{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:03:58Z","timestamp":1789016638176,"version":"build-2803163510"},"reference-count":457,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T00:00:00Z","timestamp":1745280000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research, Development, and Innovation Office\u2014NKFIH","award":["K138125"],"award-info":[{"award-number":["K138125"]}]},{"name":"National Research, Development, and Innovation Office\u2014NKFIH","award":["2022\/5S729"],"award-info":[{"award-number":["2022\/5S729"]}]},{"name":"SZTE SZAOK-KKA","award":["K138125"],"award-info":[{"award-number":["K138125"]}]},{"name":"SZTE SZAOK-KKA","award":["2022\/5S729"],"award-info":[{"award-number":["2022\/5S729"]}]},{"name":"HUN-REN Hungarian Research Network","award":["K138125"],"award-info":[{"award-number":["K138125"]}]},{"name":"HUN-REN Hungarian Research Network","award":["2022\/5S729"],"award-info":[{"award-number":["2022\/5S729"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Quinoline-derived metabolites exhibit notable chemical complexity. What causes minor structural alterations to induce significant changes in disease outcomes? Historically, eclipsed by more straightforward scaffolds, these chemicals serve as a dynamic hub in tryptophan metabolism, linking immunomodulation, excitotoxicity, and cancer. However, many of these compounds struggle to cross the blood\u2013brain barrier, and we still do not fully understand how certain structural changes affect their bioavailability or off-target effects. Thus, contemporary research highlights halogenation, esterification, and computational modeling to enhance structure\u2013activity relationships. Summary: This narrative review emphasizes the integration of rational drug design, multi-target ligands, and prodrug methods in enhancing quinoline scaffolds. We explore each molecule\u2019s therapeutic promise, refine each scaffold\u2019s design, and develop each derivative to maximize clinical utility. Translating these laboratory findings into clinical practice, however, remains a formidable challenge. Conclusions: Through the synthesis of findings regarding NMDA receptor antagonism, improved oral bioavailability, and reduced metabolic instability, we demonstrate how single-site changes might modulate excitotoxicity and immunological signaling. Advancing quinoline-based medicines will yield significant advancements in neurology, psychiatry, and oncology. This enlarged framework fosters collaborative discovery, engages various audiences, and advances the field towards next-generation disease-modifying therapies. Robust preclinical validation, patient classification, and comprehensive toxicity evaluations are crucial stages for achieving these extensive endeavors and fostering future therapeutic discoveries globally.<\/jats:p>","DOI":"10.3390\/ph18050607","type":"journal-article","created":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T20:24:52Z","timestamp":1745353492000},"page":"607","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Quinoline Quest: Kynurenic Acid Strategies for Next-Generation Therapeutics via Rational Drug Design"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4383-4024","authenticated-orcid":false,"given":"Masaru","family":"Tanaka","sequence":"first","affiliation":[{"name":"Danube Neuroscience Research Laboratory, HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, University of Szeged (HUN-REN-SZTE), Tisza Lajos krt. 113, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8571-5229","authenticated-orcid":false,"given":"Istv\u00e1n","family":"Szatm\u00e1ri","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry and HUN-REN\u2013SZTE Stereochemistry Research Group, University of Szeged, E\u00f6tv\u00f6s u. 6, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e1szl\u00f3","family":"V\u00e9csei","sequence":"additional","affiliation":[{"name":"Danube Neuroscience Research Laboratory, HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, University of Szeged (HUN-REN-SZTE), Tisza Lajos krt. 113, H-6725 Szeged, Hungary"},{"name":"Department of Neurology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3333","DOI":"10.1111\/jnc.16015","article-title":"Tryptophan metabolism as a \u2018reflex\u2019 feature of neuroimmune communication: Sensor and effector functions for the indoleamine-2,3-dioxygenase kynurenine pathway","volume":"168","author":"Stone","year":"2024","journal-title":"J. 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