Synthesis and cytotoxic activities of novel hybrid 2-phenyl-3- alkylbenzofuran and imidazole/triazole compounds

Article abstract of DOI:10.1016/j.bmcl.2013.06.001

A series of novel hybrid compounds of 2-phenyl-3-alkylbenzofuran and imidazole or triazole were prepared and evaluated in vitro against a panel of human tumor cell lines. The results suggest that the 2-ethyl-imidazole ring, and substitution of the imidazo

Full text of DOI:10.1016/j.bmcl.2013.06.001

Bioorganic & Medicinal Chemistry Letters 23 (2013) 4297–4302
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and cytotoxic activities of novel hybrid
2-phenyl-3-alkylbenzofuran and imidazole/triazole compounds
Wen Chen a, , Xiao-Yan Deng a, , Yan Li b, Li-Juan Yang c, Wei-Chao Wan a, Xue-Quan Wang a,
Hong-Bin Zhang a, Xiao-Dong Yang a,
⇑
a Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University,
Kunming 650091, PR China
b State Key Laboratory for Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Science, Kunming 650204, PR China
c Key Laboratory of Ethnic Medicine Resource Chemistry, State Ethnic Affairs Commission & Ministry of Education, Yunnan University of Nationalities, Kunming 650031, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel hybrid compounds of 2-phenyl-3-alkylbenzofuran and imidazole or triazole were
prepared and evaluated in vitro against a panel of human tumor cell lines. The results suggest that the
2-ethyl-imidazole ring, and substitution of the imidazolyl-3-position with a 2-bromobenzyl or naph-
thylacyl group, were vital for modulating inhibitory activity. In particular, hybrid compound 31 was
Received 6 April 2013
Revised 22 May 2013
Accepted 1 June 2013
Available online 11 June 2013
found to be the most potent derivative with IC50 values of 0.08–0.55 lM against five strains human tumor
cell lines and was found to be more selective against breast carcinoma (MCF-7) and colon carcinoma
(SW480) (IC50 values 40.8-fold and 40.1-fold lower than cisplatin (DDP)).
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Hybrid compound
Benzofuran
Imidazole
Triazole
Structure–activity relationships
Cancer remains one of the most difficult diseases worldwide to
treat and is one of the leading causes of human mortality.1 Devel-
oping new anticancer drugs and more effective treatment strate-
gies for cancer is of great importance.2 Natural products
represent a significant source of inspiration for the design of struc-
tural analogues with improved pharmacological profiles.3 Natu-
rally occurring substituted-benzofurans are an important class of
biologically active oxygen-containing heterocycles. Natural prod-
ucts possessing the 2-phenyl-3-alkylbenzofuran moiety exhibit a
broad range of biological and pharmacological activities.4 Recently,
natural occurring benzofurans have been identified to possess anti-
tumor activity. As exemplified in Figure 1, Moracins O5 and Ebe-
nfuran III6 are 2-phenyl-3-alkylbenzofuran derived compounds
exhibiting potent cytotoxic activities against human hepatocellular
cancer cells and breast cancer cells.5,6
reported the synthesis of a series of novel imidazolium salts, such
as MNIB (Fig. 1), and their potential antitumor activity.10 Studies
on molecular mechanisms demonstrated that the imidazolium salt
hybrids can induce the G1 phase cell cycle arrest and apoptosis in
tumor cells.10a
Molecular hybridization as a drug discovery strategy, involves
the rational design of new chemical entities by the fusion of two
drugs. The active compounds and/or pharmacophoric units are
identified and derived from known bioactive molecules, as shown
in the development of new anticancer, anti-Alzheimer, and anti-
malarial agents.11 Considering the anticancer activities of naturally
occurring 2-phenyl-3-alkylbenzofurans, as well as the potent cyto-
toxic activities of natural and synthetic imidazole or triazole deriv-
atives, we were interested in synthesizing a number of new hybrid
compounds bearing 2-phenyl-3-alkylbenzofuran (as shown pink
shadows in Fig. 1) and N-benzyl or phenacyl substituted imidazole
and triazole moieties (as shown green shadows in Fig. 1).
Although 2-benzylbenzofuran-triazole hybrid molecules were
synthesized and found to exhibit CYP26A1 inhibitory activity,12
to the best of our knowledge, no reports concerning antitumor
activity of 2,3-disubstituted benzofuran-imidazole or triazole hy-
brid compounds have been reported.
