (CH, C-7), 111.8 (CH, C-1′) ,
111.3 (CH, C-5′), 64.7 (CH2, OCH ), 56.4 (CH , OCH )
1
3
4
.8, J6,7 = 8.4 Hz, H-6), 6.59 (m, 2H, H-3′, H-5′), 3.85 (s,
1
3
H, OCH3); C-NMR (75 MHz, DMSO-d ): δ 162.2 (C, C-
6
′), 156.1 (C, C-2′), 152.7 (C, C-2) , 141.3 (C, C-8), 140.6
2
3
3
(
4
C, C-9), 129.8 (CH, C-6′), 126.1 (CH, C-6), 118.8 (CH, C-
14.7 (CH , OCH CH ); EIMS: m/z (rel. abund. %), 346
3 2 3
+
), 117.6 (C, C-5), 117.4 (CH, C-7), 110.5 (C, C-1′), 107.3
(M , 100), 348 (M+2, 93), 317 (47), 289 (15), 260 (5), 192
(
CH, C-5′), 104.4 (CH, C-3′), 55.9 (CH , OCH ); EIMS:
(2); HRMS (EI) calcd. for C H BrN O : m/z =
3
3
16 15
2 2
+
m/z (rel. abund. %), 318 (M , 100), 320 (M+2, 96), 289
14), 277 (21), 196 (5), 168 (7), 90 (4); HRMS (EI) calcd.
for C H BrN O : m/z = 318.0004, found 318.0010.
346.0317, found 346.0310.
(
2-(5-Bromo-1H-benzo[d]imidazol-2-yl)-4,6-dichlorophenol
5)
1
4
11
2 2
(
5
-Bromo-2-(4-bromo-2-fluorophenyl)-1H-benzo[d]
1
imidazole (2)
Yield: 72 %; H-NMR: (300 MHz, DMSO-d ): δ 7.97
6
(
d, 1H, J4,6 = 2.4 Hz, H-4), 7.86 (bd.s, 1H, H-6′), 7.65
1
Yield: 85 %; H-NMR: (400 MHz, DMSO-d ): δ 8.16 (d, 1H,
(d, 1H, J7,6 = 8.7 Hz, H-7), 7.54 (d, 1H, J4′,6′ = 2.4 Hz,
H-4′), 7.48 (dd, 1H, J6,4 = 1.8, J6,7 = 8.4 Hz, H-6); C-NMR
(75 MHz, DMSO-d ): δ 154.4 (C, C-2′), 152.7 (C, C-2),
6
1
3
J7,6 = 8.4 Hz, H-7), 7.85 (dd, 2H, J6,4/5′,3′ = 1.6, J6,7/5′,6′ = 9.2
Hz, H-6, H-5′), 7.64 (d, 1H, J3′,5′ = 2 Hz, H-3′), (d, 1H, J
=
4,6
6
13
1
.6 Hz, H-4), 7.4 (m, 1H, H-6′); C-NMR (75 MHz,
141.3 (C, C-8), 140.6 (C, C-9), 131.7 (CH, C-4′), 127.4 (C,
C-5′), 126.8 (CH, C-6′), 126.2 (CH, C-6), 126.0 (C, C-3′),
121.3 (C, C-1′), 118.6 (CH, C-4), 117.7 (C, C-5), 117.3
DMSO-d ): δ 160.4 (C, C-2′), 152.7 (C, C-2), 141.3
6
(
1
C, C-8), 140.6 (C, C-9), 131.2 (CH, C-6′), 127.6 (CH, C-5′),
+
26.4 (CH, C-6), 124.6 (C, C-4′), 122.3 (C, C-1′), 121.1 (CH,
(CH, C-7); EIMS: m/z (rel. abund. %), 356 (M , 78), 358
C-3′), 118.6 (CH, C-4), 117.6 (C, C-5), 117.3 (CH, C-7);
(M+2, 100), 360 (M+4, 58), 295 (19), 277 (5), 249 (5),
213 (4), 179 (7), 90 (4), 63 (6); HRMS (EI) calcd. for
C H BrCl N O: m/z = 355.9119, found 355.9113.
+
EIMS: m/z (rel. abund. %), 368 (M , 94), 370 (M+2, 100), 372
(
M+4, 70), 291 (20), 228 (49), 154 (40), 127 (11); HRMS (EI)
1
3
7
2 2
calcd. for C H Br FN : m/z = 367.8960, found 367.8968.
