Synthesis and bioactivity of novel coumarin derivatives

Article abstract of DOI:10.1007/s10593-016-1898-3

[Figure not available: see fulltext.] A series of novel coumarin derivatives were synthesized from commercially available chemical agents. All prepared compounds were evaluated for their in vitro antiproliferative activity against five selected human cancer cell lines (EC109, MGC-803, PC-3, MCF-7, and EC9706) and their in vitro antimicrobial activity against E. coli and M. albicans. 4-(3-Bromopropoxy)-2H-chromen-2-one exhibited the highest growth inhibition against MGC-803 cell line (IC₅₀ 47.7 μM) and 7-(2-bromoethoxy)-2H-chromen-2-one exhibited the highest growth inhibition against MCF-7 cell line (IC₅₀ 48.3 μM). The latter compound was also the most active against E. coli (MIC₅₀ 0.27 μg/ml).

Full text of DOI:10.1007/s10593-016-1898-3

DOI 10.1007/s10593-016-1898-3
Chemistry of Heterocyclic Compounds 2016, 52(6), 374–378
Synthesis and bioactivity of novel coumarin derivatives
Sai-Yang Zhang1, Dong-Jun Fu1, Hui-Hui Sun1, Xiao-Xin Yue2,
Ying-Chao Liu1, Yan-Bing Zhang1*, Hong-Min Liu1*
1 Collaborative Innovation Center of New Drug Research and Safety Evaluation,
School of Pharmaceutical Sciences, Zhengzhou University,
Zhengzhou 450001, PR China; е-mail: zhangyb@zzu.edu.cn
2 Henan Medical College,
Zhengzhou 450001, PR China; е-mail: xxyue1115@126.com
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2016, 52(6), 374–378
Submitted March 2, 2016
Accepted after revision May 9, 2016
O
O
O
O
O
O
Br
Br
MCF-7: IC50 48.3 1.1 M
E. coli: MIC50 0.27 g/ml
MGC-803: IC50 47.7 1.1 M
E. coli: MIC50 9.35 g/ml
A series of novel coumarin derivatives were synthesized from commercially available chemical agents. All prepared compounds were
evaluated for their in vitro antiproliferative activity against five selected human cancer cell lines (EC109, MGC-803, PC-3, MCF-7, and
EC9706) and their in vitro antimicrobial activity against E. coli and M. albicans. 4-(3-Bromopropoxy)-2H-chromen-2-one exhibited the
highest growth inhibition against MGC-803 cell line (IC50 47.7 μM) and 7-(2-bromoethoxy)-2H-chromen-2-one exhibited the highest
growth inhibition against MCF-7 cell line (IC50 48.3 μM). The latter compound was also the most active against E. coli (MIC50 0.27 μg/ml).
Keywords: coumarin, anticancer activity, antimicrobial activity.
Coumarins and their derivatives possess a wide range of
biological activities such as antimicrobial1, anti-inflam-
matory,2 anticoagulant,3 antiHIV,4 antitumor,5 and enzyme
inhibitory (E. coli topoisomerase and DNA gyrase).6
Furthermore, hydroxycoumarins, powerful chain-breaking
antioxidants, can prevent free radical injury by scavenging
reactive oxygen species.7 For example, novobiocin, an
antibiotic that acts through inhibition of DNA gyrase, has
been structurally modified to develop a series of selective
Hsp90 inhibitors (Fig. 1).8
(Scheme 2). The synthesized products 2a–f, 3a–e were
1
fully characterized by H and 13C NMR spectroscopy, as
well as by high-resolution mass spectrometry.
In order to find novel coumarin derivatives with poten-
tial cytotoxic and antimicrobial activity, a series of novel
coumarin derivatives was synthesized from 4-hydroxy-
coumarin (1a) and 7-hydroxycoumarin (1b). The Williamson
etherification reaction of compounds 1a,b with versatile
alkyl halogenides gave the corresponding ethers 2a–f in the
presence of potassium carbonate (Scheme 1). To further
investigate the structure–activity relationship for such
coumarin ethers, compounds 3a–e were designed
containing another heterocyclic moiety connected to the
coumarin system by means of a spacer. Thus, bromides
2c,d,f underwent a nucleophilic substitution reaction with
appropriate mercaptanes in the presence of potassium
carbonate and catalytic amount of potassium iodide
Figure 1. The structure motif of coumarin in the molecule of
novobiocin and its analogs.
