Synthesis and anti-acetylcholinesterase activities of novel glycosyl coumarylthiazole derivatives

Article abstract of DOI:10.1177/1747519820948358

Eleven glycosyl coumarylthiazole derivatives are synthesized by cyclization and condensation of glycosyl thiourea with 3-bromoacetyl coumarins in ethanol. The reaction conditions are optimized and good yields of products (80%–95%) are obtained. The structures of all new products were confirmed by IR, ¹H and ¹³C NMR, and by HRMS (electrospray ionization). The in vitro acetylcholinesterase (AChE) inhibitory activities of these new compounds are tested by Ellman’s method. Among them, N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyl)-4-(6-nitrocoumarinyl)-1,3-thiazole-2-amine showed the best activity with an in vitro AChE inhibitory rate of 58% and an IC₅₀ value of 12 ± 0.38 μg/mL.

Full text of DOI:10.1177/1747519820948358

9letter2020 48358CHL0010.1177/1747519820948358Journal of Chemical ResearchWang et al.
Letter to the Editor
Journal of Chemical Research
–6
1
Synthesis and anti-acetylcholinesterase activities
of novel glycosyl coumarylthiazole derivatives
© The Author(s) 2020
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1
1
1
You-Xian Wang , Shu-Hao Liu , Zhong-Bai Shao ,
1
1
1
1
Lian-Gong Cao , Kai-Jun Jiang , Xing Lu , Lei Wang ,
1
,2,3,4
1,2
1,2
Wei-Wei Liu
, Da-Hua Shi and Zhi-Ling Cao
Abstract
Eleven glycosyl coumarylthiazole derivatives are synthesized by cyclization and condensation of glycosyl thiourea with
3
-bromoacetyl coumarins in ethanol. The reaction conditions are optimized and good yields of products (80%–95%)
1
13
are obtained. The structures of all new products were confirmed by IR, H and C NMR, and by HRMS (electrospray
ionization). The in vitro acetylcholinesterase (AChE) inhibitory activities of these new compounds are tested by Ellman’s
method. Among them, N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyl)-4-(6-nitrocoumarinyl)-1,3-
thiazole-2-amine showed the best activity with an in vitro AChE inhibitory rate of 58% and an IC value of 12±0.38μg/
5
0
mL.
Keywords
acetylcholinesterase inhibitory activity, coumarylthiazole, glucosamine
Date received: 29 May 2020; accepted: 29 June 2020
Synthetic pathway to glycosyl coumarylthiazole derivatives
HO
AcO
3
steps
O
O
H
HO
HO
OH
AcO
AcO
N
NH2
NH HCl
NHAc
2
S
OAc
O
H
S
AcO
AcO
N
O
NHAc
N
O
O
2
steps
CHO
OH
Br
R
R
R
O
O
of acetylcholinesterase (AChE) and cholineacetyl trans-
ferase (ChAT). Drugs currently approved for the treatment
Introduction
Alzheimer’s disease (AD) is a degenerative disease of the
central nervous system, mainly manifested as neuropsychi-
atric symptoms, such as progressive memory disorders, 1College of Pharmaceutical Sciences, Jiangsu Ocean University,
cognitive dysfunction, personality changes, and language
Lianyungang, P.R. China
2
3
1
–3
Jiangsu Institute of Marine Resources, Lianyungang, P.R. China
Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening,
Jiangsu Ocean University, Lianyungang, P.R. China
Co-Innovation Center of Jiangsu Marine Bio-Industry Technology,
Lianyungang, P.R. China
disorders. With the aging of the global population, the
4
incidence of AD has increased year on year. The disease
has become the third leading cause of death among elderly
people after cancer and cardiovascular disease. The cho-
linergic hypothesis was the first proposed explanation
for the pathogenesis of AD. According to the cholinergic
4
Corresponding author:
Wei-Wei Liu, College of Pharmaceutical Sciences, Jiangsu Ocean
University, Lianyungang 222005, P.R. China.
5
hypothesis, the decrease of cholinergic activity and ace-
tylcholine (ACh) concentration is caused by the decrease Email: liuweiwei255@163.com
Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons
Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use,
reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and
Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).

2
Journal of Chemical Research 00(0)
of AD are mainly AChE inhibitors such as tacrine and
galantamine.
According to the literature, coumarins are an important
class of heterocyclic compounds with various biological
6
,7
In the early stage of our research, a series of glycosyl activities such as anti-arrhythmic, antibacterial, anticancer,
9
–13
thiazole derivatives, as AChE inhibitors, was synthesized anti-HIV, and anti-hypertensive.