13
7
2
2
2-Bromo-4-(5-bromo-1H-benzo[d]imidazol-2-yl)phenol (6)
5
-Bromo-2-(2-bromo-4-methoxyphenyl)-1H-benzo[d]
1
imidazole (3)
Yield: 71 %; H-NMR: (400 MHz, DMSO-d ): δ 11.05
6
(
s, 1H, NH), 8.32 (d, 1H, J4,6 = 2 Hz, H-4), 8.01 (dd, 1H,
1
Yield: 75 %; H-NMR: (400 MHz, DMSO-d ): δ 8.4 (d, 1H,
J6′,2′ = 1.6, J6′,5′ = 8.4 Hz, H-6′), 7.79 (d, 1H, J2′,6′ = 0.8
Hz, H-2′), 7.56 (d, 1H, J7,6 = 8.4 Hz, H-7), 7.04 (dd, 1H,
J6,4 = 1.6, J = 8.4 Hz, H-6), 7.13 (d, 1H, J5′,6′ = 8.8 Hz,
H-5′); C-NMR (75 MHz, DMSO-d ): δ 156.7 (C, C-4′),
152.8 (C, C-2), 141.3 (C, C-8), 140.5 (C, C-9), 133.1 (CH,
6
J4,6 = 2 Hz, H-4), 8.19 (dd, 1H, J6,4 = J6,5 = 8.8 Hz, H-6),
7
.75 (d, 1H, J3′,5′ = 1.6 Hz, H-3′), 7.54 (d, 1H, J7,6 = 8.4
6,7
1
3
Hz, H-7), 7.35 (dd, 1H, J5′,3′ = 2, J5′,6′ = 8.8 Hz, H-5′), 7.27
6
1
3
(
d, 1H, J6′,5′ = 8.8 Hz, H-6′), 3.99 (s, 3H, OCH3); C-NMR
(
75 MHz, DMSO-d ): δ 158.5 (C, C-4′), 152.7 (C, C-2),
C-2′), 129.6 (CH, C-6′), 126.3(CH, C-6), 123.8 (C, C-1′),
6

Med Chem Res
1
18.8 (CH, C-4), 118.4 (CH, C-5′), 117.6 (C, C-5), 117.3
2-(3-(Benzyloxy)-4-methoxyphenyl)-5-bromo-1H-benzo[d]
imidazole (10)
(
(
(
CH, C-7), 114.2 (C, C-3′); EIMS: m/z (rel. abund. %), 366
+
M , 100), 368 (M+2, 100), 370 (M+4, 100), 239 (2), 287
1
31), 259 (13), 208 (25), 179 (18); HRMS (EI) calcd. for
Yield: 63 %; H-NMR: (400 MHz, DMSO-d ): δ 7.88 (d,
6
C H Br N O: m/z = 365.9003, found 365.9007.
1H, J4,6 = 1.6 Hz, H-4), 7.81 (d, 1H, J2′,6′ = 1.2 Hz, H-
1
3
8
2 2
2
′), 7.79 (dd, 1H, J6,4 = 1.6, J6,7 = 8.4 Hz, H-6), 7.60 (d,
5
-Bromo-2-(2-chloro-3,4-dimethoxyphenyl)-1H-benzo[d]
1H, J7,6 = 8.8 Hz, H-7), 7.51 (d, 2H, J2′′,3′′ = J6′′,5′′ = 7.2
imidazole (7)
Hz, H-2′′, H-6′′), 7.44 (t, 3H, J3′′(2′′,4′′) = J4′′(3′′,5′′)
J5′′(3′′,4′′) = 7.2 Hz, H-3′′, H-4′′, H-5′′), 7.37 (d, 1H,
J6′,5′ = 7.2 Hz, H-6′), 7.23 (d, 1H, J5′,6′ = 8.8 Hz, H-5′),
=
1
Yield: 56 %; H-NMR: (400 MHz, DMSO-d ): δ 7.91
6
1
3
(
7
=
d, 1H, J6′,5′ = 8.8 Hz, H-6′), 7.81 (d, 1H, J4,6 = 1.6 Hz, H-4),
.60 (d, 1H, J7,6 = 8.4 Hz, H-7), 7.38 (dd, 1H, J6,4 = 1.6, J6,7
8.4 Hz, H-6), 7.22 (d, 1H, J = 8.8 Hz, H-5′), 3.98 (s, 3H,
5.19 (s, 2H, CH ), 3.39 (s, 3H, OCH ); C-NMR (75
2 3
MHz, DMSO-d ): δ 152.8 (C, C-2), 149.6 (C, C-4′),
6
148.5 (C, C-3′), 141.3 (C, C-8), 140.6 (C, C-9), 136.5
(CH , OCH ), 128.8 (CH, C-3′′), 128.6 (CH, C-5′′),
5
′,6′
1
3
OCH ), 3.86 (s, 3H, OCH ); C-NMR (75 MHz, DMSO-d6):
3
3
2
2
δ 152.8(C, C-2), 151.0 (C, C-4′), 150.8 (C, C-3′), 141.2 (C,
C-8), 140.5 (C, C-9), 131.6 (C, C-1′), 126.1 (CH, C-6), 122.3
127.7 (CH, C-4′′), 127.2 (CH, C-6′′), 127.0 (CH, C-2′′),
126.1 (CH, C-6), 123.8 (C, C-1′), 122.5 (CH, C-6′),
118.5 (CH, C-4), 117.6 (C, C-5), 117.3 (CH, C-7), 112.2
(CH, C-2′), 111.1 (CH, C-5′), 71.2 (CH , OCH ); EIMS:
(
CH, C-6′) 118.7 (CH, C-4), 118.5 (C, C-5), 117.6 (CH, C-7),
1
17.5 (C, C-2′), 109.2 (CH, C-5′), 56.3 (2CH , OCH );
3
3
3
3
+
+
EIMS: m/z (rel. abund. %), 366 (M , 100), 368 (M+2, 100),
70 (M+4, 98), 353 (31), 325 (55), 310 (23), 288 (16), 244
30) 184 (17), 166 (10); HRMS (EI) calcd. for C H
m/z (rel. abund. %), 391 (M , 33), 393 (M+2, 42),
317 (58), 291 (4), 246 (2); HRMS (EI) calcd. for
C H BrN O : m/z = 392.0524, found 392.0529.
