Novel Synthetic Strategy for Aromatic Ether Coumarin Derivatives and Evaluation of Anti-allergic Potential

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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-phenylene ether coumarin and 7-phenylene ether 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 ether 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-phenyl ether 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. aromatic ether coumarins hypervalent iodine compounds anti-allergic activity IgE RBL-2H3 BMMC mast cell degranulation organic synthesis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1. 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. 2. Results and Discussion 2.1. 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, S 1 ) 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). 2.2. Synthetic route for the preparation of 7-phenyl ether coumarins The 7-hydroxycoumarins ( 1 , 2 , and 3 ) synthesized in the previous step were used as substrates for the synthesis of 7-phenyl ether 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). 2.3. 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. The reaction was conducted at 25 o 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 o C. 9 2 DIB (3 equiv.), methanol, 25 o C. 25 3 DIB (5 equiv.), methanol, 25 o 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. 2.4 Synthesis of 4-phenylether coumarins As a readily available and inexpensive compound, 4-hydroxycoumarin ( S 2 ) 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). 2.5. 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. 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). 2.6. 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 µg/ml. 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. 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 2.7 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 6 with BIP (Binding immunoglobulin protein), IRE1a (Inositol-requiring protein 1 alpha), ATF6 (Activating Transcription Factor 6), PERK (Protein Kinase R-Like Endoplasmic Reticulum Kinase), eIF2a (eukaryotic translation initiation factor 2A), XBP1s (X-box binding protein 1, spliced), and ATF4 (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. 6. 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. 3. 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. Declarations Acknowledgements We would like to thank TopEdit (www.topeditsci.com) for its linguistic assistance during the preparation of this manuscript. Author 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 funded by the Natural Science Foundation of Hebei Natural Science Foundation, grant numbers H2023406003. Availability of data and materials All data generated or analysed during this study are included in this published article and its supplementary information files. Conflict of Interest The authors declare no conflict of interest, financial oroth- erwise. Ethics approval and consent to participate Not applicable. Consent for publication Not Applicable. References Chen N, Zhang S, Javeed A, Jian C, Liu Y, Sun J, Wu S, Fu P, Han B. Structures and Anti-Allergic Activities of Natural Products from Marine Organisms. Marine Drugs . 2023; 21(3):152. HWANG S-W, SUN X, HAN J-H, et al. Fermentation-mediated enhancement of ginseng’s anti-allergic activity against IgE-mediated passive cutaneous anaphylaxis in vivo and in vitro [J]. Food Microbiology and Biotechnology , 2018, 28(10). Ramirez, G.A., Cardamone, C., Lettieri, S. et al. 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Supplementary Files Supportinginformation20250604.docx Cite Share Download PDF Status: Published Journal Publication published 24 Nov, 2025 Read the published version in BMC Chemistry → Version 1 posted Editorial decision: Revision requested 15 Jul, 2025 Reviews received at journal 14 Jul, 2025 Reviews received at journal 13 Jul, 2025 Reviewers agreed at journal 15 Jun, 2025 Reviewers agreed at journal 15 Jun, 2025 Reviewers invited by journal 13 Jun, 2025 Editor assigned by journal 12 Jun, 2025 Submission checks completed at journal 12 Jun, 2025 First submitted to journal 08 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6849801","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":471552250,"identity":"8834abf4-bae3-44e0-b6ef-807f8bfe99e4","order_by":0,"name":"Xiaoyue