Synthesis and bioactivity of novel C2-glycosyl oxadiazole derivatives as acetylcholinesterase inhibitors

Article abstract of DOI:10.1515/hc-2018-0166

A series of glycosyl-substituted 1,3,4-oxadiazoles were synthesized by cyclization of glycosyl-acylthiosemicarbazides via a base-catalyzed reaction. The starting glycosyl-acylthiosemicarbazide derivatives were obtained by the reaction of glycosyl isothiocyanate with various hydrazides. The acetylcholinesterase (AChE) inhibitory activities of the products were tested by Ellman's method. The most active compounds were subsequently evaluated for the 50% inhibitory concentration (IC₅₀) values. N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(4-fluorophenyl)-1,3,4-oxadiazole-2-amine (6i) possesses the best AChE -inhibition activity with an IC₅₀ of 1.61±0.34 μm.

Full text of DOI:10.1515/hc-2018-0166

Heterocycl. Commun. 2018; aop
Lei Wang, Yu-Ran Wu, Shu-Ting Ren, Long Yin, Xiu-Jian Liu, Feng-Chang Cheng, Wei-Wei Liu*,
Da-Hua Shi, Zhi-Ling Cao and Hui-Min Sun
Synthesis and bioactivity of novel C2-glycosyl
oxadiazole derivatives as acetylcholinesterase
inhibitors
https://doi.org/10.1515/hc-2018-0166
one of the most abundant monosaccharides, and has been
widely used in the prevention and/or treatment of rheu-
matoid arthritis and osteoarthritis [8, 9]. Furthermore,
D-glucosamine exhibits a broad variety of bioactivities
such as anti-inflammatory [10], anti-cancer [11] and anti-
bacterial [12] properties and it suppresses tumor growth
Received September 4, 2018; accepted October 4, 2018
Abstract: A series of glycosyl-substituted 1,3,4-oxadia-
zoles were synthesized by cyclization of glycosyl-acylthio-
semicarbazides via a base-catalyzed reaction. The starting
glycosyl-acylthiosemicarbazide derivatives were obtained
by the reaction of glycosyl isothiocyanate with various
hydrazides. The acetylcholinesterase (AChE) inhibitory
activities of the products were tested by Ellman’s method.
The most active compounds were subsequently evaluated
for the 50% inhibitory concentration (IC ) values. N-(1,-
[
13]. Modified carbohydrates provide access to potential
mimetics of naturally occurring amino sugars and repre-
sent targets for the development of anti-oxidant [14], anti-
acetylcholinesterase (AChE) [15], anti-proliferative [16]
and other active agents [17–20].
The emergence of heterocyclic compounds with
novel structures may promote discovery of new drugs
and treatment of stubborn diseases [21–24]. Recently, the
oxadiazole chemistry has been developed extensively.
5
0
3
,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(4-
fluorophenyl)-1,3,4-oxadiazole-2-amine (6i) possesses the
best AChE -inhibition activity with an IC of 1.61ꢀ±ꢀ0.34 μꢁ.
5
0
Keywords: Acetylcholinesterase inhibitors; glycosyl 1,3,4-Oxadiazoles structurally resemble amides and esters
1,3,4-oxadiazoles; synthesis.
[25], and some compounds show similar pharmacokinetic
properties [26–31]. Moreover, recent studies have shown
that a number of compounds containing the 1,3,4-oxa-
diazole skeleton act as monoamine oxidase inhibitors for
the treatment of Alzheimer’s disease (AD) [32–34]. AD is a
Introduction
Carbohydrates have long interested chemists and bio- chronic, neurodegenerative disorder that causes an irre-
chemists as a large natural resource [1–4]. As an energy versible dementia in elderly people [35].
source and an element of many metabolic processes,
Researchers have been interested in molecular hybrid-
sugars are present in every part of the human body [5]. based approaches to find new compounds of potential
D-glucosamine is a naturally occurring amino sugar [6, 7], biological activities [36, 37]. Based on the aforementioned
information, herein we report the design and synthesis of
novel D-glucosamine/1,3,4-oxadiazole hybrids with the
*
Corresponding author: Wei-Wei Liu, College of Pharmaceutical
oxadiazole ring offering an important pharmacophore
to discover new potent AChE inhibitors. The synthesized
derivatives were evaluated by Ellman’s method for AChE
inhibitors and to explore the influence of D-glucosamine
against AChE inhibition.
Sciences, Huaihai Institute of Technology, Lianyungang 222005,
P.R. China; Jiangsu Institute of Marine Resources, Lianyungang
2
22005, P.R. China; Jiangsu Key Laboratory of Marine
Pharmaceutical Compound Screening, Huaihai Institute of
Technology, Lianyungang 222005, P.R. China; and Co-Innovation
Center of Jiangsu Marine Bio-industry Technology, Lianyungang
2
22005, P.R. China, e-mail: liuweiwei255@163.com
Lei Wang, Yu-Ran Wu, Shu-Ting Ren, Long Yin, Xiu-Jian Liu and
Hui-Min Sun: College of Pharmaceutical Sciences, Huaihai Institute
of Technology, Lianyungang 222005, P.R. China
Results and discussion
Feng-Chang Cheng: China University of Mining and Technology,
Xuzhou 221116, P.R. China
Da-Hua Shi and Zhi-Ling Cao: College of Pharmaceutical Sciences,
Huaihai Institute of Technology, Lianyungang 222005, P.R. China; and
Chemistry
In the development of C2-glycosyl oxadiazoles, glycosyl
Jiangsu Institute of Marine Resources, Lianyungang 222005, P.R. China isothiocyanate 3 was the critical intermediate compound.