In addition, coumarin
8
with glucosamine as the leading compound. Among them, derivatives also have an inhibitory effect on AChE, such as
glycosyl thiazole derivative 1 (the structure of which is 8-hydroxycoumarin (2) and cnidium (3);14–16 the structures
shown in Figure 1) showed the best anti-AChE activity of which are shown in Figure 2.
with an in vitro AChE inhibitory rate of 43%. This indi-
The combination of coumarin and a thiazole ring is of great
cated that the presence of a thiazole moiety improved the significance in pharmaceutical chemistry. Coumarin–thiazole
activity of the GlcNAc unit. On this basis, our research compounds have many activities such as antibacterial, antioxi-
group conducted a more in-depth exploration in order to dant, anticonvulsive, anticancer, and for treating hyperten-
17–21
obtain new compounds with better activity toward AChE.
sion.
Combining multiple active molecules within the
same structure is an important means to synthesize new sub-
stances, and it is also the main way to find compounds with
new biological and physiological activities. Based on the
above analysis, we have designed and synthesized a series of
novel glycosyl coumarylthiazole derivatives in order to find
new and effective AChE inhibitors. The AChE inhibitory
activity of the compounds was determined by Ellman’s
AcO
O
H
N
N
AcO
AcO
NO2
NHAc
S
22
method, which revealed that glycosyl heterocyclic com-
pounds with goodAChE inhibitory activity had been obtained.
Figure 1. Structure of compound 1.
Results and discussion
Chemistry
O
O
O
For the synthesis of the glycosyl coumarylthiazole derivatives,
O
O
2
-acetylamino-3,4,6-tri-O-acetyl-2-deoxy-β-D-pyranose-
OH
thiourea (8) and 3-bromoacetylcoumarins 11 are the key inter-
mediates. The acetyl group was selected as the protecting group
for glucose to achieve highly selective chemical modification
of glucosamine. First, compound 8 was synthesized based on
2
3
8
Figure 2. Structures of coumarin derivatives with AChE
previous work by our group. Next, compound 8 and coumarin
inhibitory activity.
11a were dissolved in ethanol and heated at 60°C until the
HO
HO
AcO
O
O
O
Ac O
CH COCl
KSCN
MeCN
OH
2
OH
3
AcO
Cl
HO
HO
HO
HO
AcO
MeOH
NHAc
NH HCl
NHAc
2
4
5
6
OAc
O
H
AcO
S
AcO
AcO
AcO
N
O
O
O
O
H
NH3
CH Cl , r.t.
N
NH2
NHAc
N
NCS
AcO
AcO
AcO
AcO
NHAc
NHAc
EtOH
2
2
S
1
2
7
8
R
O
O
O
CHO
OH
Br
CH COCH COOC H
CuBr2
3
2
2
5
R
R
R
EtOH, r.t.
CHCl3/EtOAc
O
O
O
9
10
11
g: 6-CH
3
(81%)
R= a: H (86%)
b: 6-Cl (80%)
c: 6-F (88%)
d: 6-Br (81%)
h: 6-OCH (94%)
3
i: 7-OCH (88%)
3
j: 8-OCH (95%)
3
e: 6,8-Br (86%)
k: 8-OC H (90%)
2
2 5
f: 6-NO (80%)
2
Scheme 1. Synthesis of the glycosyl coumarylthiazole derivatives 12a–k.

Wang et al.
3
reaction was complete. The solvent was evaporated under Table 1. Optimization of the conditions for the synthesis of
1
2a.
reduced pressure, and the coumarin derivative 12a was purified
by column chromatography (Scheme 1).
Entry
n(8):n(11a)
Time
min)
Temp
(°C)
Solvent
Yield
In the second stage, taking the reaction of glycosyl thio-
urea 8 and compound 11a as an example, optimum reaction
conditions were found. The reaction molar ratio, solvent,
temperature, and time were screened, and the results are
summarized in Table 1. The optimum conditions for synthe-
sizing compounds 12 were as follows: ethanol as solvent, a
molar ratio of glycosyl thiourea 8 to 3-bromoacetylcou-
marin 11 of 1:1.1, and the reaction was carried out at 60°C
for 35minutes.
(%)a
(
1
2
3
4
5
6
7
8
9
1:0.9
1:1.0
1:1.1
1:1.2
1:1.3
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
10
15
20
25
30
35
40
60
60
60
60
60
0
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
69
75
86
86
86
NR
8
30
57
85
85
5
14
40
82
84
NR
13
24
55
73
84
84
15
30
45
60
79
60
60
60
60
60
60
60
60
60
60
60
60
10
11
12
13
14
15
Biological activity
Using the classic Ellman colorimetric method, cholinester-
ase hydrolyzes the substrate (acetylthiocholine iodide or
butyrylthiocholine iodide) to form acetic acid or butyric acid
and thiocholine. Thiocholine reacts with 5,5-disulfide-bis-
CH Cl2
2
EtOAc
MeCN
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
2
-nitrobenzoic acid (DTNB) turning the solution yellow 16
and showing a characteristic absorption at 412nm. When 17
the sample under test is different, after the same time, the 18
absorption value is also different. The inhibition of cho- 19
linesterase by the sample under investigation slows down 20
the rate of cholinesterase hydrolysis of ACh, so the absorb- 21
2
3
2
2
2
3
ance value shows a small difference over the same time.
