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

Article abstract of DOI:10.1515/hc-2016-0163

New C2-glycosyl triazole derivatives 6a-l were synthesized by cyclization of glycosyl acylthiosemicarbazides 5 in refluxing 3 N sodium hydroxide aqueous solution. Substrates 5 were obtained by the reaction of glycosyl isothiocyanate 3 with various hydrazides. The acetylcholinesterase (AChE) inhibitory activities of compounds 6 were tested by Ellman's method. Compounds that exhibited over 85% inhibition were subsequently evaluated for the IC₅₀ values. Compound 6f possesses the best acetylcholinesterase-inhibition activity with IC₅₀ of 1.46 ±?0.25 μg/mL.

Full text of DOI:10.1515/hc-2016-0163

Heterocycl. Commun. 2017; 23(3): 231–236
Long Yin, Lei Wang, Xiu-Jian Liu, Feng-Chang Cheng, Da-Hua Shi, Zhi-Ling Cao
aSnyd Wneti-hWeei Lsiui*s and bioactivity of novel C2-glycosyl
triazole derivatives as acetylcholinesterase
inhibitors
DOI 10.1515/hc-2016-0163
Received September 28, 2016; accepted January 11, 2017; previously
published online June 9, 2017
of bioactivities including anti-inflammatory [11], antioxi-
dant [12], antibacterial [13] and antitumor properties [14].
Modified naturally occurring amino sugars are used for
the development of anti-proliferative [15], anti-acetylcho-
linesterase [16], anticandidal [17] and other active agents
[18–21].
In recent years, triazoles and their fused heterocyclic
derivatives have received considerable attention owing to
their importance in drug discovery [22–24]. 1,2,4-Triazoles
and their derivatives are commonly utilized heterocyclic
pharmacophores, which are an important class of hetero-
cyclic molecules presenting numerous biological activities
such as antimicrobial [25], antiproliferative [26], antiviral
[27], anti-inflammatory [28] and anticonvulsant [29] activ-
ities. Recent studies have shown that many compounds
Abstract: New C2-glycosyl triazole derivatives 6a–l were
synthesized by cyclization of glycosyl acylthiosemicar-
bazides 5 in refluxing 3 N sodium hydroxide aqueous
solution. Substrates 5 were obtained by the reaction of
glycosyl isothiocyanate 3 with various hydrazides. The
acetylcholinesterase (AChE) inhibitory activities of com-
pounds 6 were tested by Ellman’s method. Compounds
that exhibited over 85% inhibition were subsequently
evaluated for the IC50 values. Compound 6f possesses the
best acetylcholinesterase-inhibition activity with IC50 of
1.46ꢀ ꢀ0.25 μg/mL.
Keywords: acetylcholinesterase; C2-glycosyl triazole containing the triazole skeleton act as choline esterase
derivatives; synthesis.
inhibitors for the treatment of Alzheimer’s disease [30–32].
Up to now, researchers have been interested in mole-
cular hybrid-based approaches to find some new com-
pounds of potential biological activities [33–35]. Based on
these findings and our previous work, in an attempt to dis-
Introduction
Carbohydrates play an important role in biological and cover new potent acetylcholinesterase (AChE) inhibitors,
industrial applications [1–6]. D-Glucosamine is a naturally we designed and synthesized a series of novel C2-glycosyl
occurring amino sugar [7, 8] that has been widely used triazole derivatives. The synthesized compounds were
for the prevention and treatment of rheumatoid arthritis screened by Ellman’s method to explore the influence of
and osteoarthritis [9, 10]. It also exhibits a broad variety D-glucosamine for AChE-inhibition activity.
*Corresponding author: Wei-Wei Liu, College of Pharmaceutical
Sciences, Huaihai Institute of Technology, Lianyungang 222005,
P.R. China; Jiangsu Institute of Marine Resources, Lianyungang
222005, P.R. China; and Jiangsu Key Laboratory of Marine
Results and discussion
Pharmaceutical Compound Screening, Huaihai Institute of
Technology, Lianyungang 222005, P.R. China,
e-mail: liuww323@aliyun.com
Long Yin, Lei Wang and Xiu-Jian Liu: College of Pharmaceutical
Sciences, Huaihai Institute of Technology, Lianyungang 222005,
P.R. China
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 Jiangsu Institute of Marine Resources, Lianyungang 222005,
P.R. China
Chemistry
The
starting
material,
1,3,4,6-tetra-O-benzyl-β-D-
glucosamine hydrochloride (1), was synthesized as per
the literature [36, 37]. Treatment of compound 1 with tri-
ethylamine in acetonitrile followed by addition of carbon
disulfide to the mixture and stirring for 2 h furnished dith-
iocarbamic acid salt 2. Subsequent reaction of 2 with tosyl
chloride (TsCl) yielded the key glycosyl isothiocyanate
product 3 (Scheme 1) [38].
