Abstract
Objectives
The study aimed to explore novel aromatic ether coumarins as potential anti-allergic lead compounds.
Methods
The benzene ring of hypervalent iodine compounds was strategically introduced into the coumarin framework to facilitate the efficient synthesis of aromatic ether coumarin derivatives via the one-pot method. Two representative compounds, namely, 4-phenylether coumarin and 7-phenylether coumarin, were successfully designed and synthesized. The compounds were structurally characterized using spectroscopic techniques, including nuclear magnetic resonance (NMR), mass spectrometry (MS), and infrared (IR) spectroscopy. Their inhibitory effects on both IgE- and non-IgE-mediated degranulation of rat basophilic leukemia (RBL-2H3) cells and mouse bone marrow derived mast cells (BMMCs) were subsequently evaluated.
Results
Three representative 7-phenylether coumarins (4, 5, and 6) and 4-phenylether coumarin (7) were synthesized with high efficiency. The compounds exhibited potent anti-allergic effects, indicated by the marked inhibition of degranulation and β-HEX release from RBL-2H3 cells and BMMCs. The inhibitory effects of 7-phenylether 3-methyl ketocoumarin (6) were found to be superior to those of the tested compounds.
Conclusion
Aromatic ether coumarins can be efficiently constructed via the oxidation of hydroxycoumarins with hypervalent iodine compounds. Compound 6 inhibited both IgE-induced and calcium ionophore (A23187)-mediated degranulation of BMMCs, warranting further in-depth investigation into its pharmacogenetic and therapeutic potential.
Supplementary Information
The online version contains supplementary material available at 10.1186/s13065-025-01687-9.
Keywords: Aromatic ether coumarins, Hypervalent iodine compounds, Anti-allergic activity, IgE, RBL-2H3, BMMC, Mast cell degranulation, Organic synthesis
Introduction
Allergic diseases, including asthma, atopic dermatitis, and food allergy, have emerged as significant global public health concerns. The incidence of allergic diseases has increased significantly over the past few decades due to rapid industrialization, elevated levels of environmental pollutants, and alterations in lifestyle factors [1–5]. Although conventional anti-allergic drugs, including histamine H1 receptor antagonists (antihistamines), glucocorticoids, and leukotriene receptor antagonists, continue to play a pivotal role in the treatment of allergic conditions [6–8], they are often associated with a range of side effects such as drowsiness, dry mouth, weight gain, and potential endocrine disruptions [9, 10]. This not only diminishes the quality of life of patients, but also imposes a substantial economic burden on society. Therefore, the development of a new generation of safe and effective anti-allergic drugs, with minimal side effects, has become a critical priority for the medical community [11–13].
Coumarins are commonly occurring natural compounds that contain a distinct fluorescent lactone moiety, and over 1300 coumarin derivative monomers have been identified to date [14–17]. Coumarin derivatives exhibit a wide range of biological activities, including antitumor [18], antiviral [19, 20], antimalarial, antibacterial, anticoagulant, antituberculosis, and anti-allergic properties, among others [21, 22]. Notably, research on the antitumor and anticoagulant activities of coumarins has made significant progress; however, the application of coumarin derivatives as anti-allergic drugs remains poorly investigated, highlighting a significant opportunity for further research in the field [23–27].
In this study, aromatic groups from hypervalent iodine compounds were strategically introduced into 4- or 7-hydroxycoumarins via the one-pot method for the efficient synthesis of a series of novel aromatic ether coumarin derivatives. The aromatic ether coumarin derivatives thus synthesized were further characterized by nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, melting point determination, and mass spectrometry (MS), following which their anti-allergic activities were evaluated.
Results and discussion
Synthetic route for the preparation of 7-hydroxycoumarins
Based on our previous studies [28, 29], we utilized commercially available and cost-effective 2,4-dihydroxybenzaldehyde (Starting Material, S1) as the raw material. A Knoevenagel condensation reaction was performed with diethyl malonate in the presence of diethylamine, yielding 7-hydroxy 3-carboxylic acid ethyl ester coumarin (1), which was subsequently hydrolyzed under alkaline conditions to obtain the corresponding carboxylic acid (2). A Knoevenagel condensation was similarly conducted with 2,4-dihydroxybenzaldehyde using diethylamine as the catalyst to obtain 7-hydroxy 3-acetyl coumarin (3) (Fig. 1).
