Tanaka Masaru, Szatmári István, Vécsei László
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.
Institute of Pharmaceutical Chemistry and HUN-REN-SZTE Stereochemistry Research Group, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary.
Pharmaceuticals (Basel). 2025 Apr 22;18(5):607. doi: 10.3390/ph18050607.
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-brain 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-activity relationships.
This narrative review emphasizes the integration of rational drug design, multi-target ligands, and prodrug methods in enhancing quinoline scaffolds. We explore each molecule's therapeutic promise, refine each scaffold's design, and develop each derivative to maximize clinical utility. Translating these laboratory findings into clinical practice, however, remains a formidable challenge.
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.
喹啉衍生的代谢物具有显著的化学复杂性。是什么导致微小的结构改变引发疾病结果的显著变化？从历史上看，这些化学物质被更简单的支架结构所掩盖，它们在色氨酸代谢中起着动态枢纽的作用，连接着免疫调节、兴奋性毒性和癌症。然而，这些化合物中的许多难以穿过血脑屏障，而且我们仍然不完全了解某些结构变化如何影响它们的生物利用度或脱靶效应。因此，当代研究强调卤化、酯化和计算建模以增强构效关系。
这篇叙述性综述强调了合理药物设计、多靶点配体和前药方法在增强喹啉支架结构方面的整合。我们探索每个分子的治疗前景，优化每个支架结构的设计，并开发每个衍生物以最大化临床效用。然而，将这些实验室研究结果转化为临床实践仍然是一项艰巨的挑战。
通过综合关于N-甲基-D-天冬氨酸（NMDA）受体拮抗作用、改善口服生物利用度和降低代谢不稳定性的研究结果，我们展示了单点变化如何调节兴奋性毒性和免疫信号传导。推进基于喹啉的药物将在神经病学、精神病学和肿瘤学领域取得重大进展。这个扩大的框架促进了合作发现，吸引了不同的受众，并推动该领域朝着下一代疾病修饰疗法发展。强大的临床前验证、患者分类和全面的毒性评估是实现这些广泛努力并促进全球未来治疗发现的关键阶段。