Liu","email":"","orcid":"","institution":"Chengde Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoyue","middleName":"","lastName":"Liu","suffix":""},{"id":471552253,"identity":"46e718a9-1d7d-4f1c-b0d8-363910a15aa7","order_by":1,"name":"Xiaoxia Mao","email":"","orcid":"","institution":"Chengde Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoxia","middleName":"","lastName":"Mao","suffix":""},{"id":471552254,"identity":"13e6ac69-33ee-46bf-8f01-9b4cd766a399","order_by":2,"name":"Yuying Zhang","email":"","orcid":"","institution":"Chengde Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuying","middleName":"","lastName":"Zhang","suffix":""},{"id":471552255,"identity":"cf494fe4-46e6-4524-ad78-a40e44616258","order_by":3,"name":"Dejun Zhou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBUlEQVRIiWNgGAWjYDACCSDm4bHh4WdvbP/xgYEZLkhIS5qcZM/hA5IziNfCcNjY4EZagjQPMVrkZzcfk3gjw5zYcCDHwNimxjqav4H54G0eBrs8XFoY5xxLk5zDw5bY2HDGIDnnWHrujANsydY8DMnFuLQwS+SYSfPw8CQ2M/YYHM5tOJy7gYEHKMJwILEBhxY2iBaJxDZmHsNmS7AW/m94tfBAtBgY87CxJTMzQmxhw6tFQiIt2XIOT4KcBA/zMcYekF8OsxlbzjFIxqlFfkbywRtve/7z2N9/2Mbwo8Y6t7+9+eGNNxV2OLWAAWMPSoiACAN86kHgByEFo2AUjIJRMKIBAHRLT4DfReZuAAAAAElFTkSuQmCC","orcid":"","institution":"Chengde Medical University","correspondingAuthor":true,"prefix":"","firstName":"Dejun","middleName":"","lastName":"Zhou","suffix":""}],"badges":[],"createdAt":"2025-06-09 01:53:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6849801/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6849801/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13065-025-01687-9","type":"published","date":"2025-11-24T15:56:59+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84815473,"identity":"c1f9b925-df96-45fa-9d08-12567f1a02e3","added_by":"auto","created_at":"2025-06-17 15:33:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":66237,"visible":true,"origin":"","legend":"\u003cp\u003eSynthetic route for the preparation of 7-hydroxycoumarins compounds.\u003c/p\u003e\n\u003cp\u003eReagents 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-H\u003csub\u003e2\u003c/sub\u003eO; 80℃; 15 min; yield 98%.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6849801/v1/05129a5c62cc1ceed6af50ea.png"},{"id":84815474,"identity":"5a636ffa-ef1a-462e-96af-b15a0bde1e1b","added_by":"auto","created_at":"2025-06-17 15:33:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":84687,"visible":true,"origin":"","legend":"\u003cp\u003eSynthetic route for the preparation of 7-phenylether coumarins.\u003c/p\u003e\n\u003cp\u003eReagents and conditions: (d)\u003cstrong\u003e \u003c/strong\u003eDIB (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.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6849801/v1/ddb59d6597316e107bbba63d.png"},{"id":84816447,"identity":"81822ad8-f380-4994-a306-3e2964bd1853","added_by":"auto","created_at":"2025-06-17 15:41:06","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":50422,"visible":true,"origin":"","legend":"\u003cp\u003eSynthetic route for the preparation of 4-phenyl ether coumarins.\u003c/p\u003e\n\u003cp\u003eReagents and conditions: (g) DIB (3 equiv.), anhydrous sodium carbonate (3 equiv.), ethylene glycol dimethyl ether, and H\u003csub\u003e2\u003c/sub\u003eO; 25 \u003csup\u003eo\u003c/sup\u003eC; 3–4 h; 90% yield; (h) 80°C; 3–4 h; 87% yield; (k) reflux; 87% yield.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6849801/v1/829cfdb6106c2e32982ce576.png"},{"id":84815477,"identity":"0846e872-f777-4ed7-8c5e-8d8b8a534105","added_by":"auto","created_at":"2025-06-17 15:33:06","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":129929,"visible":true,"origin":"","legend":"\u003cp\u003eProposed reaction mechanism for the synthesis of aromatic ether coumarins.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6849801/v1/e890c26eff172923e0c20a51.png"},{"id":84817362,"identity":"91b10f04-db6d-4dd0-ae21-944f747e70b1","added_by":"auto","created_at":"2025-06-17 15:49:06","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":447617,"visible":true,"origin":"","legend":"\u003cp\u003eAnti-allergic activities of compounds \u003cstrong\u003e4\u003c/strong\u003e, \u003cstrong\u003e5\u003c/strong\u003e, \u003cstrong\u003e6\u003c/strong\u003e, and \u003cstrong\u003e7\u003c/strong\u003e,\u003cstrong\u003e \u003c/strong\u003edetermined based on the release of β-HEX from IgE/DNP- or A23187-stimulated mast cells.