Synthesis and cytotoxic activity of novel hybrid compounds between 2-alkylbenzofuran and imidazole

Article abstract of DOI:10.1007/s00044-013-0760-8

A series of novel hybrid compounds between 2-alkylbenzofuran and imidazole has been prepared and evaluated in vitro against a panel of human tumor cell lines. The results suggest that the existence of 2-methyl-imidazole or 2-ethyl-imidazole ring and substitution of the imidazolyl-3-position with a naphthylacyl or methoxyphenacyl group were vital for modulating cytotoxic activity. In particular, hybrid compound 29 was found to be the most potent compound against five strains human tumor cell lines and more active than cisplatin (DDP), while hybrid compound 26 was more selective toward colon carcinoma (SW480) and breast carcinoma (MCF-7) with IC₅₀ value 44.0- and 36.8-fold more sensitive to DDP.

Full text of DOI:10.1007/s00044-013-0760-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:1599–1611
DOI 10.1007/s00044-013-0760-8
ORIGINAL RESEARCH
Synthesis and cytotoxic activity of novel hybrid compounds
between 2-alkylbenzofuran and imidazole
•
Wei-Chao Wan Wen Chen Lan-Xiang Liu
•
•
•
Yan Li Li-Juan Yang Xiao-Yan Deng
•
•
•
Hong-Bin Zhang Xiao-Dong Yang
Received: 25 May 2013 / Accepted: 21 August 2013 / Published online: 4 September 2013
Ó Springer Science+Business Media New York 2013
Abstract A series of novel hybrid compounds between
2-alkylbenzofuran and imidazole has been prepared and
evaluated in vitro against a panel of human tumor cell
lines. The results suggest that the existence of 2-methyl-
imidazole or 2-ethyl-imidazole ring and substitution of the
imidazolyl-3-position with a naphthylacyl or methoxyph-
enacyl group were vital for modulating cytotoxic activity.
In particular, hybrid compound 29 was found to be the
most potent compound against five strains human tumor
cell lines and more active than cisplatin (DDP), while
hybrid compound 26 was more selective toward colon
carcinoma (SW480) and breast carcinoma (MCF-7) with
IC50 value 44.0- and 36.8-fold more sensitive to DDP.
Keywords Hybrid compound ꢀ Benzofuran ꢀ Imidazole ꢀ
Cytotoxic activity ꢀ Structure–activity relationships ꢀ
Molecular docking
Introduction
Cancer remains one of the most difficult diseases world-
wide to treat and is the leading cause of human mortality
exceeded only by cardiovascular diseases (Varmus, 2006).
Therefore, developing new anticancer drugs and more
effective treatment strategies for cancer is of importance
(Haskell, 2001). Natural products represent a significant
source of inspiration for the design of structural analogs
with improved pharmacological profile in medicinal
chemistry (Newman, 2008; Ojima, 2008). Naturally
occurring substituted benzofurans are an important class of
biologically active oxygen-containing heterocycles. Natu-
ral products possessing the 2-alkylbenzofuran moiety
exhibit a broad range of biological and pharmacological
activities (Mohamed et al., 2011; Song and Raskin, 2002;
Kim et al., 2002; Ng et al., 2000). Recently, naturally
occurring benzofurans have been identified to possess
antitumor activity. As exemplified in Scheme 1, 1-(6-
hydroxy-2-isopropenyl-1-benzofuran-5-yl)-1-ethanone (HIBE)
(Miert et al., 2005) and denthyrsin (Zhang et al., 2005) are
also 2-alkylbenzofuran-derived compounds exhibiting
potent cytotoxic activities against human breast cancer
cells and ovarian cancer cells (Miert et al., 2005; Zhang
et al., 2005).
Wei-Chao Wan and Wen Chen have contributed equally to this paper.
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-013-0760-8) contains supplementary
material, which is available to authorized users.
W.-C. Wan ꢀ W. Chen ꢀ L.-X. Liu ꢀ X.-Y. Deng ꢀ H.-B. Zhang ꢀ
X.-D. Yang (&)
Key Laboratory of Medicinal Chemistry for Natural Resource
(Yunnan University), Ministry of Education, School of Chemical
Science and Technology, Yunnan University, Kunming 650091,
People’s Republic of China
e-mail: xdyang@ynu.edu.cn; xdyang120@gmail.com
Y. Li
State Key Laboratory for Phytochemistry and Plant Resources in
West China, Kunming Institute of Botany, Chinese Academy of
Science, Kunming 650204, People’s Republic of China
Imidazole and its derivatives have attracted considerable
interests in recent years for their versatile properties in
chemistry and pharmacology. Biological activities of imi-
dazolium salts have been reported (Vik et al., 2007; Tseng
et al., 2012a, b; Dominianni and Yen 1989; Iqbal et al.,
L.-J. Yang
Key Laboratory of Ethnic Medicine Resource Chemistry, State
Ethnic Affairs Commission & Ministry of Education, Yunnan
University of Nationalities, Kunming 650031, People’s Republic
of China
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Med Chem Res (2014) 23:1599–1611
Scheme 1 Design of novel
hybrid compounds
2-Alkylbenzofuran moieties
Imidazolium salts
O
H
N
N
Cl
R
O
HO
Lepidiline A R = H
Lepidiline B R = CH3
HIBE
O
OMe
OMe
O
MeO
MeO
N
N
O
Br
O
Denthyrsin
MNIB
Molecular hybridization
R
R
O
O
O
N
N
N
N
R'
X
X
2013; Haque et al., 2013), especially antitumor activity
(Fortuna et al., 2008; Ballistreri et al., 2004). For example,
two new imidazolium halides (Scheme 1), Lepidiline A
and Lepidiline B, isolated from the roots of Lepidium
meyenii, showed potent cytotoxic activity against the
human cancer cell lines (Cui et al., 2003). Recently, we
have reported the synthesis of a series of novel imidazo-
lium salts such as MNIB (Scheme 1) and their potential
antitumor activity (Song et al., 2012; Zeng et al., 2010;
Yang et al., 2009). Studies on molecular mechanisms
demonstrated that the imidazolium salt hybrids can induce
the G1 phase cell cycle arrest and apoptosis in tumor cells
(Zeng et al., 2010).
reports concerning antitumor activity for hybrid com-
pounds between 2-alkylbenzofuran and imidazole have
been reported.
In previous work (Song et al., 2012), we reported a
number of hybrid compounds between 2-substituted ben-
zofuran and imidazole. The structure–activity relationships
(SARs) showed that hybrid compounds bearing a benz-
imidazole moiety were vital for modulating cytotoxic
activity. More recently, we also reported that a series of
hybrid compounds between 2-benzylbenzofuran and
imidazole (Wang et al., 2013). The SARs suggest that
electronic and steric effects have an important role in the
cytotoxic activity of benzimidazolium salt hybrids. As a
continuation of our systematic studies on imidazolium
salts, as well as to explore the influence of different
substituted groups at position-2 of benzofuran, we have
designed and synthesized a series of novel hybrid com-
pounds of imidazole scaffold-based 2-alkylbenzofurans in
the present research. The purpose of this study was to
investigate the antitumor activity of 2-alkylbenzofuran-
imidazole hybrids, with the ultimate aim of developing
novel potent antitumor agents.
Molecular hybridization as a drug discovery strategy
involves the rational design of new chemical entities by the
fusion of two drugs, both active compounds and/or phar-
macophoric units recognized and derived from known
bioactive molecules, for example, in the development of
new anticancer, anti-Alzheimer, and antimalarial agents
(Ortial et al., 2010; Getlik et al., 2009; Viegas et al., 2007).
Considering the anticancer activities of naturally occurring
2-alkylbenzofurans as well as the potent cytotoxic activi-
ties of natural and synthetic imidazole derivatives, we were
interested in synthesizing a number of new hybrid com-
pounds bearing 2-alkylbenzofuran (Scheme 1) and imid-
azole moieties (Scheme 1).
Results and discussion
Although benzofuran-triazoles hybrid molecules
through a heptyloxybenzene chain were synthesized and
found to exhibit CYP26A1 inhibitory activity by Simons
(Pautus et al., 2006), to the best of our knowledge, no
Chemistry
As shown in Scheme 2, benzofuran (1) was chosen as the
starting material for the preparation of a series of
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Med Chem Res (2014) 23:1599–1611
1601
Scheme 2 Synthesis of hybrid
compounds 5–38
O
H
NaBH4
1) POCl3, DMF
100oC, 20 h
EtOH, rt, 4h
93%
O
O
2
O
OH
2) MaOAc (aq.)
3
1
62%
MsCl, Et3N rt,
2h
DCM
R
R
HN
N
imidazole ring
5
6
7
8
imidazole
toluene
reflux, 12-24 h
two steps, 65-78%
O
X
O
OMs
N
N
benzimidazole
2-methyl-imidazole
2-ethyl-imidazole
4
5-8
R'
reflux, 24-48 h
61-95%
toluene
R
O
N
N
R'
X
9-38
2-alkylbenzofuran-imidazole hybrids (5–38). The formy-
lation of benzofuran (1) under Vilsmeier–Haack conditions
gave the known benzofuran-2-carbaldehyde (2) in 62 %
yield (Podea et al., 2008). The benzofuran-2-carbaldehyde
(2) was reduced with NaBH4 to the respective benzofuran
2-methanol compounds (3, 93 % yields) (Ruchelman et al.,
2008). Subsequently, the benzofuran 2-methanol com-
pound (3) was transformed via the mesylate to the
respective four 2-alkylbenzofuran–imidazole hybrids (5–8)
with various substituted imidazoles (imidazole, benzimid-
azole, 2-methyl-imidazole, or 2-ethyl-imidazole) by re-
fluxing under toluene with 58–71 % yields (two steps).