Fig. 1.
Synthetic route for the preparation of 7-hydroxycoumarins compounds. Reagents and conditions: (a) diethyl malonate, diethylamine, and anhydrous ethanol; 90℃; 2–3 h; yield 98%; (b) ethyl acetoacetate, diethylamine, and anhydrous ethanol; 90℃; 2–3 h; yield 98%; and (c) NaOH and ethanol-H2O; 80℃; 15 min; yield 98%
Synthetic route for the preparation of 7-phenylether coumarins
The 7-hydroxycoumarins (1, 2, and 3) synthesized in the previous step were used as substrates for the synthesis of 7-phenylether coumarins. The synthesized 7-hydroxycoumarins (1, 2, and 3) were oxidized with hypervalent iodine compounds (diacetoxyiodobenzene, DIB) to obtain reaction intermediates, and further continuation of the reaction yielded a series of 7-phenylether coumarins (4, 5, and 6) (Fig. 2).
Fig. 2.
Synthetic route for the preparation of 7-phenylether coumarins. Reagents and conditions: (d) DIB (5 equiv.) and anhydrous methanol; 25℃; 3–4 h; 78–81% yield; (e) 60℃; 3–4 h; (e) anhydrous methanol; 50 ℃; 20 h; 81–85% yield; and (f) anhydrous methanol; reflux; 81–85% yield
Optimization of reaction conditions for the synthesis of 7-phenylether coumarins
We initially used 7-hydroxycoumarin (1) as the starting material, along with 3 equiv. of DIB, and anhydrous ethanol as the solvent for the synthesis of 7-phenylether coumarins [30]. The reaction was conducted at 25 °C room temperature and resulted in a yield of only 9% (Entry 1). This limited yield was likely attributable to the poor solubility of the oxidizing agent in anhydrous ethanol. We therefore selected anhydrous methanol as the reaction solvent, which increased the yield to 25% (Entry 2). However, owing to the surplus of starting material, the amount of the oxidant was further increased to 5 equiv., resulting in an improved yield of 46% (Entry 3). The reaction yield was further increased to 85% by increasing the reaction temperature to 60 °C (Entry 4). The quantity of the oxidant was subsequently increased to 6 equiv., and the reaction temperature was raised to 80 °C, which increased the formation of by-products while decreasing the yield to 79% (Entry 5). Therefore, the optimized reaction conditions for the synthesis of 7-phenylether coumarin compounds were established as follows: 5 equiv. of the oxidizing agent, with anhydrous methanol as the solvent, at a reaction temperature of 60 ℃ (Table 1).
Table 1.
Optimization comparison of different reaction conditions for the synthesis of compound (4) from compound (1)
| Entry | Reaction conditions | Yield (%) |
|---|---|---|
| 1 | DIB (3 equiv.), ethanol, 25 °C | 9 |
| 2 | DIB (3 equiv.), methanol, 25 °C | 25 |
| 3 | DIB (5 equiv.), methanol, 25 °C. | 46 |
| 4 | DIB (5 equiv.), methanol, 60 ℃ | 85 |
| 5 | DIB (6 equiv.), methanol, 80 ℃ | 79 |
Reagents and conditions: 0.2 g of 7-hydroxycoumarin (1) and 15 ml solvent in an atmosphere of nitrogen. The progress of the reaction was monitored by thin-layer chromatography (TLC; petroleum ether: ethyl acetate = 3:1). The reaction was terminated when the starting material was completely consumed or when no further progress was observed
Synthesis of 4-phenylether coumarins
As a readily available and inexpensive compound, 4-hydroxycoumarin (S2) was used as the substrate and subjected to oxidization using DIB to obtain the intermediate. Further continuation of the reaction yielded 4-phenylether coumarin (7) (Fig. 3).
