Synthesis and biological evaluation of coumarin derivatives as α-glucosidase inhibitors

Article abstract of DOI:10.1016/j.ejmech.2019.112013

In this study, two series of coumarin derivatives 5a～i and 6a～i were synthesized, and their inhibitory activity against α-glucosidase was determined. The results indicated that most of the synthesized derivatives exhibited prominent inhibitory activities

Full text of DOI:10.1016/j.ejmech.2019.112013

Journal Pre-proof
Synthesis and biological evaluation of coumarin derivatives as α-glucosidase
inhibitors
Xue-Tao Xu, Xu-Yang Deng, Jie Chen, Qi-Ming Liang, Kun Zhang, Dong-Li Li, Pan-
Pan Wu, Xi Zheng, Ren-Ping Zhou, Zheng-Yun Jiang, Ai-Jun Ma, Wen-Hua Chen,
Shao-Hua Wang
PII:
S0223-5234(19)31170-5
DOI:
https://doi.org/10.1016/j.ejmech.2019.112013
EJMECH 112013
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 9 November 2019
Revised Date: 26 December 2019
Accepted Date: 26 December 2019
Please cite this article as: X.-T. Xu, X.-Y. Deng, J. Chen, Q.-M. Liang, K. Zhang, D.-L. Li, P.-P. Wu, X.
Zheng, R.-P. Zhou, Z.-Y. Jiang, A.-J. Ma, W.-H. Chen, S.-H. Wang, Synthesis and biological evaluation
of coumarin derivatives as α-glucosidase inhibitors, European Journal of Medicinal Chemistry (2020),
doi: https://doi.org/10.1016/j.ejmech.2019.112013.
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Synthesis and Biological Evaluation of Coumarin
Derivatives as α-glucosidase Inhibitors
Xue-Tao Xu,ab† Xu-Yang Deng,ab† Jie Chen,ab Qi-Ming Liang,ab Kun Zhang,ab
Dong-Li Li,ab Pan-Pan Wu,ab Xi Zheng,c Ren-Ping Zhou,c Zheng-Yun Jiang,c Ai-Jun
Ma,ab* Wen-Hua Chen,ab* Shao-Hua Wang abd*
aSchool of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, P. R. China
bInternational Healthcare Innovation Institute (Jiangmen), Jiangmen 529020, P. R. China
cDepartment of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State
University of New Jersey, Piscataway, NJ 08854, USA
dSchool of Pharmacy & State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, P. R. China
†Xue-Tao Xu and Xu-Yang Deng contributed equally to this work.
*Corresponding authors: Ai-Jun Ma, Wen-Hua Chen, and Shao-Hua Wang. Email:
wyuchemmaj@126.com (A-J Ma), whchen@wyu.edu.cn (W-H Chen), and wangshh@lzu.edu.cn
(S-H Wang) Tel./fax: +86 750 3299397
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Abstract
In this study, two series of coumarin derivatives 5a~i and 6a~i were synthesized,
and their inhibitory activity against α-glucosidase was determined. The results
indicated that most of the synthesized derivatives exhibited prominent inhibitory
activities against α-glucosidase. Among them, compounds 5a and 5b showed the
strongest inhibition with the IC50 values of 19.64 µM and 12.98 µM, respectively.
Enzyme kinetic studies of compounds 5a and 5b proved that their inhibition was
reversible and a mixed type. The KI and KIS values of compound 5a were calculated to
be 27.39 µM and 13.02 µM, respectively, and the corresponding values for compound
5b being 27.02 µM and 13.65 µM, respectively. The docking studies showed that
compound 5b could be inserted into the active pocket of α-glucosidase and form
hydrogen bonds with LYS293 to enhance the binding affinity.
Key words: Coumarin; cinnamic acid; synthesis; α-glucosidase; enzyme inhibition;
molecular docking
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1. Introduction
α-Glucosidase (EC 3.2.1.20), an exo-acting glycoside hydrolase, possesses key
functions in the carbohydrate quality control and in particular plays essential roles in
the process of sugar metabolism [1-4]. α-Glucosidase can hydrolyze the α-glycosidic
bonds from the non-reducing end of carbohydrate substrates [5-8]. The cleavage of
α-glucosidic bonds also relates to the number of monosaccharide units, cleavage site
position, and configuration of hydroxyl groups in the substrates [9-12]. α-Glucosidase
inhibitors can be used not only as research tools to clarify the mechanism of action of
α-glucosidase at molecular levels, but also as evolved agents against
carbohydrate-mediated diseases, such as cancer, diabetes, HIV, obesity and hepatitis
[13-17]. The mechanism of action of α-glucosidase inhibitors is closely related to
their affinity with the carbohydrate-binding region of α-glucosidase [18-20]. The
biological importance of α-glucosidase encourages researchers to discover new,
effective agents against α-glucosidase [21-23]. To date, a large amount of naturally
occurring and synthetic agents toward α-glucosidase are produced in laboratories, but
only a few are used in further applications [1-25]. Because mammalian α-glucosidase
is not commercially available, α-glucosidase from Saccharomyces cervisiae has been
generally used as a target protein for screening the activity of inhibitors.
It has been reported that coumarin and its derivatives have a wide range of
biological activities [26,27], such as anti-oxidation [28,29], anti-inflammatory [30],
anti-clotting [31], anti-bacterial [32], anti-cytotoxic [33,34], anti-cancer [35],
anti-HIV [36,37] and treatment of dyslipidemia [38]. Recent studies have shown that
many herbal and synthetic derivatives containing coumarin fractions can be used as
α-glucosidase inhibitors [39,40]. On the other hand, cinnamic acid, a natural product
extracted from cinnamon oil, has been used as fragrance and medicine [41], and this
compound and its derivatives have received increasing attention in the treatment of
type II diabetes in recent years [42].