Imidazole and triazole and their derivatives have attracted con-
siderable interests for their broad range of biological and pharma-
cological activity,7 especially antitumor activity.8 For example, two
new imidazolium halides (Fig. 1), Lepidiline A and Lepidiline B, iso-
lated from the roots of Lepidium meyenii, showed potent cytotoxic
activity against human cancer cell lines.9 We have previously
In the present research, we designed and synthesized a series of
novel hybrid compounds of 2-phenyl-3-alkylbenzofurans with
imidazole or triazole. The purpose of this study was to investigate
⇑
Corresponding author. Tel.: +86 871 65031119; fax: +86 871 65035538.
E-mail addresses: xdyang120@gmail.com, xdyang@ynu.edu.cn (X.-D. Yang).
These authors contributed equally to this Letter.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.06.001

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W. Chen et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4297–4302
formation of the 2-phenylbenzofuran backbone was achieved by
2-Phenyl-3-alkylbenzofuran
Imidazolium salts
moieties
heating benzyl salicylaldehyde ether 3 in a base-mediated conden-
sation to produce the intermediate 2-phenylbenzofuran (4, 40%
yield). The formylation of 2-phenylbenzofuran 4 under Vilsme-
ier–Haack conditions followed by hydrolysis produced the known
compound 2-phenylbenzofuran-3-carbaldehyde 5 in 90% yield.
The 2-phenylbenzofuran-3-carbaldehyde 5 was reduced via NaBH4
to the respective 2-phenylbenzofuran 3-methanol compound (6,
95% yields). Subsequently, the 2-phenylbenzofuran 3-methanol
compound 6 was transformed via the mesylate to give the respec-
tive 2-phenyl-3-alkylbenzofuran–imidazole hybrids (7–9) and 2-
phenyl-3-alkylbenzofuran–triazole hybrid 32 by refluxing under
toluene with 65–78% yields (two steps).13 Finally, thirty 2-phe-
nyl-3-alkylbenzofuran-based imidazolium salts (9–31) and 2-phe-
nyl-3-alkyl-benzofuranbased triazolium salts (33–42) were
prepared with excellent yields by reaction of 2-phenyl-3-
alkylbenzofuran–imidazole/triazole hybrids with the correspond-
ing phenacyl and alkyl halides in refluxing toluene (52–99%
yields).14 The structures and yields of hybrid compounds are
shown in Table 1.
The potential cytotoxicity of all newly synthesized hybrid com-
pounds were evaluated in vitro against a panel of human tumor
cell lines, according to procedures described in the literature.15
The panel consisted of leukemia (HL-60), myeloid liver carcinoma
(SMMC-7721), lung carcinoma (A549), breast carcinoma (MCF-7),
and colon carcinoma (SW480). Cisplatin (DDP) was used as the ref-
erence drug. The results are summarized in Table 2 (IC50 value, de-
fined as the concentrations corresponding to 50% growth
inhibition).
OH
OH
N
N
Cl
HO
O
O
R
Lepidiline A R = H
Moracins O
Lepidiline B R = CH3
OH
CHO
O
N
N
Br
OH
O
MeO
HO
Ebenfuran III
MNIB
Figure 1. Representative structures of natural 2-phenyl-3-alkylbenzofurans and
imidazolium salts.
the antitumor activity of 2-phenyl-3-alkylbenzofuran- imidazole/
triazole hybrids, with the ultimate aim of developing novel potent
antitumor agents.
To synthesize the 2-phenyl-3-alkylbenzofuran-imidazole hy-
brids, we used commercially available imidazole and triazole
derivatives that were alkylated with 2-phenylbenzofuran 3-meth-
anol, which was synthesized over four steps from readily available
starting materials as shown in scheme 1. Salicylaldehyde 1 was
chosen as the starting material for the preparation of a series of
2-phenyl-3-alkylbenzofuran-imidazole/triazole hybrids (7–42).
Salicylaldehyde 1 was reacted with benzyl bromide 2 in DMF at
100 °C to give ether the ether 3 in 96% yields. The key step in the
O
O
tBuOK
DMF,reflux
K2CO3
DMF,100oC
8 h, 96%
H
Br
H
+
OH
O
6 h
40%
1
2
3
O
1) POCl3, DMF
100oC, 20 h
NaBH4
EtOH
2) NaOAc (aq.)