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ꢀꢀꢀꢀꢁꢀL. Wang et al.: C2-glycosyl oxadiazoles as acetylcholinesterase inhibitors
OH
OBn
OH
O
O
N
HO
HO
BnO
BnO
p-methoxybenzaldehyde
OH
NaH, BnBr
O
OBn
HO
HO
N
OH
NH2·HCl
NaOH, H2O, rt, 24 h, 83%
DMF, 0°C - rt, 12 h
MeO
MeO
OBn
OBn
S
OBn
5
mol/L HCl
O
CS , Et N
2
3
O
TsCl, 0°C
0.5 h, 90%
O
BnO
BnO
BnO
BnO
BnO
OBn
NH2·HCl
BnO
OBn
OBn
Acetone, 56°C - rt
h, 62%
MeCN, 0°
C
NH
NCS
1
2 h
1
2
3
S Et NH
3
Scheme 1ꢀ
OBn
OBn
OBn
O
O
O
O
ArCONHNH2 (4)
TsCl, Et3N
BnO
BnO
BnO
BnO
BnO
BnO
OBn
O
OBn
OBn
NH
NH
N
MeCN, ∆, 3–4 h, 85%
MeCN, ∆, 2–3 h, 85%
NCS
S
3
5a–j
6a–j
NH
HN
Ar
N
Ar
a: Ar = C6H5
b: Ar = 4-CH3-C6H4
c: Ar = 2-thienyl
f: Ar = 2-Cl-C6H4
g: Ar = 4-OH-C6H4
h: Ar = 4-I-C6H4
d: Ar = 4-pyridyl
e: Ar = 3-OCH3-C6H4
i: Ar = 4-F-C6H4
j: Ar = 4-(N,N-di-Me)-C6H4
Scheme 2ꢀ
Table 1ꢀIn vitro inhibitory activities of glycosyl oxadiazoles against
disappointment, this attempt failed. The benzyl group
was used to protect the hydroxyl groups. 1,3,4,6-Tetra-
O-benzyl-β-D-glucosamine hydrochloride 1 was syn-
thesized according to the literature [38, 39]. Treatment
of compounds 1 with triethylamine in acetonitrile was
followed by the addition of carbon disulfide, which fur-
nished dithiocarbamic acid salt 2. Subsequent reaction
AChE.
Compound
ꢂ
Inhibition (%)a
IC50 (μꢁ)
ꢂꢃ.ꢄ
ꢂ7.7
ꢅ9.ꢂ
9ꢄ.ꢆ
9ꢇ.ꢄ
ꢅꢅ.ꢆ
9ꢆ.ꢈ
ꢃꢉ.ꢈ
ꢉꢈ.ꢈ
9ꢃ.ꢉ
9ꢆ.ꢆ
ꢆ7.ꢈ
ꢆꢂ.ꢅ
–
6
6
6
6
6
6
6
6
6
6
a
b
c
d
e
f
–
–
ꢄ.ꢃꢁ±ꢁꢇ.ꢅ
ꢂ.ꢄꢁ±ꢁꢇ.ꢄ of 2 with tosyl chloride (p-TsCl) yielded the key glycosyl
–
isothiocyanate immediate 3 (Scheme 1). Compound 3 was
ꢈ.ꢆꢁ±ꢁꢇ.ꢂ
treated with various hydrazides 4 to yield the glycosyl
g
h
i
–
acylthiosemicarbazide derivatives 5a–j. Cyclization of
ꢆꢆ.ꢃꢁ±ꢁꢇ.ꢉ
ꢆ.ꢃꢁ±ꢁꢇ.ꢈ the intermediate products 5 in a base-catalyzed reaction
ꢄ.7ꢁ±ꢁꢇ.ꢅ afforded the glycosyl oxadiazole derivatives 6a–j in high
j
b
m
–
–
yields (Scheme 2).
c
n
Tacrine
ꢇ.ꢄꢃ9ꢁ±ꢁꢇ.ꢇꢇꢂ
Galantamine
ꢄ.ꢃ7ꢁ±ꢁꢇ.ꢆꢅ
a
The inhibition activities of the compounds at the concentration of
Biological activity
b
5
0 μg/mL. m stands for 5-(4-(N,N-di-Me)-C H )-1,3,4-oxadiazole-2-
6
4
c
amine. n stands for D-glucosamine hydrochloride.
The AChE-inhibition activities of the compounds were
evaluated in vitro by Ellman’s method [40] using the
Our strategy began with an attempted synthesis of AChE extract from electric eel. The results are summa-
this starting material without protection of hydroxyl rized in Table 1. Selected compounds were subsequently
groups at D-glucosamine hydrochloride but, to our evaluated for the maximal inhibitory concentration,
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L. Wang et al.: C2-glycosyl oxadiazoles as acetylcholinesterase inhibitorsꢊꢁꢀꢀꢀꢊ3
1
00
2-Amino-1,3,4,ꢃ-tetra-O-benzyl-2-deoxy-β-D-
glucopyranose hydrochloride (1)
8
6
4
2
0
0
0
0
0
A solution of D-glucosamine hydrochloride (10 g, 46.4 mmol)
in water (70 mL) at room temperature was stirred and treated
with NaOH (1.86 g, 46.5 mmol), and 15 min later dropwise with
p-methoxybenzaldehyde (5.7 mL, 46.6 mmol). The mixture was
stirred at ambient temperature for an additional 24 h, after which
time the resulting white solid was filtered and washed with
5
00 mL of water to afford 2-(4-methoxy benzylidene)-2-deoxy-β-D-
glucopyranose (11.4 g, 83%). A mixture of this product and BnBr
14 mL, 118 mmol) in dimethylformamide (DMF) (50 mL) at 0°C
0
.005
0.05
0.5
5
50
Concentration (µg/mL)
(
Figure 1ꢀDose-dependent inhibition of AChE by compound ꢃi.