3
(
15
12
21 17
2
2
BrClN O : m/z = 365.9771, found 365.9777.
2
2
5-Bromo-2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]
5
-Bromo-2-(4-bromo-3,5-dimethoxyphenyl)-1H-benzo[d]
imidazole (11)
imidazole (8)
1
Yield: 68 %; H-NMR: (400 MHz, DMSO-d ): δ 7.95 (d,
6
1
Yield: 42 %; H-NMR: (400 MHz, DMSO-d ): δ 7.80
1H, J6′,5′ = 7.6 Hz, H-6′), 7.84 (m, 4H, H-4, H-2′, H-4′, H-
6
(
7
d, 1H, J4,6 = 1.6 Hz, H-4), 7.58 (d, 1H, J7,6 = 9.2 Hz, H-7),
.55 (s, 2H, H-2′, H-6′), 7.39 (dd, 1H, J = 2, J6,7 = 8.8 Hz,
5′), 7.59 (d, 1H, J7,6 = 8.8 Hz, H-7), 7.39 (dd, 1H, J
=
6,4
1
3
1.6, J6,7 =8.8 Hz, H-6); C-NMR (75 MHz, DMSO-d ): δ
6
,4
6
1
3
H-6), 4.00 (s, 6H, 2OCH3); C-NMR (75 MHz, DMSO-d6):
δ 158.4 (C, C-3′), 158.4 (C, C-5′), 152.7 (C, C-2), 141.3 (C,
C-8), 140.6 (C, C-9), 131.4 (C, C-1′), 126.1 (CH, C-6), 118.9
152.8 (C, C-2), 141.3 (C, C-8), 140.6 (C, C-9), 137.7 (C,
C-2′), 135.3 (CH, C-6′), 131.4 (C, C-3′), 129.6 (CH, C-
5′), 126.3 (CH, C-6), 125.4 (CH, C-2′), 125.0 (CH, C-4′),
(
CH, C-4), 117.6 (C, C-2), 117.4 (CH, C-7), 105.6 (CH, C-
124.2 (C, CF ), 118.8 (CH, C-4), 117.6 (C, C-5), 117.4
3
+
2
5
4
3
′) , 105.6 (CH, C-6′), 99.6 (C, C-4′), 55.0 (CH , OCH ),
(CH, C-7); EIMS: m/z (rel. abund. %), 340 (M , 99), 342
(M+2, 99), 322 (100), 301 (29), 241 (44), 152 (14); HRMS
(EI) calcd. for C H BrF N : m/z = 339.9823, found
3
3
+
5.0 (CH , OCH ); EIMS: m/z (rel. abund. %), 410 (M , 79),
3
3
12 (M+2, 100), 414 (M+4, 80), 381 (8), 352 (4), 331 (7),
01 (17), 273 (21), 247 (9), 206 (11); HRMS (EI) calcd. for
1
4
8
3 2
339.9828.
C H Br N O : m/z = 409.9266, found 409.9261.
1
5
12
2 2 2
5-Bromo-2-(4-butoxyphenyl)-1H-benzo[d]imidazole (12)
2
-(5-Bromo-1H-benzo[d]imidazol-2-yl)phenol (9)
1
Yield: 51 %; H-NMR: (400 MHz, DMSO-d ): δ 8.13
6
1
Yield: 76 %; H-NMR: (300 MHz, DMSO-d ): δ 7.80
(d, 2H, J2′,6′ = J6′,5′ = 8.8 Hz, H-2′, H-6′), 7.79 (s, 1H, H-4),
7.68 (d, 1H, J7,6 = 8.4 Hz, H-7), 7.41 (d, 1H, J6,7 = 8.4 Hz,
H-6), 7.16 (d, 2H, J3′,2′ = J5′,6′ = 8.4 Hz, H-3′, H-5′), 4.09
(t, 2H, OCH ), 1.75 (m, 2H, CH ), 1.48 (m, 2H, CH ), 0.96
6
(
d, 1H, J4,6 = 1.5 Hz, H-4), 7.73 (m, 1H, H-5′), 7.68 (d,
1
7
H, J6′,5′ = 7.8 Hz, H-6′), 7.59 (d, 1H, J7,6 = 8.7 Hz, H-7),
13
.39 (m, 2H, H-6, H-4′), 7.02 (m, 1H, H-3′); C-NMR
2
2
2
1
3
(
1
75 MHz, DMSO-d ): δ 154.2 (C, C-2′), 152.8 (C, C-2),
(t, 2H, CH3); C-NMR (75 MHz, DMSO-d ): δ 159.5 (C,
6
6
41.3 (C, C-8), 140.6 (C, C-9), 131.8 (CH, C-6′), 130.3
C-4′), 152.8 (C, C-2), 141.2 (C, C-8), 140.6 (C, C-9), 129.8
(CH, C-2′), 129.8 (CH, C-6′), 126.0 (CH, C-6), 118.9 (CH,
C-4), 117.4 (C, C-4), 117.3 (CH, C-7), 114.8 (CH, C-3′),
114.8 (CH, C-5′), 112.2 (C, C-1′), 68.6 (CH , OCH ), 31.7
(
(
CH, C-4′), 126.3 (CH, C-6), 121.9 (CH, C-5′), 118.6
C1, C-1′), 118.4 (CH, C-4), 117.6 (C, C-5), 117.6 (CH,
C-3′), 117.3 (CH, C-7); EIMS: m/z (rel. abund. %), 286
(
2
2
+
M , 100), 288 (M+2, 89), 236 (10), 192 (7), 157 (10);
(CH , O-CH CH ), 19.1 (CH2, O-CH CH CH ), 14.2
2 2 2 2 2 2
HRMS (EI) calcd. for C H BrN O: m/z = 287.9898,
found 287.9894.