0009-3122/16/52(6)-0374©2016 Springer Science+Business Media New York
374

Chemistry of Heterocyclic Compounds 2016, 52(6), 374–378
Scheme 1
Scheme 2
O
O
O
O
O
O
O
S
O
O
K2CO3
DMF
60°C, 2.5 h
K2CO3, KI
+
RX
RX
+ RSH
, 6 h
MeCN
O
OH
1a
O
Br
n
R
O
R
O
n
2a d
–
2c
3a c
–
n = 3
2d n = 2
O
O
HO
O
O
+
K2CO3
R
DMF
60°C, 2.5 h
R
Br
S
2e f
,
1b
K2CO3, KI
+ RSH
O
O
O
, 6 h
MeCN
O
O
O
O
O
O
O
O
Me
2f
3d,e
O
Me
2a
2b
O
O
O
O
O
O
O
O
O
O
O
S
O
S
S
N
O
O
Br
S
Br
N
2c
2d
3b
3a
O
O
Me
O
O
O
Br
O
O
O
S
Me
O
O
O
N
S
S
N
N
2e
2f
N
N
N
N
3d
3c
4(7)-Alkoxy-2H-chromen-2-ones 2a–f, 3a–e were eva-
luated for their cytotoxic activity in vitro against human
esophageal carcinoma (EC109 and EC9706), human
stomach cancer (MGC-803), human prostatic carcinoma
(PC-3), and human breast carcinoma (MCF-7) cell lines
(Table 1). A clinically used anticancer drug 5-fluorouracil
was used as the positive control.
Me
S
N
O
O
O
N
3e
The cytotoxicity test results show that some of the
synthesized compounds exhibited weak activity against all
the cancer cell lines assayed. However, some of the tested
compounds (2a,d,e, 3c,d) exhibited no growth inhibition
against any of the tested cancer cell lines. Compound 2c
with a bromopropyl group exhibited better cytotoxic
activity than compound 2b with a butyl group against
MGC-803 cell line while compounds containing a
bromoethyl group 2d,f or methoxybenzyl group 2a,e
showed no activity. This result indicated that both the
nature of substituent and its position on the coumarin ring
influence the anticancer activity considerably.
Table 1. The in vitro anticancer activity of the synthesized
compounds 2a–f and 3a–e (IC50, μM)*
Human cancer cell line
Compound
EC109
EC9706 MGC-803
PC-3
MCF-7
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
87.2 1.3
47.7 1.1
>128
>128
>128
>128
>128
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
>128
50.2 1.2
>128
>128
>128
>128
>128
>128
>128
48.3 1.1
>128
The length of the carbon tether between the coumarin
ring system and the terminal bromine atom can
considerably affect the antiproliferative activity. In the case
of compounds 2c and 2d, the shortening of the chain from
3 to 2 methylene groups lead to a complete loss of activity
against MGC-803 and MCF-7 cell lines. An analogous
effect on all five cell lines was observed when bromine
atom was substituted by thiazolinylsulfanyl group (com-
pounds 3b and 3a, respectively).
>128
48.2 1.2
111.9 1.4 121.5 0.9 81.3 0.9 59.4 1.0
>128
>128
>128
>128
>128
>128
>128
>128
100.3 1.6 113.8 1.6 54.6 1.2 72.7 1.4
0.3 1.3 32.4 1.5 29.3 1.9 7.5 0.7
5-Fluorouracil 2.6 0.4
* Antiproliferative activity was assayed by exposure for 72 h to the tested
substances and expressed as the concentration required to inhibit tumor
cell proliferation by 50% (IC50). The data are presented as the means with
standard deviation from the dose–response curves of three independent
experiments.
Regarding the position of the substituent at the coumarin
ring system, while 2-bromoethyl group conferred no
375

Chemistry of Heterocyclic Compounds 2016, 52(6), 374–378
activity against MCF-7 cells when in position 4 (compound
activities considerably. Some of the synthesized com-
pounds displayed either cytotoxic or antimicrobial activity
approaching that of the commercial standard drugs. Further
modifications and a SAR study are underway and will be
reported elsewhere.