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6849801/v1/e944b3bfabb6ae72a1a7d30e.png"},{"id":84815484,"identity":"b10f53e7-ab73-4dea-a12f-03a45b704469","added_by":"auto","created_at":"2025-06-17 15:33:06","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":4366734,"visible":true,"origin":"","legend":"\u003cp\u003eThree dimensional structures of the complete protein-ligand complexes, docked binding poses, and interactions of compound \u003cstrong\u003e6\u003c/strong\u003ewith (a) BIP, (b) IRE1a, (c) ATF6, (d) PERK, (e) eIF2a, (f) XBP1s, and (g) ATF4.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6849801/v1/8cd85ed96b2dffe451ecb58c.png"},{"id":97178291,"identity":"6d16388f-8610-45ac-be2d-3a13e819ac53","added_by":"auto","created_at":"2025-12-01 16:07:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6555822,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6849801/v1/a8e6ce3e-afec-4ef4-8418-f272a16c9bc6.pdf"},{"id":84815489,"identity":"2a388c19-1200-48be-bd8d-bcaaf90a8507","added_by":"auto","created_at":"2025-06-17 15:33:06","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":4147831,"visible":true,"origin":"","legend":"","description":"","filename":"Supportinginformation20250604.docx","url":"https://assets-eu.researchsquare.com/files/rs-6849801/v1/3eb597ea11d3ebddc66f1f4c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Novel Synthetic Strategy for Aromatic Ether Coumarin Derivatives and Evaluation of Anti-allergic Potential","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eAllergic 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\u003csup\u003e[\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. 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\u003csup\u003e[\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, they are often associated with a range of side effects such as drowsiness, dry mouth, weight gain, and potential endocrine disruptions\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. 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\u003csup\u003e[\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCoumarins are commonly occurring natural compounds that contain a distinct fluorescent lactone moiety, and over 1300 coumarin derivative monomers have been identified to date\u003csup\u003e[\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Coumarin derivatives exhibit a wide range of biological activities, including antitumor\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e, antiviral\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e, antimalarial, antibacterial, anticoagulant, antituberculosis, and anti-allergic properties, among others\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. 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\u003csup\u003e[\u003cspan additionalcitationids=\"CR24 CR25 CR26\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn 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.\u003c/p\u003e"},{"header":"2. Results and Discussion","content":"\u003cdiv id=\"Sec3\"\u003e\n \u003ch2\u003e2.1. Synthetic route for the preparation of 7-hydroxycoumarins\u003c/h2\u003e\n \u003cp\u003eBased on our previous studies\u003csup\u003e[28–29]\u003c/sup\u003e, we utilized commercially available and cost-effective 2,4-dihydroxybenzaldehyde (Starting Material, \u003cstrong\u003eS\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/sub\u003e) 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 (\u003cstrong\u003e1\u003c/strong\u003e), which was subsequently hydrolyzed under alkaline conditions to obtain the corresponding carboxylic acid (\u003cstrong\u003e2\u003c/strong\u003e). A Knoevenagel condensation was similarly conducted with 2,4-dihydroxybenzaldehyde using diethylamine as the catalyst to obtain 7-hydroxy 3-acetyl coumarin (\u003cstrong\u003e3\u003c/strong\u003e) (Fig. 1).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\"\u003e\n \u003ch2\u003e2.2. Synthetic route for the preparation of 7-phenyl ether coumarins\u003c/h2\u003e\n \u003cp\u003eThe 7-hydroxycoumarins (\u003cstrong\u003e1\u003c/strong\u003e, \u003cstrong\u003e2\u003c/strong\u003e, and \u003cstrong\u003e3\u003c/strong\u003e) synthesized in the previous step were used as substrates for the synthesis of 7-phenyl ether coumarins. The synthesized 7-hydroxycoumarins (\u003cstrong\u003e1\u003c/strong\u003e, \u003cstrong\u003e2\u003c/strong\u003e, and \u003cstrong\u003e3\u003c/strong\u003e) were oxidized with hypervalent iodine compounds (diacetoxyiodobenzene, \u003cstrong\u003eDIB\u003c/strong\u003e) to obtain reaction intermediates, and further continuation of the reaction yielded a series of 7-phenylether coumarins (\u003cstrong\u003e4\u003c/strong\u003e, \u003cstrong\u003e5\u003c/strong\u003e, and \u003cstrong\u003e6\u003c/strong\u003e) (Fig. 2).