(CH OCH CH CH CH ); EIMS: m/z (rel. abund. %), 344
(M , 55), 346 (M+2, 56), 319 (3), 289 (100), 260 (6), 209 (6);
1
3
9
2
2,
2
2
2
3
+

Med Chem Res
HRMS (EI) calcd. for C H BrN O: m/z = 344.0524,
5-Bromo-2-(3-bromophenyl)-1H-benzo[d]imidazole (16)
1
7
17
2
found 344.0528.
1
Yield: 76 %; H-NMR: (400 MHz, DMSO-d ): δ 8.36 (s,
6
2
-(5-Bromo-1H-benzo[d]imidazol-2-yl)-4,6-di-tert-
1H, H-4), 8.18 (d, 1H, J6′,5′ =7.6 Hz, H-6′), 7.84 (s, 1H, H-
2′), 7.76 (d, 1H, J4′,5′ = 8 Hz, H-4′), 7.62 (d, 1H, J7,6 = 8.8
butylphenol (13)
Hz, H-7), 7.57 (t, 1H, J5 = J5′,6′ = 8 Hz, H-5′), 7.42 (d,
′,4′
1
13
Yield: 65 %; H-NMR: (400 MHz, DMSO-d ): δ 7.91 (d,
1H, J6,7 = 8.4 Hz, H-6); C-NMR (75 MHz, DMSO-d ): δ
6
6
1
1
1
H, J6′,4′ = 2 Hz, H-6′), 7.74 (m, 2H, H-4, H-7), 7.43 (d,
H, J6,7 = 8 Hz, H-6), 7.37 (d, 1H, J4′,6′ = 2 Hz, H-6′),
152.7 (C, C-2), 141.0 (C, C-8), 140.6 (C, C-9), 131.8 (CH,
C-2′), 131.5 (CH, C-5′), 131.2 (C, C-1′), 128.2 (CH, C-4′),
126.6 (CH, C-6′), 126.2 (CH, C-6), 122.0 (CH, C-3′), 118.6
(CH, C-4), 117.6 (C, C-5), 117.3 (CH, C-7); EIMS: m/z (rel.
abund. %), 350 (M , 87), 352 (M+2, 100), 354 (M+4, 94),
290 (2), 271 (25), 246 (2), 192 (45), 176 (7); HRMS (EI)
1
3
.42 (s, 9H, 3CH ), 1.34 (s, 9H, 3CH ); C-NMR (75
3
3
MHz, DMSO-d ): δ 152.8 (C, C-2), 145.4 (C, C-2′), 142.5
6
+
(
1
(
7
C, C-5′), 141.2 (C, C-8), 140.6 (C, C-9), 138.3 (C, C-3′),
26.3(C, C-6), 126.1 (CH, C-4′), 124.8 (CH, C-6′), 118.6
CH, C-4), 117.4 (C, C-1′), 117.6 (C, C-5), 117.4 (CH, C-
), 34.9 (C, C(CH ) ), 34.7 (C, C(CH ) ), 31.5 (CH , C
calcd. for C H Br N : m/z = 349.9054, found 349.9058.