Fig. 3.
Synthetic route for the preparation of 4-phenyl ether coumarins. Reagents and conditions: (g) DIB (3 equiv.), anhydrous sodium carbonate (3 equiv.), ethylene glycol dimethyl ether, and H2O; 25 °C; 3–4 h; 90% yield; (h) ethyl acetate 80 °C; 3–4 h; 87% yield; (k) reflux; 87% yield
Proposed reaction mechanism for the synthesis of aromatic ether coumarins
We proposed a possible reaction mechanism for the synthesis of aromatic ethers, based on our experimental findings and relevant literature. Taking the synthesis of compound 4 as an example to explain the mechanism. In this proposed mechanism, the lone pair of electrons on the 7-hydroxy group of coumarin first attacks the iodine center of DIB, leading to the elimination of one molecule of acetic acid to form intermediate A. This is followed by an intramolecular electrophilic substitution, resulting in the loss of a negatively charged acetic ion and the formation of intermediate B. The relatively stable intermediate C is subsequently formed through aromatization, following which an intramolecular rearrangement transfers the phenyl group from the iodine atom to oxygen, yielding the final stable product (Fig. 4).
Fig. 4.
Proposed reaction mechanism for the synthesis of aromatic ether coumarins
Evaluation of anti-allergic activity of aryl ether coumarins
We subsequently evaluated the inhibitory effects of the four synthesized aryl ether coumarins on mast cells, which play a critical role in mediating allergic responses. To this end, rat basophilic leukemia (RBL-2H3) cells and mouse bone marrow derived mast cell (BMMC) lines, previously stimulated with antigen/antibody (IgE/DNP) or calcium ionophore A23187, respectively, were separately treated with the aryl ether coumarins at concentrations of 5, 10, and 20 µM (Fig. 5). And the treatment conditions of antigen/antibody (IgE/DNP)-stimulated or calcium carrier A23187-stimulated RBL-2H3 cells were compared with the positive control drug ketotifen (Keto) at 10 μm (Fig. 6). The OD value was subsequently measured at 405 nm using a microplate reader to determine the rate of β-HEX release from the mast cell lines.
Fig. 5.
Anti-allergic activities of compounds 4, 5, 6, and 7, determined based on the release of β-HEX from IgE/DNP- or A23187-stimulated mast cells. Data are expressed as means ± standard deviations (n = 3). *p < 0.05, **p < 0.01, and ***p < 0.001, ****p < 0.0001 vs. the control group
Fig. 6.
Comparison of the anti-allergic activity of compounds 4, 5, 6, 7 and positive control drug ketotifen. Data are expressed as means ± standard deviations (n = 3). ***p < 0.001 vs. the positive control group
The results demonstrated that compound 6 exhibited a superior inhibitory effect on the degranulation of RBL-2H3 cells stimulated with IgE/DNP or A23187, compared to the other compounds. The inhibitory effects of compounds 5 and 6 on the release of β-HEX from RBL-2H3 cells were concentration-dependent, and increased at higher concentrations. The inhibitory effect of compound 6 on the IgE/DNP-stimulated degranulation of BMMCs was superior to that of the other compounds. Compounds 4 and 6 inhibited the A23187-induced degranulation of BMMCs in a concentration-dependent manner, with the inhibitory effect increasing at higher concentrations. Additionally, the inhibitory activity of compound 4 was found to be superior to that of compound 6.