Meanwhile, it is well recognized that modifying the structural skeletons of natural
products is an important way to find lead compounds with certain level of biological
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activity [43]. On the other hand, hybridization appears as an effective strategy to
increase the biological activity or pharmacological efficacy of the hybrid molecule
and to overcome the resistance [44,45]. To date, numerous effective agents have been
developed based on these two methods. Inspired by these results and aiming to
develop more effective α-glucosidase inhibitors, we integrated the above two
strategies to design and synthesize two series of coumarin derivatives 5a~i and 6a~i
by conjugating substituted cinnamic acids with 4-hydroxycoumarin or
7-hydroxycoumarin. We evaluated their inhibition effect and mechanism of action
against α-glucosidase, and also carried out molecular docking studies. Here we report
our findings.
2. Results and Discussion
2.1. Chemistry
In this study, substituted cinnamic acids and coumarins were used as starting
materials to synthesize coumarin derivatives. The synthetic route of coumarin
derivatives 5a~g and 6a~g was shown in Scheme 1. Compounds 1a~g were converted
into intermediates 2a~g, which were esterified with compound 3j or 4k to afford
compounds 5a~g and 6a~g, respectively.
Because of the influence of the hydroxyl groups in substituted cinnamic acids 7h~i,
coumarin derivatives 5h~i and 6h~i were synthesized with a circuitous route as
depicted in Scheme 2. Protection of the hydroxyl groups in compounds 7h~i with
tert-butyldimethylchlorosilane (TBSCl) afforded compounds 7’h~i. Treatment of
compounds 7’h~i with thionylchloride gave compounds 8h~i, which reacted with
compound 3j or 4k to afford compounds 5h’~i’ and 6h’~i’, respectively. Finally,
compounds 5h~i and 6h~i were obtained by deprotecting the TBSCl groups.
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Scheme 1. Synthesis of compounds 5a~g and 6a~g. Reagents and conditions: (a)
SOCl2, DMF, DCM, 0 °C ~ rt, 5h; (b) DIPEA, DCM, 0 °C ~ rt, 4h.
Scheme 2. Synthesis of compounds 5h~i and 6h~i. Reagents and conditions: (a)
TBSCl, imidazole, DMAP, DMF, 0 °C ~ rt; K2CO3, THF, MeOH; (b) SOCl2, DMF,
DCM, 0 °C ~ rt, 5h; (c) DIPEA, DCM, 0 °C ~ rt, 4h; (d) HF, THF, rt.
2.2. α-Glucosidase inhibition assay
It has been reported that coumarin and its derivatives can achieve glycemic control
by inhibiting the activity of α-glucosidase [46-49]. Therefore, the in vitro activity of
compounds 5a~i and 6a~i against α-glucosidase was investigated. The inhibitory
activity of these compounds at the concentration of 100 µM was screened and
subsequently their IC50 values were evaluated. The results were shown in Table 1 and
indicated that most of the synthetic coumarin derivatives exhibited higher inhibitory
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potency than cinnamic acid and coumarins. This may be surmised to the better
interaction of these conjugates. Among them, compounds 5a and 5b showed the
strongest inhibition with the IC50 values of 19.64 µM and 12.98 µM, respectively,
which are obvious higher than the parent pieces, cinnamic acid (1.5×104µM) and
4-hydroxycoumarin (9.0×103µM), and have similar inhibition activity compared with
the positive control ursolic acid (11.38 µM), a widely accepted inhibitor again
α-glucosidase from Saccharomyces cervisiae [14,50]. Fig. 1 showed the concentration
inhibition curves of compounds 5a and 5b against α-glucosidase.
Table 1. Inhibitory activity of coumarin derivatives toward α-glucosidase.
Compound
R1
R2
H
Inhibition at 100 µM (%)
IC50 (µM)
19.64
12.98
36.88
41.73
>100
5a
H
83.51
89.92
73.15
68.50
33.10
60.99
41.87
33.19
19.51
45.65
54.74
20.25
26.23
29.93
30.10
38.22
13.11
20.26
5b
CH3
OCH3
F
H
5c
H
5d
H
5e
Cl
H
5f
Br
H
69.30
>100
5g
CF3
OH
OH
H
H
5h
H
>100
5i
OCH3
H
>100
6a
>100
6b
CH3
OCH3
F
H
94.52
>100
6c
H
6d
H
>100
6e
Cl
H
>100
6f
Br
H
>100
6g
CF3
OH
OH
H
>100
6h
H
>100
6i
OCH3
>100
Cinnamic acid
1.5×104
4.0×105
3J
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4K
9.0×103
11.38
Ursolic acidb
100
80
60
40
20
100
80
60
40
20
0
5b
5a
0
0
20
40
60
80
0
50
100
150
Concentration(µM)
Concentration(µM)
Fig. 1 The α-glucosidase inhibition effects of compounds 5a and 5b.
2.3. Structure activity relationships (SAR) analysis
Based on the data in Table 1, the SAR of compounds 5a~i and 6a~i against
α-glucosidase was analyzed. Firstly, the influence of linking positions at coumarin
ring was investigated. Since the inhibition of compounds 5a~i against α-glucosidase
was much higher than that of compounds 6a~i with the same substituent groups, this
result revealed that conjugation of substituted cinnamic acids with
4-hydroxycoumarin would be a better choice than with 7-hydroxycoumarin.
Secondly, the influence of the substituents on cinnamic acid was evaluated by
taking compound 5a as a lead structure. It was observed that introduction of CH3
group (to give compound 5b) was favorable to increase the inhibitory activity and the
introduction of OCH3, F, or Br group (to afford compounds 5c, 5d and 5f, respectively)
showed slightly negative effect on the inhibitory activity. Cl or CF3 group as the
substituent (that is compounds 5e and 5g) led to obviously low inhibitory activity,
suggesting that an electron-withdrawing group was not favorable to the activity.