Values are presented as meanꢁ±ꢁSD, nꢁ=ꢁ3.
was treated portion-wise with NaH (60%, 5 g, 125 mmol). The mix-
ture was stirred at room temperature for 12 h, then diluted with a
large amount of water and extracted with CH Cl (3ꢀ×ꢀ50 mL). The
2
2
extract was concentrated under reduced pressure to give a yel-
low viscous liquid. The solution of the yellow liquid in acetone
(
100 mL) was treated with hydrochloric acid (7 mL, 5 N) to afford
IC , with tacrine and galantamine as the reference com-
5
0
a white solid of 1 after reflux for 1 h. Product 1 was washed with
pounds. The results indicate that all compounds show
higher inhibitory activities against AChE than the pre-
cursor compound n. The best compound 6i shows the
highest activity with an IC value of 1.61ꢀ±ꢀ0.34 against
acetone; yield 7.9 g (62%).
5
0
2
-Isothiocyanato-1,3,4,ꢃ-tetra-O-benzyl-2-deoxy-β-D-
AChE and inhibits AChE in a dose-dependent rela-
tionship (Figure 1). Compounds 1 and m demonstrate
weak inhibition of AChE compared with compound 6i,
suggesting that the presence of 1,3,4-oxadiazole unit
improves the activity.
glucopyranose (3)
A solution of 1,3,4,6-tetra-O-benzyl-β-D-glucosamine hydrochloride
1
(1 mmol) and triethylamine (3 mmol) in acetonitrile (15 mL) was
cooled in an ice bath and treated dropwise with carbon disulfide
(
(
1 mmol). The mixture was stirred for 2 h, then treated with p-TsCl
1 mmol) and stirred for another 0.5 h on the ice bath. The precipi-
tate of product 3 was crystallized from ethanol; yield 90% of white
amorphous powder; mp 55–56°C; IR: 3433, 3030, 2873, 2078, 1454,
Conclusion
−1 1
1
359, 1313, 1068 cm ; H NMR: δ 7.45–7.25 (m, 18H, ArH), 7.24–7.17 (dd,
Jꢀ=ꢀ7 Hz, 2H, ArH), 4.81 (dd, Jꢀ=ꢀ16, 10 Hz, 4H, PhCH , HGlu), 4.73–4.62
2
A new series of C2-glycosyl oxadiazole derivatives were
designed, synthesized and subjected to biological evalu-
ation. These compounds were characterized by NMR,
IR and HRMS. Most of the compounds are active against 604.2130.
AChE. Compound 6i shows the best AChE-inhibition activ-
ity with an IC of 1.61ꢀ±ꢀ0.34 μꢁ.
(
3
m, 2H, PhCH ), 4.61–4.48 (m, 3H, PhCH ), 3.95–3.87 (m, 2H, HGlu),
2
2
.67 (ddd, Jꢀ=ꢀ14, 12, 7 Hz, 3H, HGlu), 3.54 (dd, Jꢀ=ꢀ12, 7 Hz, 1H, HGlu);
+
ESI-HRMS (m/z): Calcd for C H NNaO S [Mꢀ+ꢀNa] : 604.2128; found:
35
35
5
50
General procedure for the preparation of N-(1,3,4,ꢃ-tetr-
a-O-benzyl-2-deoxy-β-D-glucopyranosyl)-ꢄ-aryl-1,3,4-
oxadiazole-2-amines ꢃa–j
Experimental
Chemistry
Glycosyl isothiocyanate 3 (0.58 g, 1 mmol) was added in one por-
tion to a stirred solution of hydrazide 4 (1 mmol) in MeCN (10 mL).
The reaction mixture was heated under reflux for 3–4 h, and then
All chemicals were purchased from commercial sources and used the solvent was eliminated under reduced pressure. The residue
without further purification. Melting points were determined on a was crystallized from aqueous ethanol to obtain the desired prod-
Yanaco melting point apparatus and were uncorrected. IR spectra uct 5a–j. p-TsCl (0.21 g, 1.1 mmol) was added to a stirred solution
were recorded on a Bruker Tensor 27 spectrometer in KBr pellets. of acylthiosemicarbazide 5 (1 mmol) and triethylamine (0.16 mL,
1
H NMR spectra were recorded on a Bruker Avance 400 MHz at 2.0 mmol) in MeCN (10 mL). The mixture was stirred for about
ambient temperature using dimethyl sulfoxide-d6 (DMSO-d ) as 2–3 h at 81°C, and the reaction progress was monitored by thin-
6
a solvent and tetramethylsilane (TMS) as an internal standard. layer chromatography (TLC). The desired compound 6a–j was
HRMS (ESI) analysis was performed on an Agilent 6230 mass purified by column chromatography on silica gel eluting with
spectrometer. Flash column chromatography was performed on ethyl acetate/petroleum ether (1:2) to give a white amorphous
silica 200–300 mesh.
product.