Finally, 30 benzofuran-based imidazolium salts (9–38)
were prepared with excellent yields by reaction of
2-substituted benzofuran–imidazole hybrids with the cor-
responding phenacyl and alkyl halides in refluxing toluene
(61–95 % yields).
As shown in Table 1, the structures of the hybrid
compounds have an obvious influence on the cytotoxic
activities. 2-Alkylbenzofuran–imidazole hybrids 5–8
lacked activities against all tumor cell lines investigated at
the concentration of 40 lM. However, their imidazolium
salts 9–38 exhibited some degree of cytotoxic activities or
higher cytotoxic activities. This difference in cytotoxicity
between neutral compounds and imidazolium salts may be
due to the changes of molecular structure, charge distri-
bution, and water solubility (Ranke et al., 2007).
In terms of the imidazole ring (imidazole, benzimid-
azole, 2-methyl-imidazole, or 2-ethyl-imidazole), imi-
dazolium salt hybrids 9–16 with imidazole displayed weak
cytotoxic activities. Among them, only compounds 12 and
13, bearing a naphthylacyl or bromophenacyl substituent at
position-3 of the imidazole, showed medium cytotoxic
activities. Meanwhile, hybrid compounds 17–24 with
benzimidazole exhibited some degree of cytotoxic activi-
ties. Most of this kind of derivatives showed moderate
activities. Compounds 20 and 21, also bearing a naph-
thylacyl or bromophenacyl at position-3 of the imidazole
ring, displayed similar cytotoxic activities in vitro com-
pared with DDP. However, imidazolium salt hybrids 25–32
with 2-methyl-imidazole or hybrids 33–38 with 2-ethyl-
imidazole exhibited higher cytotoxic activities. Most of
this kind of derivatives was found to be more active than
DDP, such as compounds 26, 29, 31, 34, 36, 37, and 38.
In terms of the substituent at position-3 of imidazole
ring, imidazolium salts 15, 16, 24, and 32 with allyl or
butyl substituent at position-3 of imidazole ring showed
Biological evaluation and SAR analysis
The potential cytotoxicity of all newly synthesized hybrid
compounds was evaluated in vitro against a panel of human
tumor cell lines according to the procedures described in
the literature (Kim et al., 2001; Cao et al., 2004). The panel
consisted of leukemia (HL-60), colon carcinoma (SW480),
lung carcinoma (A549), breast carcinoma (MCF-7), and
myeloid liver carcinoma (SMMC-7721). Cisplatin (DDP)
was used as the reference drug. The results are summarized
in Table 1 (IC50 value, defined as the concentrations cor-
responding to 50 % growth inhibition).
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Med Chem Res (2014) 23:1599–1611
against four human tumor cell lines investigated and more
active than DDP (except against SMMC-7721).
Table 1 Cytotoxic activities of hybrid compounds 5–38 in vitro
(IC50, lM)
Compared with above alkyl or phenacyl substituent
imidazolium salt derivatives, hybrid compounds with a
naphthylacyl (13, 21, 29, and 37), 4-methoxyphenacyl (18,
26, and 34), or 4-bromophenacyl (12, 20, and 36) sub-
stituent at position-3 of the imidazole ring exhibited higher
cytotoxic activities. Most of this kind of derivatives
showed moderate or potent activity. Especially, com-
pounds 29, 37, 26, 34, and 20 displayed potent cytotoxic
activities in vitro compared with DDP. Interestingly,
hybrid compound 29, a naphthylacyl substituent at posi-
tion-3 of 2-methyl-imidazole, was found to be the most
potent derivative with IC50 values lower than 5.0 lM
against all human tumor cell lines investigated and more
active than DDP. Notably, compound 26, a 4-methoxyph-
enacyl substituent at position-3 of 2-methyl-imidazole,
exhibited cytotoxic activity selectively against colon car-
cinoma (SW480) and breast carcinoma (MCF-7) with IC50
value 44.0- and 36.8-fold more sensitive to DDP. This
finding shows that electronic and steric effects have an
important role in the cytotoxic activity of imidazolium salt
hybrids.
Compounds HL-60 SW480 A549 MCF-7 SMMC-7721
5
[40
[40
[40
[40
[40
[40
[40
10.35
6.27
[40
[40
[40
[40
3.91
[40
1.69
3.62
6.77
2.48
[40
[40
0.78
[40
[40
1.04
4.44
1.28
[40
[40
0.40
[40
1.87
1.45
2.25
3.10
[40
[40
[40
[40
[40
[40
[40
[40
17.06
[40
[40
[40
[40
23.13
[40
4.20
17.13
9.75
14.69
[40
[40
0.28
[40
[40
1.03
9.96
3.89
[40
[40
1.02
[40
1.34
1.69
7.15
12.32
[40
[40
[40
[40
[40
[40
[40
[40
[40
[40
[40
[40
[40
[40
[40
[40
[40
[40
[40
[40
[40
14.31
8.08
[40
[40
[40
[40
13.55
[40
3.58
6.44
14.82
6.83
[40
[40
11.59
[40
[40
3.50
11.31
10.22
[40
[40
8.43
[40
7.51
4.26
6.16
14.75
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
DDP
12.17 18.02
9.95
[40
[40
[40
[40
7.18
[40
2.54
6.73
12.70
[40
[40
[40
[40
14.56
[40
2.46
3.72
12.64 9.83
2.63
[40
[40
0.37
[40
[40
4.97
7.48
[40
[40
1.44
[40
[40
1.09
The results suggest that the existence of 2-methyl-
imidazole or 2-ethyl-imidazole ring and substitution of the
imidazolyl-3-position with a naphthylacyl or methoxyph-
enacyl group were vital for modulating cytotoxic activity.
The SAR results are summarized in Scheme 3.
Compared with hybrid compounds reported in the pre-
vious work (Song et al., 2012), the new hybrids prepared in
this work exhibited more potent cytotoxic activities against
HL-60 and MCF-7 cell lines with IC50 value over 20.0-fold.
Additionally, compared with 2-benzylbenzofuran-imidazole
hybrid compounds reported in the another previous work
(Wang et al., 2013), the new 2-alkylbenzofuran-imidazole
hybrids prepared in this work displayed more potent cyto-
toxic activities against SW480, A549, and MCF-7 cell lines,
but lower cytotoxic activities against HL-60 and SMMC-
7721 cell lines. This results suggest that changing the
2-benzylbenzofuran with 2-alkylbenzofuran caused the
changes of steric effect and charge distribution, which may
lead to the difference in cytotoxic activities between their
imidazole hybrid compounds.
14.82 6.79
2.96
[40
[40
1.13
[40
2.24
[40
[40
3.05
[40
25.65 4.47
7.44 2.59
10.28 3.30
13.61 10.64
Cytotoxicity as IC50 for each cell line is the concentration of com-
pound which reduced by 50 % the optical density of treated cells with
respect to untreated cells using the MTT assay. Data represent the
mean values of three independent determinations
lacked activities against five tumor cell lines. Meanwhile,
compounds 9, 17, 25, and 33 with phenacyl substituent and
compounds 11, 19, 27, and 35 with 4-hydroxyphenacyl
substituent at position-3 of imidazole ring were inactive.
Hybrid compounds 23 and 31 with benzyl substituent
exhibited some degree of cytotoxic activities. Among
them, only compound 31, bearing a 2-bromobenzyl sub-
stituent at position-3 of 2-methyl-imidazole, was the most
active compound with IC50 values lower than 4.0 lM
Molecular docking
In addition, we found these hybrids could inhibit the
mTOR signaling pathway during our research. In order to
rationalize the observed SARs for this series of compound,
we attempted to dock the most potent compounds 26 and
29 with some crystal structures of proteins in this signal
pathway, e.g., mTORC1, mTORC2, and PI3Kc using
Autodock 4.0. Fortunately, we found these two compounds
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Med Chem Res (2014) 23:1599–1611
1603
Scheme 3 SAR of hybrid
compounds
2-methylimidazole 2-ethylimidazole > benzimidazole > imidazole
R
R
R'
O
phenacyl > 2-bromobenzyl > benzyl > alkyl
N
N
R'
X
naphthylacyl 4-methoxyphenacyl > 4-bromophenacyl > 2'-phenyl-phenacyl
>> phenacyl 4-hydroxyphenacyl
Best Potent Compounds
O
O
O
O
N
N
N
N
Br
Br
OMe
29
26
IC50 values for 4 human tumor cell lines
29 1.03-4.97 µM; 26 0.28-1.44 µM
could dock well with PI3Kc, but they could not dock with
mTORC1 or mTORC2. Figure 1a shows the benzofuran
ring of hybrid 26 can foster van der Waals interactions with
the pocket bounded by TRP576, HIS577, PHE578, and
ARG579, and it also shows 2-methyl-imidazole ring can
interact with the gap bounded by GLU573, LEU574,
TRP576, and HIS577, while 4-methoxyphenacyl ring is
placing in the pocket bounded by GLU570, GLU573,
LEU574, LEU551, and GLN554. Similar to hybrid 26,
hybrid 29 (Fig. 1b) can foster van der Waals interactions
with the pocket bounded by GLU573, HIS577, TRP576,
and LYS597 using benzofuran ring, and it also interacts
with the gap bounded by GLU573, LEU574, TRP576,
HIS577, and PHE578 using 2-methyl-imidazole ring, while
its naphthyl ring is placing in the pocket bounded by
GLU570, LEU574, PHE578, PRO548, LEU551, and
GLN554. In addition to these, hybrid 29 establishes a
hydrogen bond with LEU574 using furan oxygen. These
interesting indications would be very useful for our next
design.
be the most potent derivative against all human tumor cell
lines investigated and more active than DDP, while com-
pound 26 was more selective toward colon carcinoma
(SW480) and breast carcinoma (MCF-7) with IC50 value
44.0- and 36.8-fold more sensitive to DDP. The 2-al-
kylbenzofuran-based imidazolium salts 26, 29, 34, and 37
can be considered promising leads for further structural
modifications guided by the valuable information derivable
from our detailed SARs.