1
3
8
2 2
3
3
3 3
3
(
CH ) ), 31.5 (CH , C(CH ) ), 31.5 (CH , C(CH ) ), 31.4
4-(5-Bromo-1H-benzo[d]imidazol-2-yl)phenol (17)
3
3
3
3 3
3
3 3
(
(
CH , C(CH ) ), 31.4 (CH , C(CH ) ), 31.4 (CH , C
3 3 3 3 3 3 3
+
1
CH ) ); EIMS: m/z (rel. abund. %), 400 (M , 40), 402 (M
Yield: 0.11 g (71 %); H-NMR: (400 MHz, DMSO-d ): δ
3
3
6
+
2, 34), 387 (100), 359 (25), 343 (21), 329 (21), 250 (3);
8.07 (dd, 2H, J2′,6′/6′,2′ = 1.6, J2′,3′/6′,5′ = 6.8 Hz, H-2′, H-6′),
7.71 (d, 1H, J4,6 = 1.6 Hz, H-4), 7.49 (d, 1H, J7,6 = 8.8 Hz,
H-7), 7.31 (dd, 1H, J6,4 = 2 J6,7 = 8.4 Hz, H-6), 6.99 (d, 2H,
HRMS (EI) calcd. for C H BrN O: m/z = 400.1150,
found 400.1154.
2
1
25
2
1
3
J3′,2′ = J5′,6′ = 8.8 Hz, H-3′, H-5′);
C-NMR (75 MHz,
DMSO-d ): δ 158.6 (C, C-4′), 152.7 (C, C-2), 141.3 (C, C-
5
-Bromo-2-(2-fluoro-4-methoxyphenyl)-1H-benzo[d]
6
imidazole (14)
8), 140.6 (C, C-9), 130.5 (CH, C-2′), 130.5 (CH, C-6′), 126.3
(CH, C-6), 118.8 (CH, C-4), 117.6 (C, C-5), 117.4 (CH, C-
1
Yield: 84 %; H-NMR: (400 MHz, DMSO-d ): δ 8.15 (m,
7), 116.6 (CH, C-3′), 116.6 (CH, C-5′), 113.2 (C, C-1′);
6
+
1
=
H, H-3′), 7.82 (d, 1H J4,6 = 1.2 Hz, H-4), 7.60 (d, 1H, J7,6
8.4 Hz, H-7), 7.42 (dd, 1H, J6,4 = 1.6, J6,7 = 8.8 Hz, H-6),
EIMS: m/z (rel. abund. %), 288 (M , 100), 290 (M+2, 91),
261 (4), 209 (9), 182 (8), 170 (2), 144 (4); HRMS (EI) calcd.
7
.13 (dd, 1H, J6′,3′ = 2, J6′,5′ = 13.6 Hz, H-6′), 7.03 (dd, 1H,
for C H BrN O: m/z = 287.9898, found 287.9892.
13
9
2
1
3
J5′,3′ = 2, J5′,6′ = 8.8 Hz, H-5′), 3.87 (s, 3H, OCH3); C-
NMR (75 MHz, DMSO-d ): δ 159.7 (C, C-4′), 159.1 (C, C-
5-Bromo-2-(naphthalen-2-yl)-1H-benzo[d]imidazole (18)
6
2
′), 152.8 (C, C-2), 141.0 (C, C-8), 140.6 (C, C-8), 130.2
1
(
5
1
CH, C-6′), 126.3(CH, C-6), 118.6 (CH, C-4), 117.6 (C, C-
), 117.4 (CH, C-7), 115.7 (C, C-1′), 110.3 (CH, C-5′),
02.8 (CH, C-3′), 55.6 (CH , OCH ); EIMS: m/z (rel.
Yield: 65 %; H-NMR: (400 MHz, DMSO-d ): δ 8.72 (s, 1H,
6
H-4), 8.36 (dd, 1H, J8′,2′ = 1.6, J8′,7′ = 8.8 Hz, H-8′), 8.06 (d,
1H, J7,6 = 8.4 Hz, H-7), 8.04 (m, 1H, H-3′), 7.99 (m,1H, H-
6′), 7.81 (d, 1H, J2′,8′ = 1.6 Hz, H-2′), 7.81 (m, 3H, H-4′, H-5′,
3
3
+
abund. %), 320 (M , 98), 322 (M+2, 100), 307 (36),
79 (15), 259 (11), 241 (3); HRMS (EI) calcd. for
C H BrFN O: m/z = 319.9961, found 319.9966.
13
2
H-7′), 7.39 (dd, 1H, J6,4 = 2 J6,7 = 8.4 Hz, H-6); C-NMR
(75 MHz, DMSO-d ): δ 152.8 (C, C-2), 141.2 (C, C-8), 140.6
1
4
10
2
6
(C, C-9), 133.8 (C, C-1′), 133.7 (C, C-9′), 133.2 (C, C-10′),
5
-Bromo-2-(3-bromo-4-fluorophenyl)-1H-benzo[d]
131.8 (CH, C-8′), 128.3 (CH, C-4′), 128.3 (CH, C-7′), 126.3
(CH, C-6), 126.1 (CH, C-5′), 126.1 (CH, C-6′), 125.8 (CH, C-
imidazole (15)
2
′), 124.6 (CH, C-8′), 118.6 (CH, C-4), 117.6 (C, C-5), 117.4
1
+
Yield: 88 %; H-NMR: (400 MHz, DMSO-d ): δ 8.49 (dd,
1
(CH, C-7); EIMS: m/z (rel. abund. %), 322 (M , 100), 324 (M
+2, 92), 242 (22), 216 (3), 189 (2), 153 (7); HRMS (EI) calcd.
for C H BrN : m/z = 322.0106, found 322.0101.