The results are summarized in Table 2. For compounds
with an inhibition rate exceeding 50%, the half of maximal
inhibitory concentration (IC ) is determined, with tacrine
NR: no reaction.
Yield of isolated product after purification.
a
5
0
and galantamine as the reference compounds.
As shown in Table 2, the AChE inhibitory activity of the
synthesized target compounds were higher than that of the
precursor compound, and three of the 11 target compounds
Table 2. In vitro inhibitory activities of compounds 12a–k
against AChE.
R
Inhibition (%)a
IC50 (μg/mL)
showed higher values than compound 1. Compound 12f Compound
showed the best activity with an IC value of 12±0.38μg/
5
0
1
1
1
1
1
1
2a
2b
2c
2d
2e
2f
H
6-Cl
6-F
6-Br
6, 8-2Br
6-NO2
6-CH3
6-OCH3
7-OCH3
5.96±0.02
11.77±0.04
45.61±0.09
10.58±0.03
9.94±0.02
58.88±0.07
6.94±0.05
9.81±0.02
25.64±0.09
55.17±0.08
22.74±0.02
2.03±0.02
43.21±0.04
98.46 ± 0.13
92.17 ±0.17
−
−
−
−
mL against AChE and inhibits AChE in a dose–dependent
relationship (Figure 3).
−
Conclusion
12±0.38
The synthesis of a new series of glycosyl coumarylthiazole 12g
derivatives under mild conditions and simple has been 12h
accomplished. All yields were above 80%. The structures 12i
−
−
−
1
13
1
1
4
1
2j
2k
8-OCH3
17±0.44
of the products were determined by H NMR, C NMR,
infrared spectroscopy (IR), and high-resolution mass spec-
trometry (HRMS). All the products 12a–k exhibited in
vitro AChE inhibitory activity, which were higher than that
of glucosamine hydrochloride. Compound 12f showed the
best activity with an in vitro AChE inhibitory rate of 58%
and an IC50 value of 12±0.38μg/mL. Compared with the
previously synthesized AChE inhibitor 1, compound 12f
exhibited an increased inhibition of AChE, suggesting that
the coumarin group may increase the inhibition of AChE to
some extent. This work provides the basis for studying
amino sugar derivatives for the treatment of AD.
2
8-OC H5
−
−
−
Tacrine
Galantamine
0.0533 ± 0.0008
0.767±0.043
aInhibition activities at a concentration of 50μg/mL.
purification. Melting points were measured on a Yanaco
melting point apparatus and are uncorrected. Infrared spec-
tra were recorded on a Bruker Tensor 27 spectrometer as
1
13
KBr disks. H NMR and C NMR spectra were recorded at
00 and 126MHz, respectively, on a Bruker Avance at
5
Experimental
ambient temperature using DMSO-d as the solvent and
TMS as the internal standard. Chemical shifts are reported
in ppm and coupling constants (J) are given in hertz (Hz).
6
Chemistry
Unless otherwise stated, all chemicals were purchased from HRMS (electrospray ionization (ESI)) analysis was per-
commercial sources and were used without further formed on an Agilent 6230 mass spectrometer. Flash

4
Journal of Chemical Research 00(0)
(
5
dd, J=9.0, 2.5Hz, 1H, ArH), 7.50 (d, J=8.5Hz, 1H, ArH),
GlcN
.34 (t, J=9.5Hz, 1H, H-1 ), 5.23 (t, J=10.0Hz, 1H,
GlcN
GlcN
H-3 ), 4.91 (t, J=10.0Hz, 1H, H-4 ), 4.22 (dd,
J=12.5, 5.0Hz, 1H, H-6a ), 4.07-3.93 (m, 3H, H-2GlcN
GlcN
,
GlcN
GlcN
H-5 , H-6b ), 2.01 (s, 3H, CH ), 1.96 (s, 3H, CH ),
1
3
3
1
3
.95 (s, 3H, CH ), 1.77 (s, 3H, CH ); C NMR (126MHz,
3 3
DMSO-d ): δ=170.2, 169.8, 169.8, 169.5, 166.6, 158.5,
6
1
1
2
51.1, 143.0, 137.4, 131.2, 128.7, 127.7, 121.5, 120.9,
18.1, 111.0, 83.5, 73.6, 72.36, 68.8, 62.0, 52.6, 22.9, 20.7,
+
0.6, 20.6. ESI-HRMS: m/z [M+Na] calcd for C H ClN-
2
6
26
NaO S: 630.0920; found: 630.0923.