90%
O
O
rt, 4h
95%
4
5
N
N
HN
OH
N
N
MsCl
N
toluene
Et3N
reflux, 24 h
DCM
rt, 2h
two steps, 78%
O
O
R1
toluene
reflux, 12-24 h
6
32
two steps, 65-78%
N
HN
toluene
reflux
R2 Br
R1
24-48 h
55-95%
N
N
R2
R2Br
Br
N
toluene
reflux
O
24-48 h
52-99%
7-9
N
N
R1
O
R2
33-42
N
N
Br
R2 = phenacyl, benzyl
imidazole ring
imidazole
O
benzimidazole
2-ethyl-imidazole
10-31
Scheme 1. Synthesis of hybrid compounds 7–42.

W. Chen et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4297–4302
4299
Table 1
inhibitory activity than DDP. However, imidazolium salt hybrids
25–31, with 2-ethyl-imidazole, exhibited powerful inhibitory
activities. Most of these derivatives were found to be much more
active than DDP (compounds 27, 28, 29, 30 and 31). Compared
with the triazolium salts 33–42, the imidazolium salts 10–31 dis-
played higher inhibitory activity. This difference of imidazolium
and triazolium salts in inhibition may be largely due to the changes
of molecular structure and charge distribution (electron rich) be-
tween imidazole ring and triazole ring. Recently, it has also been
proved that the imidazole derivatives exhibited more potent inhib-
itory activity than triazole derivatives by Oyama’s group.16
Structures and yields of hybrid compounds 7–42
Entry Compound Imidazole/
triazole ring
R2
Molecular
formula
Yields
(%)
1
2
3
7
8
9
Imidazole
Benzimidazole
2-Ethyl-
imidazole
Imidazole
Imidazole
—
—
—
C18H14N2O
C22H16N2O
C20H18N2O
70
65
78
4
5
10
11
Phenacyl
4-
C26H21BrN2O2 81
26H21BrN2O3 83
C
Hydroxyphenacyl
4- C27H23BrN2O3 84
Methoxyphenacyl
6
12
Imidazole
In terms of the substituent at position-3 of imidazole or posi-
tion-4 of triazole ring, hybrids 11, 18, 26, 34, and 42, with
4-hydroxyphenacyl or butyl substituent at position-3/4 of imidaz-
ole/triazole ring, showed decreased activities against five tumor
cell lines. However, hybrid compounds with phenacyl or substi-
tuted phenacyl substituents exhibited moderate or potent inhibi-
tory activities. Among them, compounds 15, 22, 30, and 38,
bearing a naphthylacyl substituent, were the most active com-
pounds with similar or higher inhibitory activities than DDP.
Compared with the above imidazolium salt derivatives with
phenacyl or butyl substituents, hybrid compounds 16, 24, and 31,
with a 2-bromobenzyl substituent at position-3 of the imidazole
ring, exhibited higher inhibitory activities. These hybrid com-
pounds displayed more potent inhibitory activities than DDP.
