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Synthesis and AChE inhibitory activity of N-glycosyl benzofuran derivatives

  • Yu-Ran Wu , Shu-Ting Ren , Lei Wang , Xiu-Jian Liu , You-Xian Wang , Shu-Hao Liu , Wei-Wei Liu EMAIL logo , Da-Hua Shi and Zhi-Ling Cao
Published/Copyright: December 31, 2019
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 25 Issue 1

Abstract

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%.

Keywords: D-glucosamine; amide; anti-acetylcholinesterase

Introduction

Benzofurans are an important family of oxygen-containing heterocycles. Natural benzofuran compounds have anti-tumor, anti-fungal, anti-senile dementia and anti-inflammatory activity and thus provide important heterocyclic active molecule for the development of new drugs [1, 2, 3, 4]. The main clinical drugs containing a benzofuran skeleton are the anti-arrhythmic amiodarone (I), the anti-hypertensive bufuralol (II) and the anti-fungal griseofulvin (III) [5,6], whose structures are shown in Figure 1. Some studies have shown that many compounds containing a benzofuran skeleton can be used as monoamine oxidase inhibitors, potent acetylcholinesterase (AChE) inhibitors or potent Multitarget-Directed Ligands in the treatment of Alzheimer’s disease [7, 8, 9, 10].

Figure 1 Drugs containing a benzofuran skeleton.
Figure 1

Drugs containing a benzofuran skeleton.

D-glucosamine is an important natural monosaccharide with many kinds of biological activity, such as anti-inflammatory, anti-cancer and anti-bacterial [11, 12, 13]. The synthesis of glucosamine derivatives has recently become of interest with respect to increasing their biological activity, as many studies have shown that glucosamine derivatives have strong biological properties, including anti-oxidant and anti-AChE [14, 15, 16, 17].

Due to the excessive lipid-water partition coefficient and poor water solubility of benzofuran, it cannot easily reach the anticipated site of action of the drug. Glucosamine is an active molecule with multi-hydroxyl groups and has strong water solubility. Therefore, unprotected glucosamine was linked to benzofuran via an amide bond in order to increase the water solubility of the coumarin molecule and improve its bioavailability and activity. The synthesized derivatives were tested for AChE inhibitory activity by Ellman’s method, and glycosylated heterocyclic compounds with better AChE-inhibitory activity were identified.

Results and Discussion

Chemistry

In our experiment, ethyl benzofuran-2carboxylate 1 was synthesized from substituted salicylaldehyde in acetone solution catalyzed by potassium carbonate, and hydrolyzed to benzofuran-2-carboxylic acid 3. Then, under the catalysis of N,N-diisopropylethylamine and HATU, 3 and glucosamine 4 were reacted in acetonitrile solution to produce N-glycosyl benzofuran derivatives 5a–5f in high yield (Scheme 1).

Scheme 1 Synthetic pathways of the N-glycosyl benzofuran derivatives.
Scheme 1

Synthetic pathways of the N-glycosyl benzofuran derivatives.

In the second stage, coumarilic acid 3a and the condensation agent HATU were used as representatives to select the best reaction conditions. Table 1 summarizes the molar ratio, solvent, temperature and duration of the various reactions.

Table 1

Optimizing the conditions for the synthesis of 5a

Entryn(3a) : HATUTime (min)Temp. (°C)SolventYield (%)
11:1.05030ACN56
21:1.25030ACN77
31:1.35030ACN85
41:1.45030ACN85
51:1.35020ACN66
61:1.35030ACN85
71:1.35040ACN85
81:1.35030DCMNR
91:1.35030MeOH38
101:1.35030EtOH46
111:1.35030ACN85
121:1.32030ACN32
131:1.34030ACN73
141:1.35030ACN85
151:1.36030ACN85

Biological activity

The AChE inhibition activity of the newly synthesized compounds was evaluated in vitro by Ellman’s method, using AChE extracts from Electric eel [18,19]. Table 2 summarizes the compounds’ inhibitory potency (‘inhibition rate’).

Table 2

In vitro inhibitory activity of target compounds against AChE.

CompoundInhibition rate (%)a
5a84
5b53
5c65
5d77
5e58
5f64
mb1.79

  1. a Inhibitory activity at a concentration of 1mg/mL.

    bm stands for D-glucosamine hydrochloride.

As shown in Table 2, the inhibitory activity of all the compounds to AChE is higher than that of the precursor compound, D-glucosamine hydrochloride m, and the inhibitory rate of the optimum compound 5a is 84%, indicating that the presence of benzofurans enhances the inhibitory activity.

Conclusion

Six N-glycosyl benzofuran derivatives were designed and synthesized by a green, efficient and convenient method. Optimum reaction conditions were identified and all yields were above 60%. The compounds were determined by NMR, IR and HRMS. Most of the compounds demonstrated acetylcholinesterase inhibition activity and compound 5a showed the best acetylcholinesterase inhibition with an inhibition rate of 84%.