Experimental
General procedures
Melting points were obtained on a XT-4 melting-point
apparatus and were uncorrected. Proton nuclear magnetic
resonance (1H NMR) spectra were recorded on a Bruker
Avance 300 spectrometer at 300 MHz. Carbon-13 nuclear
magnetic resonance (13C NMR) was recorded on Bruker
Avance 300 spectrometer at 75 MHz. Chemical shifts are
reported as d values in parts per million (ppm) relative to
tetramethylsilane (TMS) for all recorded NMR spectra.
Low-resolution mass spectra were recorded on a VG Auto
Spec-3000 magnetic sector MS spectrometer. High reso-
lution mass spectra were taken on AB QSTAR Pulsar mass
spectrometer. Silica gel (200–300 mesh) for column
chromatography and silica GF254 for TLC were produced
by Qingdao Marine Chemical Company (China). All air- or
moisture-sensitive reactions were conducted under an
argon atmosphere. Starting materials and reagents used in
Conclusions
In conclusion, a number of novel 2-alkylbenzofuran-
imidazole hybrid compounds prepared in this research
proved to be potent antitumor agents. The hybrids 26, 29,
34, and 37, bearing 2-methyl-imidazole or 2-ethyl-imid-
azole ring and a naphthylacyl or methoxyphenacyl sub-
stituent at position-3 of the imidazole ring, were found to
be the most potent compounds. Compound 29 was found to
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Med Chem Res (2014) 23:1599–1611
Fig. 1 Model of hybrid
compounds 25 (a) and 28
(b) docked into PI3Kc
reactions were obtained commercially from Acros,
Aldrich, Fluka and were used without purification, unless
otherwise indicated.
acetate = 5:1) to afford the products 3 (93 %) as pale oil
1
(Ruchelman et al., 2008). Yield 93 %. Pale oil. H NMR
(300 MHz, CDCl3) d: 7.40 (1H, dd, J = 16.8, 2.1 Hz),
7.37 (1H, dd, J = 17.7, 1.8 Hz), 7.20–7.10 (2H, m), 6.46
(1H, s), 4.60 (2H, s), 4.34 (1H, br. s). 13C NMR (75 MHz,
CDCl3) d: 156.83 (C), 155.32 (C), 128.34 (C), 124.32
(CH), 122.84 (CH), 121.18 (CH), 111.27 (CH), 104.07
(CH), 57.66 (CH2).
Synthesis of compound 2
POCl3 (13.2 g, 8.0 mL, 86 mmol) was added in small
portions with slight warming into a solution of benzofuran
1 (9.2 g, 78 mmol) in anhydrous DMF (15.0 g, 15.8 mL,
205 mmol). The mixture was heated for 10 h at 100 °C,
then cooled to room temperature and treated with an extra
portion of DMF (5.0 g, 5.3 mL, 68 mmol) and POCl3
(4.0 g, 2.4 mL, 26 mmol). The mixture was heated for
another 10 h. The cooled mixture was treated with satu-
rated NaOAc solution in water until the pH rose to 6. The
organic compounds were extracted with Et2O
(3 9 20 mL). The combined organic layers were washed
with saturated KHCO3 solution (3 9 10 mL) and water
(20 mL), then dried over anhydrous Na2SO4 and concen-
trated. The residue was purified by column chromatogra-
phy (silica gel, petroleum ether 60–90 °C:ethyl
acetate = 10:1) to afford the products 2 (62 %) as colorless
Synthesis of compounds 5–8
To a solution of benzofuran 2-methanol compound 3
(1 mmol) in dichloromethane (50 mL) was added meth-
anesulfonyl chloride (1.2 mmol) and triethylamine
(2 mmol) at 0 °C. The resulting mixture was stirred at
room temperature for 2 h. After quenching the reaction
with water (50 mL), the layers were separated. The organic
phase was dried over anhydrous Na2SO4 and concentrated,
and used for the next synthetic step. A mixture of the
previous methanesulfonate and imidazole or substituted
imidazole (3 mmol) was stirred in toluene (20 ml) at reflux
for 24–48 h (monitored by TLC). After cooling to room
temperature, the solvent was concentrated, and the residue
was diluted with EtOAc (20 mL). The organic layer was
washed with water (20 mL) and brine (20 mL), dried over
anhydrous Na2SO4 and concentrated. The residue was
purified by column chromatography (silica gel, petroleum
ether 60–90 °C:ethyl acetate = 1:1) to afford 5–8 in
65–78 % yield (two steps).
1
oil (Podea et al., 2008). Yield 62 %. H NMR (300 MHz,
CDCl3) d: 9.73 (1H, s), 7.61 (1H, d, J = 7.5 Hz), 7.44 (1H,
dd, J = 18.9, 2.1 Hz), 7.43 (1H, s), 7.36 (1H, dd, J = 8.4,
1.2 Hz), 7.20 (1H, ddd, J = 15.0, 7.8, 0.9 Hz). 13C NMR
(75 MHz, CDCl3) d: 179.76 (CH), 156.20 (C), 152.66 (C),
129.21 (CH), 126.64 (C), 124.19 (CH), 123.69 (CH),
117.97 (CH), 112.61 (CH).
Synthesis of compound 3
1-((Benzofuran-2-yl)methyl)-1H-imidazole (5)
To a stirred solution of benzofuran-2-carbaldehyde 2
(2.2 g, 15 mmol) in MeOH (25 mL) at 0 °C was added
NaBH4 (0.28 g, 7.5 mmol) in small portions over a period
of 20 min, and then at ambient temperature for 4 h.
Reaction progress was monitored by TLC. A small amount
of water was added and the mixture was stirred for 15 min
before rotary evaporation. The solvent was evaporated
under reduced pressure and the residue was chromato-
graphed on silica gel (petroleum ether 60–90 °C:ethyl
Yield 65 %. Yellow powder, mp 71–73 °C. 1H NMR
(300 MHz, CDCl3): d 7.62 (1H, s), 7.53 (1H, dd, J = 8.2,
7.3 Hz), 7.44 (1H, d, J = 7.9 Hz), 7.32–7.23 (2H, m), 7.09
(1H, s), 7.02 (1H, s), 6.64 (1H, s), 5.21 (2H, s). 13C NMR
(75 MHz, CDCl3): d 155.29 (C), 151.72 (C), 137.40 (CH),
129.92 (CH), 127.81 (CH), 125.03 (CH), 123.28 (CH),
121.35 (CH), 119.30 (CH), 111.45 (CH), 105.58 (CH),
44.22 (CH2). HRMS (ESI-TOF) m/z Calcd for C12H10N2O
[M?H]? 198.0793, found 198.0798.
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Med Chem Res (2014) 23:1599–1611
1605
1162, 1093, 752. 1H NMR (300 MHz, CDCl3): d 9.79 (1H,
s), 7.90 (2H, d, J = 7.5 Hz), 7.67 (1H, s), 7.49–7.07 (8H,
m), 7.03 (1H, s), 6.21 (2H, s), 5.68 (2H, s). 13C NMR
(75 MHz, CDCl3): d 190.65 (C), 155.16 (C), 148.41 (C),
137.49 (CH), 134.54 (CH), 133.32 (C), 128.97 (CH),
128.47 (CH), 127.37 (C), 125.45 (CH), 124.38 (CH),
123.35 (CH), 121.80 (CH), 121.58 (CH), 111.42 (CH),
108.65 (CH), 55.99 (CH2), 46.38 (CH2). HRMS (ESI-TOF)
m/z Calcd for C20H17N2O2 [M-Br]? 317.1285, found
317.1274.
1-((Benzofuran-2-yl)methyl)-1H-benzo[d]imidazole (6)
1
Yield 78 %. Yellow powder, mp 128–130 °C. H NMR
(300 MHz, CDCl3): d 8.03 (1H, s), 7.88–7.85 (1H, m),
7.53–7.42 (4H, m), 7.34–7.23 (3H, m), 6.63 (1H, s), 5.42
(2H, s). 13C NMR (75 MHz, CDCl3): d 155.29 (C), 151.09
(C), 143.86 (C), 143.03 (CH), 133.70 (C), 127.73 (C),
124.91 (CH), 123.29 (CH), 122.46 (CH), 121.23 (CH),
120.54 (CH), 111.37 (CH), 109.77 (CH), 105.56 (CH),
42.28 (CH2). HRMS (ESI-TOF) m/z Calcd for C16H12N2O
[M?H]? 248.0950, found 248.0944.