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ꢀꢀꢀꢀꢁꢀL. Wang et al.: C2-glycosyl oxadiazoles as acetylcholinesterase inhibitors
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5- N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(4-
phenyl-1,3,4-oxadiazole-2-amine (6a)ꢂYield 86%; mp 166–168°C; hydroxylphenyl)-1,3,4-oxadiazole-2-amine (6g)ꢂYield 86%; mp
−
1
−1
IR (cm ): 3421, 3226, 3060, 2924, 1630, 1496, 1453, 1397, 1116, 1064; 181–182°C; IR (cm ): 3421, 3142, 3030, 2956, 1650, 1611, 1497, 1398,
1
1
H NMR: δ 8.15 (d, Jꢀ=ꢀ9 Hz, 1H, NH), 7.86–7.80 (m, 2H, ArH), 7.56–7.50 1279, 1173, 1072, 1027; H NMR: δ 10.10 (s, 1H, OH), 7.98 (d, Jꢀ=ꢀ9 Hz, 1H,
(
m, 3H, ArH), 7.40–7.27 (m, 8H, ArH), 7.25–7.12 (m, 12H, ArH), 4.82 NH), 7.66 (t, Jꢀ=ꢀ9 Hz, 2H, ArH), 7.41–7.12 (m, 20H, ArH), 6.89 (d, Jꢀ=ꢀ9 Hz,
Glu
Glu
(
d, Jꢀ=ꢀ12 Hz, 1H, H-1 ), 4.80–4.65 (m, 4H, PhCH ), 4.62–4.51 (m, 2H, ArH), 4.81 (d, Jꢀ=ꢀ12 Hz, 1H, H-1 ), 4.78–4.50 (m, 8H, PhCH ), 3.83–
2
Glu
2
Glu
Glu
Glu
Glu
Glu
Glu
Glu
4
H, PhCH ), 3.85–3.69 (m, 3H, H-4 , H-6a , H-6b ), 3.65–3.50 (m, 3.68 (m, 3H, H-4 , H-6a , H-6b ), 3.69–3.50 (m, 3H, H-5 , H-3 ,
2
+
Glu
Glu
Glu
Glu
3
H, H-5 , H-3 , H-2 ); ESI-HRMS (m/z): Calcd for C H N NaO
H-2 ); ESI-HRMS (m/z): Calcd for C H N NaO [Mꢀ+ꢀNa] : 722.2837;
42 41 3 7
42
41
3
6
+
[
Mꢀ+ꢀNa] : 706.2888; found: 706.2890.
found: 722.2838.
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(4- N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(4-
methylphenyl)-1,3,4-oxadiazole-2-amine (6b)ꢂYield 88%; mp iodinylphenyl)-1,3,4-oxadiazole-2-amine (6h)ꢂYield 82%; mp
−
1
1
−1
1
59–160°C; IR (cm ): 3446, 3170, 2923, 1629, 1400, 1071, 1028; H 176–177°C; IR (cm ): 3446, 3229, 3059, 2922, 1627, 1478, 1453, 1397,
1
NMR: δ 8.08 (d, Jꢀ=ꢀ9 Hz, 1H, NH), 7.71 (d, Jꢀ=ꢀ8 Hz, 2H, ArH), 7.42–7.27 1362, 1203, 1055, 1005; H NMR: δ 8.19 (d, Jꢀ=ꢀ9 Hz, 1H, NH), 7.90 (d,
Glu
(
4
m, 10H, ArH), 7.25–7.13 (m, 12H, ArH), 4.82 (d, Jꢀ=ꢀ12 Hz, 1H, H-1 ), Jꢀ=ꢀ8.5 Hz, 2H, ArH), 7.58 (d, Jꢀ=ꢀ8.5 Hz, 2H, ArH), 7.40–7.27 (m, 8H,
Glu
.78–4.70 (m, 3H, PhCH ), 4.68–4.52 (m, 5H, PhCH ), 3.83–3.68 (m, 3H, ArH), 7.25–7.10 (m, 12H, ArH), 4.81 (d, Jꢀ=ꢀ12 Hz, 1H, H-1 ), 4.77–4.61
2
2
Glu
Glu
Glu
Glu
Glu
Glu
Glu
H-4 , H-6a , H-6b ), 3.63–3.52 (m, 3H, H-5 , H-3 , H-2 ), 2.40– (m, 4H, PhCH ), 4.60–4.50 (m, 4H, PhCH ), 3.83–3.67 (m, 3H, H-4
,
2
Glu
2
Glu
+
Glu
Glu
Glu
2
7
.32 (s, 3H, CH ); ESI-HRMS (m/z): Calcd for C H N NaO [Mꢀ+ꢀNa] : H-6a , H-6b ), 3.64–3.51 (m, 3H, H-5 , H-3 , H-2 ); ESI-HRMS
3
43 43
3
6
+
20.3044; found: 720.3046.
(m/z): Calcd for C H IN NaO [Mꢀ+ꢀNa] : 832.1854; found: 832.1860.
4
2
40
3
6
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(2- N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(4-
thienyl)-1,3,4-oxadiazole-2-amine (6c)ꢂYield 84%; mp 147–148°C; fluorophenyl)-1,3,4-oxadiazole-2-amine (6i)ꢂYield 88%; mp 156–
−
1
1
−1
IR (cm ): 3420, 3201, 3026, 2923, 1496, 1468, 1400, 1114, 1066; H 157°C; IR (cm ): 3425, 3179, 3029, 2923, 1601, 1518, 1498, 1400, 1219,
1
NMR: δ 8.36 (d, Jꢀ=ꢀ9 Hz, 1H, NH), 7.66 (d, Jꢀ=ꢀ8 Hz, 1H, ArH), 7.42 (d, 1124, 1070; H NMR: δ 8.34 (d, Jꢀ=ꢀ9 Hz, 1H, NH), 7.84–7.77 (m, 2H, ArH),
Jꢀ=ꢀ4 Hz, 1H, ArH), 7.40–7.29 (m, 8H, ArH), 7.27–7.11 (m, 13H, ArH), 4.82 7.41–7.26 (m, 11H, ArH), 7.25–7.13 (m, 11H, ArH), 4.82 (d, Jꢀ=ꢀ12.5 Hz, 1H,
Glu
Glu
(
d, Jꢀ=ꢀ12.5 Hz, 1H, H-1 ), 4.76–4.65 (m, 4H, PhCH ), 4.63–4.52 (m, 4H, H-1 ), 4.76–4.66 (m, 4H, PhCH ), 4.63–4.51 (m, 4H, PhCH ), 3.86 (t,
2
2 2
Glu Glu Glu
Glu
Glu
Glu
PhCH ), 3.86 (t, Jꢀ=ꢀ8 Hz, 1H, H-4 ), 3.78–3.67 (m, 2H, H-6a , H-6b ), Jꢀ=ꢀ8 Hz, 1H, H-4 ), 3.78–3.67 (m, 2H, H-6a , H-6b ), 3.62–3.52 (m,
2
Glu
Glu
Glu
Glu
Glu
3
.61–3.50 (m, 3H, H-5 , H-3Glu, H-2 ); ESI-HRMS (m/z): Calcd for 3H, H-5 , H-3 , H-2 ); ESI-HRMS (m/z): Calcd for C H FN NaO
42
40
3
6
+
+
C H N NaO S [Mꢀ+ꢀNa] : 712.2452; found: 712.2456.