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\"\u003e\n \u003ch2\u003e2.3. Optimization of reaction conditions for the synthesis of 7-phenylether coumarins\u003c/h2\u003e\n \u003cp\u003eWe initially used 7-hydroxycoumarin (\u003cstrong\u003e1\u003c/strong\u003e) as the starting material, along with 3 equiv. of DIB, and anhydrous ethanol as the solvent for the synthesis of 7-phenylether coumarins. The reaction was conducted at 25 \u003csup\u003eo\u003c/sup\u003eC 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)\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 1\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eOptimization Comparison of different reaction conditions for the synthesis of compound (\u003cstrong\u003e4\u003c/strong\u003e) from compound (\u003cstrong\u003e1\u003c/strong\u003e)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEntry\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eReaction conditions\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eYield (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDIB (3 equiv.), ethanol, 25 \u003csup\u003eo\u003c/sup\u003eC.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDIB (3 equiv.), methanol, 25 \u003csup\u003eo\u003c/sup\u003eC.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDIB (5 equiv.), methanol, 25 \u003csup\u003eo\u003c/sup\u003eC.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDIB (5 equiv.), methanol, 60 ℃\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDIB (6 equiv.), methanol, 80 ℃\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eReagents and conditions: 0.2 g of 7-hydroxycoumarin (\u003cstrong\u003e1\u003c/strong\u003e) 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.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\"\u003e\n \u003ch2\u003e2.4 Synthesis of 4-phenylether coumarins\u003c/h2\u003e\n \u003cp\u003eAs a readily available and inexpensive compound, 4-hydroxycoumarin (\u003cstrong\u003eS\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e) was used as the substrate and subjected to oxidization using DIB to obtain the intermediate. Further continuation of the reaction yielded 4-phenylether coumarin (\u003cstrong\u003e7\u003c/strong\u003e) (Fig. 3).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\"\u003e\n \u003ch2\u003e2.5. Proposed reaction mechanism for the synthesis of aromatic ether coumarins\u003c/h2\u003e\n \u003cp\u003eWe proposed a possible reaction mechanism for the synthesis of aromatic ethers, based on our experimental findings and relevant literature. 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 \u003cstrong\u003eA\u003c/strong\u003e. This is followed by an intramolecular electrophilic substitution, resulting in the loss of a negatively charged acetic ion and the formation of intermediate \u003cstrong\u003eB\u003c/strong\u003e. The relatively stable intermediate \u003cstrong\u003eC\u003c/strong\u003e 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).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\"\u003e\n \u003ch2\u003e2.6. Evaluation of anti-allergic activity of aryl ether coumarins\u003c/h2\u003e\n \u003cp\u003eWe 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 µg/ml. 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.