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ꢀL. Yin et al.: C2-Glycosyl triazole derivatives as acetylcholinesterase inhibitors
OH
OBn
OH
O
O
N
O
HO
HO
HO
BnO
BnO
i
ii
iii
HO
OH
OBn
OH
NH2·HCl
N
O
O
OBn
OBn
OBn
O
O
O
v
iv
BnO
BnO
BnO
BnO
BnO
BnO
OBn
OBn
OBn
NCS
NH2·HCl
NH
S
S
1
2
Et3NH
3
Scheme 1ꢁSynthesis of 1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose-2-isothiocyanate (3).
Reagents and conditions: (i) NaOH, p-methoxybenzaldehyde, H2O, rt; (ii) NaH, BnBr, DMF, 0°C – rt; (iii) 5 N HCl, acetone, reflux; (iv) Et3N, CS2,
0°C, 1.5 h; (v) TsCl, 0.5 h.
The glycosyl isothiocyanate 3 was treated with
As shown in Table 1, all compounds are better inhibi-
various hydrazides 4 to yield the glycosyl acylthiosemicar- tors of AChE than D-glucosamine hydrochloride (m). Eight
bazide derivatives 5a–l. Compounds 5 were cyclized in 3 N of the 12 tested compounds that exhibited over 85% inhi-
sodium hydroxide solution for 5 h to furnish the glycosyl bition were subsequently evaluated for the IC50 value with
triazoles 6a–l in high yield (Scheme 2) [39].
tacrine and galantamine used as reference drugs. The best
compound 6f shows the IC50 value of 1.461 and inhibit AChE
with a dose-dependent relationship (Figure 1). Other com-
pounds are much less active than tacrine and galantamine.
Biological activity
The AChE-inhibition activities of compounds 6 were
evaluated in vitro by Ellman’s method [40], in which the Conclusion
AChE extracts from Electric eel were used. Their inhibi-
tory potency is defined as the inhibition rate and the half New C2-glycosyl triazole derivatives were designed, syn-
of maximal inhibitory concentration, IC50. The results are thesized and subjected to biological evaluation. The AChE
summarized in Table 1.
inhibitor activity data revealed that most of the synthesized
OBn
S
OBn
OBn
O
O
ii
O
BnO
BnO
i
BnO
BnO
BnO
BnO
OBn
OBn
Ar
OBn
NCS
NH
N
S
3
N
5
NH
HN
HN
6
O
Ar
4a,5a,6a: Ar = Ph
4g,5g,6g: Ar = 4-NO2C6H4
4h,5h,6h: Ar = 4-[(CH3)2N]C6H4
4i,5i,6i: Ar = 4-FC6H4
4j,5j,6j: Ar = 4-CIC6H4
4k,5k,6k: Ar = 4-BrC6H4
4l,5l,6l: Ar = 4-IC6H4
4b,5b,6b: Ar = 2-thienyl
4c,5c,6c: Ar = 2-FC6H4
4d,5d,6d: Ar = 2-CIC6H4
4e,5e,6e: Ar = 4-OHC6H4
4f,5f,6f: Ar = 4-CH3C6H4
Scheme 2ꢁSynthesis of products 6.
Reagents and conditions: (i) ArCONHNH2 (4a–l), acetonitrile, reflux; (ii) 3 N NaOH, reflux.
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Table 1ꢁIn vitro inhibitory activities of glycosyl triazoles against
layer chromatography (TLC) using plates and visualized with 254 nm
ultra violet (UV) light. Melting points were determined on a Yanaco
melting point apparatus and are uncorrected. Infra red (IR) spectra
were recorded on a Bruker Tensor 27 spectrometer with KBr pellets.
1H NMR spectra were recorded with a Bruker Avance spectrometer
at 500 Hz using tetramethylsilane (TMS) as an internal standard
and DMSO-d6 as a solvent. ESI-HRMS analysis was performed on an
Agilent 6500 mass spectrometer. Flash column chromatography was
performed using a silica gel 200–300 mesh.