3
10
N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-
glucopyranosyl)-4-(6-fluoro-coumarinyl)-1,3-thiazole-2-
amine (12c): Dichloromethane/methanol (25:1) as eluent,
Figure 3. The concentration dependence curve of compound
12f in the presence of AChE.
R =0.32; yellow solid; yield 0.26g (88%); m.p. 95–96°C;
f
−1
column chromatography was performed on 200–300 mesh IR (cm ): 3344, 2938, 1754, 1730, 1670, 1547, 1492,
1
silica of Harveybio.
1091, 912; H NMR (500MHz, DMSO-d ): δ=8.59 (s, 1H,
6
ArH), 8.52 (d, J=9.0Hz, 1H, NH), 8.11 (d, J=9.0Hz, 1H,
NH), 7.77 (dd, J=8.0, 2.0Hz, 1H, ArH), 7.72 (s, 1H, thia-
zole), 7.54-7.48 (m, 2H, ArH), 5.34 (t, J=9.5Hz, 1H,
Synthesis of N-(2-acetylamino-3,4,6-tri-O-
acetyl-2-deoxy-β-D-pyranose)-4-(coumarin-
GlcN
GlcN
H-1 ), 5.23 (t, J=10.0Hz, 1H, H-3 ), 4.91 (t,
3
-yl)-1,3-thiazole-2-amines (12a–k);
GlcN
J=10.0Hz, 1H, H-4 ), 4.22 (dd, J=12.0, 4.5Hz, 1H,
general procedure
H-6aGlcN), 4.07-3.95 (m, 3H, H-2GlcN, H-5 , H-6b ),
GlcN
GlcN
A solution of compound 8 (0.5 mmol) and compound 11a-k 2.01 (s, 3H, CH ), 1.97 (s, 3H, CH ), 1.96 (s, 3H, CH ),
3
3
3
1
3
(
0.6 mmol) in EtOH (30mL) a 50 mL single-necked flask 1.77 (s, 3H, CH3); C NMR (126MHz, DMSO-d6):
was stirred in an oil bath at 60°C. The reaction was moni- δ=170.2, 169.8, 169.8, 169.5, 166.7, 158.7, 148.8, 143.0,
tored by thin-layer chromatography (TLC) and the solvent 137.7, 121.4, 120.5, 119.0, 118.8, 118.0, 113.7, 111.0,
was evaporated under reduced pressure. Purification by 83.5, 73.6, 72.3, 68.8, 62.0, 52.6, 22.9, 20.7, 20.6, 20.6.
ESI-HRMS: m/z [M+Na]+ calcd for C H FN NaO S:
column chromatography gave pure compound 12a–k.
2
6
26
3
10
6
14.1215; found: 614.1212.
N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-
glucopyranosyl)-4-coumarinyl-1,3-thiazole-2-amine N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-
12a): Dichloromethane/methanol (25:1) as eluent, glucopyranosyl)-4-(6-bromocoumarinyl)-1,3-thiazole-2-
R =0.44; white solid; yield 0.25g (86%); m.p. 237–238°C; amine (12d): Dichloromethane/methanol (25:1) as eluent,
(
f
−
1
IR (cm ): 3387, 2928, 1740, 1719, 1646, 1560, 1377, R =0.46; yellow solid; yield 0.26g (81%); m.p. 239–
f
1
−1
1
041, 926; H NMR (500MHz, DMSO-d ): δ=8.62 (s, 1H, 240°C; IR (cm ): 3348, 2928, 1746, 1735, 1666, 1556,
ArH), 8.50 (d, J=9.5Hz, 1H, NH), 8.10 (d, J=9.0Hz, 1H, 1373, 1043, 903; H NMR (500MHz, DMSO-d ): δ=8.59
NH), 7.87-7.84 (m, 1H, ArH), 7.68 (s, 1H, thiazole), 7.67- (s, 1H, ArH), 8.53 (d, J=9.0Hz, 1H, NH), 8.14 (d,
6
1
6
7
.62 (m, 1H, ArH), 7.47 (d, J=8.0Hz, 1H, ArH), 7.44-7.39 J=2.0Hz, 1H, ArH), 8.12 (d, J=9.0Hz, 1H, NH), 8.77 (dd,
GlcN
(
m, 1H, ArH), 5.34 (t, J=9.5Hz, 1H, H-1 ), 5.24 (t, J=9.0, 2.5Hz, 1H, ArH), 7.71 (s, 1H, thiazole), 7.44 (d,
GlcN
GlcN
GlcN
J=10.0Hz, 1H, H-3 ), 4.90 (t, J=9.75Hz, 1H, H-4 ), J=9.0Hz, 1H, ArH), 5.35 (t, J=9.5Hz, 1H, H-1 ), 5.22
4
H-2 , H-5 ), 3.99-3.94 (m, 1H, H-6b ), 2.01 (s, 3H, H-4 ), 4.22 (dd, J=12.0, 4.5Hz, 1H, H-6a ), 4.06-
CH ), 1.96 (s, 3H, CH ), 1.95 (s, 3H, CH ), 1.77 (s, 3H, 3.94 (m, 3H, H-2 , H-5 , H-6b ), 2.01 (s, 3H, CH ),