Additionally, the presence of a hydroxyl group in compounds 5h and 5i also gave low
inhibitory activity. Among the substituents, a methyl group at the 4-position of the
phenyl ring of cinnamic acid was the most favorable to increase the inhibitory activity
against α-glucosidase. Taken together, the above findings suggest that particular
attentions should be paid attention to an electron-donating group rather than an
electron-withdrawing group.
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2.4. a-Glucosidase inhibitory mechanism of compounds 5a and 5b
To ascertain the inhibition mechanism of compounds 5a and 5b on α-glucosidase,
the plots of the initial velocity against the concentrations of α-glucosidase in the
presence of compound 5a or 5b of varying concentrations were constructed. As
shown in Fig. 2, the plots gave a family of straight lines at each concentration of
compound 5a or 5b, and these lines passed through the origin. Moreover, the slopes of
the lines extended a descent with the increase in the concentrations of compounds 5a
and 5b. These findings suggest that the inhibition of α-glucosidase by compounds 5a
and 5b is reversible.
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1.0
0.8
0.6
0.4
0.2
0.0
0µM
0µM
10µ
20µ
35µ
M
15µM
20µM
25µM
M
M
5a
5b
0
2
4
6
8
10
12
14
16
0
2
4
6
8
10
12
14
16
18
[E](U/mL)
[E](U/mL)
Fig. 2 Plots of the relative activity against the concentrations of α-glucosidase in the
presence of compound 5a (0, 15, 20 and 25 M) or 5b (0, 10, 20 and 35 M).
µ
µ
To further explore the inhibition kinetic behavior of compounds 5a and 5b, their
activity was determined at the different concentrations of 4-nitrophenyl-β-D-
galactopyranoside (PNPG) in the presence or absence of compound 5a or 5b, and
analyzed using Lineweaver-Burk double reciprocal plots. For both compounds 5a and
5b, the plots of 1/V vs 1/[S] gave straight lines with different slopes intersecting one
another in the second quadrant. The values of Vm and Km descended with the increase
in the concentrations of compound 5a or 5b, which suggested that compounds 5a and
5b induced mixed-type inhibition on α-glucosidase. In other words, compounds 5a
and 5b are able to bind with both free enzyme and enzyme-substrate complex to
reduce the catalytic activity of α-glucosidase. To gain further insight into this, we
determined the equilibrium constants of compounds 5a and 5b with free enzyme (KI)
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and the enzyme-substrate complex (KIS), by plotting the apparent Km/Vmax and 1/Vmax
against the concentrations of compounds 5a and 5b. The KI and KIS values of
compound 5a were determined to be 27.39 µM and 13.02 µM, respectively, and the KI
and KIS of compound 5b were 27.02 µM and 13.65 µM, respectively.
2.5. Molecular docking of compound 5b
Molecular docking studies have two purposes, namely specific structural modeling
and accurate prediction of activity [51]. The sybyl programe [52] was applied to study
the interaction of compound 5b with the active site of α-glucosidase to understand the
inhibition mechanism. As described in our previous work [3,4], oligo-1,6-glucosidase
from Saccharomyces cerevisiae (PDB: 1UOK) was selected as the target protein.
Because compound 5b was
a
hybride of 4-methylcinnamic acid and
4-hydroxycoumarin, its electrophilic and lipophilic potentials were changed compared
with the parent pieces, 4-methylcinnamic acid and 4-hydroxycoumarin. Thereby the
inhibition mode and docking site of compound 5b may be apparently changed. As
shown in Fig. 3a~b, compound 5b well nested into the active pocket of α-glucosidase
and formed a hydrogen bond with the amino acid sequences of LYS293 to enhance
the affinity with α-glucosidase. Meanwhile, the electrophilic and lipophilic potential
interactions between 5b and the active pocket were analyzed. As indicated in Fig. 3c,
the exterior of the active pocket is more electrophilic than the interior. So, the
coumarin fraction of compound 5b, which is more electrophilic than 4-methylphenyl
fraction, was located in the lipophilic potential region (Fig. 3d). Similarly, the
lipophilic potential interaction between compound 5b and the active pocket was
presented in Fig. 3e~f. The integration with the methylated phenyl ring of the
cinnamic acid part is closer through the van der Waals force, and the coumarin
fraction was near the hydrophilic region for its higher hydrophilicity than
4-methylphenyl fraction.
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Fig. 3 Molecular docking of compound 5b with α-glucosidase.
3. Conclusion
In summary, two series of coumarin derivatives were synthesized from the
conjugation of substituted cinnamic acid with 4-hydroxycoumarin and
7-hydroxycoumarin, and their inhibitory activity toward α-glucosidase was evaluated.
The results show that most of the synthesized derivatives showed prominent
inhibitory potency than cinnamic acid and coumarin, and introduction of an
electron-donating group is conducive to the α-glucosidase inhibitory activity. Enzyme
kinetic studies indicated that their inhibition was reversible and a mixed type.
Molecular docking study also confirmed that the synthesized derivatives could be
effectively inserted into the active pocket of α-glucosidase. The present findings
suggest that coumarin derivatives conjugated with a suitable cinnamic acid at the C-7
position could be promising inhibitors for α-glucosidase. Further structural
optimization is under active investigation in our laboratories.
4. Materials and Methods
4.1. Chemistry
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α-Glucosidase from Saccharomyces cerevisiae (EC 3.2.1.20) and PNPG were
supplied by Sigma-Aldrich. All the other commercially available reagents were used
1
without further purification. H NMR and 13C NMR were recorded on an NMR
spectrometer (DPX-500 MHz) with chemical shifts (d) given in parts per million
(ppm) relative to TMS as an internal standard. Mass spectrometry was determined on
a (LCQTM) LC-MS supplied by Thermo Fisher Scientific (Shanghai) Co., Ltd.