2d), compound 2f with 2-bromoethyl group in position 7
was active against the same cell line. A similar observation
could be made with compounds 3d and 3a with respect to
PC-3 cells.
As to the choice of the heterocyclic end group, 4-sub-
stituted coumarin 3d with oxazoline ring at the end of two-
carbon spacer showed no cytotoxic activity, while com-
pound 3e with methyltetrazole at the same position was
moderately active against four cell lines. Conversely,
4-substituted coumarin 3b with oxazoline ring at the end of
three-carbon spacer was moderately active against the same
four cell lines, while compound 3c with methyltetrazole at
the same position showed no activity.
The test results show that both the end group and the
length of the linker of the substituent, as well as its position
at the coumarin ring system determine the cytotoxicity in
this series of compounds. The cytotoxicity of the most
active compounds against MGC-803 (compound 2c) and
PC-3 (compound 3e) cell lines approached that of 5-fluoro-
uracil.
The synthesized compounds 2a–f and 3a–e were also
screened for their antimicrobial activities in vitro against
Escherichia coli and Monilia albicans (Table 2). Clinically
used antimicrobial drugs levofloxacin and fluconazole,
respectively, were used as the positive controls. All pre-
pared coumarin compounds could effectively inhibit the
growth of Gram-negative bacteria E. coli, and compounds
2a,e, 3a,c,d displayed activity against fungi M. albicans in
vitro. Especially, compounds 2d,f, and 3a had a high
activity against E. coli approaching that of the standard drug.
In summary, a series of novel coumarin derivatives was
synthesized and evaluated for their antiproliferative and
antimicrobial activity. The nature (both the end group and
the length of the linker) and position of the substituent
group at the coumarin ring system influenced the biological
Experimental
1H and 13C NMR spectra were recorded on a Bruker
DPX-400 spectrometer (400 and 100 MHz, respectively)
with TMS as internal standard. Mass spectra were recorded
on a Bruker 3000 mass spectrometer using electrospray
ionization. Melting points were determined on a Beijing Keyi
XT4A apparatus. Thin-layer chromatography was carried
out on glass plates coated with silica gel and visualized by
UV light (254 nm). All reagents and solvents used were of
analytical grade purchased from commercial sources.
Synthesis of 4(7)-alkoxy-2H-chromen-2-ones 2a–f
(General method). Compound 1a or 1b (65 mg, 0.40 mmol)
was dissolved in DMF (2 ml), followed by addition of
anhydrous K2CO3 (138 mg, 1.00 mmol). Then an
appropriate alkyl halide (0.40 mmol) was added dropwise
to the stirred reaction mixture. The stirring was continued
for 2.5 h at 60°C. The reaction mixture was extracted with
CH2Cl2 (80 ml), the organic extracts were washed with
water (100 ml), dried over Na2SO4, filtered, and the solvent
was removed in vacuo. The residue was recrystallized from
EtOH.
4-[(4-Methoxybenzyl)oxy]-2H-chromen-2-one (2a).
Yield 92%, white powder, mp 137.2–138.2°C. 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 7.85 (1H, dd, J = 7.9,
J = 1.4, H Ar); 7.61–7.51 (1H, m, H Ar); 7.40 (2H, d,
J = 8.6, H Ar); 7.34 (1H, d, J = 8.3, H Ar); 7.29–7.23 (1H,
m, H Ar); 6.99 (2H, d, J = 8.6, H Ar); 5.81 (1H, s, H-3);
5.15 (2H, s, CH2); 3.86 (3H, s, OCH3). 13C NMR spectrum
(CDCl3), δ, ppm: 165.4; 162.9; 160.1; 153.4; 132.4; 129.7;
126.4; 123.9; 123.2; 116.8; 115.8; 114.3; 91.1; 71.1; 55.4.
Found, m/z: 283.0970 [M+H]+. C17H15O4. Calculated, m/z:
283.0965.