GlcN
GlcN
.21 (dd, J=12.5, 4.5Hz, 1H, H-6a ), 4.06-4.00 (m, 2H, (t, J=10.0Hz, 1H, H-3 ), 4.91 (t, J=10.0Hz, 1H,
GlcN
GlcN
GlcN
GlcN
GlcN
GlcN
GlcN
GlcN
3
3
3
3
1
3
13
CH3); C NMR (126MHz, DMSO-d ): δ=170.2, 169.8, 1.97 (s, 3H, CH ), 1.96 (s, 3H, CH3), 1.77 (s, 3H, CH ); C
6
3
3
1
1
6
69.8, 169.5, 166.6, 158.9, 152.5, 143.3, 138.7, 131.8, NMR (126MHz, DMSO-d ): δ=170.2, 169.8, 169.8,
6
28.8, 124.9, 120.6, 119.4, 116.1, 110.1, 83.5, 73.6, 72.2, 169.5, 166.6, 158.1, 156.0, 144.0, 142.7, 137.5, 126.1,
8.8, 62.1, 52.7, 22.9, 20.7, 20.6, 20.6. ESI-HRMS: m/z 124.6, 122.2, 120.0, 117.6, 111.5, 83.4, 73.7, 72.3, 68.8,
[
M+Na]+ calcd for C H N NaO S: 596.1309; found: 62.0, 52.6, 22.9, 20.7, 20.6, 20.6. ESI-HRMS: m/z
26 27 3 10
+
5
96.1313.
[M+Na] calcd for C H BrN NaO S: 674.0414; found:
26 26 3 10
6
74.0418.
N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-
glucopyranosyl)-4-(6-chlorocoumarinyl)-1,3-thiazole-2-amine N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-
(
12b): Dichloromethane/methanol (25:1) as eluent, R =0.46; glucopyranosyl)-4-(6,8-dibromocoumarinyl)-1,3-thiazole-2-
f
yellow solid; yield 0.24g (80%); m.p. 148–150°C; IR amine (12e): Dichloromethane/methanol (25:1) as eluent,
−
1
(
cm ): 3367, 2931, 1747, 1733, 1607, 1557, 1481, 1043, R =0.35; yellow solid; yield 0.31g (86%); m.p. 250–
f
1
−1
9
8
8
33; H NMR (500MHz, DMSO-d ): δ=8.59 (s, 1H, ArH), 251°C; IR (cm ): 3445, 2985, 1742, 1637, 1565, 136,
.53 (d, J=9.0Hz, 1H, NH), 8.12 (d, J=9.0Hz, 1H, NH), 1044, 903; H NMR (500MHz, DMSO-d ): δ=8.57-8.52
.02 (d, J=2.0Hz, 1H, ArH), 7.71 (s, 1H, thiazole), 7.67 (m, 2H, NH, ArH), 8.17 (d, J = 2.0 Hz, 1H, ArH), 8.14
6
1
6

Wang et al.
5
(
(
(
d, J=2.5Hz, 1H, ArH), 8.12 (d, J=9.0Hz, 1H, NH), 7.73 (s, 1H, ArH), 8.49 (d, J = 9.0 Hz, 1H, NH), 8.11 (d,
GlcN
s, 1H, thiazole), 5.35 (t, J = 9.5 Hz, 1H, H-1 ), 5.22 J = 9.0 Hz, 1H, NH), 7.69 (s, 1H, thiazole), 7.43-7.38
GlcN
t, J=9.5Hz, 1H, H-3 ), 4.91 (t, J=10.0Hz, 1H, (m, 2H, ArH), 7.23 (dd, J=9.0, 3.0Hz, 1H, ArH), 5.38 (t,
GlcNu
GlcN
GlcN
GlcN
H-4
), 4.22 (dd, J=12.5, 5.0Hz, 1H, H-6a ), 4.06- J=9.5Hz, 1H, H-1 ), 5.24 (t, J=9.5Hz, 1H, H-3 ),
GlcN
GlcN
GlcN
GlcN
3
2
1
.99 (m, 2H, H-2 , H-5 ), 3.99-3.95 (m, 1H, H-6b ), 4.91 (t, J=10.0Hz, 1H, H-4 ), 4.22 (dd, J=13.0, 5.0Hz,
.01 (s, 3H, CH ), 1.97 (s, 3H, CH ), 1.95 (s, 3H, CH ), 1H, H-6a ), 4.07-4.00 (m, 2H, H-2 , H-5 ), 3.99-
.77 (s, 3H, CH3); C NMR (126MHz, DMSO-d6): 3.94 (m, 1H, H-6b ), 3.86 (s, 3H, -OCH ), 2.01 (s, 3H,
GlcN
GlcN
GlcN
3
3
3
1
3
GlcN
3
δ=170.2, 169.8, 169.8, 169.5, 166.7, 157.9, 148.3, 142.7, CH ), 1.97 (s, 3H, CH ), 1.95 (s, 3H, CH ), 1.78 (s, 3H,
3
3
3
1
3
1
37.0, 135.8, 130.4, 122.5, 122.1, 116.5, 111.6, 110.0, CH3); C NMR (126MHz, DMSO-d ): δ=170.2, 169.8,
6
8
3.4, 73.6, 72.27, 68.8, 62.0, 52.5, 22.9, 20.7, 20.6, 20.6. 169.8, 169.5, 166.5, 159.1, 156.0, 146.9, 143.3, 138.7,
+
ESI-HRMS: m/z [M+Na] calcd for C H Br N NaO S: 120.8, 119.9, 119.5, 117.2, 110.7, 110.3, 83.4, 73.6, 72.2,
2
6
25
2
3
10
7
51.9520; found: 751.9517.