[Mꢀ+ꢀNa] : 724.2793; found: 724.2796.
4
0
39
3
6
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(4- N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(4-
pyridyl)-1,3,4-oxadiazole-2-amine (6d)ꢂYield 86%; mp 182–183°C; dimethylaminophenyl)-1,3,4-oxadiazole-2-amine
(6j)ꢂYield
−1
1
−1
IR (cm ): 3421, 3230, 3060, 2924, 1627, 1465, 1398, 1061, 1028; H NMR: δ 83%; mp 123–124°C; IR (cm ): 3422, 3234, 3060, 2906, 1633, 1614,
1
8
.98 (d, Jꢀ=ꢀ2 Hz, 1H, ArH), 8.70 (dd, Jꢀ=ꢀ5, 2 Hz, 1H, ArH), 8.26 (d, Jꢀ=ꢀ9 Hz, 1519, 1397, 1197, 1068, 1028; H NMR: δ 7.89 (d, Jꢀ=ꢀ9 Hz, 1H, NH), 7.62
1
H, NH), 8.16 (2t, Jꢀ=ꢀ2 Hz, 1H, ArH), 7.56 (dd, Jꢀ=ꢀ8.5 Hz, 1H, ArH), 7.40– (d, Jꢀ=ꢀ9 Hz, 2H, ArH), 7.41–7.25 (m, 8H, ArH), 7.24–7.15 (m, 12H, ArH),
Glu
Glu
7
4
.27 (m, 8H, ArH), 7.25–7.10 (m, 12H, ArH), 4.82 (d, Jꢀ=ꢀ12 Hz, 1H, H-1 ), 6.80 (d, Jꢀ=ꢀ9 Hz, 2H, ArH), 4.81 (d, Jꢀ=ꢀ12.5 Hz, 1H, H-1 ), 4.78–4.62
Glu
.79–4.64 (m, 4H, PhCH ), 4.62–4.52 (m, 4H, PhCH ), 3.84–3.69 (m, 3H, (m, 4H, PhCH ), 4.60–4.51 (m, 4H, PhCH ), 3.83–3.66 (m, 3H, H-4
,
2
2
Glu
2
Glu
2
Glu
Glu
Glu
Glu
Glu
Glu
Glu
Glu
Glu
H-4 , H-6a , H-6b ), 3.65–3.55 (m, 3H, H-5 , H-3 , H-2 ); ESI-HRMS H-6a , H-6b ), 3.63–3.49 (m, 3H, H-5 , H-3 , H-2 ), 2.98 (s, 6H,
+
+
(m/z): Calcd for C H N NaO [Mꢀ+ꢀNa] : 707.2840; found: 707.2843.
CH ); ESI-HRMS (m/z): Calcd for C H N NaO [Mꢀ+ꢀNa] : 749.3310;
41
40
4
6
3
44 46
4
6
found: 749.3312.
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(3-
methoxyphenyl)-1,3,4-oxadiazole-2-amine (6e)ꢂYield 90%; mp
−1
1
47–148°C; IR (cm ): 3426, 3174, 3028, 2926, 1598, 1497, 1453, 1400,
1
In vitro cholinesterase activity assay
1
216, 1125, 1069, 1043; H NMR: (δ 8.37 (d, Jꢀ=ꢀ9 Hz, 1H, NH), 7.43–7.27
(
m, 12H, ArH), 7.25–7.15 (m, 11H, ArH), 7.05–7.01 (m, 1H, ArH), 4.83 (d,
Glu
Jꢀ=ꢀ12.5 Hz, 1H, H-1 ), 4.78–4.67 (m, 4H, PhCH ), 4.64–4.51 (m, 4H, AChE, acetylthiocholine iodide (ATCI), 5,5-dithiobis-(2-nitrobenzoic
2
Glu
PhCH ), 3.87 (t, Jꢀ=ꢀ8 Hz, 1H, H-4 ), 3.82 (s, 3H, OCH ), 3.77–3.68 (m, acid) (DTNB), galantamine and tacrine were purchased from Sigma-
2
3
Glu
Glu
Glu
Glu
Glu
2
H, H-6a , H-6b ), 3.61–3.51 (m, 3H, H-5 , H-3 , H-2 ); ESI-HRMS Aldrich. AChE activities were measured using Ellman’s colorimetric
+
(
m/z): Calcd for C H N NaO [Mꢀ+ꢀNa] : 736.2993; found: 736.2998.