Molecular docking-based validation
The inhibition of A23187-induced degranulation by compound 6 suggested that it likely regulates endoplasmic reticulum stress (ERS). This was further validated by docking compound 6 with seven ERS-related proteins known to be closely associated with mast cell degranulation. The proteins were retrieved from UniProt Knowledgebase or the Protein Data Bank (PDB), and docking was performed using AutoDock. The results demonstrated that the docking scores of compound 6with BIP (Binding immunoglobulin protein), IRE1a (Inositol-requiring protein 1 alpha), ATF6 (Activating Transcription Factor 7), PERK (Protein Kinase R-Like Endoplasmic Reticulum Kinase), eIF2a (eukaryotic translation initiation factor 2 A), XBP1s (X-box binding protein 1, spliced), and ATF4 [31] (Activating Transcription Factor 4) were − 5.66,−7.72, −6.34, −7.85, −7.38, −5.09, and − 4.53 kcal/mol, respectively (Table 2). The binding interactions between compound 6 and the selected target proteins were visualized using PyMol-2.5.2 for in-depth analysis. The structures of the entire protein-ligand complexes, the docked pose of compound 6 in the binding sites of target proteins, and the protein-ligand interactions are depicted in Fig. 7. Compound 6 is depicted using an earthy yellow stick representation, while the interacting residues of the target proteins are depicted in blue stick representation, and the overall structure of the target proteins is rendered as a off-white surface representation. The hydrophobic interactions between compound 6 and the binding site residues of the target proteins are represented as yellow lines, the hydrogen bonds are depicted as green lines, the π-π stacking interactions are illustrated as pink lines, and the ionic and dipole interactions are indicated by red lines. Further validation indicated that compound 6 exhibited measurable binding affinity toward several ERS-associated proteins, particularly PERK, IRE1a, and eIF2a.
Table 2.
Docking scores of compound 6 with ERS-related proteins
| Target protein | UniProt/PDB ID | Organism | Docking score (kcal/mol)a |
|---|---|---|---|
| BIP | 6HAB | Cricetulus griseus | − 5.66 |
| IRE1a | 6W3B | Homo sapiens | − 7.72 |
| ATF6 | G3V909 | Rattus norvegicus | − 6.34 |
| PERK | Q9Z1Z1 | Rattus norvegicus | − 7.85 |
| eIF2a | 8DYS | Homo sapiens | − 7.38 |
| XBP1s | Q9R1S4 | Rattus norvegicus | − 5.09 |
| ATF4 | Q9ES19 | Rattus norvegicus | −4.53 |
aLower docking scores indicate a higher potential for binding
Fig. 7.
Three dimensional structures of the complete protein-ligand complexes, docked binding poses, and interactions of compound 6 with (a) BIP, (b) IRE1a, (c) ATF6, (d) PERK, (e) eIF2a, (f) XBP1s, and (g) ATF4
Experimental section
Synthesis of Ethyl 7-hydroxy-3-carboxylate coumarin (1)
The raw material 2,4-dihydroxybenzaldehyde (S1) (2.0 g, 1 eq) was dissolved in 40 ml of anhydrous ethanol, and diethyl malonate (6.56 ml, 3 eq) was added to the reaction system at room temperature with stirring, followed by the addition of diethylamine (8.95 ml, 6 eq), and then the reaction was carried out at 90 ℃ for 2–3 h. The extent of the reaction was monitored by TLC, and was stopped after the raw material was consumed or the reaction was no longer in progress. The reaction was stopped when the raw material was consumed or the reaction was no longer proceeding. When the reaction system returned to room temperature, 10% hydrochloric acid was added to adjust the pH to 1–2, and the solid was precipitated by stirring in an ice bath for 15 min, the dark brown solid was obtained by filtration, and the light brown solid (1) was obtained by recrystallization from 50% ethanol (3.37 g). Brown solid, m.p. 167–169 °C, yield 98%. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.76 (d, J = 8.6 Hz, 1 H), 6.84 (dd, J = 8.6, 2.1 Hz, 1 H), 6.73 (d, J = 2.1 Hz, 1 H), 4.26 (q, J = 7.1 Hz, 2 H), 1.29 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, DMSO-d6) δ 164.54, 163.43, 157.59, 156.88, 149.92, 132.59, 114.48, 112.57, 110.90, 102.27, 61.28, 14.60. HRMS-ESI (m/z): [M + Na] + Calcd for C12H10O5Na 257.0426, Found: 257.0421. IR (KBr, cm− 1): 3217.27, 1699.29, 1591.27, 1215.15, 1118.71, 827.46, 794.67, 640.37.