7
8
9
10
11
12
13
14
15
16
17
18
Imidazole
Imidazole
Imidazole
Imidazole
Benzimidazole Phenacyl
Benzimidazole 4-
Hydroxyphenacyl
Benzimidazole 4-
Methoxyphenacyl
Benzimidazole 4-Fluorophenacyl C30H22BrFN2O2 68
Benzimidazole 4-Bromophenacyl C30H22Br2N2O2 76
Benzimidazole Naphthylacyl
Benzimidazole Benzyl
Benzimidazole 2-Bromobenzyl
2-Ethyl-
imidazole
2-Ethyl-
imidazole
2-Ethyl-
imidazole
2-Ethyl-
imidazole
2-Ethyl-
imidazole
2-Ethyl-
imidazole
2-Ethyl-
imidazole
1,2,4-Triazole
1,2,4-Triazole
1,2,4-Triazole
4-Fluorophenacyl C26H20BrFN2O2 87
4-Bromophenacyl C26H20Br2N2O2 75
Naphthylacyl
2-Bromobenzyl
C30H23BrN2O2 55
C25H20BrN2O 52
C30H23BrN2O2 93
C30H23BrN2O3 52
13
19
C31H25BrN2O3 92
14
15
16
17
18
19
20
21
22
23
24
25
C35H25BrN2O2 96
C29H23BrN2O 99
C29H22BrN2O 53
C28H25BrN2O2 95
Phenacyl
20
21
22
23
24
25
26
27
28
29
30
31
4-
C28H25BrNO3 91
C29H27BrN2O3 82
Interestingly, hybrid compound 31, with
a 2-bromobenzyl
Hydroxyphenacyl
4-
Methoxyphenacyl
4-Fluorophenacyl C28H24BrFN2O2 91
4-Bromophenacyl C28H24Br2N2O2 99
Table 2
Cytotoxic activities of hybrid compounds 7–42 in vitroa (IC50
,
l
Mb)
Entry
Compound
HL-60
SMMC-7721
A549
MCF-7
SW480
Naphthylacyl
C32H27BrN2O2 93
C27H24Br2N2O 84
1
2
7
8
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
2-Bromobenzyl
3
9
>40
>40
>40
>40
>40
4
5
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
39
40
41
42
DDP
2.49
>40
9.83
>40
>40
>40
16.27
>40
13.76
13.97
11.23
12.21
33.99
9.12
11.79
5.25
4.50
15.45
>40
15.49
>40
26
27
28
32
33
34
—
C17H13N3O
C
C
78
25H20BrN3O2 90
25H20BrN3O3 92
Phenacyl
4-
2.28
2.98
1.57
2.06
1.86
1.97
13.04
0.61
2.03
2.11
2.34
1.96
0.64
2.09
13.15
0.58
0.99
0.72
0.61
0.08
>40
16.49
13.44
17.77
9.42
6.61
8.46
20.66
16.60
9.41
2.94
2.63
4.81
2.10
5.01
13.13
11.81
8.13
6.07
2.30
0.52
>40
10.27
14.62
3.65
3.68
5.58
3.92
16.22
23.78
3.13
4.08
3.24
3.49
4.78
7.53
17.39
3.17
5.03
2.89
3.03
0.51
>40
11.92
15.54
3.36
3.48
10.35
3.44
18.16
>40
3.29
4.37
3.61
3.26
5.56
11.89
>40
Hydroxyphenacyl
4- C26H22BrN3O3 95
Methoxyphenacyl
4-Fluorophenacyl C25H9BrFN3O2 86
4-Bromophenacyl C25H19Br2N3O2 85
29
35
1,2,4-Triazole
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
30
31
32
33
36
37
38
39
1,2,4-Triazole
1,2,4-Triazole
1,2,4-Triazole
1,2,4-Triazole
Naphthylacyl
20-Phenyl-
phenacyl
C29H22BrN3O2 88
C31H24BrN3O2 77
34
35
36
40
41
42
1,2,4-Triazole
1,2,4-Triazole
1,2,4-Triazole
Benzyl
C24H20BrN3O 88
2-Bromobenzyl
Butyl
C
C
24H19Br2N3O 75
21H22BrN3O 55
7.09
3.34
12.50
27.08
12.90
14.56
12.76
5.35
5.69
11.33
3.58
3.14
0.47
>40
As shown in Table 2, the structures of the hybrid compounds
have an obvious influence on the inhibitory activities. 2-Phenyl-
3-alkylbenzofuran–imidazole hybrids 7–9 and the 2-phenyl-
3-alkylbenzofuran–triazole hybrid 32 lacked activities against all
tumor cell lines investigated at the concentration of 40 lM. How-
ever, their imidazolium salts 10–31 and triazolium salts 33–42
0.55
>40
3.51
>40
5.76
>40
13.74
>40
13.68
15.08
14.58
2.06
16.80
>40
33.06
>40
14.67
>40
17.09
>40
3.22
9.67
9.71
2.33
15.90
>40
9.00
>40
1.69
5.76
9.21
10.82
1.86
16.12
>40
21.90
>40
12.49
14.92
16.36
10.44
3.11
20.71
>40
16.34
>40
20.82
17.20
16.75
14.63
2.89
20.92
>40
18.89
>40
18.85
exhibited some degree of inhibitory activities.