6
H, J6′,2′ = 2, J6′,5′ = 6.4 Hz, H-6′), 8.22 (m, 1H, H-5′), 7.81
(
1
s, 1H, H-2′), 7.62 (m, 2H, H-4, H-7), 7.39 (dd, 1H, J
=
6,4
17 11
2
1
3
.6, J6,7 = 8.8 Hz, H-6); C-NMR (75 MHz, DMSO-d ): δ
6
1
65.3 (C, C-4′), 152.7 (C, C-2), 141.3 (C, C-8), 140.8 (C,
5-Bromo-2-(4-ethoxyphenyl)-1H-benzo[d]imidazole (19)
C-9), 134.6 (CH, C-2′), 128.3 (CH, C-6′), 126.7 (C, C-1′),
1
1
26.1(CH, C-6), 118.9 (CH, C-4), 118.3 (CH, C-5′), 117.6
Yield: 70 %; H-NMR: (400 MHz, DMSO-d ): δ 8.14 (d,
6
(
(
C, C-5), 117.3 (CH, C-7), 110.4 (CH, C-3′); EIMS: m/z
rel. abund. %), 368 (M , 71), 370 (M+2, 100), 372 (M+4,
2H, J2′,3′ = J6′,5′ = 8.8 Hz H-2′, H-6′), 7.72 (d, 1H, J4,6 =
+
1.6 Hz, H-4), 7.51 (d, 1H, J7,6 = 8.4 Hz, H-7), 7.32 (dd, 1H,
J6,4 = 2 J6,7 = 8.4 Hz, H-6), 7.08 (d, 2H, J3′,2′ = J5′,6′ = 8.8
Hz, H-3′, H-5′), 4.17 (m, 2H, OCH ), 1.41 (t, 3H, CH );
6
8), 289 (25), 262 (3), 210 (34), 187 (9); HRMS (EI) calcd.
for C H Br FN : m/z = 367.8960, found 367.8965.
1
3
7
2
2
2
3

Med Chem Res
1
3
C-NMR (75 MHz, DMSO-d ): δ 159.3 (C, C-4′), 152.8
= 2.8 Hz, H-7), 7.4 (dd, 1H, J6,4 = 2, J6,7 = 8.8 Hz, H-6),
6
1
3
(
1
(
5
C, C-2), 141.2 (C, C-8), 140.6 (C, C-9), 129.8 (CH, C-2′),
29.8 (CH, C-6′), 126.3 (CH, C-6), 118.6 (CH, C-4), 117.7
C, C-5), 117.3 (CH, C-7), 114.8 (CH, C-3′), 114.8 (CH, C-
′), 112.4 (C, C-1′), 64.5 (CH , OCH CH ), 14.9 (CH ,
3.93 (s, 3H, OCH ), 3.90 (s, 3H, OCH ); C-NMR (75
3 3
MHz, DMSO-d ): δ 152.8 (C, C-2), 150.3 (C, C-4′), 149.2
6
(C, C-5′), 141.0 (C, C-8), 140.6 (C, C-9), 133.0 (C, C-1′),
126.3 (CH, C-6), 118.6 (CH, C-4), 117.7 (C, C-5), 117.5
(CH, C-7), 115.5 (CH, C-3′), 114.4 (CH, C-6′), 113.6 (C,
C-2′), 56.2 (CH , O CH ), 56.1 (CH , O CH ); EIMS: m/z
2
2
3
3
+
OCH CH ); EIMS: m/z (rel. abund. %), 316 (M , 100), 318
2
3
(
(
M+2, 100), 287 (100), 259 (98), 237 (22), 208 (67), 192
23), 180 (91), 153 (30); HRMS (EI) calcd. for
3
3
+
3
3
(rel. abund. %), 410 (M , 49), 412 (M+2, 100), 414 (M+4,
51), 381 (24), 366 (19), 315 (88), 273 (23), 236 (14);
HRMS (EI) calcd. for C H Br N O : m/z = 409.9266,
C H BrN O: m/z = 316.0211, found 316.0217.
1
5
13
2
1
5
12
2 2 2
found 409.9260.