method with a slight modification [39]; galantamine and tacrine were
the reference compounds. For the determination, a 96-well plate was
43
43
3
7
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(2- used as the carrier. First, 130 μL of buffer solution, 20 μL of AChE solu-
chlorophenyl)-1,3,4-oxadiazole-2-amine (6f)ꢂYield 83%; mp 121– tion, 20 μL of color developer and 10 μL of methanol were added to
−
1
1
1
1
22°C; IR (cm ): 3421, 3231, 3062, 2924, 1627, 1508, 1454, 1397, 1362, the first column of the 96-well plate as a control blank system. Then,
1
149, 1076, 1028; H NMR: δ 8.25 (d, Jꢀ=ꢀ9 Hz, 1H, NH), 7.78 (dd, Jꢀ=ꢀ8, 130 μL of buffer solution, 20 μL of AChE solution, 20 μL of developer
.8 Hz, 1H, ArH), 7.65 (dd, Jꢀ=ꢀ8, 1.1 Hz, 1H, ArH), 7.58–7.47 (m, 2H, ArH), and 10 μL of the analyte solution were added. After all samples were
7
.40–7.27 (m, 8H, ArH), 7.26–7.13 (m, 12H, ArH), 4.83 (d, Jꢀ=ꢀ12.5 Hz, 1H, added, the plate was treated with 20 μL of substrate and shaken
Glu
H-1 ), 4.79–4.63 (m, 4H, PhCH ), 4.62–4.51 (m, 4H, PhCH ), 3.84–3.68 evenly. The plate was quickly placed in the microplate reader and
2
2
Glu
Glu
Glu
Glu
Glu
Glu
(
m, 3H, H-4 , H-6a , H-6b ), 3.63–3.50 (m, 3H, H-5 , H-3 , H-2 ); the temperature was maintained at 20–25°C. The reaction rates were
+
ESI-HRMS (m/z): Calcd for C H ClN NaO [Mꢀ+ꢀNa] : 740.2498; found: compared and the percent inhibition due to the presence of tested
42
40
3
6
740.2501.
compounds was calculated. All samples were assayed in triplicate.
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L. Wang et al.: C2-glycosyl oxadiazoles as acetylcholinesterase inhibitorsꢊꢁꢀꢀꢀꢊꢄ
The 50% inhibitory concentration (IC ) was calculated from a dose- [12] Blagodatskikh, I. V.; Kulikov, S. N.; Vyshivannaya, O. V.;
5
0
response curve obtained by plotting the percentage of inhibition ver-
sus the log concentration with the use of the Origin 8.0 software. The
results were described as meanꢀ±ꢀstandard deviation (SD).
Bezrodnykh, E. A.; Yamskov, I. A.; Tikhonov, V. E. Influence
of glucosamine on oligochitosan solubility and antibacterial
activity. Carbohydr. Res. 2ꢅ13, 381, 28–32.
[
[
13] Quastel, J. Inhibition of tumour growth by D-glucosamine.
Nature 19ꢄ3, 171, 252–254.
Acknowledgments: This work was supported by the
Postgraduate Research and Practice Innovation Pro-
gram of Jiangsu Province (KYCX17-2074), Natural Science
Foundation of Jiangsu Province (BK20151281), Open-end
Funds of Jiangsu Key Laboratory of Marine Biotechnology
14] Xing, R.; Liu, S.; Guo, Z.; Yu, H.; Li, C.; Ji, X.; Feng, J.; Li, P. The
antioxidant activity of glucosamine hydrochloride in vitro.
Bioorg. Med. Chem. 2ꢅꢅꢃ, 14, 1ꢌ06–1ꢌ0ꢋ.
[
15] Liu, W. W.; Li, Q. X.; Shi, D. H. Synthesis, characterization, and
biological evaluation of some novel glycosyl 1,3,4-thiadiazole
derivatives as acetylcholinesterase inhibitors. Heterocycles
(
HS2014007) and Public Science and Technology Research
2
ꢅ1ꢄ, 91, 2ꢌ5–286.
Funds Projects of Ocean (201505023).
[16] Punganuru, S. R.; Mostofa, A. G. M.; Madala, H. R.; Basak,
D.; Srivenugopal, K. S. Potent anti-proliferative actions of a
non-diuretic glucosamine derivative of ethacrynic acid. Bioorg.
Med. Chem. Lett. 2ꢅ1ꢃ, 26, 282ꢋ–2835.
References
[1ꢌ] Garifullin, B. F.; Strobykina, I. Y.; Sharipova, R. R.; Kravchenko,
M. A.; Andreeva, O. V.; Bazanova, O. B.; Kataev, V. E. Synthesis
and antituberculosis activity of the first macrocyclic glycoter-
penoids comprising glucosamine and diterpenoid isosteviol.
Carbohydr. Res. 2ꢅ1ꢃ, 431, 15–21.
18] Yang, J.; Li, J. R.; Yang, J. X.; Li, L. L.; Ouyang, W. J.; Wu, S. W.;
Zhang, F. Synthesis and anti-HIV-1 activity of the conjugates
of gossypol with oligopeptides and D-glucosamine. Chinese
Chem. Lett. 2ꢅ14, 25, 1052–1058.
1ꢋ] Mendis, E.; Kim, M. M.; Rajapakse, N.; Kim, S. K. The inhibitory
mechanism of a novel cationic glucosamine derivative against
MMP-2 and MMP-ꢋ expressions. Bioorg. Med. Chem. Lett.
2ꢅꢅ9, 19, 2ꢌ55–2ꢌ60.
