Synthesis and biological evaluation of novel 3-benzylcoumarin-imidazolium salts

Article abstract of DOI:10.1016/j.bmcl.2019.126896

A series of novel 3-benzylcoumarin-imidazolium salts were prepared and evaluated in vitro against a panel of human tumor cell lines. The results showed that the existence of 5,6-dimethyl-benzimidazole ring and substitution of the imidazolyl-3-position wit

Full text of DOI:10.1016/j.bmcl.2019.126896

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Synthesis and biological evaluation of novel 3-benzylcoumarin-imidazolium
salts
Xue-Quan Wang, Xue-Bing Chen, Ping-Ting Ye, Zhi-Xin Yang, Meng-Jiao
Bai, Su-Yue Duan, Yan Li, Xiao-Dong Yang
PII:
S0960-894X(19)30874-1
DOI:
https://doi.org/10.1016/j.bmcl.2019.126896
BMCL 126896
Reference:
Bioorganic & Medicinal Chemistry Letters
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Accepted Date:
26 October 2019
6 December 2019
7 December 2019
Please cite this article as: Wang, X-Q., Chen, X-B., Ye, P-T., Yang, Z-X., Bai, M-J., Duan, S-Y., Li, Y., Yang, X-
D., Synthesis and biological evaluation of novel 3-benzylcoumarin-imidazolium salts, Bioorganic & Medicinal
Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.126896
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Synthesis and biological evaluation of novel 3-benzylcoumarin-imidazolium salts
Xue-Quan Wanga , Xue-Bing Chena, Ping-Ting Yea, Zhi-Xin Yanga, Meng-Jiao Baia, Su-Yue Duana, Yan
Lic, , Xiao-Dong Yangb, 
aKey Laboratory of Natural Pharmaceutical and Chemical Biology of Yunnan Province, School of Science, Honghe University, Mengzi, Yunnan 661100, P. R.
China
bKey Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology,
Yunnan University, Kunming, 650091, P. R. China
cState Key Laboratory for Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Science, Kunming, 650204, P.
R. China
———
ARTICLE INFO
ABSTRACT
Corresponding author.
Article history:
A series of novel 3-benzylcoumarin-imidazolium salts were prepared and evaluated in vitro
Received
Revised
against a panel of human tumor cell lines. The results showed that the existence of 5,6-dimethyl-
benzimidazole ring and substitution of the imidazolyl-3-position with a naphthylacyl group were
E-mail addresses: xdyang@ynu.edu.cn (X. D. Yang), liyanb@mail.kib.ac.cn (Y. Li).
Accepted
Available online
vital for modulating cytotoxic activity. Notably, compound 38 was found to be the most potent
derivative with IC50 values of 2.04–4.51 μM against five human tumor cell lines, while
compound 34 were more selective to SW-480 cell lines with IC50 value 40.0-fold lower than
DDP. Mechanism of action studies indicated that compound 38 can cause the G0/G1 phase cell
cycle arrest and apoptosis in SMMC-7721 cell lines.
Keywords:
3-Benzylcoumarin
Imidazolium salts
Biological evaluation
Cytotoxic activity
Structure-activity relationships
2019 Elsevier Ltd. All rights reserved.
Coumarins are an important class of biologically active
heterocycles consisting of benzene and 2-pyrone rings. Natural
and synthetic products with 3-benzylcoumarin moiety exhibit a
broad range of biological and pharmacological activities.1 In
particular, 3-benzylcoumarin derivatives have been identified to
possess antitumor activity.2 As illuminated in Fig. 1, compound 1
exhibited potent cytotoxic activity against colon carcinoma cells
(HCT116) with IC50 values of 8 nM,3 while compound 2 showed
effective cytotoxicity to urinary bladder carcinoma cells (EJ-60)
and leukemia cells (HL-60).4
Hence, considering the potent cytotoxic activities of natural
and synthetic 3-benzylcoumarin derivatives, as well as the
anticancer activities of imidazole derivatives, we report design
and synthesis of novel 3-benzylcoumarin-imidazolium
derivatives as potent antitumor agents. To the best of our
knowledge, no reports concerning antitumor activity for 3-
benzylcoumarin-imidazolium salt hybrids have been reported.
In the present research, twenty-four new 3-benzylcoumarin-
imidazolium hybrids were synthesized to explore the antitumor
activity of these derivatives. The synthetic route for 3-
benzylcoumarin-imidazolium salt was shown in Scheme 1.
Salicylaldehyde 6 and ethyl 3-oxo-3-phenylpropanoate 7 were
selected as the starting materials. Initially, Knoevenagel
condensation of salicylaldehyde 6 with ethyl benzoylacetate 7
afforded 3-benzoyl-coumarin 8 in 95% yield. Subsequently,
Heterocycles are of great interest to medicinal chemists owing
to their widespread biological and pharmacological activities.5
Particularly, imidazole and imidazolium salts are key building
block of many bioactive compounds. Natural products and
biologically active agents possessing the imidazole or
imidazolium salts moieties display a variety of biological
activities, such as antitumor, antiprotozoal, antidengue virus and
antifungal activities.6 For example, two natural imidazolium salts,
Lepidiline A and B (Fig. 1) isolated from Lepidium meyenii were
found to be potently active against four human cancer cell lines.7
Recently, we have reported the synthesis of a series of novel
imidazolium derivatives, such as NMIB (Fig. 1) and their
potential antitumor activities.8 Further mechanism study
demonstrated that the imidazolium salt derivatives can induce the
cell cycle arrest and apoptosis in tumor cells.8h In previous
structure-activity relationships (SARs) studies, we found that the
existence of substituted benzimidazole (such as 5,6-dimethyl-
benzimidazole) ring and substitution of the imidazolyl-3-position
with a substituted phenacyl group (such as 2-naphthylacyl) could
be crucial for antitumor activity, which provides the valuable
information for further rational design and synthesis of
imidazolium salts.
reduction of
8
using NaBH4-CeCl3 in methanol and
dichloromethane gave the 3-(hydroxy(phenyl)methyl)-coumarin
(9, 87% yield). The 3-(hydroxy(phenyl)methyl)-coumarin 9 was
transformed via the mesylate to the respective four 3-
benzylcoumarin-imidazole hybrids 11–14 with various
substituted imidazole (imidazole, benzimidazole, 2-methyl-
benzimidazole or 5,6-dimethyl-benzimidazole) by refluxing
under acetonitrile with 49–72% yields for two steps. Finally,
twenty-four novel 3-benzylcoumarin-imidazolium salts 15–38
were prepared with excellent yields by reaction of 3-
benzylcoumarin-imidazole hybrids 11–14 with the corresponding
phenacyl bromides in refluxing acetone (65–98% yields). The
structures and yields of 3-benzylcoumarin-imidazole derivatives
are shown in Table 1.
The potential cytotoxicity of 3-benzylcoumarin-imidazole
derivatives 11–38 were then evaluated in vitro against five
human cancer cell lines by MTS assay. 9 The cell lines include
1