Experimental

Chemistry

All chemicals were purchased from commercial sources and used without further purification unless otherwise stated. Melting points were determined on a Yanaco melting point apparatus and were uncorrected. IR spectra were recorded on a Bruker Tensor 27 spectrometer with KBr pellets. 1H NMR spectra were recorded on a Bruker Avance 500 MHz at ambient temperature using DMSO-d6 as solvent and TMS as an internal standard. Chemical shifts were reported in ppm. HRMS (ESI) analysis was performed on an Agilent 6230 mass spectrometer.

General procedure for synthesis of ethyl benzofuran-2carboxylate (1)

Potassium carbonate, anhydrous (10 mmol) was added to an acetone solution of various salicylaldehydes (8 mmol) 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%.

General procedure for synthesis of benzofuran-2-carboxylic acid (3)

A sodium hydroxide (4 mmol) water (10 mL) solution was added to 20 mL ethanol containing 1 (3 mmol). After dropping, 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%.

Synthesis of Glucosamine (4)

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%.

General procedure for Synthesis of 5a–5f

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 give 5a–5f.

N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)benzofuran-2-carboxamide (5a)

Yield 85%; mp 212–214°C; IR (cm−1): 3401, 3065, 2360, 1593, 1447, 1215, 795; 1H NMR: 7.97 (d, J = 8.5 Hz, 1H, NH), 7.79 (d, J = 7.5 Hz, 1H, ArH), 7.71 (d, J = 8.5 Hz, 1H, 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, OH), 3.23–3.17 (m, 1H, HGlu); ESI-HRMS (m/z): calcd for C15H17NO8Na+ [M+Na]+: 346.0896; Found: 346.0907.

5-Methyl-N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)benzofuran-2-carboxamide (5b)

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, 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, J = 5.5 Hz, 1H, HGlu), 3.84−3.80 (m, 1H, HGlu), 3.75−3.71 (m, 1H, OH) 3.67−3.64 (m, 2H, OH), 3.53–3.49 (m, 1H, OH), 3.22−3.16 (m, 1H, HGlu), 2.42 (s, 3H, C-H); ESI-HRMS (m/z): calcd for C16H20NO7+ [M + H]+: 338.1234; Found: 338.1244.

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, 1583, 1424, 1254, 780; 1H NMR: 8.07 (d, J = 6.5 Hz, 1H, 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.

5-Methoxy-N-(2,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-3-yl)benzofuran-2-carboxamide (5e)

Yield 72%; mp 181–182°C; IR (cm−1): 3420, 3017, 2360, 1579, 1436, 1208, 780; 1H NMR: 7.90 (d, J = 3.5 Hz, 1H, NH), 7.60 (d, J = 9.0 Hz, 1H, ArH), 7.55 (s, 1H, ArH), 7.27 (d, J = 3.0 Hz, 1H, ArH), 7.07 (m, 1H, ArH), 6.60 (d, J = 4.5 Hz, 1H, HGlu), 5.09 (t, J = 3.5 Hz, 1H, HGlu), 5.01 (d, J = 5.5 Hz, 1H, HGlu), 4.84 (d, J = 5.5 Hz, 1H, HGlu), 3.81 (s, 3H, −OCH3) 3.73−3.70 (m, 1H, 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.

5-Fluoro-N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)benzofuran-2-carboxamide (5f)

Yield 76%; mp 132–133°C; IR (cm−1): 3421, 3009, 2401, 1573, 1438, 1213, 791; 1H NMR : 8.06 (d, J = 8.0 Hz, 1H, NH), 7.63 (s, 1H, ArH), 7.61 (d, J = 8.0 Hz, 1H, ArH), 7.21 (s, 1H, ArH), 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.

Acknowledgments

This work was supported by the Postgraduate 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).

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Received: 2019-01-22
Accepted: 2019-04-25
Published Online: 2019-12-31

© 2019 Yu-Ran Wu et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 Public License.

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https://doi.org/10.1515/hc-2019-0021
Keywords for this article
D-glucosamine; amide; anti-acetylcholinesterase
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BY 4.0

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  24. Naphthalene substituted benzo[c]coumarins: Synthesis, characterization and evaluation of antibacterial activity and cytotoxicity
  25. A Green Synthesis and Antibacterial Activity of N-Arylsulfonylhydrazone Compounds
  26. Preliminary Communications
  27. Facile Synthesis of Spiro[cyclohexane-1,3’-indoline]-2,2’-diones
  28. Research Article
  29. Synthesis and AChE inhibitory activity of N-glycosyl benzofuran derivatives
  30. [DMImd-DMP]: A highly efficient and reusable catalyst for the synthesis of 4H-benzo[b]pyran derivatives
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