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The structural similarities of the existing HDAC inhibitors have resulted in an increase in the drug resistance. In this study, coumarin was employed as the core scaffold for structural derivatisation to develop a novel class of HDAC inhibitors based on computer-aided design (CADD). Their anti-tumor activity was evaluated against esophageal squamous cell lines. The results showed that most compounds exhibited potent anti-proliferative activity against KYSE70 and KYSE150. Among them, compound 4s and 4p exhibited the most potent activity with IC50 values of 3.44 \u03bcM and 3.39 \u03bcM against KYSE70. To validate the target of the synthesized compounds, transcriptome sequencing was performed and the results revealed that a total of 487 genes were differentially expressed, including 190 up-regulated and 297 down-regulated genes. Among these, 79 genes were associated with the HDAC regulatory network, accounting for 16.2% of the differentially expressed genes. Molecular docking demonstrated that compound 4s could effectively enter the active site of HDAC, engaging with the cap group, zinc-binding group, and linker region. This multiple interaction network provides a structural basis for the potent inhibitory activity of compound 4s. In conclusion, a series of novel HDAC inhibitors with a coumarin scaffold were discovered, and their mode of action was revealed. This provides a valuable guide for the development of novel HDAC-targeting therapeutics.<\/jats:p>","DOI":"10.3390\/biom16070978","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T09:34:11Z","timestamp":1783071251000},"page":"978","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, and Antitumor Activities of Novel Coumarin-Based Histone Deacetylase Inhibitors"],"prefix":"10.3390","volume":"16","author":[{"given":"Sichang","family":"Yan","sequence":"first","affiliation":[{"name":"College of Chemistry and Chemical Engineering, Xinjiang Agricultural University, Urumqi 830052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Chang","sequence":"additional","affiliation":[{"name":"College of Chemistry and Chemical Engineering, Xinjiang Agricultural University, Urumqi 830052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyu","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Physiology, Preclinical School, Xinjiang Medical University, Urumqi 830011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyang","family":"Lv","sequence":"additional","affiliation":[{"name":"College of Chemistry and Chemical Engineering, Xinjiang Agricultural University, Urumqi 830052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanzhuo","family":"Li","sequence":"additional","affiliation":[{"name":"College of Chemistry and Chemical Engineering, Xinjiang Agricultural University, Urumqi 830052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhuo","sequence":"additional","affiliation":[{"name":"College of Chemistry and Chemical Engineering, Xinjiang Agricultural University, Urumqi 830052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6513-6206","authenticated-orcid":false,"given":"Lu","family":"Jin","sequence":"additional","affiliation":[{"name":"College of Chemistry and Chemical Engineering, Xinjiang Agricultural University, Urumqi 830052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Pan","sequence":"additional","affiliation":[{"name":"College of Chemistry and Chemical Engineering, Xinjiang Agricultural University, Urumqi 830052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17048","DOI":"10.1038\/nrdp.2017.48","article-title":"Oesophageal Cancer","volume":"3","author":"Smyth","year":"2017","journal-title":"Nat. Rev. Dis. Primer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/s41392-024-01875-4","article-title":"Clinical Efficacy and Identification of Factors Confer Resistance to Afatinib (Tyrosine Kinase Inhibitor) in EGFR-Overexpressing Esophageal Squamous Cell Carcinoma","volume":"9","author":"Wang","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3485","DOI":"10.1038\/s41591-025-03792-7","article-title":"A Bispecific Antibody-Drug Conjugate Targeting EGFR and HER3 in Metastatic Esophageal Squamous Cell Carcinoma: A Phase 1b Trial","volume":"31","author":"Liu","year":"2025","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"104032","DOI":"10.1016\/j.clon.2026.104032","article-title":"Immune Checkpoint Inhibitor Therapy for Advanced, Unresectable Esophageal Squamous Cell Carcinoma: A Series of Patient-Level Meta-Analyses From Phase III Trials","volume":"51","author":"Beshr","year":"2026","journal-title":"Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4283","DOI":"10.1158\/1078-0432.CCR-16-0292","article-title":"New Strategies in Esophageal Carcinoma: Translational Insights from Signaling Pathways and Immune Checkpoints","volume":"22","author":"Wang","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"112958","DOI":"10.1016\/j.ejca.2023.112958","article-title":"A Demand-Offer Critical Analysis of Current Drug Development: Phase I Drugs versus TCGA Sequencing Data","volume":"190","author":"Repetto","year":"2023","journal-title":"Eur. J. Cancer"},{"key":"ref_7","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.bioorg.2016.05.005","article-title":"Inhibitors of Histone Deacetylase as Antitumor Agents: A Critical Review","volume":"67","author":"Manal","year":"2016","journal-title":"Bioorg. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"108577","DOI":"10.1016\/j.bioorg.2025.108577","article-title":"Design, Synthesis, and Biological Evaluation of N-(2-Amino-Phenyl)-5-(4-Aryl- Pyrimidin-2-Yl) Amino)-1H-Indole-2-Carboxamide Derivatives as Novel Inhibitors of CDK9 and Class I HDACs for Cancer Treatment","volume":"162","author":"Chen","year":"2025","journal-title":"Bioorg. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4810","DOI":"10.1021\/acs.jmedchem.0c02210","article-title":"Tetrahydroquinoline-Capped Histone Deacetylase 6 Inhibitor SW-101 Ameliorates Pathological Phenotypes in a Charcot\u2013Marie\u2013Tooth Type 2A Mouse Model","volume":"64","author":"Shen","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.cbpa.2016.06.019","article-title":"Histone Deacetylase 3 (HDAC 3) as Emerging Drug Target in NF-kappaB-Mediated Inflammation","volume":"33","author":"Leus","year":"2016","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/nrg2485","article-title":"The Many Roles of Histone Deacetylases in Development and Physiology: Implications for Disease and Therapy","volume":"10","author":"Haberland","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s13058-025-02006-9","article-title":"Histone Acetylation Modulators in Breast Cancer","volume":"27","author":"Yuan","year":"2025","journal-title":"Breast Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/s12276-020-0382-4","article-title":"A Short Guide to Histone Deacetylases Including Recent Progress on Class II Enzymes","volume":"52","author":"Park","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4839","DOI":"10.1016\/j.bmc.2008.03.050","article-title":"Synthesis and Structure\u2013Activity Relationship of Histone Deacetylase (HDAC) Inhibitors with Triazole-Linked Cap Group","volume":"16","author":"Chen","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.bmcl.2007.12.031","article-title":"Exploration of the Internal Cavity of Histone Deacetylase (HDAC) with Selective HDAC1\/HDAC2 Inhibitors (SHI-1:2)","volume":"18","author":"Methot","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3430","DOI":"10.1039\/D5RA09034B","article-title":"HDAC Inhibitors as Anticancer Drugs: Chemical Diversity, Clinical Trials, Challenges and Perspectives","volume":"16","author":"Abdallah","year":"2026","journal-title":"RSC Adv."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2666","DOI":"10.1158\/1078-0432.CCR-14-3119","article-title":"FDA Approval: Belinostat for the Treatment of Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma","volume":"21","author":"Lee","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/nrd2227","article-title":"Vorinostat","volume":"6","author":"Grant","year":"2007","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"djv165","DOI":"10.1093\/jnci\/djv165","article-title":"FDA Approves New Agent for Multiple Myeloma","volume":"107","author":"Fenichel","year":"2015","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7239","DOI":"10.1007\/s11696-024-03613-0","article-title":"Heterocycles Fused on a 6,7-Coumarin Framework: An in-Depth Review of Their Structural and Pharmacological Diversity","volume":"78","author":"Jibroo","year":"2024","journal-title":"Chem. Pap."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"104023","DOI":"10.1016\/j.bioorg.2020.104023","article-title":"Design, Synthesis and Biological Evaluation of Coumarin-Based N-Hydroxycinnamamide Derivatives as Novel Histone Deacetylase Inhibitors with Anticancer Activities","volume":"101","author":"Ding","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e202402542","DOI":"10.1002\/cbdv.202402542","article-title":"Synthesis and Fungicidal Activities of Coumarin Derivatives as Succinate Dehydrogenase Inhibitors","volume":"22","author":"Pu","year":"2025","journal-title":"Chem. Biodivers."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.ejmech.2016.07.056","article-title":"Therapeutic Potential of Coumarins as Antiviral Agents","volume":"123","author":"Hassan","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"104427","DOI":"10.1016\/j.bioorg.2020.104427","article-title":"Synthesis and Antioxidant Activity of Conjugates of Hydroxytyrosol and Coumarin","volume":"105","author":"Li","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"32821","DOI":"10.1039\/D5RA04395F","article-title":"Design, Synthesis and Molecular Modeling of New Coumarin\u2013Thiazole Derivatives as Dual EGFR\/HDAC1 Inhibitors: In Vitro and in Vivo Anticancer Assays","volume":"15","author":"Ahmed","year":"2025","journal-title":"RSC Adv."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kubrak, T.P., Makuch-Kocka, A., and Aebisher, D. (2025). Coumarins in Anticancer Therapy: Mechanisms of Action, Potential Applications and Research Perspectives. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17050595"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"144426","DOI":"10.1016\/j.molstruc.2025.144426","article-title":"Coumarins as Versatile Scaffolds: Innovative Synthetic Strategies for Generating Diverse Heterocyclic Libraries in Drug Discovery","volume":"1352","author":"Firoz","year":"2026","journal-title":"J. Mol. Struct."