Melting points were measured on a Micro melting point instrument supplied by
Shanghai Yidian Physical Optical Instrument Co., Ltd, and the temperature was not
corrected.
4.2. General procedures
4.2.1. Synthesis of compounds 5a~g and 6a~g
SOCl2 (2.4 mmol) and DMF (2 drops) were added to a solution of compounds 1a~g
(2.0 mmol) in anhydrous DCM (5 mL) at 0 °C. The reaction mixture was stirred at
room temperature for 5 h, and then concentrated to afford cinnamoyl chlorides 2a~g.
Then to a solution of compound 3J or 4k (1.6 mmol) and DIPEA (3.2 mmol) in
anhydrous DCM (5 mL) was added slowly a solution of compounds 2a~g in
anhydrous DCM (5 mL) at 0 °C. After 30 min, the reaction mixture was warmed to
the room temperature and stirring continued until the reaction was completed. Then
the reaction mixture was quenched with saturated aqueous NaHCO3 solution and
extracted with ethyl acetate. The organic layer was washed subsequently with water
and brine, dried over anhydrous Na2SO4 and concentrated. The obtained residues
were purified by column chromatography to give compounds 5a~g and 6a~g.
2-oxo-2H-chromen-4-yl cinnamate 5a. White solid; yield 66.3 %; mp: 156-157
;
1H NMR (500 MHz, Chloroform-d) δ 7.98 (d, J = 15.9 Hz, 1H), 7.72 (dd, J = 7.9, 1.6
Hz, 1H), 7.66 - 7.57 (m, 3H), 7.52 - 7.43 (m, 3H), 7.39 (dd, J = 8.4, 1.1 Hz, 1H), 7.33
(dd, J =7.4, 1.0 Hz, 1H), 6.69 (d, J = 15.9 Hz, 1H), 6.61 (s, 1H); 13C NMR (126 MHz,
Chloroform-d) δ 162.77, 161.59, 158.67, 153.73, 149.36, 133.55, 132.78, 131.60,
129.22, 128.69, 124.35, 122.88, 117.15, 115.68, 115.35, 105.25; ESI-MS: m/z 315.57
11/25

([M+Na]+); IR (cm-1) (KBr) ν 2924 (=C-H, aromatic), 1706 (C=O, ester), 1612 (C=C),
1385, 1328 (3C-H, alkene), 1116 (C-O-C, ester), 940, 841, 763 (9C-H, aromatic).
2-oxo-2H-chromen-4-yl(E)-3-(p-tolyl)acrylate 5b. White solid; yield 43.5 %; mp:
139-140 ; 1H NMR (500 MHz, Chloroform-d) δ 7.95 (d, J = 16.0 Hz, 1H), 7.72 (dd,
J = 7.9, 1.6 Hz, 1H), 7.59 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 7.55 - 7.51 (m, 2H), 7.38
(dd, J = 8.3, 1.1 Hz, 1H), 7.32 (td, J = 7.7, 1.1 Hz, 1H), 7.27 (d, J = 6.7 Hz, 2H), 6.63
(d, J = 15.9 Hz, 1H), 6.60 (s, 1H), 2.42 (s, 3H); 13C NMR (126 MHz, Chloroform-d) δ
162.95, 161.64, 158.74, 153.73, 149.40, 142.37, 132.74, 130.86, 129.96, 128.72,
124.32, 122.92, 117.13, 115.75, 114.14, 105.18, 21.65; ESI-MS: m/z 329.07
([M+Na]+); IR (cm-1) (KBr) ν 2923 (=C-H, aromatic), 1714 (C=O, ester), 1616 (C=C),
1385 (3C-H, alkene), 1326 (CH3), 1127 (C-O-C, ester), 937, 846, 810, 759 (8C-H,
aromatic).
2-oxo-2H-chromen-4-yl (E)-3-(4-methoxyphenyl)acrylate 5c. White solid; yield
1
52.8 %; mp: 149-151 ; H NMR (500 MHz, Chloroform-d) δ 7.93 (d, J = 15.9 Hz,
1H), 7.72 (dd, J = 7.9, 1.6 Hz, 1H), 7.61 - 7.57 (m, 3H), 7.38 (dd, J = 8.4, 1.1 Hz, 1H),
7.32 (td, J = 7.6, 1.1 Hz, 1H), 6.99 - 6.95 (m, 2H), 6.59 (s, 1H), 6.53 (d, J = 15.9 Hz,
1H), 3.88 (s, 3H); 13C NMR (126 MHz, Chloroform-d) δ 163.11, 162.49, 161.70,
158.82, 153.73, 149.07, 132.71, 130.59, 126.32, 124.30, 122.94, 117.12, 115.81,
114.67, 112.51, 105.11, 55.52; ESI-MS: m/z 344.98 ([M+Na]+); IR (cm-1) (KBr) ν
2925 (=C-H, aromatic), 1728 (C=O, ester), 1609 (C=C), 1381 (3C-H, alkene), 1293
(C-O-C, ether), 1112 (C-O-C, ester), 946, 837, 765 (8C-H, aromatic).
2-oxo-2H-chromen-4-yl (E)-3-(4-fluorophenyl)acrylate 5d. White solid; yield
1
54.5 %; mp: 146-147 ; H NMR (500 MHz, Chloroform-d) δ 7.94 (d, J = 15.9 Hz,
1H), 7.70 (dd, J = 7.9, 1.6 Hz, 1H), 7.66 - 7.62 (m, 2H), 7.60 (ddd, J = 8.7, 7.4, 1.6
Hz, 1H), 7.39 (dd, J = 8.4, 1.1 Hz, 1H), 7.32 (td, J = 7.7, 1.1 Hz, 1H), 7.16 (t, J = 8.6
13
Hz, 2H), 6.61 (d, J = 16.2 Hz, 2H); C NMR (126 MHz, Chloroform-d) δ 165.68,
163.66, 162.66, 161.55, 158.63, 153.73, 147.96, 132.81, 130.76, 130.69, 129.86,
129.83, 124.35, 122.84, 117.17, 116.58, 116.41, 115.64, 115.10, 115.08, 105.27;
ESI-MS: m/z 333.39 ([M+Na]+); IR (cm-1) (KBr) ν 2923 (=C-H, aromatic), 1711
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(C=O, ester), 1619 (C=C), 1387 (3C-H, alkene), 1331 (C-F), 1133 (C-O-C, ester), 939,
837, 758 (8C-H, aromatic).