1-((Benzofuran-2-yl)methyl)-3-(2-(4-methoxyphenyl)-2-
1-((Benzofuran-2-yl)methyl)-2-methyl-1H-imidazole (7)
oxoethyl)-1H-imidazol-3-ium bromide (10)
Yield 71 %. Yellow powder, mp 76–78 °C. 1H NMR
(300 MHz, CDCl3): d 7.51 (1H, dd, J = 8.5, 7.2 Hz), 7.46
(1H, d, J = 7.6 Hz), 7.29–7.18 (2H, m), 6.93–6.91 (2H,
Yield 91 %. White powder, mp 165–167 °C. IR mmax
(cm-1): 3427, 1682, 1582, 1412, 1348, 1242, 1166, 1025,
749, 627. 1H NMR (300 MHz, CDCl3): d 9.91 (1H, s), 7.94
(2H, d, J = 8.7 Hz), 7.62 (1H, s), 7.53 (1H, s), 7.49 (1H, d,
J = 7.8 Hz), 7.38 (1H, d, J = 8.4 Hz), 7.29–7.15 (2H, m),
7.08 (1H, s), 6.83 (2H, d, J = 8.7 Hz), 6.18 (2H, s), 5.75
(2H, s), 3.75 (3H, s). 13C NMR (75 MHz, CDCl3): d 188.72
(C), 164.65 (C), 155.25 (C), 148.32 (C), 137.66 (CH),
131.05 (CH), 127.40 (C), 126.25 (C), 125.51 (CH), 124.33
(CH), 123.38 (CH), 121.83 (CH), 121.48 (CH), 114.32
(CH), 111.46 (CH), 108.77 (CH), 55.60 (CH2), 55.60
(CH3), 46.46 (CH2). HRMS (ESI-TOF) m/z Calcd for
C21H19N2O3 [M-Br]? 347.1390, found 347.1378.
m), 6.51(1H, d, J = 1.0 Hz), 5.08 (2H, s), 2.44 (3H, s). 13
C
NMR (75 MHz, CDCl3): d 155.11 (C), 152.00 (C), 144.81
(C), 127.75 (C), 127.36 (CH), 124.76 (CH), 123.13 (CH),
121.15 (CH), 119.64 (CH), 111.28 (CH), 104.91 (CH),
43.37 (CH2), 12.90 (CH3). HRMS (ESI-TOF) m/z Calcd for
C13H12N2O [M?H]? 212.0950, found 212.0941.
1-((Benzofuran-2-yl)methyl)-2-ethyl-1H-imidazole (8)
1
Yield 70 %. Yellow oil. H NMR (300 MHz, CDCl3): d
7.49 (1H, dd, J = 8.3, 7.2 Hz), 7.45 (1H, d, J = 7.6 Hz),
7.27–7.16 (2H, m), 6.96 (1H, s), 6.89 (1H, s), 6.49 (1H, s),
5.05 (2H, s), 2.73 (2H, q), 1.34 (3H, t, J = 7.5 Hz). 13C
NMR (75 MHz, CDCl3): d 155.07 (C), 152.16 (C), 149.35
(C), 127.75 (C), 127.35 (CH), 124.70 (CH), 123.10 (CH),
121.13 (CH), 119.54 (CH), 111.24 (CH), 104.89 (CH),
42.94 (CH2), 20.00 (CH2), 11.97 (CH3). HRMS (ESI-TOF)
m/z Calcd for C14H14N2O [M?H]? 226.1106, found
226.1101.
1-((Benzofuran-2-yl)methyl)-3-(2-(4-hydroxyphenyl)-2-
oxoethyl)-1H-imidazol-3-ium bromide (11)
Yield 88 %. White powder, mp 210–212 °C. IR mmax
(cm-1): 3105, 1881, 1597, 1443, 1360, 1236, 1160, 993,
1
825, 754. H NMR (300 MHz, DMSO): d 9.34 (1H, s),
8.01–7.98 (3H, m), 7.87 (2H, d, J = 8.7 Hz), 7.82 (1H, s),
7.73 (1H, d, J = 7.5 Hz), 7.60 (1H, d, J = 8.4 Hz),
7.40–7.28 (2H, m), 7.19 (1H, s) 6.13 (2H, s), 5.90 (2H, s).
13C NMR (75 MHz, DMSO): d 190.66 (C), 154.61 (C),
150.16 (C), 137.58 (CH), 132.68 (C), 132.18 (CH), 130.07
(CH), 128.62 (C), 127.35 (C), 125.33 (CH), 124.44 (CH),
123.38 (CH), 122.31 (CH), 121.80 (CH), 111.30 (CH),
107.64 (CH), 55.61 (CH2), 45.50 (CH2). HRMS (ESI-TOF)
m/z Calcd for C20H17N2O3 [M-Br]? 333.1234, found
333.1239.
Synthesis of compounds 9–38
A mixture of 2-alkylbenzofuran–imidazole hybrids 5–8
(1 mmol) and phenacyl bromides or alkyl bromides
(1.2 mmol) was stirred in toluene (10 ml) at reflux for
24–48 h. An insoluble substance was formed. After com-
pletion of the reaction as indicated by TLC, the precipitate
was filtered through a small pad of Celite, and washed with
toluene (3 9 10 ml), then dried to afford imidazolium salts
9–38 in 61–95 % yields.
1-((Benzofuran-2-yl)methyl)-3-(2-(2-(4-bromophenyl)-2-
oxoethyl)-1H-imidazol-3-ium bromide (12)
1-((Benzofuran-2-yl)methyl)-3-(2-oxo-2-phenylethyl)-1H-
Yield 90 %. White powder, mp 228–230 °C. IR mmax
(cm-1): 3426, 3098, 3061, 1697, 1582, 1443, 1399, 1351,
1240, 1163, 1072, 991, 818, 752. 1H NMR (300 MHz,
DMSO): d 10.65 (1H, s), 9.30 (1H, s), 7.93 (1H, s), 7.95
(2H, d, J = 8.4 Hz), 7.77 (1H, s), 7.69 (1H, d,
imidazol-3-ium bromide (9)
Yield 87 %. White powder, mp 185–187 °C. IR mmax
(cm-1): 3427, 3067, 1696, 1583, 1443, 1409, 1352, 1234,
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Med Chem Res (2014) 23:1599–1611
J = 7.5 Hz), 7.57 (1H, d, J = 8.1 Hz), 7.36–7.24 (2H, m),
7.15 (1H, s), 6.94 (2H, d, J = 8.4 Hz), 5.99 (2H, s), 5.84
(2H, s). 13C NMR (75 MHz, DMSO): d 189.08 (C), 163.19
(C), 154.62 (C), 150.18 (C), 137.61 (CH), 130.79 (CH),
127.35 (C), 125.31 (CH), 125.04 (C), 124.49 (CH), 123.37
(CH), 122.17 (CH), 121.78 (CH), 115.65 (CH), 111.30
(CH), 107.60 (CH), 55.09 (CH2), 45.46 (CH2). HRMS
(ESI-TOF) m/z Calcd for C20H16BrN2O2 [M-Br]?
395.0390, found 395.0398.
dd, J = 14.4, 6.9 Hz), 7.22-7.17 (2H, m), 6.04–5.94 (3H,
m), 5.45 (2H, dd, J = 19.8, 10.2 Hz), 4.98 (2H, d,
J = 6.3 Hz). 13C NMR (75 MHz, CDCl3): d 155.19 (C),
148.48 (C), 136.57 (CH), 129.56 (CH), 127.38 (C), 125.44
(CH), 123.34 (CH), 122.86 (CH2), 122.70 (CH), 122.25
(CH), 121.79 (CH), 111.36 (CH), 108.79 (CH), 52.19
(CH2), 46.41 (CH2). HRMS (ESI-TOF) m/z Calcd for
C15H15N2O [M-Br]? 239.1179, found 239.1168.
1-((Benzofuran-2-yl)methyl)-3-butyl-1H-imidazol-3-ium
1-((Benzofuran-2-yl)methyl)-3-(2-(2-(naphthalen-2-yl)-2-
iodide (16)
oxoethyl)-1H-imidazol-3-ium bromide (13)
Yield 68 %. Yellow oil. IR mmax (cm-1): 3427, 3072, 1570,
1445, 1252, 1159, 939, 823, 751, 626. 1H NMR (300 MHz,
CDCl3): d 10.06 (1H, s), 7.69 (1H, s), 7.61 (1H, s), 7.55
(1H, d, J = 7.5 Hz), 7.43 (1H, d, J = 8.1 Hz), 7.35–7.30
(1H, m), 7.27–7.19 (2H, m), 5.90 (2H, s), 4.31 (2H, t,
J = 7.2 Hz), 1.95–1.85 (2H, m), 1.41–1.33 (2H, s), 0.93
(3H, t, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3): d 155.20
(C), 148.22 (C), 136.04 (CH), 127.34 (C), 125.53 (CH),
123.40 (CH), 122.63 (CH), 121.83 (CH), 111.39 (CH),
108.93 (CH), 50.12 (CH2), 46.50 (CH2), 31.93 (CH2),
19.39 (CH2), 13.40 (CH3). HRMS (ESI-TOF) m/z Calcd for
C16H19N2O [M-I]? 255.1492, found 255.1484.