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1634\/theoncologist.12-10-1247","article-title":"FDA Approval Summary: Vorinostat for Treatment of Advanced Primary Cutaneous T-Cell Lymphoma","volume":"12","author":"Mann","year":"2007","journal-title":"Oncologist"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.freeradbiomed.2009.05.011","article-title":"The Inhibitors of Histone Deacetylase Suberoylanilide Hydroxamate and Trichostatin A Release Nitric Oxide upon Oxidation","volume":"47","author":"Samuni","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1038\/s41419-021-04344-w","article-title":"Transcriptional Inhibition by CDK7\/9 Inhibitor SNS-032 Suppresses Tumor Growth and Metastasis in Esophageal Squamous Cell Carcinoma","volume":"12","author":"Zeng","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"i884","DOI":"10.1093\/bioinformatics\/bty560","article-title":"Fastp: An Ultra-Fast All-in-One FASTQ Preprocessor","volume":"34","author":"Chen","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: A Fast Spliced Aligner with Low Memory Requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"R22","DOI":"10.1186\/gb-2011-12-3-r22","article-title":"Improving RNA-Seq Expression Estimates by Correcting for Fragment Bias","volume":"12","author":"Roberts","year":"2011","journal-title":"Genome Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq\u2014A Python Framework to Work with High-Throughput Sequencing Data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated Estimation of Fold Change and Dispersion for RNA-Seq Data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"The Gene Ontology Consortium (2019). The Gene Ontology Resource: 20 Years and Still GOing Strong. Nucleic Acids Res., 47, D330\u2013D338.","DOI":"10.1093\/nar\/gky1055"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"D480","DOI":"10.1093\/nar\/gkm882","article-title":"KEGG for Linking Genomes to Life and the Environment","volume":"36","author":"Kanehisa","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene Set Enrichment Analysis: A Knowledge-Based Approach for Interpreting Genome-Wide Expression Profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/ng1180","article-title":"PGC-1alpha-Responsive Genes Involved in Oxidative Phosphorylation Are Coordinately Downregulated in Human Diabetes","volume":"34","author":"Mootha","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Eastman, P., Swails, J., Chodera, J.D., McGibbon, R.T., Zhao, Y., Beauchamp, K.A., Wang, L.-P., Simmonett, A.C., Harrigan, M.P., and Stern, C.D. (2017). OpenMM 7: Rapid Development of High Performance Algorithms for Molecular Dynamics. PLoS Comput. Biol., 13.","DOI":"10.1371\/journal.pcbi.1005659"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.1021\/acs.jctc.5b00255","article-title":"ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB","volume":"11","author":"Maier","year":"2015","journal-title":"J. Chem. Theory Comput."},{"key":"ref_43","unstructured":"Lu, T. (2026, May 11). Sobtob, Available online: http:\/\/sobereva.com\/soft\/Sobtop."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High Performance Molecular Simulations through Multi-Level Parallelism from Laptops to Supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3593","DOI":"10.1021\/acs.jcim.3c01344","article-title":"DSSP in GROMACS: Tool for Defining Secondary Structures of Proteins in Trajectories","volume":"64","author":"Gorelov","year":"2024","journal-title":"J. Chem. Inf. Model."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6281","DOI":"10.1021\/acs.jctc.1c00645","article-title":"gmx_MMPBSA: A New Tool to Perform End-State Free Energy Calculations with GROMACS","volume":"17","author":"Valiente","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Li, W., and Sun, Z. (2019). Mechanism of Action for HDAC Inhibitors\u2014Insights from Omics Approaches. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20071616"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"11262","DOI":"10.1038\/ncomms11262","article-title":"Insights into the Activation Mechanism of Class I HDAC Complexes by Inositol Phosphates","volume":"7","author":"Watson","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"26926","DOI":"10.1074\/jbc.M113.490706","article-title":"Histone Deacetylase (HDAC) Inhibitor Kinetic Rate Constants Correlate with Cellular Histone Acetylation but Not Transcription and Cell Viability","volume":"288","author":"Lauffer","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/nchembio.2134","article-title":"Histone Deacetylase 6 Structure and Molecular Basis of Catalysis and Inhibition","volume":"12","author":"Hai","year":"2016","journal-title":"Nat. Chem. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Alrouji, M., Yasmin, S., Alshammari, M.S., Alhumaydhi, F.A., Sharaf, S.E., Shahwan, M., and Shamsi, A. (2025). Virtual Screening and Molecular Dynamics Simulations Identify Repurposed Drugs as Potent Inhibitors of Histone Deacetylase 1: Implication in Cancer Therapeutics. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0316343"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/7\/978\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,5]],"date-time":"2026-07-05T04:23:53Z","timestamp":1783225433000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/7\/978"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,3]]},"references-count":51,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["biom16070978"],"URL":"https:\/\/doi.org\/10.3390\/biom16070978","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,3]]}}}