In terms of the imidazole ring (imidazole, benzimidazole, or
2-ethyl-imidazole) and triazole ring, imidazolium salts 10–16 with
imidazole and triazolium salts 33–42 displayed some inhibitory
activities. Meanwhile, hybrid compounds 17–24, with benzimid-
azole, exhibited medium inhibitory activities. Among them, com-
pounds 15, 16, 22, 24, and 38, bearing a naphthylacyl or 2-
bromobenzyl substituent at position-3/4 of the imidazole/triazole,
showed similar or higher inhibitory activity in vitro than DDP.
Compounds 22 and 24, also bearing a naphthylacyl or 2-bromob-
enzyl at position-3 of the imidazole ring, displayed higher
14.09
a
Data represent the mean values of three independent determinations.
Cytotoxicity as IC50 for each cell line, is the concentration of compound which
b
reduced by 50% the optical density of treated cells with respect to untreated cells
using the MTT assay.

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W. Chen et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4297–4302
R1
Y
R1
A, B: Y = CH
C, D: Y = N
Y
N
N
N
R2
N
Br
O
O
(A, C)
(B, D)
hybrids:
benzofuran-imidazolium salt (B) > benzofuran-imidazole hybrids (A)
benzofuran-triazolium salt (D) > benzofuran-triazole hybrids (C)
benzofuran-imidazoliumsalt (B) > benzofuran-triazolium salt (D)
Better
imidazole / triazole ring:
2-ethylimidazole > benzimidazole > imidazole > triazole
Best
R2
2-bromobenzyl > benzyl > phenacyl > alkyl
Best
=
O
O
O
phenacyl =
>
>
>
F
Br
Among the best
O
O
O
Figure 3. Model of hybrid compound 31 docked into PI3Kc.
>
>>
OMe
OH
dock hybrids 31 and 38 with some crystal structure of proteins
in this signaling pathway, for example, mTORC1, mTORC2, and
PI3K using Autodock 4.0 (see Supplementary data for a detailed
description of the docking experiments). Although these two com-
pounds could not dock with mTORC1 or mTORC2, they could dock
Best Potent Compounds
Cytotoxic Activities
IC50 values
0.08-0.55 µM
Br
N
N
Br
well with PI3Kc (PDB code 3PRZ). Figure 3 shows hybrid 31 is pre-
dicted to engage a hydrogen bond with HIS577 using furan oxygen,
and it also shows 2-ethyl-imidazole ring and benzofuran ring can
foster van der Waals interactions with the gap bounded by
PHE578, ALA545, and GLU546. Similarly, hybrid 38 establishes a
hydrogen bond with ARG579 using carbonylic oxygen, and its 2-
phenyl-3-alkylbenzofuran moiety can interact with the gap
bounded by PHE578, GLU546, GLU584, and ALA545, while its tria-
zole ring placed in the pocket bounded by PHE578, HIS577,
TRP576, and ARG579 (Fig. 4). All these favorable interactions con-
tribute to achieve a good docking score (AutoDock binding energy
of 31 is—4.48 kcal/mol, and AutoDock binding energy of 38 is—
4.84 kcal/mol) and an excellent inhibitory activity as it results from
the experimental data. These interesting findings would be helpful
for our further research.
In conclusion, a number of novel 2-phenyl-3-alkylbenzofuran-
imidazole/triazole hybrid compounds proved to be potent antitu-
mor agents. Hybrids 22, 24, 30, and 31, bearing a 2-ethyl-imidazole
or benzimidazole ring, and 2-bromobenzyl or naphthylacyl substi-
tuent at position-3 of the imidazole ring, were found to be the most
potent activity. Compound 31 was found to have the most potent
O
31
Figure 2. Structure–activity relationships of hybrid compounds.
substituent at position-3 of 2-ethyl-imidazole, was found to be the
most potent derivative with IC50 values of 0.08–0.55 M against all
l
of human tumor cell lines investigated, and much more active than
DDP. Notably, this compound exhibited inhibitory activity selec-
tively against breast carcinoma (MCF-7) and colon carcinoma
(SW480), with IC50 values 40.8-fold and 40.1-fold lower than DDP.