Yield 93 %. White powder, mp 225–227 °C. IR mmax
(cm-1): 3426, 3098, 3061, 1697, 1582, 1480, 1443, 1399,
1351, 1240, 1163, 1071, 991, 818, 752. 1H NMR
(300 MHz, CDCl3): d 9.95 (1H, s), 8.64 (1H, s), 7.89 (1H,
d, J = 6.6 Hz), 7.80 (1H, d, J = 6.6 Hz), 7.67–7.62 (3H,
m), 7.44–7.28 (5H, m), 7.22–7.14 (2H, m), 6.99 (1H, s),
6.18 (2H, s), 5.63 (2H, s). 13C NMR (75 MHz, CDCl3): d
190.43 (C), 155.22 (C), 148.17 (C), 137.77 (CH), 135.91
(C), 132.19 (C), 131.31 (CH), 130.55 (C), 130.03 (CH),
129.24 (CH), 128.83 (CH), 127.64 (CH), 127.35 (C),
127.05 (CH), 125.51 (CH), 124.53 (CH), 123.38 (CH),
123.23 (CH), 121.84 (CH), 121.57 (CH), 111.48 (CH),
108.86 (CH), 56.24 (CH2), 46.64 (CH2). HRMS (ESI-TOF)
m/z Calcd for C24H19N2O2 [M-Br]? 367.1441, found
367.1460.
1-((Benzofuran-2-yl)methyl)-3-(2-oxo-2-phenylethyl)-1H-
benzo[d]imidazol-3-ium bromide (17)
Yield 95 %. White powder, mp 228–230 °C. IR mmax
(cm-1): 3424, 3110, 3028, 1691, 1587, 1542, 1446, 1330,
1266, 1181, 1003, 938, 824, 753. 1H NMR (300 MHz,
MeOD): d 8.20–8.16 (3H, m), 7.93 (1H, dd, J = 8.4,
1.2 Hz), 7.77–7.61 (6H, m), 7.47 (1H, d, J = 8.4 Hz),
7.34–7.26 (2H, m), 7.24 (1H, s), 6.38 (2H, s), 6.10 (2H, s).
13C NMR (75 MHz, MeOD): d 191.75 (C), 156.89 (c),
150.11 (C), 135.89 (C), 135.16 (CH), 133.75 (C), 132.40
(C), 130.26 (CH), 129.61 (CH), 129.02 (C), 128.67 (CH),
128.55 (CH), 126.69 (CH), 124.60 (CH), 122.83 (CH),
114.4 (CH), 114.76 (CH), 112.23 (CH), 109.32 (CH), 54.33
(CH2), 45.31 (CH2). HRMS (ESI-TOF) m/z Calcd for
C24H19N2O2 [M-Br]? 367.1441, found 367.1460.
1-((Benzofuran-2-yl)methyl)-3-(2-(2-bromobenzyl)-1H-
imidazol-3-ium bromide (14)
Yield 82 %. White powder, mp 170–172 °C. IR mmax
(cm-1): 3426, 3098, 3061, 1697, 1582, 1480, 1443, 1399,
1351, 1240, 1163, 1071, 991, 818, 752. 1H NMR
(300 MHz, CDCl3): d 10.20 (1H, s), 7.73 (1H, d,
J = 7.8 Hz), 7.65 (1H, s), 7.49 (2H, d, J = 7.5 Hz),
7.39–7.31 (3H, m), 7.29–-7.14 (4H, m), 5.90 (2H, s), 5.64
(2H, s). 13C NMR (75 MHz, CDCl3): 155.18 (C), 148.54
(C), 137.01 (CH), 133.34 (CH), 132.31 (CH), 131.37 (CH),
128.70 (CH), 127.45 (C), 125.38 (CH), 124.37 (C), 123.29
(CH), 122.67 (CH), 122.10 (CH), 121.82 (CH), 111.33
(CH), 108.77 (CH), 53.22 (CH2), 46.54 (CH2). HRMS
(ESI-TOF) m/z Calcd for C19H16BrN2O [M-Br]? 367.0441,
found 367.0455.
1-((Benzofuran-2-yl)methyl)-3-(2-(4-methoxyphenyl)-1H-
benzo[d]imidazol-3-ium bromide (18)
Yield 92 %. White powder, mp 220–222 °C. IR mmax
(cm-1): 3435, 3022, 1683, 1593, 1422, 1382, 1242, 1176,
1019, 981, 833, 756. 1H NMR (300 MHz, CDCl3): d 11.00
(1H, s), 8.09 (2H, d, J = 8.7 Hz), 7.96 (1H, d,
J = 7.5 Hz), 7.67 (1H, dd, J = 7.2, 1.2 Hz), 7.51–7.47
(3H, m), 7.38 (1H, d, J = 8.1 Hz) 7.30–7.14 (3H, m), 6.90
(2H, d, J = 8.7), 6.50 (2H, s), 6.06 (2H, s), 3.79 (3H, s).
13C NMR (75 MHz, CDCl3): d 188.07 (C), 164.78 (C),
1-((Benzofuran-2-yl)methyl)-3-allyl-1H-imidazol-3-ium
bromide (15)
Yield 61 %. Yellow oil. IR mmax (cm-1): 3429, 3060, 1589,
1443, 1409, 1157, 939, 752, 632. 1H NMR (300 MHz,
CDCl3): d 10.26 (1H, s), 7.73 (1H, s), 7.56 (1H, s), 7.52
(1H, d, J = 7.5 Hz), 7.39 (1H, d, J = 8.1 Hz), 7.28 (1H,
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1607
155.12 (C), 148.16 (C), 143.32 (CH), 132.08 (C), 131.21
(CH), 130.82 (C), 127.46 (CH), 127.31 (CH), 127.24 (CH),
126.26 (CH), 125.38 (CH), 123.32 (CH), 121.76 (CH),
114.36 (CH), 113.67 (CH), 111.46 (CH), 108.67 (CH),
55.64 (CH3), 53.66 (CH2), 44.60 (CH2). HRMS (ESI-TOF)
m/z Calcd for C25H21N2O3 [M-Br]? 397.1547, found
397.1550.
7.80–7.72 (5H, m), 7.58 (1H, d, J = 8.1 Hz), 7.37–7.27
(3H, m), 6.64 (2H, s), 6.28 (2H, s). 13C NMR (75 MHz,
DMSO): d 191.11 (C), 154.62 (C), 149.59 (C), 143.67
(CH), 135.54 (C), 132.07 (CH), 132.00 (C), 131.02 (C),
130.92 (CH), 130.56 (C), 129.69 (CH), 129.36 (CH),
128.69 (CH), 127.88 (CH), 127.39 (CH), 127.35 (CH),
127.02 (C), 126.92 (C), 125.34 (CH), 123.40 (CH), 123.33
(CH), 121.81 (CH), 114.23 (CH), 113.87 (CH), 111.30
(CH), 108.04 (CH), 53.52 (CH2), 43.66 (CH2). HRMS
(ESI-TOF) m/z Calcd for C28H21N2O2 [M-Br]? 417.1598,
found 417.1563.
1-((Benzofuran-2-yl)methyl)-3-(2-(4-hydroxyphenyl)-2-
oxoethyl)-1H-benzo[d]imidazol-3-ium bromide (19)
Yield 94 %. White powder, mp 240–242 °C. IR mmax
(cm-1): 3431, 3102, 1685, 1599, 1442, 1344, 1237, 1172,
1-((Benzofuran-2-yl)methyl)-3-(2-oxo-1,2-diphenylethyl)-
1
981, 938, 834, 755. H NMR (300 MHz, DMSO): d 9.96
1H-benzo[d]imidazol-3-ium bromide (22)
(1H, s), 8.26 (1H, d, J = 7.5 Hz), 8.08 (1H, d,
J = 7.2 Hz), 8.01 (2H, d, J = 7.8 Hz), 7.73–7.68 (3H, m),
7.55 (1H, d, J = 7.5 Hz), 7.34–7.27 (3H, m), 7.01 (2H, d,
J = 7.8 Hz), 6.38 (1H, s), 6.23 (2H, s). 13C NMR
(75 MHz, DMSO): d 188.99 (C), 163.25 (C), 154.59 (C),
149.57 (C), 143.62 (C), 132.02 (C), 131.12 (CH), 130.49
(C), 127.33 (C), 126.95 (CH), 126.85 (CH), 125.32 (CH),
125.14 (CH), 123.38 (CH), 121.78 (CH), 115.60 (CH),
114.14 (CH), 113.80 (CH), 112.80 (CH), 107.98 (CH),
52.90 (CH2), 43.60 (CH2). HRMS (ESI-TOF) m/z Calcd for
C24H19N2O3 [M-Br]? 389.1390, found 389.1409.