68.8, 62.1, 55.9, 52.6, 22.9, 20.7, 20.6, 20.6. ESI-HRMS:
m/z [M+Na]+ calcd for C H N NaO S: 626.1415;
2
7
29
3
11
N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D- found: 626.1415.
glucopyranosyl)-4-(6-nitrocoumarinyl)-1,3-thiazole-2-
amine (12f): Dichloromethane/methanol (25:1) as eluent, N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-
R =0.42; yellow solid; yield 0.25g (80%); m.p. 152–154°C; glucopyranosyl)-4-(7-methoxycoumarinyl)-1,3-thiazole-
f
−
1
IR (cm ): 3358, 2937, 1742, 1667, 1535, 1375, 1093, 907; 2-amine (12i): Dichloromethane/methanol (25:1) as
1
H NMR (500MHz, DMSO-d ): δ=8.87 (d, J=3.0Hz, 1H, eluent, R = 0.30; pale yellow solid; yield 0.27 g (88%);
6
f
−
1
NH), 8.78 (s, 1H, ArH), 8.56 (d, J=9.0Hz, 1H, NH), 8.42 m.p. 236–237 °C; IR (cm ): 3422, 2925, 1743, 1716,
(
7
(
4
1
3
CH ), 1.96 (s, 3H, CH ), 1.78 (s, 3H, CH ); C NMR 4.89 (t, J = 9.5 Hz, 1H, H-4 ), 4.21 (dd, J = 13.0, 5.0 Hz,
(
1
1
dd, J=9.0, 2.5Hz, 1H, ArH), 8.13 (d, J=9.0Hz, 1H, NH), 1619, 1552, 1367, 1043, 913; H NMR (500 MHz,
.74 (s, 1H, thiazole), 7.69 (d, J = 9.0 Hz, 1H, ArH), 5.39 DMSO-d ): δ = 8.58 (s, 1H, ArH), 8.46 (d, J = 9.0 Hz,
6
GlcN
GlcN
t, J=9.5Hz, 1H, H-1 ), 5.23 (t, J=9.5Hz, 1H, H-3 ), 1H, NH), 8.09 (d, J = 9.0 Hz, 1H, NH), 7.77 (d, J = 9.0 Hz,
.92 (t, J=10.0Hz, 1H, H-4 ), 4.23 (dd, J=13.0, 5.0Hz, 1H, ArH), 7.57 (s, 1H, thiazole), 7.07 (d, J = 2.5 Hz,
H, H-6a ), 4.07-4.02 (m, 2H, H-2 , H-5 ), 4.01- 1H, ArH), 7.02 (dd, J = 8.5, 2.5 Hz, 1H, ArH), 5.34 (t,
.96 (m, 1H, H-6b ), 2.02 (s, 3H, CH ), 1.97 (s, 3H, J = 9.5 Hz, 1H, H-1 ), 5.23 (t, J = 9.5 Hz, 1H, H-3 ),
GlcN
GlcN
GlcN
GlcN
GlcN
GlcN
GlcN
3
1
3
GlcN
3
3
3
GlcN
GlcN
GlcN
126MHz, DMSO-d ): δ=170.2, 169.8, 169.8, 169.5, 1H, H-6a ), 4.04-3.99 (m, 2H, H-2 , H-5 ), 3.98-
6
GlcN
66.6, 158.1, 156.0, 144.0, 142.7, 137.5, 126.1, 124.6, 3.93 (m, 1H, H-6b ), 3.89 (s, 3H, -OCH ), 2.01 (s, 3H,
3
1
5
22.2, 120.0, 117.6, 111.5, 83.4, 73.7, 72.3, 68.8, 62.0, CH ), 1.96 (s, 3H, CH ), 1.95 (s, 3H, CH ), 1.77 (s, 3H,
3
3
3
2.6, 22.9, 20.7, 20.6, 20.6. ESI-HRMS: m/z [M+Na]+ CH ); C NMR (126 MHz, DMSO-d ): δ = 170.2, 169.8,
13
3
6
calcd for C H N NaO S: 641.1160; found: 641.1156.