[20] Shen, C.; Shen, H.; Yang, M.; Xia, C.; Zhang, P. A novel
D-glucosamine-derived pyridyl-triazole for solvent-free
Mizoroki–Heck reactions and its application in the synthesis
of Axitinib. Green Chem. 2ꢅ1ꢄ, 17, 225–230.
[21] Bepary, S.; Yoon, I. K.; Lee, G. H. Novel 3-amino-
ꢌ-(aminomethyl)-1H-indazol-4-ol as the PI3Kγ enzyme inhibitor.
Bull. Korean. Chem. Soc. 2ꢅ1ꢃ, 37, 2054–205ꢌ.
[22] Dighe, S. U.; Khan, S.; Soni, I.; Jain, P.; Shukla, S.; Yadav, R.;
Sen, P.; Meeran, S. M.; Batra, S. Synthesis of β-carboline-based
N-heterocyclic carbenes and their antiproliferative and anti-
metastatic activities against human breast cancer cells. J. Med.
Chem. 2ꢅ1ꢄ, 58, 3485–34ꢋꢋ.
[23] Chen, Y.; Yu, K.; Tan, N. Y.; Qiu, R. H.; Liu, W.; Luo, N. L.; Yin, S.
F. Synthesis, characterization and anti-proliferative activity of
heterocyclic hypervalent organoantimony compounds. Eur. J.
Med. Chem. 2ꢅ14, 79, 3ꢋ1–3ꢋ8.
[24] Mathew, V.; Keshavayya, J.; Vaidya, V. P. Heterocyclic system
containing bridgehead nitrogen atom: synthesis and pharmaco-
logical activities of some substituted 1,2,4-triazolo [3,4-b]-1,3,4-
thiadiazoles. Eur. J. Med. Chem. 2ꢅꢅꢃ, 41, 1048–1055.
[25] Borg, S.; Estenne-Bouhtou, G.; Luthman, K.; Csoeregh, I.;
Hesselink, W.; Hacksell, U. Synthesis of 1,2,4-oxadiazole-,
1,3,4-oxadiazole- and 1,2,4-triazole-derived dipeptidomimetics.
J. Org. Chem. 199ꢄ, 60, 3112–311ꢌ.
[
1] Tsvetkov, Y. E.; Burg-Roderfeld, M.; Loers, G.; Ardá, A.;
Sukhova, E. V.; Khatuntseva, E. A.; Jiménez-Barbero, J.
Synthesis and molecular recognition studies of the HNK-1
trisaccharide and related oligosaccharides. The specificity
of monoclonal anti-HNK-1 antibodies as assessed by surface
plasmon resonance and STD NMR. J. Am. Chem. Soc. 2ꢅ11, 134,
[
426–435.
[
[
[
2] Kimura, M.; Masui, Y.; Shirai, Y.; Honda, C.; Moriwaki, K.;
Imai, T.; Nakano, H. Preparation of branched cyclomalto-
heptaose with 3-O-α-L-fucopyranosyl-α-D-mannopyranose
and changes in fucosylation of HCT116 cells treated with the
fucose-modified cyclomaltoheptaose. Carbohydr. Res. 2ꢅ13,
3
74, 4ꢋ–58.
3] Delbianco, M.; Bharate, P.; Varela-Aramburu, S.; Seeberger,
P. H. Carbohydrates in supramolecular chemistry. Chem. Rev.
2ꢅ1ꢃ, 116, 16ꢋ3–1ꢌ52.
[
[
[
[
4] Ernst, B.; Magnani, J. L. From carbohydrate leads to glycomi-
metic drugs. Nat. Rev. Drug Discov. 2ꢅꢅ9, 8, 661–6ꢌꢌ.
5] Bertozzi, C. R.; Kiessling, L. L. Chemical glycobiology. Science
2ꢅꢅ1, 291, 235ꢌ–2364.
6] Xie, J. Synthesis of new sugar amino acid derivatives of
D-glucosamine. Carbohydr. Res. 2ꢅꢅ3, 338, 3ꢋꢋ–405.
ꢌ] Xu, C.; Hall, R.; Cummings, J.; Raushel, F. M. Tight binding
inhibitors of N-acyl amino sugar and N-acyl amino acid dea-
cetylases. J. Am. Chem. Soc. 2ꢅꢅꢃ, 128, 4244–4245.
[
8] Fu, M.; Qin, C.; Li, W.; Yan, Y.; Zeng, L.; Yang, X. Effect of
glucosamine and chitooligomer on the toxicity of arsenite
against Escherichia coli. Carbohyd. Polym. 2ꢅ13, 91, 3ꢋ0–3ꢋ6.
ꢋ] Terencio, M. C.; Ferrándiz, M. L.; Carceller, M. C.; Ruhí, R.;
Dalmau, P.; Vergés, J.; Alcaraz, M. J. Chondroprotective effects
of the combination chondroitin sulfate-glucosamine in a model
of osteoarthritis induced by anterior cruciate ligament transec-
tion in ovariectomised rats. Biomed. Pharmacother. 2ꢅ1ꢃ, 79,
[
120–128.
[
[
10] Nagaoka, I.; Igarashi, M.; Hua, J.; Ju, Y.; Yomogida, S.;
Sakamoto, K. Recent aspects of the anti-inflammatory actions
of glucosamine. Carbohyd. Polym. 2ꢅ11, 84, 825–831.
11] Oh, H. J.; Lee, J. S.; Song, D. K.; Shin, D. H.; Jang, B. C.;
Suh, S. I.; Baek, W. K. D-glucosamine inhibits proliferation of
human cancer cells through inhibition of pꢌ0S6K. Biochem.
Bioph. Res. Commun. 2ꢅꢅ7, 360, 840–846.