Synthesis of coumarin 2 7-hydroxy-3-carboxylic acid (2)
Compound (1) (2.0 g,1 eq) was dissolved in 10 ml of ethanol and 5 ml of water, stirred at room temperature, NaOH (1.37 g,4 eq) was added to the reaction system, and the reaction was heated up to 80 ℃ for 15 min, and the extent of the reaction was monitored by TLC, and the reaction was stopped after the raw materials were consumed or the reaction was no longer proceeding. When the reaction system returned to room temperature, 10% hydrochloric acid was added to adjust the pH to 1–2, and the solid was precipitated by stirring in an ice bath for 15 min, and the white solid (2) was obtained by filtration (1.72 g). White solid, m.p. 255–257 ℃, yield 98%. 1H NMR (600 MHz, DMSO-d6) δ 8.67 (s, 1 H), 7.74 (d, J = 8.6 Hz, 1 H), 6.83 (dd, J = 8.6, 2.2 Hz, 1H), 6.72 (d, J = 2.2 Hz, 1H). 13C NMR (150 MHz, DMSO-d6) δ 164.81, 158.22, 157.53, 149.60, 132.48, 114.70, 111.02, 102.32. HRMS-ESI (m/z): [M + Na] + Calcd for C10H6O5Na 229.0109, Found: 229.0107. IR (KBr, cm− 1): 3136.25, 1712.76, 1683.86, 1618.28, 1220.94, 1136.07, 819.75, 796.60, 750.31, 644.22.
Synthesis of 7-hydroxy-3-methyl ketocoumarin (3)
The raw material 2,4-dihydroxybenzaldehyde (S1) (1.0 g,1 eq) was dissolved in 20 ml of anhydrous ethanol, stirred at room temperature, ethyl acetoacetate (2.84 ml,3 eq) was added to the reaction system, followed by the addition of diethylamine (4.48 ml,6 eq), and then the reaction was carried out at a temperature of 90 ℃ for 2–3 h. The extent of the reaction was monitored by TLC, and was stopped when the raw material was consumed or the reaction was no longer in progress. The reaction was stopped when the raw material was consumed or the reaction was no longer proceeding. When the reaction system returned to room temperature, 10% hydrochloric acid was added to adjust the pH to 1–2, and the solid was precipitated by stirring in an ice bath for 15 min, and the dark yellow solid was obtained by filtration, and then 1.48 g of light yellow solid (3) was obtained by recrystallization from 50% ethanol. Yellow solid, m.p. 243–245 ℃, yield 98%. 1H NMR (600 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.59 (s, 1 H), 7.79 (d, J = 8.6 Hz, 1 H), 6.85 (dd, J = 8.6, 2.0 Hz, 1 H), 6.75 (d, J = 2.0 Hz, 1 H), 2.55 (s, 3 H). 13C NMR (150 MHz, DMSO-d6) δ 195.17, 164.67, 159.53, 157.73, 148.37, 133.18, 119.72, 114.70, 111.27, 102.24, 30.55. HRMS-ESI (m/z): [M + H] + Calcd for C11H9O4 205.0501, Found: 205.0492. IR (KBr, cm− 1): 3215.34, 3057.17, 1705.07, 1681.93, 1625.99, 1614.42, 1213.23, 1134.14, 825.53, 644.22.
Synthesis of 7-phenylether-3-carboxylic acid Ethyl ester coumarin intermediate (4′)
Compound 1 (0.2 g,1 eq) was dissolved in 25 ml of anhydrous methanol and stirred at room temperature, iodobenzene diacetic acid (1.38 g,5 eq) was added to the reaction system, the reaction was carried out at 25 ℃ for 3–4 h. The extent of the reaction was monitored by TLC, and the reaction was stopped after the raw material was consumed or the reaction was no longer proceeding. Post-treatment: the solvent was removed by rotary evaporation, followed by further separation and purification of the product by column chromatography, dry sampling. White solid, m.p. 197–199 ℃, yield 78%. 1H NMR (600 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.92 (brd, J = 7.9 Hz, 2 H), 7.56 (brt, J = 7.4 Hz, 1 H), 7.44 (m, 3 H), 6.38 (d, J = 9.1 Hz, 1 H), 4.20 (q, J = 7.1 Hz, 2 H), 1.26 (t, J = 7.1 Hz, 3 H). 13C NMR (150 MHz, DMSO-d6) δ 174.44, 164.07, 160.54, 157.00, 149.44, 134.58, 134.58, 131.79, 131.79, 130.92, 120.46, 119.93, 115.46, 104.59, 101.22, 97.69, 60.39, 14.78.