2-oxo-2H-chromen-4-yl(E)-3-(4-chlorophenyl)acrylate 5e. White solid; yield
1
62.3 %; mp: 184-185 ; H NMR (500 MHz, Chloroform-d) δ 7.92 (d, J = 15.9 Hz,
1H), 7.70 (dd, J = 7.9, 1.6 Hz, 1H), 7.63 - 7.55 (m, 3H), 7.47 - 7.42 (m, 2H), 7.39 (dd,
13
J = 8.3, 1.1 Hz, 1H), 7.35 - 7.30 (m,1H), 6.66 (d, J = 16.0 Hz, 1H), 6.60 (s, 1H); C
NMR (126 MHz, Chloroform-d) δ 162.55, 161.51, 158.58, 153.73, 147.80, 137.68,
132.83, 132.01, 129.81, 129.56, 124.36, 122.82, 117.19, 115.92, 115.60, 105.31;
ESI-MS: m/z 348.84 ([M+Na]+); IR (cm-1) (KBr) ν 2922 (=C-H, aromatic), 1721
(C=O, ester), 1625 (C=C), 1382, 1317 (3C-H, alkene), 1131 (C-O-C, ester), 940, 868,
821 (8C-H, aromatic), 755 (C-Cl).
2-oxo-2H-chromen-4-yl(E)-3-(4-bromophenyl)acrylate 5f. White solid; yield
1
61.7 %; mp: 194-195 ; H NMR (500 MHz, Chloroform-d) δ 7.90 (d, J = 15.9 Hz,
1H), 7.70 (dd, J = 8.0, 1.5 Hz, 1H), 7.60 (dq, J = 8.7, 2.3, 1.6 Hz, 3H), 7.53 - 7.47 (m,
2H), 7.39 (dd, J = 8.4, 1.1 Hz, 1H), 7.32 (td, J = 7.7, 1.1 Hz, 1H), 6.68 (d, J = 15.9 Hz,
1H), 6.60 (s, 1H); 13C NMR (126 MHz, Chloroform-d) δ 162.54, 161.51, 158.57,
153.73, 147.88, 132.84, 132.53, 132.51, 132.43, 129.97, 126.10, 124.36, 122.82,
117.18, 116.03, 115.59, 105.30; ESI-MS: m/z 393.05 ([M+Na]+); IR (cm-1) (KBr) ν
2922 (=C-H, aromatic), 1755 (C=O, ester), 1623 (C=C), 1380, 1314 (3C-H, alkene),
1128 (C-O-C, ester), 938, 867, 818 (8C-H, aromatic), 754 (C-Br).
2-oxo-2H-chromen-4-yl (E)-3-(4-(trifluoromethyl)phenyl)acrylate 5g. White solid;
yield 58.9 %; mp: 165-166 ; 1H NMR (500 MHz, Chloroform-d) δ 7.99 (d, J = 16.0
Hz, 1H), 7.78 - 7.68 (m, 5H), 7.65 - 7.58 (m, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.33 (t, J
= 7.6 Hz, 1H), 6.77 (d, J = 16.0 Hz, 1H), 6.61 (s, 1H); 13C NMR (126 MHz,
Chloroform-d) δ 162.25, 161.44, 158.47, 153.74, 147.27, 136.80, 133.05, 132.90,
132.79, 128.78, 126.24, 126.21, 126.18, 126.14, 124.40, 122.77, 118.02, 117.22,
115.50, 105.41; ESI-MS: m/z 382.78 ([M+Na]+); IR (cm-1) (KBr) ν 2924 (=C-H,
aromatic), 1754 (C=O, ester), 1626 (C=C), 1383 (3C-H, alkene), 1323 (3C-F), 1117
(C-O-C, ester), 941, 834, 755 (8C-H, aromatic).
13/25

2-oxo-2H-chromen-7-ylcinnamate 6a. White solid; yield 65.4 %; mp: 152-154
;
1H NMR (500 MHz, Chloroform-d) δ 7.91 (d, J = 16.0 Hz, 1H), 7.72 (d, J = 9.6 Hz,
1H), 7.64 - 7.58 (m, 2H) , 7.52 (d, J = 8.4 Hz, 1H), 7.44 (dd, J = 5.1, 1.9 Hz, 3H),
7.21 (d, J = 2.2 Hz, 1H), 7.15 (dd, J = 8.4, 2.2 Hz, 1H), 6.63 (d, J = 16.0 Hz, 1H),
6.41 (d, J = 9.5 Hz, 1H); 13C NMR (126 MHz, Chloroform-d) δ 164.71, 160.45,
154.77, 153.42, 147.76, 142.93, 133.92, 131.10, 129.11, 128.58, 128.47, 118.52,
116.66, 116.44, 116.07, 110.53; ESI-MS: m/z 314.96 ([M+Na]+); IR (cm-1) (KBr) ν
2925 (=C-H, aromatic), 1725 (C=O, ester), 1623 (C=C), 1410, 1312 (4C-H, alkene),
1134 (C-O-C, ester), 986, 864, 757, 692 (8C-H, aromatic).