Yield 94 %. White powder, mp 262–264 °C. IR mmax
(cm-1): 3435, 3107, 3030, 1690, 1586, 1564, 1448, 1245,
1
1188, 990, 824, 752, 698. H NMR (300 MHz, DMSO): d
10.16 (1H, s), 8.34 (1H, s), 8.29 (1H, dd, J = 7.5, 2.1 Hz),
8.20–8.17 (3H, m), 7.72–7.68 (6H, m), 7.60–7.52 (6H, m),
7.35–7.24 (3H, m), 6.15 (2H, s). 13C NMR (75 MHz,
DMSO): d 191.62 (C), 154.49 (C), 149.73 (C), 143.22
(CH), 134.74 (CH), 133.23 (C), 132.00 (C), 131.19 (C),
130.56 (C), 130.29 (CH), 130.04 (CH), 129.53 (CH),
129.46 (CH), 129.06 (CH), 127.31 (CH), 127.21 (CH),
127.04 (CH), 125.28 (CH), 123.37 (CH), 121.75 (CH),
114.56 (CH), 113.98 (CH), 111.22 (CH), 107.66 (CH),
65.36 (CH), 43.87 (CH2). HRMS (ESI-TOF) m/z Calcd for
C30H23N2O2 [M-Br]? 443.1754, found 443.1740.
1-((Benzofuran-2-yl)methyl)-3-(2-(2-(4-bromophenyl)-2-
oxoethyl)-1H-benzo[d]imidazol-3-ium bromide (20)
Yield 88 %. White powder, mp 216–218 °C. IR mmax
(cm-1): 3434, 3128, 3040, 1695, 1566, 1482, 1440, 1367,
1258, 1183, 943, 825, 754. 1H NMR (300 MHz, MeOD): d
9.91 (1H, s), 8.13 (1H, d, J = 7.8 Hz), 8.04 (2H, d,
J = 8.4 Hz), 7.91 (1H, d, J = 7.5 Hz), 7.78 (2H, d,
J = 8.4 Hz), 7.74–7.62 (2H, m), 7.43 (1H, d, J = 7.8 Hz),
7.34–7.21 (3H, m), 7.18 (1H, s), 6.06 (2H, s), 5.93 (2H, s).
13C NMR (75 MHz, MeOD): d 190.98 (C), 165.32 (C),
156.90 (C), 147.55 (C), 144.23 (C), 133.07 (C), 132.78
(CH), 132.39 (CH), 131.26 (C), 130.85 (CH), 130.01 (CH),
129.00 (CH), 128.17 (CH), 126.71 (CH), 124.62 (CH),
122.82 (CH), 114.81 (CH), 114.74 (CH), 112.32 (CH),
109.32 (CH), 54.33 (CH2), 45.27 (CH2). HRMS (ESI-TOF)
m/z Calcd for C24H18BrN2O2 [M-Br]? 445.0546, found
445.0536.
1-((Benzofuran-2-yl)methyl)-3-(2-(2-bromobenzyl)-1H-
benzo[d]imidazol-3-ium bromide (23)
Yield 83 %. White powder, mp 210–212 °C. IR mmax
(cm-1): 3431, 3099, 3035, 1697, 1582, 1445, 1176, 991,
820, 751. 1H NMR (300 MHz, MeOD): d 9.83 (1H, s), 8.14
(1H, d, J = 7.8 Hz), 7.88 (1H, d, J = 8.1 Hz), 7.38–7.67
(3H, m), 7.63–7.57 (2H, m) 7.50–7.37 (3H, m), 7.33–7.21
(2H, m), 7.18 (1H, s), 6.03 (2H, s), 5.88 (2H, s). 13C NMR
(75 MHz, MeOD): d 156.79 (C), 150.20 (C), 144.10 (C),
135.01 (CH), 133.17 (C), 132.89 (C), 132.74 (CH), 132.64
(CH), 129.80 (CH), 128.99 (C), 128.71 (CH), 126.66 (CH),
125.11 124.59 (CH), 122.81 (CH), 115.03 (CH), 112.23
(CH), 109.08 (CH), 52.68 (CH2), 45.26 (CH2). HRMS
(ESI-TOF) m/z Calcd for C23H18BrN2O [M-Br]? 417.0597,
found 417.0620.
1-((Benzofuran-2-yl)methyl)-3-(2-(2-(naphthalen-2-yl)-2-
oxoethyl)-1H-benzo[d]imidazol-3-ium bromide (21)
1-((Benzofuran-2-yl)methyl)-3-butyl-1H-benzo[d]imidazol-
Yield 87 %. White powder, mp 210–-212 °C. IR mmax
(cm-1): 3433, 3056, 1670, 1576, 1483, 1438, 1362, 1227,
1135, 982, 819, 749. 1H NMR (300 MHz, DMSO): d 10.02
(1H, s), 8.97 (1H, s), 8.30 (1H, d, J = 8.1 Hz), 8.25 (1H, d,
J = 7.8 Hz), 8.20–8.15 (2H, m), 8.10–8.07 (2H, m),
3-ium iodide (24)
Yield 68 %. Yellow oil. IR mmax (cm-1): 3426, 3072, 1582,
1447, 1250, 1163, 989, 820, 753. 1H NMR (300 MHz,
CDCl3): d 10.95 (1H, s), 8.05 (1H, dd, J = 8.7, 3.6 Hz),
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Med Chem Res (2014) 23:1599–1611
7.76–7.66 (3H, m), 7.55 (1H, d, J = 7.5 Hz), 7.40–7.18
(4H, m), 6.18 (2H, s), 4.56 (t, J = 7.2 Hz), 2.12–2.05 (2H,
m), 1.51–1.45 (2H, m), 0.99 (3H, t, J = 7.2 Hz). 13C NMR
(75 MHz, CDCl3): d 155.12 (C), 148.21 (C), 141.54 (CH),
131.41 (C), 131.20 (C), 127.67 (CH), 127.51 (CH), 125.47
(CH), 123.41 (CH), 123.15 (C), 121.90 (CH), 114.10 (CH),
113.10 (CH), 111.36 (CH), 109.03 (CH), 47.87 (CH2),
44.68 (CH2), 31.10 (CH2), 19.86 (CH2), 13.50 (CH3).
HRMS (ESI-TOF) m/z Calcd for C20H21N2O [M-I]?
305.1648, found 305.1637.
7.94 (2H, d, J = 8.7 Hz), 7.67 (1H, d, J = 1.8 Hz), 7.58
(1H, d, J = 7.2 Hz), 7.49 (1H, d, J = 1.8 Hz), 7.44 (1H, d,
J = 8.1 Hz), 7.29–7.22 (2H, m), 7.01 (1H, s), 6.89 (2H, d,
J = 8.7 Hz), 5.89 (2H, s), 5.65 (2H, s), 2.65 (3H, s). 13C
NMR (75 MHz, MeOD): d 189.85 (C), 165.15 (C), 156.87
(C), 150.74 (C), 147.95 (C), 132.31 (CH), 128.99 (C),
126.75 (C), 126.60 (CH), 124.59 (CH), 124.33 (CH),
122.77 (CH), 116.82 (CH), 112.31 (CH), 108.49 (CH),
55.47 (CH2), 46.34 (CH2), 10.26 (CH3). HRMS (ESI-TOF)
m/z Calcd for C21H19N2O3 [M-Br]? 347.1390, found
347.1397.
1-((Benzofuran-2-yl)methyl)-3-(2-oxo-2-phenylethyl)-2-
methyl-1H-imidazol-3-ium bromide (25)
1-((Benzofuran-2-yl)methyl)-3-(2-(2-(4-bromophenyl)-2-
oxoethyl)-2-methyl-1H-imidazol-3-ium bromide (28)
Yield 93 %. White powder, mp 222–224 °C. IR mmax
(cm-1): 3434, 3079, 1692, 1592, 1527, 1448, 1265, 1223,
Yield 91 %. White powder, mp 238–240 °C. IR mmax
(cm-1): 3399, 3103, 1696, 1582, 1529, 1447, 1398, 1366,
1235, 1179, 1070, 996, 822, 769. 1H NMR (300 MHz,
MeOD): d 8.03 (2H, d, J = 8.4 Hz), 7.78 (2H, d,
J = 8.4 Hz), 7.77 (1H, s), 7.65 (1H, d, J = 7.8 Hz), 7.58
(1H, d, J = 1.8 Hz), 7.51 (1H, d, J = 8.1 Hz), 7.39–7.26
(2H, m), 7.09 (1H, s), 6.05 (2H, s), 5.74 (2H, s), 2.75 (3H,
s). 13C NMR (75 MHz, MeOD): d 191.10 (C), 156.88 (C),
150.71 (C), 148.04 (C), 134.02 (C), 133.51 (CH), 131.30
(CH), 130.78 (C), 128.99 (C), 126.63 (CH), 124.61 (CH),
124.32 (CH), 122.85 (CH), 112.31 (CH), 108.56 (CH),
55.91 (CH2), 46.38 (CH2), 10.29(CH3). HRMS (ESI-TOF)
m/z Calcd for C21H18BrN2O2 [M-Br]? 409.0546, found
409.0560.
1
1180, 931, 811, 754, 692. H NMR (300 MHz, DMSO): d
8.07 (2H, d, J = 7.5 Hz), 7.93 (1H, d, J = 1.8 Hz),
7.79–7.70 (3H, m), 7.64–7.59 (3H, m), 7.39–7.27 (2H, m),
7.16 (1H, s), 6.15 (2H, s), 5.86 (2H, s), 2.72 (3H, s). 13C
NMR (75 MHz, DMSO): d 191.10 (C), 154.60 (C), 150.22
(C), 146.23 (C), 134.49 (CH), 133.69 (C), 128.96 (CH),
128.37 (CH), 127.33 (C), 125.21 (CH), 123.35 (CH),
123.00 (CH), 121.71 (CH), 121.66 (CH), 111.28 (CH),
107.02 (CH), 54.71 (CH2), 44.59 (CH2), 9.66 (CH3).