Table 2. The in vitro antibacterial activity of the synthesized
compounds 2a–f and 3a–e (MIC50, μg/ml)
4-Butoxy-2H-chromen-2-one (2b). Yield 95%, white
1
powder, mp 87.5–88.1°C. H NMR spectrum (CDCl3),
Compound
E. coli
32.87
10.67
9.35
M. albicans
20.38
>128
δ, ppm (J, Hz): 7.83 (1H, d, J = 7.8, H Ar); 7.55 (1H, t,
J = 7.6, H Ar); 7.42–7.16 (2H, m, H Ar); 5.68 (1H, s, H-3);
4.14 (2H, t, J = 6.3, OCH2); 2.01–1.80 (2H, m, CH2); 1.68–
1.45 (2H, m, CH2); 1.03 (3H, t, J = 7.3, CH3). 13C NMR
spectrum (CDCl3), δ, ppm: 165.8; 163.1; 153.4; 132.3; 123.8;
123.0; 116.8; 115.8; 90.4; 69.1; 30.5; 19.2; 13.8. Found, m/z:
241.0840. [M+Na]+. C13H14NaO4. Calculated, m/z: 241.0835.
4-(3-Bromopropoxy)-2H-chromen-2-one (2c). Yield
91%, white powder, mp 104.9–111.7°C. 1H NMR spectrum
((CD3)2CO), δ, ppm (J, Hz): 7.92 (1H, dd, J = 7.9, J = 1.4,
H Ar); 7.73–7.55 (1H, m, H Ar); 7.37–7.28 (2H, m, H Ar);
5.81 (1H, s, H-3); 4.43 (2H, t, J = 5.9, OCH2); 3.78 (2H, t,
J = 6.6, CH2Br); 2.51 (2H, quint, J = 6.2, CH2). 13C NMR
spectrum ((CD3)2CO), δ, ppm: 165.9; 162.2; 154.4; 133.4;
124.8; 124.0; 117.3; 116.6; 91.5; 68.1; 32.5; 30.5. Found, m/z:
304.9789 [M(79Br)+Na]+. C12H11BrNaO3. Calculated, m/z:
304.9784.
2a
2b
2c
2d
2e
2f
>128
0.29
>128
4.18
81.00
>128
0.27
0.41
30.97
3a
8.95
>128
3b
7.75
3.32
4.47
<0.25
–
71.40
9.93
>128
–
3c
3d
3e
Levofloxacin
Fluconazole
4-(2-Bromoethoxy)-2H-chromen-2-one (2d). Yield
<0.5
92%, white powder, mp 142.8–146.2°C. 1H NMR spectrum
376

Chemistry of Heterocyclic Compounds 2016, 52(6), 374–378
(CDCl3), δ, ppm (J, Hz): 7.89 (1H, dd, J = 7.9, J = 1.4,
165.3; 162.7; 153.7; 153.3; 132.6; 124.0; 122.9; 116.8;
115.5; 90.8; 67.1; 33.4; 29.6; 28.3. Found, m/z: 341.0684
[M+Na]+. C14H14N4NaO3S. Calculated, m/z: 344.0386.
7-{2-[(4,5-Dihydrothiazol-2-yl)sulfanyl]ethoxy}-2H-
chromen-2-one (3d). Yield 96%, white powder, mp 141.7–
H Ar); 7.64–7.54 (1H, m, H Ar); 7.40–7.27 (2H, m, H Ar);
5.70 (1H, s, H-3); 4.41 (2H, t, J = 5.4, OCH2); 3.96 (2H, t,
J = 5.4, CH2Br). 13C NMR spectrum (CDCl3), δ, ppm:
165.0; 162.5; 153.4; 132.7; 124.1; 123.1; 116.8; 115.3;
90.9; 68.8; 41.0. Found, m/z: 290.9633 [M(79Br)+Na]+.
C11H9BrNaO3. Calculated, m/z: 290.9628.