2-oxo-2H-chromen-7-yl(E)-3-(p-tolyl)acrylate 6b. White solid; yield 43.7%; mp:
174-176 ; 1H NMR (500 MHz, Chloroform-d) δ 7.88 (d, J = 15.9 Hz, 1H), 7.71 (d, J
= 9.5 Hz, 1H), 7.51 (dd, J = 9.6, 7.9 Hz, 3H), 7.24 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 2.2
Hz, 1H), 7.14 (dd, J= 8.4, 2.2 Hz, 1H), 6.58 (d, J = 16.0 Hz, 1H), 6.41 (d, J = 9.6 Hz,
1H), 2.40 (s, 3H); 13C NMR (126 MHz, Chloroform-d) δ 164.89, 160.47, 154.77,
153.51, 147.79, 142.94, 141.73, 131.22, 129.85, 128.56, 128.49, 118.56, 116.61,
116.01, 115.27, 110.54, 21.59; ESI-MS: m/z 328.97 ([M+Na]+); IR (cm-1) (KBr) ν
2923 (=C-H, aromatic), 1723 (C=O, ester), 1619 (C=C), 1404 (4C-H, alkene), 1260
(CH3), 1129 (C-O-C, ester), 987, 811, 747 (7C-H, aromatic).
2-oxo-2H-chromen-7-yl(E)-3-(4-methoxyphenyl)acrylate 6c. White solid; yield
1
53.7 %; mp: 196-198 ; H NMR (500 MHz, Chloroform-d) δ 7.86 (d, J = 15.9 Hz,
1H), 7.71 (d, J = 9.5 Hz, 1H), 7.58 - 7.54 (m, 2H) , 7.51 (d, J = 8.5 Hz, 1H), 7.20 (d, J
= 2.2 Hz, 1H), 7.14 (dd, J = 8.4, 2.2 Hz, 1H), 6.97 - 6.93 (m, 2H), 6.49 (d, J = 15.9 Hz,
1H), 6.41 (d, J = 9.6 Hz, 1H), 3.87 (s, 3H); 13C NMR (126 MHz, Chloroform-d) δ
165.04, 162.06, 160.48, 154.77, 153.59, 147.45, 142.95, 130.27, 128.53, 126.68,
118.59, 116.56, 115.97, 114.55, 113.72, 110.55, 55.47; ESI-MS: m/z 345.10
([M+Na]+); IR (cm-1) (KBr) ν 2925 (=C-H, aromatic), 1736 (C=O, ester), 1610 (C=C),
1417 (4C-H, alkene), 1260 (C-O-C, ether), 1136 (C-O-C, ester), 995, 887, 825 (7C-H,
aromatic).
14/25

2-oxo-2H-chromen-7-yl(E)-3-(4-fluorophenyl)acrylate 6d. White solid; yield
1
63.8 %; mp: 208-210 ; H NMR (500 MHz, Chloroform-d) δ 7.87 (d, J = 16.0 Hz,
1H), 7.72 (d, J = 9.5 Hz, 1H), 7.63 - 7.57 (m, 2H) , 7.53 (d, J = 8.4 Hz, 1H), 7.21 (d, J
= 2.2 Hz, 1H), 7.17 - 7.10 (m, 3H), 6.56 (d, J = 16.0 Hz, 1H), 6.42 (d, J = 9.5 Hz, 1H);
13C NMR (126 MHz, Chloroform-d) δ 164.58, 160.43, 154.77, 153.36, 146.39,
142.91, 130.47, 130.40, 128.60, 118.48, 116.69, 116.43, 116.25, 116.19, 116.10,
110.51; ESI-MS: m/z 333.11 ([M+Na]+); IR (cm-1) (KBr) ν 2924 (=C-H, aromatic),
1734 (C=O, ester), 1615 (C=C), 1411 (4C-H, alkene), 1235 (C-F), 1137 (C-O-C,
ester), 993, 835 (7C-H, aromatic).
2-oxo-2H-chromen-7-y(E)-3-(4-chlorophenyl)acrylate 6e. White solid; yield 41.7%;
mp: 201-203 ; 1H NMR (500 MHz, Chloroform-d) δ 7.85 (d, J = 16.0 Hz, 1H), 7.72
(d, J = 9.6 Hz, 1H), 7.53 (dd, J = 8.4, 5.5 Hz, 3H), 7.45 - 7.37 (m, 2H), 7.20 (d, J =
2.2 Hz, 1H), 7.14 (dd, J = 8.4, 2.2 Hz, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.41 (d, J = 9.6
Hz, 1H); 13C NMR (126 MHz, Chloroform-d) δ 164.46, 160.40, 154.77, 153.31,
146.23, 142.89, 137.11, 132.39, 129.60, 129.43, 128.61, 118.44, 117.03, 116.72,
116.13, 110.49; ESI-MS: m/z 349.31 ([M+Na]+); IR (cm-1) (KBr) ν 2924 (=C-H,
aromatic), 1726 (C=O, ester), 1620 (C=C), 1406 (4C-H, alkene), 1273, 1125 (C-O-C,
ester), 817 (7C-H, aromatic), 755 (C-Cl).
2-oxo-2H-chromen-7-yl(E)-3-(4-bromophenyl)acrylate 6f. White solid; yield
1
64.6%; mp: 217-218 ; H NMR (500 MHz, Chloroform-d) δ 7.83 (d, J = 16.0 Hz,
1H), 7.72 (d, J = 9.6 Hz, 1H), 7.61 - 7.56 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.49 -
7.43 (m, 2H), 7.20 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 8.4, 2.2 Hz, 1H), 6.62 (d, J =
16.0 Hz, 1H), 6.42 (d, J = 9.5 Hz, 1H); 13C NMR (126 MHz, Chloroform-d) δ 164.45,
160.40, 154.76, 153.30, 146.30, 142.89, 132.81, 132.40, 129.78, 128.61, 125.50,
118.44, 117.15, 116.73, 116.13, 110.49; ESI-MS: m/z 393.33 ([M+Na]+); IR (cm-1)
(KBr) ν 2924 (=C-H, aromatic), 1723 (C=O, ester), 1615 (C=C), 1404 (4C-H, alkene),
1268, 1122 (C-O-C, ester), 986, 847, 812 (7C-H, aromatic), 600 (C-Br).