\u003c/p\u003e\n \u003cp\u003eThe results demonstrated that compound \u003cstrong\u003e6\u003c/strong\u003e 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 \u003cstrong\u003e5\u003c/strong\u003e and \u003cstrong\u003e6\u003c/strong\u003e on the release of β-HEX from RBL-2H3 cells were concentration-dependent, and increased at higher concentrations. The inhibitory effect of compound \u003cstrong\u003e6\u003c/strong\u003e on the IgE/DNP-stimulated degranulation of BMMCs was superior to that of the other compounds. Compounds \u003cstrong\u003e4\u003c/strong\u003e and \u003cstrong\u003e6\u003c/strong\u003e 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 \u003cstrong\u003e4\u003c/strong\u003e was found to be superior to that of compound \u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\"\u003e\n \u003ch2\u003e2.7 Molecular docking-based validation\u003c/h2\u003e\n \u003cp\u003eThe inhibition of A23187-induced degranulation by compound \u003cstrong\u003e6\u003c/strong\u003e suggested that it likely regulates endoplasmic reticulum stress (ERS). This was further validated by docking compound \u003cstrong\u003e6\u003c/strong\u003e 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 \u003cstrong\u003e6\u003c/strong\u003e with BIP (Binding immunoglobulin protein), IRE1a (Inositol-requiring protein 1 alpha), ATF6 (Activating Transcription Factor 6), PERK (Protein Kinase R-Like Endoplasmic Reticulum Kinase), eIF2a (eukaryotic translation initiation factor 2A), XBP1s (X-box binding protein 1, spliced), and ATF4 (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 \u003cstrong\u003e6\u003c/strong\u003e 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 \u003cstrong\u003e6\u003c/strong\u003e in the binding sites of target proteins, and the protein-ligand interactions are depicted in Fig. 6. Compound \u003cstrong\u003e6\u003c/strong\u003e 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 \u003cstrong\u003e6\u003c/strong\u003e 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 \u003cstrong\u003e6\u003c/strong\u003e exhibited measurable binding affinity toward several ERS-associated proteins, particularly PERK, IRE1a, and eIF2a.\u003c/p\u003e\n \u003cp\u003e\u003cimg 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\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3. Conclusion","content":"\u003cp\u003eThe 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 (\u003cb\u003e4\u003c/b\u003e, \u003cb\u003e5\u003c/b\u003e, \u003cb\u003e6\u003c/b\u003e, and \u003cb\u003e7\u003c/b\u003e). The proposed reaction mechanisms were further discussed based on the identification and characterization of three relatively stable intermediates (\u003cb\u003e4'\u003c/b\u003e, \u003cb\u003e6'\u003c/b\u003e, and \u003cb\u003e7'\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eThe 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 \u003cb\u003e6\u003c/b\u003e significantly inhibited RBL-2H3 and BMMC degranulation, and subsequent validation through molecular docking revealed that compound \u003cb\u003e6\u003c/b\u003e can potentially bind to several ERS-related proteins, including PERK, IRE1a, and eIF2a. Therefore, the anti-allergic potential of compound \u003cb\u003e6\u003c/b\u003e warrants further in-depth preclinical research, and it may serve as a novel lead compound for the future development of anti-allergic therapeutics.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e We would like to thank TopEdit (www.topeditsci.com) for its linguistic assistance during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e Xiaoyue Liu\u0026nbsp;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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e This research was funded by the Natural Science Foundation of Hebei Natural Science Foundation, grant numbers H2023406003.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003eAll data generated or analysed during this study are included in this published article and its supplementary information files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e The authors declare no conflict of interest, financial oroth- erwise.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e Not applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003eNot Applicable.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eChen N, Zhang S, Javeed A, Jian C, Liu Y, Sun J, Wu S, Fu P, Han B. 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Coord Chem Rev, 2000, 205(1): 3-40.\u003c/li\u003e\n\u003cli\u003eHelal A, Or Rashid M H, Choi C H, et al. Chromogenic and fluorogenic sensing of Cu2+ based on coumarin [J]. Tetrahedron, 2011, 67(15): 2794-2802.\u003c/li\u003e\n\u003cli\u003eGuha S, Lohar S, Banerjee A, et al. Thiophene anchored coumarin derivative as a turn-on fluorescent probe for Cr3+: Cell imaging and speciation studies [J]. Talanta, 2012, 91: 18-25.