1
146.7°C. H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.65
(1H, d, J = 9.5, H Ar); 7.39 (1H, d, J = 8.6, H Ar); 6.92
(1H, d, J = 2.1, H Ar); 6.88 (1H, dd, J = 8.6, J = 2.3, H Ar);
6.27 (1H, d, J = 9.5, H Ar); 4.32 (2H, t, J = 6.6, CH2); 4.26
(2H, t, J = 8.0, CH2); 3.50 (2H, t, J = 6.6, CH2); 3.45 (2H, t,
J = 8.0, CH2). 13C NMR spectrum (CDCl3), δ, ppm: 164.7;
161.6; 161.2; 155.9; 143.4; 128.8; 113.3; 113.0; 112.8;
101.7; 66.9; 64.1; 35.9; 31.0. Found, m/z: 330.0235
[M+Na]+. C14H13NNaO3S2. Calculated, m/z: 330.0229.
7-{2-[(1-Methyl-1H-tetrazol-5-yl)sulfanyl]ethoxy}-2H-
chromen-2-one (3e). Yield 95%, white powder, mp 73.4–
7-[(4-Methoxybenzyl)oxy]-2H-chromen-2-one (2e).
1
Yield 95%, white flocculent solid, mp 156.4–158.4°C. H
NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.63 (1H, d, J = 9.5,
H Ar); 7.40–7.33 (3H, m, H Ar); 6.99–6.84 (4H, m, H Ar);
6.24 (1H, d, J = 9.5, H Ar); 5.05 (2H, s, CH2); 3.82 (3H, s,
OCH3). 13C NMR spectrum (CDCl3), δ, ppm: 162.0; 161.2;
159.8; 155.8; 143.4; 129.4; 128.8; 127.8; 114.2; 113.3; 113.2;
112.7; 101.9; 70.4; 55.3. Found, m/z: 283.0957 [M+H]+.
C17H15O4. Calculated, m/z: 283.0965.
1
7-(2-Bromoethoxy)-2H-chromen-2-one (2f) was synthe-
sized according to a literature procedure.9 Yield 85%, white
flocculent solid, mp 134–135°C (mp 134–135°C9). The
spectral characteristics of compound 2f were consistent
with the literature data.9
76.6°C. H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.65
(1H, d, J = 9.5, H Ar); 7.40 (1H, d, J = 8.6, H Ar); 6.86 (1H,
dd, J = 8.6, J = 2.2, H Ar); 6.82 (1H, br. s, H Ar); 6.26 (1H,
d, J = 9.5, H Ar); 4.44 (2H, t, J = 5.9, CH2); 3.95 (3H, s, CH3);
3.77 (2H, t, J = 5.9, CH2). 13C NMR spectrum (CDCl3),
δ, ppm: 161.2; 161.0; 155.7; 153.7; 143.3; 129.0; 113.6;
113.1; 112.3; 102.0; 66.4; 33.5; 32.1. Found, m/z: 327.0528
[M+Na]+. C13H12N4NaO3S. Calculated, m/z: 327.0523.
Antiproliferative activity assay.10 Cancer cell lines
were purchased from the China Center for Type Culture
Collection (CCTCC, Shanghai, China). All cancer cell
lines were maintained in minimal essential medium supple-
mented with 10% fetal bovine serum and 1% penicillin–
streptomycin in a humidified atmosphere (5% CO2 and
95% air) at 37°C. Cancer cells were maintained in
RPMI1640 medium. For pharmacological investigations,
10 mM stock solutions of the tested compounds were
prepared with DMSO.
Synthesis of 4(7)-alkoxy-2H-chromen-2-ones 3a–e
(General method). Bromide 2c,d,f (0.43 mmol) was
completely dissolved in anhydrous MeCN (5 ml) followed
by the addition of anhydrous K2CO3 (116 mg, 0.84 mmol)
and a catalytic amount of KI (14.3 mg, 0.086 mmol). Then
an appropriate thiol (0.43 mmol) was added, and the
reaction mixture was refluxed for 6 h, filtered to remove
K2CO3, and purified by silica gel chromatography with
hexane–EtOAc, 6:1, as eluent.