HRMS (ESI-TOF) m/z Calcd for C21H19N2O2 [M-Br]?
331.1441, found 331.1434.
1-((Benzofuran-2-yl)methyl)-3-(2-(4-methoxyphenyl)-2-
oxoethyl)-2-methyl-1H-imidazol-3-ium bromide (26)
1-((Benzofuran-2-yl)methyl)-3-(2-(2-(naphthalen-2-yl)-2-
Yield 92 %. White powder, mp 213–215 °C. IR mmax
(cm-1): 3416, 3086, 1679, 1602, 1520, 1453, 1362, 1322,
1269, 1023, 936, 830, 752, 668. 1H NMR (300 MHz,
MeOD): d 8.09 (2H, d, J = 9.0 Hz), 7.75 (1H, d,
J = 2.1 Hz), 7.65 (1H, dd, J = 6.9, 0.9 Hz), 7.57 (1H, d,
J = 2.1 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.39–7.26 (2H, m),
7.12 (1H, s), 7.09 (2H, d, J = 2.7 Hz), 5.99 (2H, s), 5.73
(2H, s), 3.92 (3H, s), 2.73 (3H, s). 13C NMR (75 MHz,
MeOD): d 190.10 (C), 166.45 (C), 156.88 (C), 150.76 (C),
147.98 (C), 132.07 (CH), 128.99 (C), 127.87 (C), 126.61
(CH), 124.59 (CH), 124.33 (CH), 122.78 (CH), 115.44
(CH), 112.31 (CH), 108.49 (CH), 56.34 (CH3), 55.59
(CH2), 46.34 (CH2), 10.26 (CH3). HRMS (ESI-TOF) m/
z Calcd for C22H21N2O3 [M-Br]? 361.1547, found
361.1570.
oxoethyl)-2-methyl-1H-imidazol-3-ium bromide (29)
Yield 94 %. White powder, mp 245–247 °C. IR mmax
(cm-1): 3434, 3099, 3061, 1697, 1583, 1480, 1417, 1399,
1351, 1240, 1177, 1071, 997, 817, 750. 1H NMR
(300 MHz, MeOD): d 8.80 (1H, s), 8.13 (1H, d,
J = 7.8 Hz), 8.05–7.94 (4H, m), 7.84 (1H, s), 7.81–7.60
(4H, m), 7.51 (1H, d, J = 8.1 Hz), 7.38–7.26 (2H, m), 7.10
(1H, s), 6.21 (2H, s), 5.74 (2H, s), 2.77 (3H, s). 13C NMR
(75 MHz, MeOD): d 191.77 (C), 156.89 (C), 150.76 (C),
148.04 (C), 137.68 (C), 133.91 (C), 132.36 (C), 132.22
(CH), 130.98 (CH), 130.55 (CH), 130.04 (CH), 129.01
(CH), 128.42 (CH), 126.64 (CH), 124.62 (CH), 124.39
(CH), 122.84 (CH),112.35 (CH), 108.58 (CH), 56.08 (CH2),
46.40 (CH2), 10.39 (CH3). HRMS (ESI-TOF) m/z Calcd for
C25H21N2O2 [M-Br]? 381.1598, found 381.1602.
1-((Benzofuran-2-yl)methyl)-3-(2-(4-hydroxyphenyl)-2-
oxoethyl)-2-methyl-1H-imidazol-3-ium bromide (27)
1-((Benzofuran-2-yl)methyl)-3-(2-oxo-1,2-diphenylethyl)-
2-methyl-1H-imidazol-3-ium bromide (30)
Yield 90 %. White powder, mp 210–212 °C. IR mmax
(cm-1): 3400, 3065, 1678, 1594, 1517, 1443, 1349, 1235,
Yield 88 %. White powder, mp 120–122 °C. IR mmax
1
1172, 999, 932, 832, 753. H NMR (300 MHz, MeOD): d
(cm-1): 3417, 3059, 1687, 1584, 1485, 1243, 1107, 930,
123

Med Chem Res (2014) 23:1599–1611
1609
837, 743. 1H NMR (300 MHz, CDCl3): d 8.57 (1H, s), 8.16
(2H, d, J = 7.5 Hz), 7.71–7.68 (2H, m), 7.62 (1H, s),
7.50–7.44 (3H, m), 7.40–7.08 (8H, m), 6.65 (1H, d,
J = 1.5 Hz), 5.74 (1H, s), 5,71 (1H, s), 2.98 (3H, s). 13C
NMR (75 MHz, CDCl3): d 192.66 (C), 155.26 (C), 148.29
(C), 145.77 (C), 134.59 (CH), 133.32 (C), 130.76 (C),
130.58 (CH), 129.98 (CH), 129.86 (CH), 129.02 (CH),
127.41 (C), 125.41 (CH), 123.37 (CH), 121.76 (CH),
121.04 (CH), 120.73 (CH), 111.47 (CH), 108.47 (CH),
67.87 (CH), 45.81 (CH2), 12.38 (CH3). HRMS (ESI-TOF)
m/z Calcd for C27H23N2O2 [M-Br]? 407.1754, found
407.1770.
(3H, t, J = 7.5 Hz). 13C NMR (75 MHz, DMSO): d 191.59
(C), 154.56 (C), 150.30 (C), 149.46 (C), 134.51 (CH),
133.67 (C), 128.94 (CH), 128.42 (CH), 127.31 (C), 125.27
(CH), 123.39 (CH), 121.86 (CH), 121.75 (CH), 111.27
(CH), 107.24 (CH), 54.63 (CH2), 44.48 (CH2), 16.13
(CH2), 11.50 (CH3). HRMS (ESI-TOF) m/z Calcd for
C22H21N2O2 [M-Br]? 345.1598, found 345.1605.
1-((Benzofuran-2-yl)methyl)-3-(2-(4-methoxyphenyl)-2-
oxoethyl)-2-ethyl-1H-imidazol-3-ium bromide (34)
Yield 89 %. White powder, mp 223–225 °C. IR mmax
(cm-1): 3418, 3092, 1682, 1582, 1416, 1243, 1174, 1103,
1
1-((Benzofuran-2-yl)methyl)-3-(2-(2-bromobenzyl)-2-
1047, 750. H NMR (300 MHz, MeOD): d 8.11 (2H, d,
methyl-1H-imidazol-3-ium bromide (31)
J = 8.1 Hz), 7.75 (1H, s), 7.67–7.59 (2H, m), 7.50 (1H, d,
J = 6.6 Hz), 7.38–7.28 (2H, m), 7.13 (1H, d, J = 4.5 Hz),
7.10 (2H, d, J = 8.1 Hz), 6.02 (2H, s), 5.75 (2H, s), 3.91
(3H, s), 3.22 (2H, q), 1.25 (3H, t, J = 7.2 Hz). 13C NMR
(75 MHz, MeOD): d 190.64 (C), 166.45 (C), 156.84 (C),
151.27 (C), 150.81 (C), 132.15 (CH), 129.01 (C), 127.88
(C), 126.67 (CH), 124.64 (CH), 122.95 (CH), 122.85 (CH),
115.46 (CH), 112.32 (CH), 108.81 (CH), 56.39 (CH3),
55.57 (CH2), 46.26 (CH2), 18.06 (CH2), 11.86 (CH3).
HRMS (ESI-TOF) m/z Calcd for C23H23N2O3 [M-Br]?
375.1703, found 375.1720.
Yield 86 %. White powder, mp 120–122 °C. IR mmax
(cm-1): 3425, 3053, 1679, 1580, 1522, 1442, 1250, 1179,
1
1030, 935, 823, 750. H NMR (300 MHz, CDCl3): d 7.85
(1H, d, J = 1.8 Hz), 7.51–7.48 (2H, m), 7.41 (1H, d,
J = 7.5 Hz), 7.36–7.16 (7H, m), 5.88 (2H, s), 5.48 (2H, s),
2.95 (3H, s). 13C NMR (75 MHz, CDCl3): d 155.02 (C),
148.87 (C), 144.84 (C), 133.36 (CH), 131.84 (C), 131.41
(CH), 131.06 (CH), 128.55 (CH), 127.43 (C), 125.24 (CH),
123.73 (C), 123.26 (CH), 122.34 (CH), 121.75 (CH),
121.33 (CH), 111.22 (CH), 108.33 (CH), 52.30 (CH2),
45.85 (CH2), 11.58 (CH3). HRMS (ESI-TOF) m/z Calcd for
C20H18BrN2O [M-Br]? 381.0597, found 381.0610.