\u003c/li\u003e\n\u003cli\u003eGuha S, Lohar S, Hauli I, et al. Vanillin-coumarin hybrid molecule as an efficient fluorescent probe for trace level determination of Hg(II) and its application in cell imaging [J]. Talanta, 2011, 85(3): 1658-1664.\u003c/li\u003e\n\u003cli\u003eRosa, I.A., Almeida, L., Alves, K.F. et al. Synthesis and in vitro evaluation of leishmanicidal activity of 7-hydroxy-4-phenylcoumarin derivatives. Med Chem Res 26, 131\u0026ndash;139 (2017).\u003c/li\u003e\n\u003cli\u003eYadav S, Singh S.B, Gupta C.D, Environmental Benign Synthesis of Some Novel Biologically Active 7-Hydroxy-4-Methyl Coumarin Derivatives. SSRN Electronic Journal (2022).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ccjo","sideBox":"Learn more about [BMC Chemistry](https://bmcchem.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ccjo/default.aspx","title":"BMC Chemistry","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"aromatic ether coumarins, hypervalent iodine compounds, anti-allergic activity, IgE, RBL-2H3, BMMC, mast cell degranulation, organic synthesis","lastPublishedDoi":"10.21203/rs.3.rs-6849801/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6849801/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eOBJECTIVES\u003c/h2\u003e \u003cp\u003eThe study aimed to explore novel aromatic ether coumarins as potential anti-allergic lead compounds.\u003c/p\u003e\u003ch2\u003eMETHODS\u003c/h2\u003e \u003cp\u003eThe 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-phenylene ether coumarin and 7-phenylene ether 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.\u003c/p\u003e\u003ch2\u003eRESULTS\u003c/h2\u003e \u003cp\u003eThree representative 7-phenylether ether coumarins (\u003cb\u003e4\u003c/b\u003e, \u003cb\u003e5\u003c/b\u003e, and \u003cb\u003e6\u003c/b\u003e) and 4-phenylether coumarin (\u003cb\u003e7\u003c/b\u003e) 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-phenyl ether 3-methyl ketocoumarin (\u003cb\u003e6\u003c/b\u003e) were found to be superior to those of the tested compounds.\u003c/p\u003e\u003ch2\u003eCONCLUSION\u003c/h2\u003e \u003cp\u003eAromatic ether coumarins can be efficiently constructed via the oxidation of hydroxycoumarins with hypervalent iodine compounds. Compound \u003cb\u003e6\u003c/b\u003e inhibited both IgE-induced and calcium ionophore (A23187)-mediated degranulation of BMMCs, warranting further in-depth investigation into its pharmacogenetic and therapeutic potential.\u003c/p\u003e","manuscriptTitle":"Novel Synthetic Strategy for Aromatic Ether Coumarin Derivatives and Evaluation of Anti-allergic Potential","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-17 15:33:01","doi":"10.21203/rs.3.rs-6849801/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-07-15T07:48:17+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-14T13:38:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-13T17:40:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"238530236482928448009067535897915429023","date":"2025-06-15T18:25:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"248275565447828845218567702221910788482","date":"2025-06-15T09:01:42+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-13T13:10:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-12T07:45:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-12T07:43:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Chemistry","date":"2025-06-09T01:39:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ccjo","sideBox":"Learn more about [BMC Chemistry](https://bmcchem.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ccjo/default.aspx","title":"BMC Chemistry","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d38f6768-f48c-4256-9d9c-fa2e81140837","owner":[],"postedDate":"June 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-01T16:00:22+00:00","versionOfRecord":{"articleIdentity":"rs-6849801","link":"https://doi.org/10.1186/s13065-025-01687-9","journal":{"identity":"bmc-chemistry","isVorOnly":false,"title":"BMC Chemistry"},"publishedOn":"2025-11-24 15:56:59","publishedOnDateReadable":"November 24th, 2025"},"versionCreatedAt":"2025-06-17 15:33:01","video":"","vorDoi":"10.1186/s13065-025-01687-9","vorDoiUrl":"https://doi.org/10.1186/s13065-025-01687-9","workflowStages":[]},"version":"v1","identity":"rs-6849801","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6849801","identity":"rs-6849801","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}