Synthesis of Ethyl 7-phenylether-3-carboxylate coumarin (4)
Compound 1 (0.2 g,1 eq) was dissolved in 25 ml of anhydrous methanol and stirred at room temperature, iodobenzene diacetic acid (1.38 g,5 eq) was added to the reaction system, and the reaction was heated up to 60 ℃ for 3–4 h. The extent of the reaction was monitored by TLC, and the reaction was stopped when the raw materials were consumed or the reaction was no longer proceeding. Post-treatment: the solvent was removed by rotary evaporation, followed by further separation and purification of the product by column chromatography, dry sampling. White solid, m.p. 204–206 ℃, yield 85%. 1H NMR (600 MHz, DMSO-d6) δ 8.74 (s, 1 H), 7.90 (d, J = 8.6 Hz, 1 H), 7.48(t, J = 7.4 Hz, 2 H), 7.28 (tt, J = 7.4, 1.1 Hz, 1 H), 7.13 (brd, J = 7.4 Hz, 2 H), 6.82 (d, J = 8.6 Hz, 1 H), 4.30 (q, J = 7.1 Hz, 2 H), 1.32 (t, J = 7.1 Hz, 3 H). 13C NMR (150 MHz, DMSO-d6) δ 162.87, 162.28, 156.69, 156.33, 155.56, 149.25, 132.40, 130.95, 125.53, 119.97, 116.02, 114.75, 114.56, 78.80, 61.68, 14.56. HRMS-ESI (m/z): [M + H] + Calcd for C18H14IO5 436.9886, Found: 436.9882. IR (KBr, cm− 1): 3055.24, 3003.17, 1714.72, 1490.97, 1369.46, 1280.73, 1195.87, 808.17.
Synthesis of coumarin 5 from 7-phenylether-3-carboxylic acid (5)
Compound 2 (0.2 g,1 eq) was dissolved in 25 ml of anhydrous methanol and stirred at room temperature, iodobenzene diacetic acid (1.56 g, 5 eq) was added to the reaction system, and the reaction was heated up to 60 ℃ for 3–4 h. The extent of the reaction was monitored by TLC, and the reaction was stopped when the raw materials were consumed or the reaction was no longer proceeding. Post-treatment: the solvent was removed by rotary evaporation, followed by further separation and purification of the product by column chromatography, dry sampling. White solid, m.p. 242–244 ℃, yield 81%. 1H NMR (600 MHz, CDCl3) δ12.03 (s, 1 H), 8.81 (s, 1 H), 7.59 (d, J = 8.7 Hz, 1 H), 7.48 (t, J = 7.5 Hz, 2 H), 7.32 (brt, J = 7.4 Hz, 1 H), 7.13 (brd, J = 8.0 Hz, 2 H), 6.79 (d, J = 8.7 Hz, 1 H). 13C NMR (151 MHz, CDCl3) δ 164.40, 163.92, 162.41, 154.39, 150.85, 131.60, 130.54, 126.13, 120.60, 114.21, 114.01, 112.67. ESI-MS (m/z): [M-H]−: 407.19. IR (KBr, cm− 1): 3053.32, 1734.01, 1689.64, 1610.56, 1585.49, 1224.80, 1197.79, 798.53, 692.44.