4-{2-[(4,5-Dihydrothiazol-2-yl)sulfanyl]ethoxy}-2H-
chromen-2-one (3a). Yield 96%, white powder, mp 126.7–
1
127.8°C. H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.83
(1H, d, J = 7.9, H Ar); 7.57 (1H, t, J = 7.8, H Ar); 7.38–
7.28 (2H, m, H Ar); 5.81 (1H, s, H-3); 4.43 (2H, t, J = 6.5,
CH2); 4.25 (2H, t, J = 8.0, CH2); 3.58 (2H, t, J = 6.5, CH2);
3.46 (2H, t, J = 8.0, CH2). 13C NMR spectrum (CDCl3),
δ, ppm: 165.1; 164.3; 162.8; 153.4; 132.5; 123.9; 123.1;
116.8; 115.5; 91.0; 67.4; 64.0; 35.9; 30.5. Found, m/z:
330.0235 [M+Na]+. C14H13NNaO3S2. Calculated, m/z:
330.0229.
Antimicrobial activity assays. The microbial species
were purchased from the China Center for Type Culture
Collection (CCTCC, Shanghai, China). Antibacterial
activity was determined using the broth microdilution
method according to the National Committee for Clinical
Laboratory Standards (NCCLS).11 The bacterial species
(E. coli) were grown in Luria broth medium, and the fungal
species (M. albicans) were grown in RPMI 1640 medium
until exponential growth was achieved. The tests were
performed in a 96-well microtiter plates. All the compounds
were dissolved in DMSO at an initial concentration of
10 mg/ml, and the stock solutions were diluted with the test
medium. A series of concentrations ranging from 1 to
128 μg/ml to a final volume of 200 μl in plate was obtained
by twofold dilutions. Each well, except for the blank well,
was inoculated with the test bacteria and incubated for 24 h
at 37°C. The plates were read using ELIASA at 492 nm.
The MIC50 value is the lowest concentration of compound
that inhibits growth to half the absorption value of the
untreated control. The reported MIC50 was the mean value
of three independent experiments.
4-{3-[(4,5-Dihydrothiazol-2-yl)sulfanyl]propoxy}-2H-
chromen-2-one (3b). Yield 90%, white powder, mp 143.8–
1
145.8°C. H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.85
(1H, dd, J = 7.9, J = 1.4, H Ar); 7.62–7.52 (1H, m, H Ar);
7.37–7.26 (2H, m, H Ar); 5.69 (1H, s, H-3); 4.25 (2H, t,
J = 6.0, CH2); 4.20 (2H, t, J = 8.0, CH2); 3.41 (2H, t,
J = 8.0, CH2); 3.34 (2H, t, J = 6.9, CH2); 2.36 (2H, quin,
J = 6.4, CH2). 13C NMR spectrum (CDCl3), δ, ppm: 165.5;
164.8; 162.9; 153.3; 132.5; 123.9; 123.1; 116.8; 115.6;
90.6; 67.5; 64.2; 35.6; 28.9; 28.6. Found, m/z: 344.0391
[M+Na]+. C15H15NNaO3S2. Calculated, m/z: 344.0386.
4-{3-[(1-Methyl-1H-tetrazol-5-yl)sulfanyl]propoxy}-
2H-chromen-2-one (3c). Yield 92%, white powder, mp
117.5–118.5°C.1H NMR spectrum (CDCl3), δ, ppm (J, Hz):
7.83 (1H, d, J = 7.8, H Ar); 7.57 (1H, t, J = 7.8, H Ar); 7.35–
7.25 (2H, m, H Ar); 5.69 (1H, s, H-3); 4.30 (2H, t, J = 5.8,
CH2); 3.94 (3H, s, CH3); 3.60 (2H, t, J = 7.0, CH2); 2.56–
2.45 (2H, m, CH2). 13C NMR spectrum (CDCl3), δ, ppm:
Supplementary information file to this article containing
the 1H and 13C NMR spectra of the synthesized compounds
is available at http://link.springer.com/journal/10593.
377

Chemistry of Heterocyclic Compounds 2016, 52(6), 374–378
5. Žalubovskis, R. Chem. Heterocycl. Compd. 2015, 51, 607.
The authors are grateful for the financial support from
the National Natural Science Foundation of China
(No. 81273393).
[Khim. Geterotsikl. Soedin. 2015, 51, 607.]
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7. Roussaki, M.; Kontogiorgis, C. A.; Hadjipavlou-Litina, D.;
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