2-oxo-2H-chromen-7-yl (E)-3-(4-(trifluoromethyl)phenyl)acrylate 6g. White solid;
yield 45.3 %; mp: 178-180 ; 1H NMR (500 MHz, Chloroform-d) δ 7.92 (d, J = 16.0
15/25

Hz, 1H), 7.75 - 7.67 (m, 5H), 7.54 (d, J = 8.5 Hz, 1H) , 7.22 (d, J = 2.1 Hz, 1H), 7.15
(dd, J = 8.4, 2.2 Hz, 1H), 6.71 (d, J = 16.0Hz, 1H), 6.42 (d, J = 9.5 Hz, 1H); 13C NMR
(126 MHz, Chloroform-d) δ 164.15, 160.35, 154.77, 153.17, 145.73, 142.87, 128.66,
128.56, 126.13, 126.10, 126.07, 126.04, 119.10, 118.37, 116.81, 116.21, 110.47;
ESI-MS: m/z 382.73 ([M+Na]+); IR (cm-1) (KBr) ν 2924 (=C-H, aromatic), 1727
(C=O, ester), 1619 (C=C), 1411, 1328 (4C-H, alkene), 1270 (3C-F), 1119, 1068
(C-O-C, ester), 985, 864, 830 (7C-H, aromatic).
4.2.2 Synthesis of compounds 5h~i and 6h~i
Compounds 7h~i (2 mmol), imidazole (9 mmol), TBSCl (6 mmol) and DMAP (0.2
mmol) were dissolved in dry DMF (5 mL) in sequence under ice bath and the
resulting solution was stirred for 3 h. After concentrated, the obtained residues were
dissolved in a solution of K2CO3 (0.2 g) in MeOH/THF (1/2, 12 mL). The mixture
was stirred for 3 h and concentrated under reduced pressure. The obtained residues
were partitioned between ethyl acetate and water. The organic layer was separated,
washed with water and brine, and dried over anhydrous Na2SO4. Removal of the
organic layer under vacuum gave compounds 7h’~i’. Then compounds 7h’~i’ (2.0
mmol), SOCl2 (2.4 mmol) and DMF(2 drops) were added to dry DCM (5 mL) at 0 ,
and the resulting solution was stirred at room temperature for 5 h, followed by
concentration to give compounds 8h~i. To a solution of compound 3J or 4k (1.6
mmol) and DIPEA (3.2 mmol) in dry DCM (5 mL) at 0
was added slowly a
solution of compounds 8h~i in dry DCM (5 mL). Then the reaction mixture was
warmed to room temperature and stirred until the reaction was completed on TLC.
The reaction was quenched with saturated aqueous NaHCO3 solution, followed by
extraction with ethyl acetate. The organic layer was washed with water and brine,
dried over anhydrous Na2SO4 and concentrated. The obtained residues were purified
by column chromatography to give compounds 5h~i and 6h~i.
2-oxo-2H-chromen-4-yl(E)-3-(4-hydroxyphenyl)acrylate 5h. White solid; yield
29.7 %; mp: 170-171 ; 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.91 (d, J =
15.9 Hz, 1H), 7.80 (dd, J = 8.0, 1.8 Hz, 1H) , 7.71 (td, J = 6.9, 5.5, 2.0 Hz, 3H), 7.53 -
16/25

7.47 (m, 1H), 7.41 (tt, J = 7.6, 1.4 Hz, 1H), 6.88 - 6.82 (m, 2H), 6.81 - 6.74 (m, 1H),
13
6.63 (d, J = 1.5 Hz, 1H); C NMR (126 MHz, DMSO-d6) δ 163.36, 160.97, 160.79,
158.92, 153.19, 149.19, 133.33, 131.42, 124.87, 124.83, 123.35, 116.84, 116.07,
115.48, 111.65, 105.26; ESI-MS: m/z 330.72 ([M+Na]+); IR (cm-1) (KBr) ν 3435
(O-H), 2925 (=C-H, aromatic), 1737 (C=O, ester), 1596, 1511 (C=C), 1384 (3C-H,
alkene), 1146 (C-O-C, ester), 894, 847, 755 (8C-H, aromatic).
2-oxo-2H-chromen-4-yl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate 5i. Light
yellow solid; yield 40.0%; mp: 177-178 ; 1H NMR (500 MHz, DMSO-d6) δ 9.89 (s,
1H), 7.91 (d, J = 15.9 Hz, 1H), 7.81 (dd, J = 7.9, 1.6 Hz, 1H), 7.73 (ddd, J = 8.6, 7.3,
1.6 Hz, 1H), 7.53 - 7.49 (m, 2H), 7.45 - 7.41 (m, 1H), 7.29 (dd, J = 8.2, 2.0 Hz, 1H),
6.90 - 6.83 (m, 2H), 6.64 (s, 1H), 3.85 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ
163.79, 161.18, 159.31, 153.58, 150.95, 149.93, 148.55, 133.73, 125.72, 125.23,
124.96, 123.69, 117.24, 116.10, 115.87, 112.26, 112.22, 105.62, 56.27; ESI-MS: m/z
359.46 ([M+Na]+); IR (cm-1) (KBr) ν 3431 (O-H), 2925 (=C-H, aromatic), 1723 (C=O,
ester), 1621 (C=C), 1385 (3C-H, alkene), 1274 (C-O-C, ether), 1117 (C-O-C, ester),
944, 851, 759 (7C-H, aromatic).