Synthesis of 7-phenylether-3-methyl ketocoumarin (6′)
Compound 3 (0.2 g,1 eq) was dissolved in 25 ml of anhydrous methanol and stirred at room temperature, iodobenzene diacetic acid (1.58 g,5 eq) was added to the reaction system, the reaction was carried out at 25 ℃ for 3–4 h. The extent of the reaction was monitored by TLC, and the reaction was stopped after the raw material was consumed or the reaction was no longer proceeding. Post-treatment: the solvent was removed by rotary evaporation, followed by further separation and purification of the product by column chromatography, dry sampling. Yellow solid, m.p. 155–158 ℃, yield 81%. 1H NMR (600 MHz, DMSO-d6) δ 8.39 (s, 1 H), 7.96–7.92 (m, 2 H), 7.60–7.55 (m, 1 H), 7.50 (d, J = 9.2 Hz, 1 H), 7.45 (t, J = 7.8 Hz, 2 H), 6.41 (d, J = 9.1 Hz, 1 H), 2.48 (s, 3 H). 13C NMR (150 MHz, DMSO-d6) δ 193.93, 160.80, 160.03, 147.86, 135.29, 134.63, 131.85, 131.67, 130.96, 120.86, 119.92, 115.50, 105.44, 97.95, 30.51.
Synthesis of 7-phenylether-3-methylketone coumarin 6
Compound 3 (0.2 g,1 eq) was dissolved in 25 ml of anhydrous methanol and stirred at room temperature, iodobenzene diacetic acid (1.58 g, 5 eq) was added to the reaction system, and the reaction was heated up to 60 ℃ for 3–4 h. The extent of the reaction was monitored by TLC, and the reaction was stopped when the raw materials were consumed or the reaction was no longer proceeding. Post-treatment: the solvent was removed by rotary evaporation, followed by further separation and purification of the product by column chromatography, dry sampling. Yellow solid, m.p. 185–187 ℃, yield 85%. 1H NMR (600 MHz, DMSO-d6) δ 8.63 (s, 1 H), 7.93 (d, J = 8.6 Hz, 1 H), 7.49 (t, J = 7.8 Hz, 2 H), 7.29 (t, J = 7.4 Hz, 1 H), 7.13 (d, J = 8.0 Hz, 2 H), 6.84 (d, J = 8.6 Hz, 1 H), 2.51 (s, 3 H). 13C NMR (150 MHz, DMSO-d6) δ 195.15, 162.24, 158.83, 155.60, 147.47, 132.87, 130.95, 125.51, 119.91, 115.10, 114.76, 79.16, 30.48. HRMS-ESI (m/z): [M + H] + Calcd for C17H12IO4 406.9780, Found: 406.9775. IR (KBr, cm− 1): 3228.84, 2978.09, 1681.93, 1622.13, 1598.99, 1273.02, 1136.07, 839.03, 704.02.
Synthesis of 4-phenylether coumarin intermediate (7′)
The raw material (S2) (0.2 g,1 eq) was dissolved in 4 ml of ethylene glycol dimethyl ether and 1 ml of distilled water, stirred at room temperature, iodobenzene diacetic acid (1.19 g,3 eq) was added to the reaction system, followed by the addition of anhydrous sodium carbonate (0.39 g,3 eq), and the reaction was conducted at room temperature for 3–4 h. The extent of the reaction was monitored by TLC, and was stopped after the raw material had been consumed or the reaction was no longer proceeding. The reaction was stopped when the raw material was consumed or the reaction was no longer proceeding. Post-treatment: the solvent was removed by rotary evaporation, ethyl acetate was added, water was extracted three times, and 0.36 g of yellow solid (7’) was obtained by rotary evaporation in 80% yield. Yellow solid, m.p. 142–145 ℃, yield 80%. 1H NMR (400 MHz, DMSO-d6) δ 7.90 (dd, J = 7.8, 1.6 Hz, 1 H, H-5), 7.85 (dd, J = 8.3, 1.0 Hz, 2 H, H-2’, 6’), 7.57(td, J = 7.8, 1.6 Hz, 1 H, H-7), 7.52(m, 1 H, H-4’), 7.42 (t, J = 7.8 Hz, 2 H, H-3’, 5’), 7.31–7.20 (m, 2 H, H-6, H-8). 13C NMR (100 MHz, DMSO-d6) δ 172.50, 160.90, 153.90, 133.03, 132.78, 131.07, 130.65, 125.62, 123.38, 119.83, 116.21, 114.96, 81.90.