169.8, 169.5, 166.5, 162.6, 159.2, 154.4, 143.5, 139.1,
29.9, 117.3, 113.1, 112.9, 108.6, 100.5, 83.5, 73.6, 72.2,
2
6
26
4
12
1
N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D- 68.8, 62.1, 56.2, 52.7, 22.9, 20.7, 20.6, 20.6. ESI-HRMS:
glucopyranosyl)-4-(6-nitrocoumarinyl)-1,3-thiazole-2- m/z [M+Na]+ calcd for C H N NaO S: 626.1415;
2
7
29
3
11
amine (12g): Dichloromethane/methanol (25:1) as eluent, found: 626.1409.
R =0.40; pale yellow solid; yield 0.24g (81%); m.p. 238–
f
−
1
2
1
39°C; IR (cm ): 3318, 2927,1742, 1716, 1652, 1550, N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-
1
376, 1036, 904; H NMR (500MHz, DMSO-d ): δ=8.57 glucopyranosyl)-4-(8-methoxycoumarinyl)-1,3-thiazole-2-
6
(
s, 1H, ArH), 8.51 (d, J=9.5Hz, 1H, NH), 8.10 (d, amine (12j): Dichloromethane/methanol (25:1) as eluent,
J=9.0Hz, 1H, NH), 7.67 (s, 1H, thiazole), 7.64 (d, R =0.33; white solid; yield 0.29g (95%); m.p. 200–201°C;
f
−1
J=1.0Hz, 1H, ArH), 7.48-7.43 (m, 1H, ArH), 7.36 (d, IR (cm ): 3434, 2945,1748, 1730, 1669, 1580, 1371, 1089,
GlcN
1
J=8.5Hz, 1H, ArH), 5.36 (t, J=9.0Hz, 1H, H-1 ), 5.24 944; H NMR (500MHz, DMSO-d ): δ=8.59 (s, 1H, ArH),
6
GlcN
GlcN
(
4
t, J=10.0Hz, 1H, H-3 ), 4.90 (t, J=9.5Hz, 1H, H-4 ), 8.51 (d, J=9.0Hz, 1H, NH), 8.09 (d, J=9.0Hz, 1H, NH),
.21 (dd, J=12.5, 5.0Hz, 1H, H-6a ), 4.06-4.01 (m, 2H, 7.69 (s, 1H, thiazole), 7.41-7.38 (m, 1H, ArH), 7.37-7.30
H-2 , H-5 ), 3.98-3.93 (m, 1H, H-6b ), 2.41 (s, 3H, (m, 2H, ArH), 5.36 (t, J=9.5Hz, 1H, H-1 ), 5.24 (t,
CH ), 2.01 (s, 3H, CH ), 1.96 (s, 3H, CH ), 1.95 (s, 3H, J=10.0Hz, 1H, H-3 ), 4.89 (t, J=10.0Hz, 1H, H-4 ),
CH ), 1.77 (s, 3H, CH ); C NMR (126MHz, DMSO-d ): 4.21 (dd, J=12.5, 4.5Hz, 1H, H-6a ), 4.05-4.00 (m, 3H,
δ=170.2, 169.8, 169.8, 169.5, 166.6, 159.1, 157.5, 150.6, H-2 , H-5 , H-6b ), 3.94 (s, 3H, -OCH ), 2.01 (s,
GlcN
GlcN
GlcN
GlcN
GlcN
GlcN
GlcN
3
3
3
1
3
GlcN
3
3
6
GlcN
GlcN
GlcN
3
1
8
2
6
43.3, 138.7, 120.5, 119.2, 119.0, 115.9, 115.4, 110.0, 3H, CH ), 1.96 (s, 3H, CH ), 1.95 (s, 3H, CH ), 1.76 (s, 3H,
3 3 3
1
3
3.4, 73.6, 72.3, 68.8, 62.1, 52.7, 22.9, 20.7, 20.6, 20.6, CH3); C NMR (126MHz, DMSO-d ): δ=170.2, 169.8,
6
+
0.5.ESI-HRMS:m/z[M+Na] calcdforC H N NaO S: 169.8, 169.5, 166.7, 166.6, 158.7, 146.5, 143.1, 141.7,
2
7
29
3
10
10.1466; found: 610.1469.
