{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T10:17:00Z","timestamp":1783592220826,"version":"3.55.0"},"reference-count":40,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Key Research Project of the Science and Technology Department of Jilin Province","award":["20240305099YY"],"award-info":[{"award-number":["20240305099YY"]}]},{"DOI":"10.13039\/100012905","name":"Natural Science Foundation of Shandong","doi-asserted-by":"publisher","award":["ZR2022MB064"],"award-info":[{"award-number":["ZR2022MB064"]}],"id":[{"id":"10.13039\/100012905","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The tryptophan\u2013kynurenine pathway, mediated by indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO), is critically involved in the pathogenesis of depression. A series of novel morpholine\u2013coumarin derivatives were designed and synthesized as dual IDO1\/TDO inhibitors. Through in vitro enzyme screening, compound 14d exhibited potent inhibitory activity with IC50 values of 0.34 \u00b5M and 0.75 \u00b5M, respectively. In lipopolysaccharide (LPS)-stimulated BV2 microglial cells, 14d downregulated IDO1\/TDO expression, suppressed pro-inflammatory cytokines (IL-1\u03b2, COX-2, iNOS, TNF-\u03b1), and upregulated the anti-inflammatory cytokine IL-10. In an LPS-induced acute depressive mouse model established in C57BL\/6 mice, intraperitoneal administration of 14d (20 mg\/kg) significantly reduced immobility time in the forced swim and tail suspension tests, without affecting spontaneous locomotor activity. Mechanistic studies revealed that 14d inhibited microglial activation in the hippocampal dentate gyrus, reduced cerebral kynurenine levels, increased serotonin content, and upregulated BDNF\/PKA signaling. Molecular docking further predicted the binding interactions of 14d with the active sites of IDO1 and TDO. These findings suggest that 14d represents a promising dual IDO1\/TDO inhibitor lead compound for the treatment of inflammation-associated depression through modulation of the kynurenine pathway and neuroinflammatory responses.<\/jats:p>","DOI":"10.3390\/biom16071002","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T08:50:56Z","timestamp":1783587056000},"page":"1002","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, and Biological Evaluation of Novel Morpholine\u2013Coumarin Derivatives for Inflammation-Associated Depression"],"prefix":"10.3390","volume":"16","author":[{"given":"Hui","family":"Liu","sequence":"first","affiliation":[{"name":"Key Laboratory of Natural Medicines of the Changbai Mountain, Yanbian University, Ministry of Education, Yanji 133002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Macromolecular Drugs and Large-Scale Preparation, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalan","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Natural Medicines of the Changbai Mountain, Yanbian University, Ministry of Education, Yanji 133002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheshan","family":"Quan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Natural Medicines of the Changbai Mountain, Yanbian University, Ministry of Education, Yanji 133002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Medicine, Foshan University, Foshan 528000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiben","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Macromolecular Drugs and Large-Scale Preparation, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingkun","family":"Shen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Natural Medicines of the Changbai Mountain, Yanbian University, Ministry of Education, Yanji 133002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"149313","DOI":"10.1016\/j.brainres.2024.149313","article-title":"Depression unveiled: Insights into etiology and animal models for behavioral assessment, exploring the multifactorial nature and treatment of depression","volume":"1847","author":"More","year":"2025","journal-title":"Brain Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"105014","DOI":"10.1016\/j.ajp.2026.105014","article-title":"Short-term effects of oral ketamine for the treatment of depression: A systematic review and meta-analysis of randomized controlled trials","volume":"121","author":"Shenoy","year":"2026","journal-title":"Asian J. 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