leukemia (HL-60), lung carcinoma (A549), colon carcinoma
(SW480), breast carcinoma (MCF-7) and liver carcinoma
(SMMC-7721). Cisplatin (DDP) was chosen as the reference
drug. The results are summarized in Table 2 (IC50 value, defined
as the concentrations corresponding to 50% growth inhibition).
3-Benzylcoumarin moieties
Imidazolium salts
F
H
Cl-
F
N
NH2
O
S
N
N
O
O
N
O
O
O
R
1
3
Lepidiline A R = H ( )
OEt
4
Lepidiline B R = CH3 ( )
O
O
O
O
Coumarin
OH
Br-
N
N
O
O
OH
O
OH
5
NMIB ( )
2
Fig. 1. Representative structures of coumarin, 3-benzylcoumarins and imidazolium salts.
O
O
O
piperidine, MeCN
rt, 12h, 95%
H
O
O
OH
O
O
CeCl 7H O, NaBH
4
MeOH/CH2Cl2, 0 °C
87%
·
3
2
7
6
8
R1
MsCl, Et3N
CH2Cl2, rt, 2h
NH
N
OH
OMs
N
N
solvent, reflux
12-24h
two steps
49%-72%
O
O
O
O
R1
O
O
9
10
11-14
acetone, reflux
12-24h
65%-98%
R2 Br
imidazole ring
imidazole
benzimidazole
2-methyl-benzimidazole
5, 6-dimethyl-benzimidazole
R2 = phenacyl
N
R2
Br-
N
R1
O
O
15-38
Scheme 1. Synthesis of 3-benzylcoumarin–imidazolium salts 15–38.
Table 1
Structures and yields of compounds 11–38.
Entry
Compound
Imidazole ring
imidazole
R2
Molecular formula
C19H14N2O2
Yields (%)
1
2
3
4
5
6
11
12
13
14
15
16
-
72
49
52
58
88
98
benzimidazole
2-methyl-benzimidazole
5,6-dimethyl-benzimidazole
imidazole
-
C23H16N2O2
-
C24H18N2O2
-
C25H20N2O2
phenacyl
C27H21BrN2O3
C27H20Br2N2O3
imidazole
4-bromophenacyl
2