138.9, 124.9, 120.6, 120.0, 114.0, 110.2, 83.4, 73.6, 72.2,
6
8.8, 62.1, 56.3, 52.7, 22.9, 20.7, 20.6, 20.6. ESI-HRMS:
+
N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D- m/z [M+Na] calcd for C H N NaO S: 626.1415;
2
7
29
3
11
glucopyranosyl)-4-(6-methoxycoumarinyl)-1,3-thiazole-2- found: 626.1415.
amine (12h): Dichloromethane/methanol (25:1) as eluent,
R =0.39; pale yellow solid; yield 0.28g (94%); m.p. 226– N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-m,-
f
−1
2
1
27°C; IR (cm ): 3317, 2958, 1746, 1711, 1649, 1557, glucopyranosyl)-4-(8-ethoxycoumarinyl)-1,3-thiazole-2-
1
377, 1038, 909; H NMR (500MHz, DMSO-d ): δ=8.61 amine (12k): Dichloromethane/methanol (25:1) as eluent,
6

6
Journal of Chemical Research 00(0)
R =0.44; pale yellow solid; yield 0.28g (90%); m.p. 231– References
f
−
1
2
1
32°C; IR (cm ): 3335, 2984, 1750, 1731, 1639, 1577,
387, 1095, 917; H NMR (500MHz, DMSO-d ): δ=8.59
1
. Wenk GL. J Clin Psych 2003; 64: 7.
1
6
2. Selkoe DJ. Science 2002; 298: 789.
(
s, 1H, ArH), 8.50 (d, J = 9.0 Hz, 1H, NH), 8.09 (d,
J=9.0Hz, 1H, NH), 7.69 (s, 1H, thiazole), 7.40-7.36 (m,
H, ArH), 7.34-7.30 (m, 2H, ArH), 5.36 (t, J=9.5Hz, 1H,
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1
GlcN
GlcN
H-1 ), 5.23 (t, J=10.0Hz, 1H, H-3 ), 4.89 (t,
GlcN
J=10.0Hz, 1H, H-4 ), 4.24-4.18 (m, 3H, -CH CH ,
2
3
H-6a ), 4.05-4.01 (m, 2H, H-2GlcN, H-5 ), 3.99-3.93
GlcN
GlcN
7
8
9
. Lamb HM and Goa KL. Pharmacoeconomics 2001; 19: 303.
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2018; 53: 121.
(
1
-
1
1
7
m, 1H, H-6bGlcN), 2.01 (s, 3H, CH ), 1.96 (s, 3H, CH ),
3
3
.95 (s, 3H, CH ), 1.77 (s, 3H, CH ), 1.44 (t, J=7.0Hz, 3H,
3 3
1
3
CH CH ); C NMR (126MHz, DMSO-d ): δ=170.2,
2
3
6
69.8, 169.8, 169.5, 166.6, 158.7, 145.7, 143.2, 141.8,
38.9, 124.9, 120.7, 120.1, 119.9, 114.8, 110.2, 83.4, 73.6,
1
0. Singh I, Kaur H, Kumar S, et al. Int J Chemtech Res 2010; 2:
745.
1
2.2, 68.8, 64.5, 62.1, 52.7, 22.9, 20.7, 20.6, 20.6, 14.8. 11. Thakur A, Singla R and Jaitak V. Eur J Med Chem 2015;
+
ESI-HRMS: m/z [M+Na] calcd for C H N NaO S:
6
101: 476.
2
8
31
3
11
40.1572; found: 640.1571.
12. Kumar V, Pandey IP, Jain J, et al. Indian J Pharm Educ
2
019; 53: 624.
1
1
1
3. Razavi BM, Arasteh E, Imenshahidi M, et al. Iran J Basic
Med Sci 2015; 18: 153.
4. Anand P, Singh B and Singh N. Bioorg Med Chem 2012; 20:
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
1
175.
5. Ali MY, Jannat S, Jung HA, et al. Asian Pac J Trop Med
016; 9: 103.
16. Chimenti F, Carradori S, Secci D, et al. J Heterocycl Chem
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2
Funding
2
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article:
This work was supported by the Postgraduate Research and
Practice Innovation Program of Jiangsu Province (KYCX20-
1
1
7. Wang G, He D, Li X, et al. Bioorg Chem 2016; 65: 167.
8. Gouda MA, Berghot MA, Baz EA, et al. Med Chem Res
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012; 21: 1062.
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9. Arshad MF, Siddiqui N, Elkerdasy A, et al. Am J Pharmacol
Toxicol 2014; 9: 132.
0. Abdellatif KRA, Abdelgawad MA, Elshemy HAH, et al. Lett
Drug Des Discov 2017; 14: 773.
2
894, KYCX20-2297 and SJCX20-1212), a Project Funded by
the Priority Academic Program Development of Jiangsu Higher
Education Institutions (PAPD), Project 521 Funded by
Lianyungang (LYG52105-2018023), and the Student Innovation
and Entrepreneurship Program (SY201911641319002).
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ORCID iD
You-Xian Wang
https://orcid.org/0000-0002-5840-488X
23. Shetab-Boushehri SV. EXCLI J 2018; 17: 798.