1-((Benzofuran-2-yl)methyl)-3-(2-(4-hydroxyphenyl)-2-
oxoethyl)-2-ethyl-1H-imidazol-3-ium bromide (35)
1-((Benzofuran-2-yl)methyl)-3-allyl-2-methyl-1H-imidazol-
Yield 90 %. White powder, mp 245–247 °C. IR mmax
3-ium bromide (32)
(cm-1): 3419, 3057, 1677, 1592, 1517, 1453, 1348, 1287,
1
1236, 1174, 1000, 834, 751. H NMR (300 MHz, MeOD):
Yield 88 %. Yellow oil. IR mmax (cm-1): 3427, 3055, 1583,
1417, 1088, 752. 1H NMR (300 MHz, CDCl3): d 7.92 (1H,
s), 7.52–7.44 (2H, m), 7.34 (1H, dd, J = 16.5, 8.1 Hz),
7.27–7.08 (3H, m), 6.04–5.94 (3H, m), 5.25 (dd, J = 25.5,
10.2 Hz), 4.86 (2H, d, J = 3.9 Hz), 2.72 (3H, s). 13C NMR
(75 MHz, CDCl3): d 155.08 (C), 148.85 (C), 144.45 (C),
129.77 (CH), 127.44 (C), 125.34 (CH), 123.35 (CH),
122.19 (CH), 121.79 (CH), 121.73 (CH), 120.80 (CH),
111.29 (CH), 108.38 (CH), 51.13 (CH2), 45.83 (CH2),
11.13 (CH3). HRMS (ESI-TOF) m/z Calcd for C16H17N2O
[M-Br]? 253.1335, found 253.1348.
d 10.69 (1H, s), 7.98 (2H, d, J = 8.1 Hz), 7.70 (1H, s),
7.62 (1H, d, J = 7.2 Hz), 7.52 (1H, s), 7.47 (1H, d,
J = 8.1 Hz), 7.53–7.25 (2H, m), 7.08 (1H, s), 6.91 (2H, d,
J = 8.1 Hz), 6.04 (2H, s), 5.84 (2H, s), 3.15 (2H, q), 1.21
(3H, t, J = 6.9 Hz). 13C NMR (75 MHz, DMSO): d 189.35
(C), 163.24 (C), 154.55 (C), 150.30 (C), 149.34 (C), 131.08
(CH), 127.31 (C), 125.26 (CH), 125.11 (C), 123.39 (CH),
121.74 (CH), 115.53 (CH), 111.26 (CH), 107.20 (CH),
54.05 (CH2), 44.44 (CH2), 16.14 (CH2), 11.43 (CH3).
HRMS (ESI-TOF) m/z Calcd for C22H21N2O3 [M-Br]?
361.1547, found 361.1571.
1-((Benzofuran-2-yl)methyl)-3-(2-oxo-2-phenylethyl)-2-
1-((Benzofuran-2-yl)methyl)-3-(2-(2-(4-bromophenyl)-2-
ethyl-1H-imidazol-3-ium bromide (33)
oxoethyl)-2-ethyl-1H-imidazol-3-ium bromide (36)
Yield 89 %. White powder, mp 162–164 °C. IR mmax
Yield 93 %. White powder, mp 221–223 °C. IR mmax
(cm-1): 3371, 3043, 1693, 1579, 1517, 1449, 1391, 1242,
1176, 1107, 1067, 1002, 930, 820, 750. 1H NMR
(300 MHz, DMSO): d 8.01 (2H, d, J = 8.4 Hz), 7.89 (1H,
s), 7.87 (2H, d, J = 8.4 Hz), 7.71 (2H, s), 7.60 (1H, d,
J = 8.1 Hz), 7.37–7.30 (2H, m), 7.18 (1H, s), 6.12 (2H, s),
(cm-1): 3429, 3057, 1693, 1589, 1526, 1447, 1359, 1231,
1
1183, 1110, 1000, 750. H NMR (300 MHz, DMSO): d
8.10 (2H, d, J = 7.8 Hz), 7.92 (1H, d, J = 1.8 Hz),
7.81–7.72 (3H, m), 7.68–7.63 (3H, m), 7.40–7.28 (2H, m),
7.21 (1H, s), 6.19 (2H, s), 5.88 (2H, s), 3.25 (2H, q), 1.09
123

1610
Med Chem Res (2014) 23:1599–1611
5.84 (2H, s), 3.21 (2H, q), 1.08 (3H, t, J = 7.2 Hz). 13C
NMR (75 MHz, DMSO): d 190.95 (C), 154.55 (C), 150.24
(C), 149.48 (C), 132.75 (C), 132.02 (CH), 130.36 (CH),
128.62 (C), 127.30 (C), 125.28 (CH), 123.40 (CH), 121.87
(CH), 121.75 (CH), 111.26 (CH), 107.24 (CH), 54.51
(CH2), 44.47 (CH2), 16.08 (CH2), 11.50 (CH3). HRMS
(ESI-TOF) m/z Calcd for C22H20BrN2O2 [M-Br]?
423.0703, found 423.0720.
dispersed in replicate 96-well plates. Compounds were then
added. After 48 h exposure to the compounds, cells via-
bility were determined by the [3-(4,5-dimethylthiazol-2-
yl)-2,5-diphenyltetrazolium bromide] (MTT) cytotoxicity
assay by measuring the absorbance at 570 nm with a
microplate spectrophotometer. Each test was performed in
triplicate.
Docking calculations
1-((Benzofuran-2-yl)methyl)-3-(2-(2-(naphthalen-2-yl)-2-
oxoethyl)-2-ethyl-1H-imidazol-3-ium bromide (37)
Compounds 26 and 29 were docked into PI3Kc [from the
complex between PI3K and 4-amino-2-methyl-N-(1H-
pyrazol-3-yl)quinazoline-8-carboxamide, PDB code 3PRZ]
using AutoDock (Version 4.0). A grid of 118, 126, and 126
points in the x, y, and z directions was constructed centered
Yield 95 %. White powder, mp 215–217 °C. IR mmax
(cm-1): 3408, 3111, 3056, 1666, 1624, 1589, 1517, 1460,
1362, 1277, 1236, 1187, 1118, 1052, 1007, 930, 821, 753.
1H NMR (300 MHz, MeOD): d 8.72 (1H, s), 8.03 (2H, d,
J = 7.8 Hz), 7.99–7.90 (2H, m), 7.87 (2H, d, J = 8.1 Hz),
7.65 (1H, s), 7.61–7.53 (4H, m), 7.41 (1H, d, J = 8.4 Hz),
7.28–7.16 (2H, m), 7.02 (1H, s), 6.20 (1H, s), 5.65 (2H, s),
3.14 (2H, q), 1.17 (3H, t, J = 7.5 Hz). 13C NMR (75 MHz,
MeOD): d 192.22 (C), 156.88 (C), 151.37 (C), 150.77 (C),
137.71 (C), 133.93 (C), 132.37 (C), 132.23 (CH), 130.97
(CH), 130.57 (CH), 130.04 (CH), 129.01 (CH), 128.43
(CH), 126.69 (CH), 124.76 (C), 124.65 (CH), 124.34 (CH),
123.02 (CH), 122.83 (CH), 112.30 (CH), 108.77 (CH),
55.87 (CH2), 46.24 (CH2), 18.00 (CH2), 11.83 (CH3).
HRMS (ESI-TOF) m/z Calcd for C26H23N2O2 [M-Br]?
395.1754, found 395.1760.
˚
on 8.0, -7.0, and 8.0. We used a grid spacing of 0.375 A
and a distance-dependent function of the dielectric constant
for the energetic map calculations. Docking simulations of
the compounds were carried out using the Lamarckian
genetic algorithm and through a protocol with an initial
population of 150 randomly placed individuals, a maxi-
mum number of 250 million energy evaluations, a mutation
rate of 0.02, a crossover rate of 0.8, and an elitism value of
1. Fifty independent docking runs were carried out for each
compound, and the resulting conformations that differed by
˚
1.5 A in positional root-mean-square deviation (RMSD)
were clustered together. Cluster analysis was performed by
selecting the most populated cluster, which in all cases
coincided with the one endowed with the best energy.
1-((Benzofuran-2-yl)methyl)-3-(2-oxo-1,2-diphenylethyl)-
Acknowledgments This work was supported by Grants from NSFC
(30960460, 20925205, and 21062026), NSFYN (2010GA014 and
2012FB113), the Project of Recruited Top Talent of Sciences and
Technology of Yunnan Province (2009C1120), and National Basic
Research Program of China (973 Program, 2009CB522300).
2-ethyl-1H-imidazol-3-ium bromide (38)
Yield 94 %. White powder, mp 224–226 °C. IR mmax
(cm-1): 3419, 3058, 1688, 1584, 1502, 1449, 1253, 1187,
1
1108, 930, 836, 743, 694. H NMR (300 MHz, MeOD): d
8.08 (2H, d, J = 7.5 Hz), 7.73 (1H, s), 7.65–7.62 (3H, m),
7.52–7.48 (8H, m), 7.40–7.14 (3H, m), 7.10 (1H, s), 5.71
(2H, d, J = 3.0 Hz), 3.55–3.34 (2H, m), 1.16 (3H, t,
J = 7.5 Hz). 13C NMR (75 MHz, MeOD): d 193.66 (C),
156.87 (C), 150.53 (C), 150.26 (C), 135.98 (CH), 134.73
(C), 133.12 (C), 131.75 (CH), 131.28 (CH), 130.63 (CH),
130.25 (CH), 128.96 (C), 126.71 (CH), 124.64 (CH),
123.07 (CH), 122.82 (CH), 112.30 (CH), 108.95 (CH),
68.50 (CH), 46.23 (CH2), 18.43 (CH2), 11.79(CH3). HRMS
(ESI-TOF) m/z Calcd for C28H25N2O2 [M-Br]? 421.1911,
found 421.1930.
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