2
-(4-(Benzyloxy)phenyl)-5-bromo-1H-benzo[d]imidazole
(
20)
2-(Anthracen-9-yl)-5-bromo-1H-benzo[d]imidazole (23)
1
Yield: 69 %; H-NMR: (400 MHz, DMSO-d ): δ 8.16 (d,
2
6
1
Yield: 72 %; H-NMR: (400 MHz, DMSO-d ): δ 8.78 (s,
1
7
6
H, J2′,3′ = J6′,5′ = 9.2 Hz, H-2′, H-6′), 7.72 (d, 1H, J4,6 = 1.2
H, H-6′), 8.19 (d, 2H, J2′,3′ = J10′,9′ = 8.4 Hz, H-2′, H-10′),
.92 (s, 1H, H-4), 7.80 (d, 2H, J5′,4′ = J7′,8′ = 8.8 Hz, H-5′,
H-7′), 7.71 (d, 1H, J7,6 = 8.4 Hz, H-7), 7.57 (m, 5H, H-6, H-
′, H-4′, H-8′, H-9′); C-NMR (75 MHz, DMSO-d ): δ
Hz, H-4), 7.52 (m, 3H, H-2′′, H-4′′, H-6′′), 7.43 (t, 2H, J3′′(2′
=
7.2 Hz, H-3′′, H-5′′), 7.36 (d, 1H, J7,6 = 7.2
Hz, H-7), 7.32 (dd, 1H, J6,4 = 1.6, J6,7 = 8.4 Hz, H-6), 7.19
d, 2H, J = J5′,6′ = 9.2 Hz, H-3′, H-5′), 5.22 (s, 2H,
′,4′′) = J5′′(4′′,6′′)
13
3
1
1
1
6
(
3′,2′
52.8 (C, C-2), 141.2 (C, C-8), 140.6 (C, C-9), 134.2 (C, C-
′), 132.1 (C, C-11′), 132.1 (C, C-13′), 130.5 (C, C-12′),
30.5 (C, C-14′), 129.7 (CH, C-6′), 128.1 (CH, C-5′), 128.1
1
3
OCH2); C-NMR (75 MHz, DMSO-d ): δ 159.2 (C, C-4′),
6
1
1
1
1
52.7 (C, C-2), 141.0 (C, C-8), 140.6 (C, C-9), 136.6 (C, C-
′′), 130.2 (CH, C-2′), 130.2 (CH, C-6′), 128.7 (CH, C-3′′),
28.7 (CH, C-5′′), 127.7 (CH, C-4′′), 127.0 (CH, C-2′′),
27.0 (CH, C-6′′), 126.3 (CH, C-6), 118.8 (CH, C-4), 117.6
(
CH, C-7′), 126.4 (CH, C-6), 125.6 (CH, C-4′), 125.6 (CH,
C-8′), 125.8 (CH, C-3′), 125.8 (CH, C-9′), 124.1 (CH, C-
2
1
3
′), 124.1 (CH, C-10′), 118.6 (CH, C-4), 117.6 (C, C-5),
(
C, C-5), 117.5 (CH, C-7), 114.9 (CH, C-3′), 114.9 (CH, C-
′), 113.2 (C, C-1′), 70.7 (CH , OCH C H ); EIMS: m/z (rel.
+
17.3 (CH, C-7); EIMS: m/z (rel. abund. %), 371 (M , 84),
5
2
2 6 6
73 (M+2, 100), 313 (54), 292 (45), 264 (5), 232 (15);
HRMS (EI) calcd. for C H BrN : m/z = 372.0262, found
+
abund. %), 378 (M , 16), 380 (M+2, 17), 248 (49), 218 (53),
01 (20), 189 (100), 161 (35), 135 (76); HRMS (EI) calcd.
for C H BrN O: m/z = 378.0368, found 378.0362.
2
1
13
2
2
372.0267.
2
0
15
2
4-(5-Bromo-1H-benzo[d]imidazol-2-yl)-2-methoxyphenyl
4
-(5-Bromo-1H-benzo[d]imidazol-2-yl)-N,N-
acetate (24)
dimethylaniline (21)
1
Yield: 63 %; H-NMR: (400 MHz, DMSO-d ): δ 7.93 (d,
6
1
Yield: 59 %; H-NMR: (400 MHz, DMSO-d ): δ 7.99 (d,
1H, J4,6 = 2 Hz, H-4), 7.79 (m, 2H, H-2′, H-6′), 7.57 (d, 1H,
J7,6 = 8.4 Hz, H-7), 7.37 (dd, 1H, J6,4 = 2, J6,7 = 8.4 Hz, H-
6), 7.23 (d, 1H, J
2.27 (s, 3H, CH3); C-NMR (75 MHz, DMSO-d ): δ 169.1
(C, O=C), 152.7 (C, C-2), 151.3 (C, C-3′), 141.7 (C, C-4′),
41.2 (C, C-8), 140.6, (C, C-9), 128.3 (C, C-1′), 126.1 (CH,
C-6), 123.0 (CH, C-5′), 122.2 (CH, C-6′), 118.6 (CH, C-4),
117.6 (C, C-5), 117.4 (CH, C-7), 126.2 (CH, C-6), 111.6
(CH, C-2′), 55.9 (CH , O=C-CH ), 20.2 (CH , OCH );
EIMS: m/z (rel. abund. %), 360 (M , 9), 362 (M+2, 12), 318
(100), 305 (5), 290 (7), 275 (9), 239 (6), 196 (5); HRMS
(EI) calcd. for C H BrN O : m/z = 360.0110, found
6
2
7
H, J2′,3′ = J6′,5′ = 9.2 Hz, H-2′, H-6′), 7.76 (s, 1H, H-4),
.54 (d, 1H, J7,6 = 8.4 Hz, H-7), 7.42 (d, 1H, J6,7 = 8.8 Hz,
5′,6′ = 8 Hz, H-5′), 3.94 (s, 3H, O=C-CH ),
3
1
3
H-6), 6.89 (d, 2H, J
= J5′,6′ = 9.2 Hz, H-3′, H-5′), 3.03
3
′,2′
6
13
(
s, 6H, N(CH ) ); C-NMR (75 MHz, DMSO-d ): δ 155.4
3
2
6
(
1
(
3
C, C-4′), 152.8 (C, C-2), 141.0 (C, C-8), 140.6 (C, C-9),
28.3 (CH, C-2′), 128.3 (CH, C-6′), 126.4 (CH, C-6), 118.6
CH, C-4), 117.6 (C, C-5), 117.3 (CH, C-7), 112.6 (CH, C-
′), 112.6 (CH, C-5′), 115.7 (C, C-1′), 41.2 (CH , N
1
3
3
3
+
3
3
(
CH ) ), 41.2 (CH , N(CH ) ); EIMS: m/z (rel. abund. %),
3
2
3
3 2
+
3
2
3
15 (M , 100), 317 (M+2, 96), 301 (13), 273 (3), 236 (11),
21 (4); HRMS (EI) calcd. for C H BrN : m/z =
15.0371, found 315.0376.