This finding suggests that the existence of 2-ethyl-imidazole
ring, and substitution of the imidazolyl-3-position with a 2-bro-
mobenzyl or naphthylacyl group, were important for modulating
inhibitory activity. The structure–activity relationship (SAR) re-
sults are summarized in Figure 2.
In addition, the inhibition of mTOR (mammalian target of rapa-
mycin) signaling of some newly synthesized hybrid compounds
were evaluated according to procedures described in the litera-
ture.17 Rapamycin was used as the reference drugs. The results
are summarized in Table 3 (Ratio, defined as Eukaryotic initiation
factor 4E (eIF4E) Cytoplasmic-to-Nuclear). In order to rationalize
the observed SARs for this series of compound, we attempted to
derivative, with IC50 values of 0.08–0.55 lM against all human tu-
mor cell lines investigated and more selective towards breast car-
cinoma (MCF-7) and colon carcinoma (SW480), with IC50 values
40.8-fold and 40.1-fold lower than DDP. The 2-phenyl-
3-alkylbenzofuran-based imidazolium salts 22, 24, 30, and 31 are
Table 3
Eukaryotic initiation factor 4E (eIF4E) Cytoplasmic-to-Nuclear of representative hybrid compounds
Entry
1
2
3
4
5
6
7
8
9
10
Compound
Ratioa
Control
0.85
12
1.12
19
1.32
23
1.54
24
1.52
30
1.55
31
1.07
33
1.11
38
0.96
Rapamycin
1.59
a
Ratio, defined as Eukaryotic initiation factor 4E (eIF4E) Cytoplasmic-to-Nuclear.

W. Chen et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4297–4302
4301
Figure 4. Model of hybrid compound 38 docked into PI3Kc.
2970; (c) D’hooghe, M.; Mollet, K.; De Vreese, R.; Jonckers, T. H. M.; Dams, G.;
De Kimpe, N. J. Med. Chem. 2012, 55, 5637; (d) Getlik, M.; Grütter, C.; Simard, J.
R.; Klüter, S.; Rabiller, M.; Rode, H. B.; Robubi, A.; Rauh, D. J. Med. Chem. 2009,
52, 3915; (e) Shrestha, A. R.; Shindo, T.; Ashida, N.; Nagamatsu, T. Bioorg. Med.
Chem. 2008, 16, 8685; (f) Kaliappan, K. P.; Ravikumar, V. Org. Biomol. Chem.
2005, 3, 848.
promising leads for further structural modifications, guided by the
valuable information obtained from our SARs.
Acknowledgments
12. Pautus, S.; Yee, S. W.; Jayne, M.; Coogan, M. P.; Simons, C. Bioorg. Med. Chem.
2006, 14, 3643.
This work was supported by the NSFC (30960460, 20925205
and 21062026), NSFYN (2010GA014 and 2012FB113), PRTTSTYN
(Y. Li, 2009C1120) and NBRPC (973 Program, 2009CB522300).
13. General procedure for the preparation of hybrids 7–9 and 32. To a solution of 2-
phenyl-benzofuran 3-methanol 6 (1 mmol) in dichloromethane (50 mL) was
added methanesulfonyl 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 carried
over to the next synthetic step. To the resulting, methanesulfonate was added
imidazole, or substituted imidazole or 1,2,4-triazole (3 mmol), and the mixture
was stirred in toluene (20 mL) at reflux for 12–24 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 using column chromatography (silica gel, petroleum ether
60–90 °C:ethyl acetate = 1:1) to afford 7–9 and 32 in 65–78% yield (two steps).
Compound 7: yellow powder, yield 70%, mp 102–104 °C. IR mmax (cmꢀ1): 3101,
3055, 1601, 1501, 1449, 1283, 1221, 1112, 1074, 806, 750, 687. 1H NMR
(300 MHz, CDCl3): d 7.63 (2H, ddd, J = 6.6, 2.1, 1.2 Hz), 7.56 (1H, s), 7.51–7.36
(4H, m), 7.31–7.25 (1H, m), 7.23–7.14 (2H, m), 7.04 (1H, s), 6.89 (1H, s), 5.29
(2H, s). 13C NMR (75 MHz, CDCl3): d 153.91 (C), 153.72 (C), 136.73 (CH), 129.69
(CH), 129.45 (C), 129.31 (CH), 128.91 (CH),128.49 (C), 127.25 (CH), 125.06
(CH), 123.30 (CH), 118.96 (CH), 118.73 (CH), 111.30 (CH), 109.69 (C), 41.20
(CH2). HRMS (ESI-TOF) m/z Calcd for C18H14N2ONa [M+Na]+ 297.0998, found
297.1015.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.06.