AchE.
Compound
Ar
Inhibition
(%)a
IC50 (μg/mL)
6a
6b
6c
6d
6e
6f
6g
6h
6i
C6H5
2-C5H3S
2-FC6H4
2-ClC6H4
4-OHC6H4
4-CH3C6H4
4-NO2C6H4
94.07ꢂ ꢂ1.36
92.43ꢂ ꢂ1.05
92.11ꢂ ꢂ0.99
85.51ꢂ ꢂ0.48
79.01ꢂ ꢂ0.83
94.43ꢂ ꢂ1.60
64.41ꢂ ꢂ3.41
5.64ꢂ ꢂ0.86
4.51ꢂ ꢂ0.49
2.16ꢂ ꢂ0.20
9.14ꢂ ꢂ0.41
–
1.46ꢂ ꢂ0.25
–
Preparation of 2-amino-1,3,4,6-tetra-O-benzyl-2-deoxy-
β-D-glucopyranose hydrochloride (1)
4-4-(N,N-di-Me)-C6H4 69.39ꢂ ꢂ2.42
4-FC6H4
–
98.38ꢂ ꢂ1.05
3.41ꢂ ꢂ0.54
Sodium hydroxide (1.86 g, 46.5 mmol) was added to a solution of
D-glucosamine hydrochloride (10 g, 46.4 mmol) in water (70 mL)
at room temperature with stirring followed by dropwise addition
of p-methoxybezaldehyde (5.7 mL, 46.6 mmol) 15 min later. The
mixture was stirred at ambient temperature for an additional 24 h,
after which time the resulting white solid was filtrated and washed
with 500 mL water to afford 2-(4-methoxy benzylidene)-2-deoxy-
β-D-glucopyranose (11.4 g, 83%). A mixture of this product (6.6 g,
22.2 mmol) and BnBr (14 mL, 117.9 mmol) in DMF (50 mL) was treated
portion-wise at 0°C with NaH (60%, 5 g, 125 mmol) and then stirred at
room temperature for 12 h. After addition of a large amount of water,
the mixture was extracted with dichloromethane (3ꢀ×ꢀ50 mL). The
extract was concentrated under reduced pressure and the resultant
yellow viscous liquid was dissolved in acetone (100 mL). Treatment
of this solution with hydrochloric acid (7 mL, 5 N) and heating under
reflux for 1 h afforded a white solid of 1. The product was filtered off
and washed with acetone: yield 7.9 g, (62%).
6j
4-ClC6H4
4-BrC6H5
4-IC6H5
–
93.96ꢂ ꢂ0.86
87.23ꢂ ꢂ0.89
74.42ꢂ ꢂ1.55
14.46ꢂ ꢂ1.49
19.80ꢂ ꢂ1.84
98.46ꢂ ꢂ0.13 0.0533ꢂ ꢂ0.0008
92.17ꢂ ꢂ0.17 0.767ꢂ ꢂ0.043
1.99ꢂ ꢂ0.13
6k
9.68ꢂ ꢂ0.89
6l
–
–
–
mb
nc
–
Tacrine
Galantamine
aThe inhibition activities at the concentration of 50 μg/mL.
bm stands for D-glucosamine hydrochloride.
cn stands for 5-(4-methylphenyl)-1,2,4-triazole-3-thione.
100
90
80
70
60
50
40
30
20
10
0
Synthesis of 2-isothiocyanato-1,3,4,6-tetra-O-benzyl-2-
deoxy-β-D-glucopyranose (3)
0.005
0.05
0.5
5
50
Concentration (µg/mL)
To a solution of 1,3,4,6-tetra-O-benzyl-β-D-glucosamine hydrochlo-
ride (1,1 mmol) in acetonitrile (15 mL) was added triethylamine
(3 mmol). The mixture was cooled in an ice bath, treated dropwise
via a syringe pump with carbon disulfide (1 mmol) and stirred for
2 h. Then tosyl chloride (TsCl) (1 mmol) was added and the mixture
was stirred for an additional 0.5 h. Product 3 was crystallized from
ethanol; yield 90%, white amorphous powder; mp 55–56°C; IR: v
3433, 3030, 2873, 2078, 1454, 1359, 1313, 1068 cm−1; 1H NMR: δ 7.48–7.19
(m, 20H), 4.81 (dd, Jꢀ=ꢀ10.0 Hz and 5.0 Hz, 4H), 4.74–4.63 (m, 2H),
4.61–4.48 (m, 3H), 3.94–3.86 (m, 2H), 3.68–3.47 (m, 3H), 3.54 (t,
Figure 1ꢁDose-dependent inhibition of AChE by compound 6f.
Values are meansꢂ ꢂSD, nꢂ=ꢂ3.
compounds are active against acetyl cholinesterase
enzymes. The present study finds that it is ineffective to
remove the benzyl group by catalytic hydrogenation using
Pd/C or Pd(OH)2/C due to the poisoning of the catalyst by
the sulfur atom in the molecule. In the following work, we
will be searching for other methods to solve this problem.
+
Jꢀ=ꢀ9.0 Hz, 1H). ESI-HRMS. Calcd for C35H35NNaO5S, [Mꢀ+ꢀNa] : m/z
604.2128. Found: m/z 604.2130.
General procedure for the preparation of compounds
6a–l
Experimental
Chemistry
Glycosyl isothiocyanate 3 (0.581 g, 1 mmol) was added in one por-
tion to a stirred solution of hydrazide 4a–l (1 mmol) in MeCN (10 mL).
The mixture was heated under reflux for 3–4 h and then concentrated
All chemicals were purchased from commercial sources and used under reduced pressure to give 5a–l. Without purification, 5a–l
without further purification. All reactions were monitored by thin was added to 3 N sodium hydroxide aqueous solution (20 mL). The
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234ꢀ
2H, Ar-H), 6.83 (d, Jꢀ=ꢀ8.0 Hz, 2H, Ar-H), 6.20 (d, Jꢀ=ꢀ8.0 Hz, 1H, HGlu
-
mixture was heated under reflux for 5–6 h and then extracted with
dichloromethane (3ꢀ×ꢀ10 mL). The extract was washed with water,
dried over anhydrous sodium sulfate and concentrated. Compound
6a–l was purified by silica gel column chromatography eluting with
AcOEt/petroleum ether.
1), 5.62 (t, Jꢀ=ꢀ9.0 Hz, 1H, HGlu-3), 4.81 (d, Jꢀ=ꢀ12.5 Hz, 1H, PhCH2), 4.68
(dd, Jꢀ=ꢀ11.0, 7.5 Hz, 2H, PhCH2), 4.59–4.49 (m, 4H, PhCH2), 4.38 (d,
Jꢀ=ꢀ11.0 Hz, 1H, PhCH2), 3.95 (t, Jꢀ=ꢀ9.0 Hz, 1H, HGlu-4), 3.75–3.62 (m,
3H, HGlu-5,6,6′), 3.50 (t, Jꢀ=ꢀ9.0 Hz, 1H, HGlu-2). ESI-HRMS. Calcd for
+
C42H42N3O6S, [Mꢀ+ꢀH] : m/z 716.2789. Found: m/z 716.2785.
5-Phenyl-4-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose-
2-yl)-1,2,4-triazole-3-thione (6a)ꢁYield 88%, white solid; mp 139–
140°C; IR: v 3431 (NH), 3088 (C-H, Ph), 2927 (CH2-Ph), 1557 (C=N), 1359
5-(4-Methylphenyl)-4-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-
glucopyranose-2-yl)-1,2,4-triazole-3-thione (6f)ꢁYield 88%,
white solid; mp 136–137°C; IR: v 3439 (NH), 3089 (C-H, Ph), 2948
1
(C=S), 1048 cm−1 (C-O-C); H NMR: δ 14.08 (s, 1H), 7.57–7.44 (m, 5H,
1
(CH2-Ph), 1516 (C=N), 1360 (C=S), 1057 cm−1 (C-O-C); H NMR: δ 14.02
Ar-H), 7.36–7.24 (m, 14H, Ar-H), 7.23–7.19 (m, 2H, Ar-H), 7.18–7.12 (m,
2H, Ar-H), 7.07–7.03 (m, 2H, Ar-H), 6.21 (d, Jꢀ=ꢀ8.0 Hz, 1H, HGlu-1), 5.65
(dd, Jꢀ=ꢀ10.0 Hz and 8.0 Hz, 1H, HGlu-3), 4.82 (d, Jꢀ=ꢀ12.0 Hz, 1H, PhCH2),
4.71 (dd, Jꢀ=ꢀ11.0 Hz and 4.0 Hz, 2H, PhCH2), 4.59–4.48 (m, 4H, PhCH2),
4.41 (d, Jꢀ=ꢀ11.0 Hz, 1H, PhCH2), 3.93 (t, Jꢀ=ꢀ9.0 Hz, 1H, HGlu-4), 3.75–3.63
(m, 3H, HGlu-5,6,6), 3.50 (t, Jꢀ=ꢀ8.0 Hz, 1H, HGlu-2). ESI-HRMS. Calcd for
(s, 1H, NH), 7.39–7.32 (m, 7H, Ar-H), 7.31–7.25 (m, 11H, Ar-H), 7.24–7.20
(m, 2H, Ar-H), 7.17–7.12 (m, 2H, Ar-H), 7.07–7.02 (m, 2H, Ar-H), 6.20 (d,
Jꢀ=ꢀ8.0 Hz, 1H, HGlu-1 ), 5.63 (t, Jꢀ=ꢀ8.5 Hz, 1H, HGlu-3), 4.82 (d, Jꢀ=ꢀ12.0 Hz,
1H, PhCH2), 4.71 (d, Jꢀ=ꢀ11.0 Hz, 2H, PhCH2), 4.58–4.48 (m, 4H, PhCH2),
4.40 (d, Jꢀ=ꢀ11.0 Hz, 1H, PhCH2), 3.92 (t, Jꢀ=ꢀ8.5 Hz, 1H, HGlu-4), 3.75–3.63
(m, 3H, HGlu-5,6,6′), 3.49 (t, Jꢀ=ꢀ8.0 Hz, 1H, HGlu-2), 3.30 (s, 3H, CH3).
+
C42H42N3O5S, [Mꢀ+ꢀH] : m/z 700.2840. Found: m/z 700.2832.
+
ESI-HRMS. Calcd for C43H44N3O5S, [Mꢀ+ꢀH] : m/z 714.2996. Found: m/z
5-(2-Thienyl)-4-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-gluco-
pyranose-2-yl)-1,2,4-triazole-3-thione (6b)ꢁYield 93%, pale yellow
solid; mp 145–146°C; IR: v 3447 (NH), 3073 (C-H, Ph), 2929 (CH2-Ph),
1582 (C=N), 1359 (C=S), 1076 cm−1 (C-O-C); 1H NMR: δ 14.13 (s, 1H, -NH),
7.86 (d, Jꢀ=ꢀ5.0 Hz, 1H, thiophene), 7.46 (d, Jꢀ=ꢀ5.0 Hz, 1H, thiophene),
7.39–7.31 (m, 7H, Ar-H), 7.30–7.20 (m, 10 H, Ar-H), 7.15–7.10 (m, 2H,
Ar-H, thiophene ), 7.02 (s, 2H, Ar-H), 6.18 (d, Jꢀ=ꢀ8.5 Hz, 1H, HGlu-1), 5.59
(t, Jꢀ=ꢀ9.0 Hz, 1H, HGlu-3), 4.82 (d, Jꢀ=ꢀ12.0 Hz, 1H, PhCH2), 4.74–4.68 (m,
2H, PhCH2), 4.60–4.51 (m, 4H, PhCH2), 4.39 (d, Jꢀ=ꢀ11.5 Hz, 1H, PhCH2),
4.15 (t, Jꢀ=ꢀ9.0 Hz, 1H, HGlu-4 ), 3.77–3.64 (m, 4H, HGlu-5,6,6′), 3.58 (t,
714.2999.
5-(4-Nitrophenyl)-4-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-
glucopyranose-2-yl)-1,2,4-triazole-3-thione (6g)ꢁYield 79%,
yellow solid; mp 103–104°C; IR: v 3424 (NH), 3090 (C-H, Ph), 2924
1
(CH2-Ph), 1559 (C=N), 1347 (C=S), 1057 cm−1 (C-O-C); H NMR: δ 14.28
(s, 1H, -NH), 8.41–8.31 (m, 2H, Ar-H), 7.82–7.69 (m, 2H, Ar-H), 7.44–6.99
(m, 20H, Ar-H), 6.19 (t, Jꢀ=ꢀ8.0 Hz, 1H, HGlu-1), 5.63 (t, Jꢀ=ꢀ8.5 Hz, 1H,
HGlu-3), 4.81 (t, Jꢀ=ꢀ11.0 Hz, 1H, PhCH2), 4.77–4.67 (m, 2H, PhCH2), 4.60–
4.48 (m, 4H, PhCH2), 4.41 (t, Jꢀ=ꢀ10.0 Hz, 1H, PhCH2), 3.89 (t, Jꢀ=ꢀ8.5 Hz,
1H, HGlu-4), 3.75–3.63 (m, 3H, HGlu-5,6,6), 3.56 (t, Jꢀ=ꢀ8.5 Hz, 1H, HGlu-2).
+
Jꢀ=ꢀ9.0 Hz, 1H, HGlu-2). ESI-HRMS. Calcd for C40H40N3O5S2, [Mꢀ+ꢀH] : m/z
+
706.2406. Found: m/z 706.2405.
ESI-HRMS. Calcd for C42H41N4O7S, [Mꢀ+ꢀH] : m/z 745.2690. Found: m/z
745.2694.
5-(2-Fluorophenyl)-4-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-
glucopyranose-2-yl)-1,2,4-triazole-3-thione (6c)ꢁYield 91%,
white solid; mp 112–113°C; IR: v 3433 (NH), 3089 (C-H, Ph), 2925 (CH2-
Ph), 1560 (C=N), 1359 (C=S), 1059 cm−1 (C-O-C); 1H NMR: δ 14.25 (s, 1H,
-NH), 7.68–7.60 (m, 1H, Ar-H), 7.42 (t, Jꢀ=ꢀ9.0 Hz, 1H, Ar-H), 7.38–7.25 (m,
16H, Ar-H), 7.20 (d, Jꢀ=ꢀ7.0 Hz, 2H, Ar-H), 7.15 (d, Jꢀ=ꢀ7.0 Hz, 2H, Ar-H),
7.10 (d, Jꢀ=ꢀ4.5 Hz, 2H, Ar-H), 6.12 (d, Jꢀ=ꢀ8.0 Hz, 1H, HGlu-1), 5.61 (t,
Jꢀ=ꢀ9.0 Hz, 1H, HGlu-3), 4.80 (d, Jꢀ=ꢀ12.5 Hz, 1H, PhCH2), 4.73–4.65 (m, 2H,
PhCH2), 4.58–4.43 (m, 5H, PhCH2), 3.73–3.58 (m, 4H, HGlu-4,5,6,6′), 3.47
5-(4-N,N-Dimethylphenyl)-4-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-
D-glucopyranose-2-yl)-1,2,4-triazole-3-thione (6h)ꢁYield 81%,
pale yellow solid; mp 131–132°C; IR: v 3423 (NH), 3087 (C-H, Ph), 2868
1
(CH2-Ph), 1614 (C=N), 1362 (C=S), 1058 cm−1 (C-O-C); H NMR: δ 13.87
(s, 1H), 7.37–7.25 (m, 16H, Ar-H), 7.25–7.21 (m, 2H, Ar-H), 7.17–7.13 (m,
2H, Ar-H), 7.06–7.02 (m, 2H, Ar-H), 6.75 (d, Jꢀ=ꢀ9.0 Hz, 2H, Ar-H), 6.22
(d, Jꢀ=ꢀ8.0 Hz, 1H, HGlu-1), 5.64 (dd, Jꢀ=ꢀ10.5 Hz and 8.0 Hz, 1H, HGlu-3),
4.83 (d, Jꢀ=ꢀ12.5 Hz, 1H, PhCH2), 4.69 (t, Jꢀ=ꢀ10.0 Hz, 2H, PhCH2), 4.59–
4.49 (m, 4H, PhCH2), 4.40 (d, Jꢀ=ꢀ11.0 Hz, 1H, PhCH2), 4.03 (dd, Jꢀ=ꢀ10.5,
8.5 Hz, 1H, HGlu-4), 3.75–3.63 (m, 3H, HGlu-5,6,6′), 3.49 (t, Jꢀ=ꢀ8.0 Hz,
1H, HGlu-2), 2.95 (s, 6H, -CH3). ESI-HRMS. Calcd for C44H45N4NaO5S,
+
(t, Jꢀ=ꢀ9.0 Hz, 1H, HGlu-2). ESI-HRMS. Calcd for C42H41FN3O5S, [Mꢀ+ꢀH] :
m/z 718.2745. Found: m/z 718.2744.
+
[Mꢀ+ꢀNa] : m/z 765.3081. Found: m/z 765.3072.
5-(2-Chlorophenyl)-4-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-
glucopyranose-2-yl)-1,2,4-triazole-3-thione (6d)ꢁYield 84%,
white solid; mp 106–107°C; IR: v 3421 (NH), 3063 (C-H, Ph), 2926 (CH2-
Ph), 1604 (C=N), 1361 (C=S), 1061 cm−1 (C-O-C); 1H NMR: δ 14.18 (s, 1H,
-NH), 7.62–7.34 (m, 3H, Ar-H), 7.33–7.24 (m, 15H, Ar-H), 7.23–7.16 (m,
4H, Ar-H), 7.15–7.13 (m, 2H, Ar-H), 6.11 (d, Jꢀ=ꢀ8.0 Hz, 1H, HGlu-1), 5.63
(t, Jꢀ=ꢀ9.0 Hz, 1H, HGlu-3), 4.88–4.73 (m, 2H, PhCH2), 4.71–4.61 (m, 1H,
PhCH2), 4.56–4.45 (m, 5H, PhCH2), 3.69 (t, Jꢀ=ꢀ9.0 Hz, 1H, HGlu-4), 3.68–
3.47 (m, 3H, HGlu-5,6,6′), 3.45 (t, Jꢀ=ꢀ9.0 Hz, 1H, HGlu-2). ESI-HRMS. Calcd
5-(4-Fluorophenyl)-4-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-
glucopyranose-2-yl)-1,2,4-triazole-3-thione (6i)ꢁYield 87%, white
solid; mp 127–128°C; IR: v 3429 (NH), 3063 (C-H, Ph), 2869 (CH2-Ph),
1611 (C=N), 1361 (C=S), 1058 cm−1 (C-O-C); 1H NMR: δ 14.25 (s, 1H, -NH),
7.68–7.60 (m, 1H, Ar-H), 7.42–7.25 (m, 17H, Ar-H), 7.20–7.10 (m, 6H,
Ar-H), 6.12 (d, Jꢀ=ꢀ8.0 Hz, 1H, HGlu-1), 5.61 (dd, Jꢀ=ꢀ10.0, 8.5 Hz, 1H, HGlu
-
3), 4.80 (d, Jꢀ=ꢀ12.0 Hz, 1H, PhCH2), 4.73–4.65 (m, 2H, PhCH2), 4.58–
+
4.43 (m, 5H, PhCH2), 3.75–3.58 (m, 4H, HGlu-4,5,6,6′), 3.47 (t, Jꢀ=ꢀ8.0 Hz,
for C42H40ClN3NaO5S, [Mꢀ+ꢀNa] : m/z 756.2269. Found: m/z 756.2265.
+
1H, HGlu-2). ESI-HRMS. Calcd for C42H41FN3O5S, [Mꢀ+ꢀH] : m/z 718.2745.
5-(4-Hydroxyphenyl)-4-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-
glucopyranose-2-yl)-1,2,4-triazole-3-thione (6e)ꢁYield 82%,
white solid; mp 96–97°C; IR: v 3418 (NH), 3201 (O-H), 3062 (C-H, Ph),
Found: m/z 718.2748.
5-(4-Chlorophenyl)-4-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-
glucopyranose-2-yl)-1,2,4-triazole-3-thione (6j)ꢁYield 85%, white
solid; mp 123–124°C. IR: v 3446 (NH), 3088 (C-H, Ph), 2941 (CH2-Ph),
1606 (C=N), 1361 (C=S), 1057 cm−1 (C-O-C); 1H NMR: δ 14.12 (s, 1H, -NH),
1
2924 (CH2-Ph), 1513 (C=N), 1386 (C=S), 1053 cm−1 (C-O-C); H NMR: δ
13.92 (s, 1H, -NH), 10.07 (s, 1H, OH), 7.38–7.24 (m, 16H, Ar-H), 7.21 (d,
Jꢀ=ꢀ7.0 Hz, 2H, Ar-H), 7.14 (d, Jꢀ=ꢀ7.0 Hz, 2H, Ar-H), 7.03 (d, Jꢀ=ꢀ7.0 Hz,
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7.53–7.48 (m, 2H, Ar-H), 7.38–7.26 (m, 16H, Ar-H), 7.25–7.21 (m, 2H,
Ar-H), 7.17–7.12 (m, 2H, Ar-H), 7.07–7.03 (m, 2H, Ar-H), 6.19 (d, Jꢀ=ꢀ8.0 Hz,
1H, HGlu-1), 5.63 (dd, Jꢀ=ꢀ10.0, 8.0 Hz, 1H, HGlu-3), 4.82 (d, Jꢀ=ꢀ12.5 Hz, 1H,
PhCH2), 4.71 (dd, Jꢀ=ꢀ11.0 Hz and 5.0 Hz, 2H, PhCH2), 4.60–4.48 (m,
4H, PhCH2), 4.40 (d, 1H, Jꢀ=ꢀ11.0 Hz, PhCH2), 3.87 (dd, Jꢀ=ꢀ10.5, 8.0 Hz,
Acknowledgments: This work was supported by the Pri-
ority Academic Development Program of Jiangsu Higher
Education Institutions, Natural Science Foundation of
Jiangsu Province (BK20151281), Open-end Funds of Jiangsu
Key Laboratory of Marine Biotechnology (HS2014007), the
1H, HGlu-4), 3.75–3.63 (m, 3H, HGlu-5,6,6), 3.52 (t, Jꢀ=ꢀ8.0 Hz, 1H, HGlu-2).
+
ESI-HRMS. Calcd for C42H41ClN3O5S, [Mꢀ+ꢀH] : m/z 734.2450. Found: Science and Technology Project of Lianyungang (CG1415)
m/z 734.2447.
and Public Science and Technology Research Funds Pro-
jects of Ocean (201505023).
5-(4-Bromophenyl)-4-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-
glucopyranose-2-yl)-1,2,4-triazole-3-thione (6k)ꢁYield 90%,
white solid; mp 132–133°C. IR: v 3427 (NH), 3086 (C-H, Ph), 2941 (CH2-
Ph), 1602 (C=N), 1357 (C=S), 1058 cm−1 (C-O-C); 1H NMR: δ 14.17 (s, 1H,
References
NH), 7.75 (d, Jꢀ=ꢀ7.0 Hz, 2H, Ar-H), 7.40–7.24 (m, 18H, Ar-H), 7.16–6.95
(m, 4H, Ar-H), 6.19 (d, Jꢀ=ꢀ7.0 Hz, 1H, HGlu-1), 5.62 (t, Jꢀ=ꢀ8.5 Hz, 1H, HGlu
-
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3), 4.82 (d, Jꢀ=ꢀ11.5 Hz, 1H, PhCH2), 4.76–4.64 (m, 2H, PhCH2), 4.57–4.47
(m, 4H, PhCH2), 4.40 (d, Jꢀ=ꢀ10.5 Hz, 1H, PhCH2), 3.88 (t, Jꢀ=ꢀ8.0 Hz,
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2). ESI-HRMS. Calcd for C42H41BrN3O5S, [Mꢀ+ꢀH] : m/z 778.1945. Found:
m/z 778.1942.
5-(4-Iodophenyl)-4-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-
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1
(CH2-Ph), 1600 (C=N), 1360 (C=S), 1027 cm−1 cm−1 (C-O-C); H NMR:
δ 14.12 (s, 1H, NH), 7.90 (d, Jꢀ=ꢀ7.5 Hz, 2H, Ar-H), 7.40–7.21 (m, 18H,
Ar-H), 7.14 (d, Jꢀ=ꢀ7.5 Hz, 2H, Ar-H), 7.04 (d, Jꢀ=ꢀ7.0 Hz, 2H, Ar-H),
6.19 (d, Jꢀ=ꢀ8.0 Hz, 1H, HGlu-1), 5.61 (t, Jꢀ=ꢀ8.5 Hz, 1H, HGlu-3), 4.81 (d,
Jꢀ=ꢀ12.5 Hz, 1H, PhCH2), 4.70 (d, Jꢀ=ꢀ11.0 Hz, 2H, PhCH2), 4.60–4.47 (m,
4H, PhCH2), 4.39 (d, Jꢀ=ꢀ11.0 Hz, 1H, PhCH2), 3.88 (t, Jꢀ=ꢀ9.0 Hz, 1H,
HGlu-4), 3.75–3.60 (m, 3H, HGlu-5,6,6), 3.54 (t, Jꢀ=ꢀ8.5 Hz, 1H, HGlu-2). ESI-
+
HRMS. Calcd for C42H4IN3NaO5S, [Mꢀ+ꢀNa] : m/z 848.1626. Found: m/z
848.1621.
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236ꢀ
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