1
5
14
3
1
6
13
2 3
360.0117.
5
-Bromo-2-(2-bromo-4,5-dimethoxyphenyl)-1H-benzo[d]
2-Bromo-6-(5-bromo-1H-benzo[d]imidazol-2-yl)-4-
imidazole (22)
chlorophenol (25)
1
1
Yield: 49 %; H-NMR: (400 MHz, DMSO-d ): δ 7.83 (d,
6
yield: 72 %; H-NMR: (400 MHz, DMSO-d ): δ 10.33 (s,
6
1
H, J4,6 = 1.6 Hz, H-4), 7.61 (s, 1H, H-3′), 7.59 (d, 1H, J7,6
1H, NH), 7.88 (m, 2H, H-4, H-6′), 7.62 (d, 1H, J7,6 = 8.8

Med Chem Res
Gao C, Li B, Zhang B, Sun Q, Li L, Li X, Chen C, Tan C, Liu H, Jiang
Y (2015) Synthesis and biological evaluation of benzimidazole
acridine derivatives as potential DNA-binding and apoptosis-
inducing agents. Bioorg Med Chem 23:1800–1807
Gao H, Huang YN, Xu PY, Kawabata J (2007) Inhibitory effect on α-
glucosidase by the fruits of Terminalia chebula Retz. Food Chem
Hz, H-7), 7.38 (d, 1H, J6 = 8.4 Hz, H-6), 6.50 (s, 1H, H-
,7
3
1
4
1
′), 6.48 (s, 1H, OH); C-NMR (75 MHz, DMSO-d ): δ
6
52.9 (C, C-2), 152.7 (C, C-2′), 141.3 (C, C-8), 140.6 (C,
C-9), 133.7 (CH, C-4′), 129.5 (C, C-5′), 127.7 (CH, C-6′),
1
26.3 (CH, C-6), 121.8 (C, C-1′), 118.6 (CH, C-4), 117.5
1
05:628–634
(
(
C, C-5), 117.3 (CH, C-7), 115.6 (C, C-3′); EIMS: m/z
Groopman JE (1990) Current advances in the diagnosis and treatment
of AIDS: An introduction. Rev Infect Dis 12:908–911
+
rel. abund. %), 400 (M , 74), 402 (M+2, 76), 385 (100),
3
57 (54), 345 (25), 329 (11); HRMS (EI) calcd. for
Guo XZ, Shi L, Wang R, Liu XX, Li BG, Lu XX (2008) Synthesis and
biological activities of novel nonpeptide angiotensin II receptor
C H Br ClN O: m/z = 399.8614, found 399.8610.
1
3
7
2
2
antagonists based on benzimidazole derivatives bearing
a
heterocyclic ring. Bioorg Med Chem 16:10301–10310
Acknowledgments The authors are thankful to the Higher Education
Commission (HEC) Pakistan, for their financial support to Research
Project No. 20-2073 under National Research Program for
Universities.
Kashtoh H, Hussain S, Khan A, Saad SM, Khan JAJ, Khan KM,
Perveen S, Choudhary MI (2014) Oxadiazoles and thiadiazole:
Novel α-glucosidase inhibitors. Bioorg Med Chem 22:5454–5465
Kazimierczuk Z, Upcroft JA, Upcroft P, Gorska A, Starosciak B,
Laudy A (2002) Synthesis, antiprotozoal and antibacterial activity
of nitro and halogeno-substituted benzimidazole derivatives. Acta
Biochem Pol 49:185–196. English edition
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interests.
Khan KM, Rahat S, Choudhary MI, Rahman Atta-ur, Ghani U,
Perveen S, Khatoon S, Dar A, Malik A (2002) Synthesis and
biological screening of 2-[4-substituted phenyl] 4-(2-cyanoethyl)-
4
(H)-1,3,4-oxadiazine-5(6H)-ones and their intermediates. Helv
Chem Acta 85:559–570
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