2-oxo-2H-chromen-7-yl(E)-3-(4-hydroxyphenyl)acrylate 6h. White solid; yield
29.0%; mp: 242-244 ; 1H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.10 (d, J =
9.6 Hz, 1H), 7.85 - 7.78 (m, 2H), 7.70 - 7.66 ( m, 2H), 7.37 (d, J = 2.3 Hz, 1H), 7.24
(dd, J = 8.4, 2.2 Hz, 1H), 6.86 - 6.82 (m, 2H), 6.67 (d, J = 15.9 Hz, 1H ), 6.50 (d, J =
9.6 Hz, 1H); 13C NMR (126 MHz, DMSO-d6) δ 165.35, 160.96, 160.26, 154.64,
153.59, 147.99, 144.37, 131.41, 129.81, 125.36, 119.25, 117.07, 116.39, 115.96,
113.02, 110.67; ESI-MS: m/z 330.98 ([M+Na]+); IR (cm-1) (KBr) ν 3424 (O-H), 2924
(=C-H, aromatic), 1736 (C=O, ester), 1598 (C=C), 1389 (4C-H, alkene), 1128 (C-O-C,
ester), 817 (7C-H, aromatic).
2-oxo-2H-chromen-7-yl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate 6i. White
1
solid; yield 59.3%; mp: 213-215 ; H NMR (500 MHz, DMSO-d6) δ 9.79 (s, 1H),
8.10 (d, J = 9.6 Hz, 1H), 7.80 (dd, J = 12.2, 3.7 Hz, 2H), 7.45 (d, J = 2.0 Hz, 1H),
7.37 (d, J = 2.2 Hz, 1H), 7.24 (dd, J = 8.3, 2.2 Hz, 2H), 6.83 (d, J = 8.1 Hz, 1H) , 6.75
17/25

13
(d, J = 15.9 Hz, 1H), 6.49 (d, J = 9.6 Hz, 1H), 3.84 (s, 3H); C NMR (126 MHz,
DMSO-d6) δ 165.38, 160.26, 154.64, 153.60, 150.51, 148.51, 148.33, 144.38, 129.83,
125.84, 124.38, 119.23, 117.06, 116.07, 115.95, 113.31, 112.03, 110.63, 56.23;
ESI-MS: m/z 359.65 ([M+Na]+); IR (cm-1) (KBr) ν 3433 (O-H), 2924 (=C-H,
aromatic), 1709 (C=O, ester), 1607 (C=C), 1420 (4C-H, alkene), 1232 (C-O-C, ether),
1128 (C-O-C, ester), 983, 849 (6C-H, aromatic).
4.3. Inhibitory activity toward α-glucosidase
The inhibitory activity of compounds 5a~i and 6a~i against α-glucosidase and their
inhibition mechanism of action were investigated according to the method of
Worawalai with a slight modification [53]. Those compounds were dissolved in
DMSO. α-Glucosidase enzyme and PNPG were dissolved in 0.1 M potassium
phosphate buffer (pH 6.8). Then 10 µL of α-glucosidase (final concentration 0.1
U/mL), 130 µL of phosphate buffer and 10 µL of the test compounds were added into
96-well plates, in succession. After incubated at 37 for 10 min
(final concentration 1 mmol/L) was added into the mixture, followed by incubation at
37 for 30 min The enzymatic activity was quantified by measuring the absorbance
, 50 µL of PNPG
.
at 405 nm using Multimodel Reader. The inhibition percentage was calculated by the
formula: % Inhibition = [(A1 – A0) / A0] × 100%, where A1 and A0 are the absorbance
with and without the test compound, respectively. The IC50 value was determined
from a plot of the inhibition percentage vs the concentrations of test compounds. The
experiment was performed in duplicate and the man values were taken.
4.4. Kinetics of enzyme inhibition
The enzyme inhibition kinetics experiments were performed using similar assays as
described above, in the presence of different concentrations of test compound and
α-glucosidase or PNPG. The enzyme inhibitory kinetics was analyzed with the plot of
enzyme concentrations vs the concentrations of test compounds, and the substrate
inhibitory kinetics was assessed with the plots of substrate concentrations vs the
concentrations of test compounds using the Lineweaver-Burk plot.
18/25

4.5. Molecular modeling
Sybyl-2.1.1 (Tripos, shanghai, China) was used to simulate the interaction between
compound 5b and α-glucosidase. After hydrogen atoms were added, compound 5b
was energy minimized using MM2 program, with the energy convergence criterion of
0.001 kcal/mol by using Gasteiger-Hückle charges and optimizing the energy gradient
with 2500 times. The crystal structure of α-glucosidase was retrieved from RCSB
Protein Database (PDB: 1UOK). The α-glucosidase protein was prepared by
procedure of termini treatment, including removing H2O, adding hydrogens, adding
charges, fixing side chain amides, and stageding minimization. The active pocket of
α-glucosidase was simulated by automatic mode. Then the docking between
compound 5b and α-glucosidase was carried out in the default format.
5. Acknowledgements
This work was financially supported by the National Natural Science Foundation of
China (Nos. 21472077, 21772071 and 81803390), the Department of Education of
Guangdong Province (Nos. 2017KTSCX185, 2017KSYS010, 2017KQNCX200 and
2016KCXTD005), the Department of Science and Technology of Jiangmen (No:
2016350100170008351 and 2018110100330005446), Jiangmen Program for
Innovative Research Team (No. 2018630100180019806) and High-level Talent
Research Start-up Project of Wuyi University (Nos. 2018AL002 and 2018AL003).
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Highlights
1. Coumarin derivatives 5 (a ~ i) and 6 (a ~ i) were synthesized.
2. The synthetic compounds were screened for α-glucosidase inhibitory activity.
3. Kinetic studies determined the mechanism of synthetic compounds on
α-glucosidase.
4. In silico studies were performed to confirm the binding interactions of synthetic
compounds with the enzyme active site.

Declaration of interests
√The authors declare that they have no known competing financialinterestsor personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: