Synthesis and AChE inhibitory activity of N-glycosyl benzofuran derivatives

Article abstract of DOI:10.1515/hc-2019-0021

Six N-glycosyl benzofuran derivatives were synthesized by the catalysis of organic bases and condensation agents. The benzofuran derivatives were obtained by the reaction of various salicylaldehydes in acetone, and then hydrolyzed to the corresponding carboxylic acids. Finally, the target compounds were synthesized by acylation and the reaction conditions were optimized. The acetylcholinesterase (AChE) inhibitory activity of the desired compounds was tested using Ellman's method. Most of the compounds showed acetylcholinesterase-inhibition activity; N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)benzofuran-2-carbxamide (5a) showed the best acetylcholinesterase inhibition, with an inhibitory rate of 84%.

Full text of DOI:10.1515/hc-2019-0021

Heterocycl. Commun. 2019; 25: 162–166
Research Article
Open Access
Yu-Ran Wu, Shu-Ting Ren, Lei Wang, Xiu-Jian Liu, You-Xian Wang,
SShyu-nHatohLieu,sWiesi-WaeinLiud*, ADaC-HhuaEShiinanhd Zihbi-iLitnog Crayo activity
of N-glycosyl benzofuran derivatives
https://doi.org/10.1515/hc-2019-0021
Received January 22, 2019; accepted April 25, 2019.
anti-tumor, anti-fungal, anti-senile dementia and anti-
inflammatory activity and thus provide important hetero-
Abstract: Six N-glycosyl benzofuran derivatives were syn- cyclic active molecule for the development of new drugs
thesized by the catalysis of organic bases and condensa- [1-4]. The main clinical drugs containing a benzofuran
tion agents. The benzofuran derivatives were obtained by skeleton are the anti-arrhythmic amiodarone (I), the anti-
the reaction of various salicylaldehydes in acetone, and hypertensive bufuralol (II) and the anti-fungal griseoful-
then hydrolyzed to the corresponding carboxylic acids. vin (III) [5,6], whose structures are shown in Figure 1. Some
Finally, the target compounds were synthesized by acyla- studies have shown that many compounds containing a
tion and the reaction conditions were optimized. The ace- benzofuran skeleton can be used as monoamine oxidase
tylcholinesterase (AChE) inhibitory activity of the desired inhibitors, potent acetylcholinesterase (AChE) inhibitors
compounds was tested using Ellman’s method. Most of or potent Multitarget-Directed Ligands in the treatment of
the compounds showed acetylcholinesterase-inhibition Alzheimer’s disease [7-10].
activity; N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-
D-glucosamine is an important natural monosac-
2H-pyran-3-yl)benzofuran-2-carbxamide (5a) showed the charide with many kinds of biological activity, such as
best acetylcholinesterase inhibition, with an inhibitory anti-inflammatory, anti-cancer and anti-bacterial [11-13].
rate of 84%.
The synthesis of glucosamine derivatives has recently
become of interest with respect to increasing their biologi-
Keywords: D-glucosamine; amide; anti-acetylcholinesterase. cal activity, as many studies have shown that glucosamine
derivatives have strong biological properties, including
anti-oxidant and anti-AChE [14-17].
Due to the excessive lipid-water partition coefficient
and poor water solubility of benzofuran, it cannot easily
Introduction
Benzofurans are an important family of oxygen-containing reach the anticipated site of action of the drug. Glucosa-
heterocycles. Natural benzofuran compounds have mine is an active molecule with multi-hydroxyl groups and
has strong water solubility. Therefore, unprotected glucosa-
mine was linked to benzofuran via an amide bond in order
to increase the water solubility of the coumarin molecule
* Corresponding author: Wei-Wei Liu, College of Pharmaceutical
and improve its bioavailability and activity. The synthe-
Sciences, Huaihai Institute of Technology, Lianyungang 222005,
sized derivatives were tested for AChE inhibitory activity
by Ellman’s method, and glycosylated heterocyclic com-
pounds with better AChE-inhibitory activity were identified.
P. R. China; Jiangsu Institute of Marine Resources, Lianyungang
222005, P. R. China; Jiangsu Key Laboratory of Marine
Pharmaceutical Compound Screening, Huaihai Institute of
Technology, Lianyungang 222005, P. R. China; Co-Innovation Center
of Jiangsu Marine Bio-industry Technology, Lianyungang 222005,
P. R. China,e-mail: liuweiwei255@163.com
Yu-Ran Wu, Shu-Ting Ren, Lei Wang, Xiu-Jian Liu, You-Xian Wang
and Shu-Hao Liu, College of Pharmaceutical Sciences, Huaihai
Institute of Technology, Lianyungang 222005, P. R. China
Da-Hua Shi and Zhi-Ling Cao, College of Pharmaceutical Sciences,
Huaihai Institute of Technology, Lianyungang 222005, P. R. China;
Jiangsu Institute of Marine Resources, Lianyungang 222005,
P. R. China
Results and Discussion
Chemistry
In our experiment, ethyl benzofuran-2carboxylate 1 was
synthesized from substituted salicylaldehyde in acetone
Open Access. © 2019 Yu-Ran Wu et al., published by De Gruyter.ꢀ
Attribution alone 4.0 License.
ꢀThis work is licensed under the Creative Commons
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Y.-R. Wu et al.: Synthesis and AChE inhibitory activity of N-glycosyl benzofuran derivativesꢁ
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solution catalyzed by potassium carbonate, and hydro-
As shown in Table 2, the inhibitory activity of all the
lyzed to benzofuran-2-carboxylic acid 3. Then, under the compounds to AChE is higher than that of the precursor
catalysis of N,N-diisopropylethylamine and HATU, 3 and compound, D-glucosamine hydrochloride m, and the
glucosamine 4 were reacted in acetonitrile solution to inhibitory rate of the optimum compound 5a is 84%,
produce N-glycosyl benzofuran derivatives 5a–5f in high indicating that the presence of benzofurans enhances the
yield (Scheme 1).
inhibitory activity.
In the second stage, coumarilic acid 3a and the con-
densation agent HATU were used as representatives to
select the best reaction conditions. Table 1 summarizes Conclusion
the molar ratio, solvent, temperature and duration of the
various reactions.
Six N-glycosyl benzofuran derivatives were designed
and synthesized by a green, efficient and convenient
method. Optimum reaction conditions were identi-
fied and all yields were above 60%. The compounds
were determined by NMR, IR and HRMS. Most of the
Biological activity
The AChE inhibition activity of the newly synthesized com- compounds demonstrated acetylcholinesterase inhi-
pounds was evaluated in vitro by Ellman’s method, using bition activity and compound 5a showed the best
AChE extracts from Electric eel [18,19]. Table 2 summarizes acetylcholinesterase inhibition with an inhibition rate
the compounds’ inhibitory potency (‘inhibition rate’).
of 84%.
Figure 1ꢁDrugs containing a benzofuran skeleton.
Scheme 1ꢂSynthetic pathways of the N-glycosyl benzofuran derivatives.
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Y.-R. Wu et al.: Synthesis and AChE inhibitory activity of N-glycosyl benzofuran derivatives
Table 1ꢂOptimizing the conditions for the synthesis of 5a
and stirred sufficiently. Ethyl chloroacetate (20 mmol)
was added to the solution and the reaction mixture was
stirred under reflux for 8 h. After removing the solvent,
adding H2O and extracting with ethyl acetate, product 1
was obtained, yield 70%.
Entry
n(3a) :
HATU
Time
(min)
Temp.
(°C)
Solvent
Yield
(%)
1
1:1.0
1:1.2
1:1.3
1:1.4
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
50
50
50
50
50
50
50
50
50
50
50
20
40
50
60
30
30
30
30
20
30
40
30
30
30
30
30
30
30
30
ACN
ACN
ACN
ACN
ACN
ACN
ACN
DCM
MeOH
EtOH
ACN
ACN
ACN
ACN
ACN
56
77
85
85
66
85
85
NR
38
46
85
32
73
85
85
2
3
4
General procedure for synthesis
of benzofuran-2-carboxylic acid (3)
5
6
7
8
A sodium hydroxide (4 mmol) water (10 mL) solution was
added to 20 mL ethanol containing 1 (3 mmol). After drop-
ping, the reaction liquid was heated to 40°C and stirred
for 1 h. After the reaction, the pH was adjusted to 1 by
5 mol/L HCl and the precipitate was filtered, washed with
H2O and ice ethanol, and dried. Product 3 was obtained,
yield 90%.
9
10
11
12
13
14
15
Table 2ꢂIn vitro inhibitory activity of target compounds against AChE.
Synthesis of Glucosamine (4)
Compound
Inhibition rate (%)a
Glucosamine hydrochloride (2 mmol) and N,N-
diisopropylethylamine (2 mmol) were added to a 50 ml
flask and stirred for 3 h to obtain compound 4, yield 99%.
5a
5b
5c
5d
5e
5f
84
53
65
77
58
64
General procedure for Synthesis of 5a–5f
mb
1.79
a Inhibitory activity at a concentration of 1mg/mL.
3 (2 mmol) was added to 15 ml Na2SO4 dried acetonitrile,
and N,N-diisopropylethylamine (4 mmol) was added after
stirring and dissolving. HATU (2.6 mmol) was dissolved in
5 ml acetonitrile and slowly dripped. When the solution
turned yellow, 4 (2.6 mmol) was added. The reaction was
complete after 50 minutes’ continuous stirring at 30°C.
The mixture was filtered and washed with acetonitrile to
b
m stands for D-glucosamine hydrochloride.
Experimental
Chemistry
All chemicals were purchased from commercial sources give 5a–5f.
and used without further purification unless otherwise
stated. Melting points were determined on a Yanaco
melting point apparatus and were uncorrected. IR spectra N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-
pyran-3-yl)benzofuran-2-carboxamide (5a)
were recorded on a Bruker Tensor 27 spectrometer with
1
KBr pellets. H NMR spectra were recorded on a Bruker
Avance 500 MHz at ambient temperature using DMSO-d6 Yield 85%; mp 212–214°C; IR (cm−1): 3401, 3065, 2360,
1
as solvent and TMS as an internal standard. Chemical 1593, 1447, 1215, 795; H NMR: 7.97 (d, J = 8.5 Hz, 1H,
shifts were reported in ppm. HRMS (ESI) analysis was NH), 7.79 (d, J = 7.5 Hz, 1H, ArH), 7.71 (d, J = 8.5 Hz, 1H,
performed on an Agilent 6230 mass spectrometer.
ArH), 7.64 (s, J = 8.5 Hz, 1H, ArH), 7.51 (m, 1H, ArH), 7.36
(t, J = 10.0 Hz, 1H, ArH), 6.61 (d, J = 4.0 Hz, 1H, HGlu), 5.10
(t, J = 4.0 Hz, 1H, HGlu), 5.02 (d, J = 5.5 Hz, 1H, HGlu), 4.85
(d, J = 6.0 Hz, 1H, HGlu), 3.84–3.80 (m, 1H, HGlu), 3.75–3.71
(m, 1H, OH), 3.67–3.64 (m, 2H, OH), 3.55–3.50 (m, 1H,
General procedure for synthesis of ethyl
benzofuran-2carboxylate (1)
Potassium carbonate, anhydrous (10 mmol) was added to OH), 3.23–3.17 (m, 1H, HGlu); ESI-HRMS (m/z): calcd for
an acetone solution of various salicylaldehydes (8 mmol) C15H17NO8Na+ [M+Na]+: 346.0896; Found: 346.0907.
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Y.-R. Wu et al.: Synthesis and AChE inhibitory activity of N-glycosyl benzofuran derivativesꢁ
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5-Methyl-N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahy-
dro-2H-pyran-3-yl)benzofuran-2-carboxamide (5b)
HGlu), 3.68−3.63 (m, 2H, OH) 3.54−3.50 (m, 1H, OH), 3.46–
3.42 (m, 1H, OH), 3.22−3.18 (m, 1H, HGlu); ESI-HRMS (m/z):
calcd for C16H19NO8Na+ [M+Na]+: 376.1003; Found: 376.1015.
Yield 77%; mp 189–190°C; IR (cm−1): 3403, 3060, 2345,
1588, 1437, 1201, 792; 1H NMR: 7.92 (d, J = 8.0 Hz, 1H, NH),
7.56 (m, 2H, ArH), 7.30 (d, J = 8.5 Hz, 1H, ArH), 7.17 (d, 5-Fluoro-N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-
J = 4.0 Hz, 1H, ArH), 6.61 (d, J = 4.0 Hz, 1H, HGlu), 5.09 (t,
J = 3.5 Hz, 1H, HGlu), 5.02 (d, J = 5.5 Hz, 1H, HGlu), 4.85 (d,
2H-pyran-3-yl)benzofuran-2-carboxamide (5f)
J = 5.5 Hz, 1H, HGlu), 3.84−3.80 (m, 1H, HGlu), 3.75−3.71 (m, Yield 76%; mp 132–133°C; IR (cm−1): 3421, 3009, 2401, 1573,
1H, OH) 3.67−3.64 (m, 2H, OH), 3.53–3.49 (m, 1H, OH), 1438, 1213, 791; 1H NMR : 8.06 (d, J = 8.0 Hz, 1H, NH), 7.63
3.22−3.16 (m, 1H, HGlu), 2.42 (s, 3H, C-H); ESI-HRMS (m/z): (s, 1H, ArH), 7.61 (d, J = 8.0 Hz, 1H, ArH), 7.21 (s, 1H, ArH),
calcd for C16H20NO7+ [M + H]+: 338.1234; Found: 338.1244.
7.10 (m, 1H, ArH), 6.61 (d, J = 4.0 Hz, 1H, HGlu), 5.09 (t, J =
4.0 Hz, 1H, HGlu), 5.02 (d, J = 5.5 Hz, 1H, HGlu), 4.85 (d, J = 6.0
Hz, 1H, HGlu), 3.85−3.81 (m, 1H, HGlu), 3.74−3.70 (m, 1H, OH),
3.65−3.62 (m, 2H, OH), 3.53–3.46 (m, 1H, OH), 3.24−3.18
(m, 1H, HGlu); ESI-HRMS (m/z): calcd for C15H16FNO8Na+
[M+Na]+: 364.0803; Found: 364.0811.
7-Methoxy-N-(2,4,5-trihydroxy-6-(hydroxymethyl)
tetrahydro-2H-pyran-3-yl)benzofuran-2-carboxamide (5c)
Yield 64%; mp 265–266°C; IR (cm−1): 3412, 3050, 2344,
1
1583, 1424, 1254, 780; H NMR: 8.07 (d, J = 6.5 Hz, 1H,
Acknowledgments: This work was supported by the Post-
graduate Research and Practice Innovation Program of
Jiangsu Province (KYCX18-2580, KYCX19-2277, KYCX19-
2281), Open-end Funds of Jiangsu Key Laboratory of
Marine Biotechnology (HS2014007), Project 521 Funded
by Lianyungang (LYG52105-2018023), A Project Funded
by the Priority Academic Program Development of
Jiangsu Higher Education Institutions (PAPD) and Public
Science and Technology Research Funds Projects of Ocean
(201505023).
NH), 7.20 (s, 1H, ArH), 7.12 (m, 2H, ArH), 6.94 (d, J = 8.5
Hz, 1H, ArH), 6.56 (d, J = 4.0 Hz, 1H, HGlu), 5.09 (t, J = 3.5
Hz, 1H, HGlu), 5.02 (d, J = 5.5 Hz, 1H, HGlu), 4.85 (d, J = 5.5
Hz, 1H, HGlu), 3.94 (s, 3H, −OCH3) 3.84−3.80 (m, 1H, HGlu),
3.75−3.71 (m, 1H, OH) 3.67−3.64 (m, 2H, OH), 3.53–3.49 (m,
1H, OH), 3.22−3.16 (m, 1H, HGlu); ESI-HRMS (m/z): calcd for
C16H19NO8Na+ [M+Na]+: 376.1003; Found: 376.1009.
6-Methoxy-N-(2,4,5-trihydroxy-6-(hydroxymethyl)
tetrahydro-2H-pyran-3-yl)benzofuran-2-carboxamide (5d)
Yield 68%; mp 168–169°C; IR (cm−1): 3377, 3010, 2340, 1606,
1437, 1197, 812; 1H NMR: 8.30 (d, J = 9.0 Hz, 1H, NH), 7.73 (d,
J = 8.5 Hz, 1H, ArH), 7.56 (s, 1H, ArH), 7.27 (d, J = 1.5 Hz, 1H,
ArH), 6.98 (m, 1H, ArH), 6.61 (d, J = 6.0 Hz, 1H, HGlu), 5.09
(t, J = 4.0 Hz, 1H, HGlu), 5.07 (d, J = 5.5 Hz, 1H, HGlu), 4.85 (d,
J = 5.5 Hz, 1H, HGlu), 3.84 (s, 3H, −OCH3) 3.83−3.80 (m, 1H,
HGlu), 3.75−3.71 (m, 1H, OH) 3.67−3.64 (m, 2H, OH), 3.53–3.49
(m, 1H, OH), 3.22−3.16 (m, 1H, HGlu); ESI-HRMS (m/z): calcd
for C16H19NO8Na+ [M+Na]+: 376.1003; Found: 376.1015.
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