7
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
imidazole
4-trifluoromethylphenacyl
4-methoxyphenacyl
4-phenylphenacyl
naphthylacyl
C28H20BrF3N2O3
C28H23BrN2O4
C33H25BrN2O3
C31H23BrN2O3
C31H23BrN2O3
C31H22Br2N2O3
C32H22BrF3N2O3
C32H25BrN2O4
C37H27BrN2O3
C35H25BrN2O3
C32H25BrN2O3
C32H24Br2N2O3
C33H24BrF3N2O3
C33H27BrN2O4
C38H29BrN2O3
C36H27BrN2O3
C33H27BrN2O3
C33H26Br2N2O3
C34H26BrF3N2O3
C34H29BrN2O4
C39H31BrN2O3
C37H29BrN2O3
95
98
98
94
65
65
76
74
80
87
82
92
68
78
86
88
82
85
79
81
87
87
8
imidazole
9
imidazole
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
imidazole
benzimidazole
phenacyl
benzimidazole
4-bromophenacyl
4-trifluoromethylphenacyl
4-methoxyphenacyl
4-phenylphenacyl
naphthylacyl
benzimidazole
benzimidazole
benzimidazole
benzimidazole
2-methyl-benzimidazole
2-methyl-benzimidazole
2-methyl-benzimidazole
2-methyl-benzimidazole
2-methyl-benzimidazole
2-methyl-benzimidazole
5,6-dimethyl-benzimidazole
5,6-dimethyl-benzimidazole
5,6-dimethyl-benzimidazole
5,6-dimethyl-benzimidazole
5,6-dimethyl-benzimidazole
5,6-dimethyl-benzimidazole
phenacyl
4-bromophenacyl
4-trifluoromethylphenacyl
4-methoxyphenacyl
4-phenylphenacyl
naphthylacyl
phenacyl
4-bromophenacyl
4-trifluoromethylphenacyl
4-methoxyphenacyl
4-phenylphenacyl
naphthylacyl
As show in Table 2, the 3-benzylcoumarin-imidazole
9.13 μM. Among them, compound 31, bearing a 4-
derivatives gave more selectivity towards colon carcinoma (SW-
480) and breast carcinoma (MCF-7) cell lines. Meanwhile, the
structures of hybrid compounds have an obvious influence on the
inhibitory activities. 3-benzylcoumarin-imidazoles 11–14 and 3-
benzylcoumarin-imidazolium salts 15–20 lacked activity against
five tumor cell lines investigated at the concentration of 20 μM.
Nevertheless, their benzimidazolium salts 21–38 displayed some
extent of activity or higher levels activity. This difference in
cytotoxicity between neutral compounds and imidazolium salts
may be dependent on variations of molecular structure, charge
distribution and water solubility.10
phenylphenacyl substituent at position-3 of the benzimidazole,
showed higher cytotoxic activities in vitro compared with DDP.
However, benzimidazolium salt hybrids 33–38 with 5,6-
dimethyl-benzimidazole ring displayed powerful cytotoxic
activities. Most of this kind of derivatives was found to be much
more active than DDP, such as compounds 34, 36, 37 and 38.
Among them, compounds 34, 36 and 38, with
a 4-
methoxyphenacyl, 4-bromophenacyl or naphthylacyl substituent
at position-3 of the 5,6-dimethyl-benzimidazole, showed potent
cytotoxic activities with IC50 values of 0.20–4.89 μM against five
human tumor cell lines investigated.
In terms of the various substituted imidazole ring (imidazole,
benzimidazole, 2-methyl-benzimidazole or 5,6-dimethyl-
benzimidazole), imidazolium salts 15–18 with imidazole ring
lacked activity against all tumor cell lines, only 19 and 20 with a
4-phenylphenacyl or naphthylacyl substituent at position-3 of the
imidazole ring displayed weak cytotoxic activities against HL-60
and MCF-7 cell lines. Meanwhile, benzimidazolium salt hybrids
21–26 with benzimidazole ring and 27–32 with 2-methyl-
benzimidazole ring exhibited medium cytotoxic activities, but
these hybrids displayed the better selective cytotoxic activity
against SW-480 and MCF-7 cell lines with IC50 values of 0.96–
In terms of the substituent at position-3 of imidazole ring, a
phenacyl, 4-bromophenacyl or 4-trifluoromethylphenacyl
substituent at position-3 of imidazole rings, such as 15, 16, 17,
21, 22, 27, 28, 29 and 35, lacked or decreased activities against
all tumor cell lines. However, compound 34 with 4-
bromophenacyl displayed cytotoxic activity selectively against
colon carcinoma (SW-480) with IC50 value 40-fold more
sensitive to DDP. A 4-methoxyphenacyl substituent at position-3
of imidazole rings, such as 24, 30 and 36, slightly improve the
inhibitory activities. Especially, compound 36 was more selective
to MCF-7 and SW-480 cell lines with IC50 value 6.2-fold and
22.2-fold lower than DDP. Interestingly, compared with above
substituents, hybrid compounds 25, 31 and 37 with substituted 4-
phenylphenacyl or 26, 32 and 38 with naphthylacyl substituent at
position-3 of imidazole ring exhibited potent activities. Most of
these kinds of derivatives showed higher activities than DDP.
Furthermore, compounds 38, bearing a naphthylacyl substituent
at position-3 of the 5,6-dimethyl-benzimidazole was found to be
the most potent derivatives with IC50 values of 2.04–4.51μM
against all of human tumor cell lines investigated. Notably,
hybrid 25 with a 4-phenylphenacyl substituent at position-3 of
benzimidazole were more selective to MCF-7 and SW-480 cell
lines with IC50 value 10.2-fold and 4.9-fold lower than DDP.
The results indicated that the existence of 5,6-dimethyl-
benzimidazole ring and substitution of the imidazolyl-3-position
with a 2-naphthylacyl or 4-phenylphenacyl group were important
for the antitumor activity. The structure-activity relationship
(SAR) results were summarized in Scheme 2.
SMMC-7721 cells were exposed to increasing concentrations
of compound 38 and cell apoptosis was determined with Annexin
V-FITC/PI double-labeled cell cytometry. As shown in Fig. 2,
after treatment of cells with compound 38 at 2, 4, 8 μM for 48 h,
the apoptotic cell rate was 1.89 ± 0.03%, 5.70 ± 0.14% and 37.30
± 1.81%, respectively, which were statistically significantly
3