[26] Li, P.; Yin, J.; Xu, W.; Wu, J.; He, M.; Hu, D.; Song, B. Synthesis,
antibacterial activities, and 3D-QSAR of sulfone derivatives
containing 1,3,4-oxadiazole moiety. Chem. Biol. Drug Des.
2ꢅ13, 82, 546–551.
[2ꢌ] Padmaja, A.; Pedamalakondaiah, D.; Sravya, G.; Reddy, G.
M.; Kumar, M. V. J. Synthesis and antioxidant activity of a
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ꢃꢀꢀꢀꢀꢁꢀL. Wang et al.: C2-glycosyl oxadiazoles as acetylcholinesterase inhibitors
new class of sulfone/sulfonamide-linked bis(oxadiazoles),
(MAO) inhibitors: synthesis, evaluation, and role of urea moi-
bis(thiadiazoles), and bis(triazoles). J. Med. Chem. Res. 2ꢅ1ꢄ,
ety. Bioorg. Med. Chem. 2ꢅꢅ8, 16, ꢌ565–ꢌ5ꢌ2.
24, 2011–2020.
[34] Mazouz, F.; Lebreton, L.; Milcent, R.; Burstein, C. 5-Aryl-1,3,4-
oxadiazol-2 (3H)-one derivatives and sulfur analogues as new
selective and competitive monoamine oxidase type B inhibi-
tors. Eur. J. Med. Chem. 199ꢅ, 25, 65ꢋ–663.
[35] Raza, R.; Saeed, A.; Arif, M.; Mahmood, S.; Muddassar, M.;
Raza, A.; Iqbal, J. Synthesis and biological evaluation of
3-thiazolocoumarinyl Schiff-base derivatives as cholinesterase
inhibitors. Chem. Biol. Drug Des. 2ꢅ12, 80, 605–615.
[36] Wei, H.; Ruan, J.; Zhang, X. Coumarin–chalcone hybrids: prom-
ising agents with diverse pharmacological properties. RSC Adv.
2ꢅ1ꢃ, 6, 10846–10851.
[3ꢌ] Havrylyuk, D.; Roman, O.; Lesyk, R. Synthetic approaches,
structure activity relationship and biological applications for
pharmacologically attractive pyrazole/pyrazoline–thiazolidine-
based hybrids. Eur. J. Med. Chem. 2ꢅ1ꢃ, 113, 145–150.
[38] Cheng, F. C.; Yin, L.; Liu, W. W.; Li, Q. X.; Tang, L. J.; Shi, D. H.;
Cao, Z. L. Expedient synthesis of novel glycosyl thiazole deriva-
tives. Heterocycles 2ꢅ1ꢄ, 91, 2113–2125.
[
[
[
[
28] Wu, W.; Chen, Q.; Tai, A.; Jiang, G.; Ouyang, G. Synthesis and
antiviral activity of 2-substituted methylthio-5-(4-amino-
2
-methylpyrimidin-5-yl)-1,3,4-oxadiazole derivatives. Bioorg.
Med. Chem. Lett. 2ꢅ1ꢄ, 25, 2243–2250.
2ꢋ] Zhang, M. Z.; Mulholland, N.; Beattie, D.; Irwin, D.; Gu, Y.
C.; Chen, Q.; Clough, J. Synthesis and antifungal activity of
3
-(1,3,4-oxadiazol-5-yl)indoles and 3-(1,3,4-oxadiazol-5-yl)
methylindoles. Eur. J. Med. Chem. 2ꢅ13, 63, 22–28.
30] Dekhane, D. V.; Pawar, S. S.; Gupta, S.; Shingare, M. S.; Patil, C.
R.; Thore, S. N. Synthesis and anti-inflammatory activity of some
new 4,5-dihydro-1,5-diaryl-1H-pyrazole-3-substituted heteroa-
zole derivatives. Bioorg. Med. Chem. Lett. 2ꢅ11, 21, 652ꢌ–6531.
31] Zhang, Y.; Liu, X. H.; Zhan, Y. Z.; Zhang, L. Y.; Li, Z. M.; Li, Y.
H.; Wang, B. L. Synthesis and biological activities of novel
5
-substituted-1,3,4-oxadiazole Mannich bases and bis-Man-
nich bases as ketol-acid reductoisomerase inhibitors. Bioorg.
Med. Chem. Lett. 2ꢅ1ꢃ, 26, 4661–466ꢌ.
[
32] Distinto, S.; Meleddu, R.; Yanez, M.; Cirilli, R.; Bianco, G.; Sanna, [3ꢋ] Tao, C. Z.; Liu, F.; Liu, W. W.; Zhu, Y. M.; Li, Y. F.; Liu, X. L.;
M. L.; Ortuso, F. Drug design, synthesis, in vitro and in silico
evaluation of selective monoaminoxidase B inhibitors based on
3-acetyl-2-dichlorophenyl-5-aryl-2,3-dihydro-1,3,4-oxadiazole
Zhao, J. Synthesis of N-aryl-D-glucosamines through
copper-catalyzed C–N coupling. Tetrahedron Lett. 2ꢅ12, 53,
ꢌ0ꢋ3–ꢌ0ꢋ6.
chemical scaffold. Eur. J. Med. Chem. 2ꢅ1ꢃ, 108, 542–548.
33] Ke, S.; Li, Z.; Qian, X. 1,3,4-Oxadiazole-3(2H)-carboxamide
derivatives as potential novel class of monoamine oxidase
[40] Ellman, G. L.; Courtney, K. D.; Andres Jr, V.; Featherstone, R. M.
A new and rapid colorimetric determination of acetylcholinest-
erase activity. Biochem. Pharmacol. 19ꢃ1, 7, 88–ꢋ5.
[
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