Synthesis of 4-phenylether coumarin (7)
The raw material (S2) (0.5 g,1 eq) was dissolved in 10 ml of ethylene glycol dimethyl ether and 2.5 ml of distilled water, stirred at room temperature, iodobenzene diacetic acid (2.98 g,3 eq) was added to the reaction system, followed by the addition of anhydrous sodium carbonate (0.98 g,3 eq), and then the reaction was carried out at 80 ℃ for 3–4 h. The extent of the reaction was monitored by TLC, and was stopped when the raw materials were consumed or the reaction was no longer in progress. The reaction was stopped when the raw material was consumed or the reaction was no longer proceeding. Post-treatment: the solvent was removed by rotary evaporation, 30 ml of ethanol was added to dissolve the solvent, then water was added to produce flocculent, the solid was precipitated by stirring for 30 min, and 0.39 g of yellow solid (7) was obtained by filtration in 87% yield. Yellow solid, m.p. 188–190 ℃, yield 87%. 1H NMR (600 MHz, DMSO-d6) δ 7.69 (brt, J = 7.9 Hz, 1 H, H-7), 7.54 (brd, J = 8.3 Hz, 1 H, H-5), 7.43 (brd, J = 8.0 Hz, 1 H, H-8), 7.38 (t, J = 7.7 Hz, 2 H, H-3’,5’), 7.29 (brt, J = 7.6 Hz, 1 H, H-6), 7.13 (m, 3 H, H-2’, 4’, 6’). 13C NMR (150 MHz, DMSO-d6) δ 164.20, 159.86, 155.95, 153.61, 133.57, 130.69, 125.14, 123.91, 123.76, 117.18, 116.33, 116.23, 84.01. HRMS-ESI (m/z): [M + H]+ Calcd for C15H10IO3 364.9675, Found: 364.9668. IR (KBr, cm− 1): 1734.01, 1591.27, 1556.55, 1481.33, 1336.67, 1271.09, 1161.15, 891.11, 758.02, 684.73.
Conclusion
The present study explored a novel strategy for the synthesis of aromatic ether coumarin compounds, and the findings revealed that both 4-hydroxycoumarin and 7-hydroxycoumarin can be oxidized by hypervalent iodine compounds to obtain aromatic ether coumarins. This synthetic approach was employed to effectively synthesize four representative aromatic ether coumarin compounds (4, 5, 6, and 7). The proposed reaction mechanisms were further discussed based on the identification and characterization of three relatively stable intermediates (4′, 6′, and 7′).
The aromatic ether coumarin derivatives thus synthesized were characterized by spectroscopic techniques, including NMR, MS, and IR spectroscopy, following which their inhibitory effects on mast cell degranulation were evaluated using RBL-2H3 cells and BMMCs. Compound 6 significantly inhibited RBL-2H3 and BMMC degranulation, and subsequent validation through molecular docking revealed that compound 6 can potentially bind to several ERS-related proteins, including PERK, IRE1a, and eIF2a. Therefore, the anti-allergic potential of compound 6 warrants further in-depth preclinical research, and it may serve as a novel lead compound for the future development of anti-allergic therapeutics.
Supplementary Information
Acknowledgements
We would like to thank TopEdit (www.topeditsci.com) for its linguistic assistance during the preparation of this manuscript.
Authors contributions
Xiaoyue Liu synthesized most of the compounds and writing the paper, Xiaoxia Mao conducted anti-allergic activity testing experiments and network molecular docking verification, Yuying Zhang Assisted in the synthesis of some compounds, Dejun Zhou designed the program and provided technical guidance to the experiment. All authors read and approved the final manuscript.
Funding
This research was supported by Hebei Natural Science Foundation, grant numbers H2023406003.
Data availability
All data generated or analyzed during this study are included in this published article and its supplementary information files.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Xiaoxia Mao contributed to this work.
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Data Availability Statement
All data generated or analyzed during this study are included in this published article and its supplementary information files.