different from the control (1.88 ± 0.00003%). The results of cell
cycle analysis on SMMC-7721 cells treated with compound 38
were presented in Fig. 3. Compared with the control cells, the
percentage of cells of G1 phase increased during the cells
incubated with compound 38 with a dose dependent manner.
Compound 38 treatment caused 70.88 ± 0.23% cells in G0/G1
Table 2
phase as compared to control showing 63.71 ± 0.31%.
Meanwhile, the percentage of S phase cells decreased slightly
accordingly, while the proportion of cells in G2/M and Sub G1
phases showed no obvious change. The data suggest that
compound 38 may induce G0/G1 phase arrest in the cell cycle.
Cytotoxic activities of compounds 11–38 in vitrob (IC50, μMa).
Entry
1
Compound
11
HL-60
>20
SMMC-7721
>20
A-549
>20
MCF-7
>20
SW-480
>20
2
12
>20
>20
>20
>20
>20
3
13
>20
>20
>20
>20
>20
4
14
>20
>20
>20
>20
>20
5
15
>20
>20
>20
>20
>20
6
16
>20
>20
>20
>20
>20
7
17
>20
>20
>20
>20
>20
8
18
>20
>20
>20
>20
>20
9
19
5.28
4.38
18.61
5.95
4.49
7.13
2.91
4.13
>20
>20
>20
12.65
7.27
5.10
1.24
1.29
1.74
0.96
1.28
>20
>20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
20
>20
>20
8.03
6.36
1.65
1.55
4.82
1.63
1.48
>20
21
>20
>20
22
8.20
6.15
8.84
4.70
5.72
>20
11.90
7.07
>20
23
24
25
7.47
9.11
>20
26
27
28
>20
>20
>20
>20
>20
29
7.72
3.69
2.77
8.34
4.81
2.45
8.81
1.55
2.07
2.07
3.02
>20
>20
8.15
1.21
2.86
2.81
4.17
2.29
6.61
1.58
1.66
2.04
9.80
9.13
3.43
2.88
6.02
1.24
0.20
8.19
0.36
8.03
2.32
7.99
30
6.92
5.05
11.36
7.17
4.19
9.50
4.72
1.91
3.77
5.70
8.56
5.10
15.83
12.42
4.89
11.68
5.65
2.14
4.51
7.21
31
32
33
34
35
36
37
38
DDP
aCytotoxicity as IC50 for each cell line, is the concentration of compound which reduced by 50% the optical density of treated cells with respect to untreated cells
using the MTS assay.
bData represent the mean values of three independent determinations.
N
N
N
R2
Br-
N
R1
R1
O
O
O
O
(A)
(B)
hybrids:
3-benzylcoumarin-imidazolium salts (B) > 3-benzylcoumarin-imidazole hybrids (A)
better
imidazole ring:
5,6-dimethyl-benzimidazole > benzimidazole > 2-methyl-benzimidazole > imidazole
Best
R2 = phenacyl:
4
O
O
O
>
>