001.
References and notes
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14. General procedure for the preparation hybrids 10–31 and 33–42. A mixture of
hybrids 7–9 or 32 (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 completion of the reaction, as indicated by TLC,
the precipitate was filtered through a small pad of Celite, and washed with
toluene (3 ꢁ 10 mL), then dried to afford imidazolium salts 10–31 and 33–42
in 52–99% yields.
Compound 31: yellow oil, yield 84%. IR mmax (cmꢀ1): 3049, 2935, 2864, 1618,
1583, 1513, 1445, 1244,1194, 1105, 1031, 754, 700. 1H NMR (300 MHz, CDCl3):
d 7.85 (2H, d, J = 6.0 Hz), 7.79 (1H, s), 7.76–7.68 (2H, m), 7.65–7.53 (4H, m),
7.53–7.24 (5H, m), 7.04 (1H, d, J = 6.3 Hz), 5.93 (2H, s), 5.53 (2H, s), 3.06 (2H, q,
J = 7.5 Hz), 0.88 (3H, t, J = 7.5 Hz). 13C NMR (75 MHz, CDCl3):
d 153.29
(C),152.94 (C), 148.01 (C), 132.80 (C), 132.59 (CH), 130.17 (CH), 129.33 (CH),
129.05 (CH), 128.64 (CH), 128.15 (C), 127.83 (CH), 127.07 (CH), 124.99 (CH),
122.99 (CH), 121.98 (C), 121.44 (CH), 119.13 (CH), 110.99 (CH), 107.96 (CH),
50.52 (CH2), 42.11 (CH2), 16.29 (CH2), 9.99 (CH3). HRMS (ESI-TOF) m/z Calcd for
C27H24BrN2O [MꢀBr]+ 471.1067, found 471.1070.
Compound 38: white powder, yield 88%, mp 232–234 °C. IR m
max (cmꢀ1): 3050,
2958, 2865, 1698, 1560, 1450, 1364, 1262, 1161, 818, 716, 698. 1H NMR
(300 MHz, CDCl3): d 10.62 (1H, s), 8.95 (1H, s), 8.72 (1H, s), 8.06 (1H, d,
J = 7.8 Hz), 8.00 (1H, d, J = 8.7 Hz), 7.93–7.86 (4H, m), 7.75 (1H, d, J = 6.3 Hz),
7.67–7.51 (6H, m), 7.37 (2H, s), 6.38 (2H, s), 5.92 (2H, s). 13C NMR (75 MHz,
CDCl3): d 193.02 (C), 159.62 (C), 157.71 (C), 149.23 (CH), 147.29 (CH), 139.95

4302
W. Chen et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4297–4302
(C), 136.03 (C), 134.89 (CH), 133.89 (C), 133.60 (CH), 133.17 (CH), 132.83 (CH),
132.68 (CH), 131.45 (CH), 130.91 (CH), 129.18 (CH), 127.51 (CH), 126.65 (CH),
Hou, X.; Chen, H.; Guan, H.; Ma, Y.; Peng, W.; Xu, A. Bioorg. Med. Chem. 2004, 12,
4613.
122.90 (CH), 115.13 (CH), 110.00 (C), 58.06 (CH2), 51.31 (CH2). HRMS (ESI-TOF)
16. Matsui, H.; Sakanashi, Y.; Oyama, T. M.; Oyama, Y.; Yokota, S.; Ishida, S.; Okano,
Y.; Oyama, T. B.; Nishimura, Y. Toxicology 2008, 248, 142.
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2009, 16, 1240.
m/z Calcd for C29H22N3O2 [MꢀBr]+ 444.1707, found 444.1718.
15. (a) Kim, D.-K.; Ryu, D. H.; Lee, J. Y.; Lee, N.; Kim, Y.-W.; Kim, J.-S.; Chang, K.; Im,
G.-J.; Kim, T.-K.; Choi, W.-S. J. Med. Chem. 2001, 44, 1594; (b) Cao, R.; Chen, Q.;