Compound 38
48h
A
DMSO
2 μΜ
4 μΜ
8 μΜ
Annexin
B
Compound 38 (μΜ)
Fig. 2. Compound 38 caused significant apoptosis of SMMC-7721 cells. (A) Cells were treated with 2, 4 and 8 μM compound 38 for 48 h. Cell apoptosis was
determined by Annexin V-FITC/PI double-staining assay. (B) The quantification of cell apoptosis. Data represents the mean ± S.D. of three independent
experiments.
Compound 38
24h
A
4 μΜ
2 μΜ
8 μΜ
DMSO
B
SMMC-7721(%)
Treatment
5
G0/G1
S
G2/M
Sub G1
DMSO
63.71±0.31
23.26±0.57
6.70±0.63
3.173±0.26

Fig. 3. Compound 38 induces G1 phase arrest in SMMC-7721 cells. (A) Cells were treated with 2, 4 and 8 μM of compound 38 for 24 h. Cell cycle was
determined by PI staining and cell cytometry. (B) The percentages of cells in different phases were quantified. At least three independent experiments were
performed.
In summary, a series of novel 3-benzylcoumarin-imidazolium
salts were designed and prepared. Their antitumor activities of
these agents were evaluated in vitro against five human tumor
cell lines. The results showed that the hybrids gave more
selectivity towards MCF-7 and SW-480. Compounds 31, 34, 36,
37 and 38 with a 5,6-dimethyl-benzimidazole or 2-methyl-
benzimidazole ring, and 2-naphthylacyl, 4-phenylphenacyl, 4-
bromophenacyl or 4-methoxyphenacyl substituent at position-3
of imidazole ring were found to be the most potent compounds.
Notably, compound 38 was found to be the most potent
derivative with IC50 values of 2.04–4.51 μM against five human
tumor cell lines. Compounds 25, 34 and 36 were more selective
to MCF-7 and SW-480 cell lines with IC50 values 10.2-fold, 40.0-
fold and 22.2-fold lower than DDP. Study on the antitumor
mechanism of action indicated that compound 38 can cause the
G0/G1 phase cell cycle arrest and apoptosis in SMMC-7721 cell
lines. The SARs was also established in this study, and the
information showed that the 3-benzylcoumarin-based
imidazolium salts 31, 34, 36, 37 and 38 can be considered
promising leads for design of new stronger antitumor
compounds.
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