Design, Synthesis, and Biological Evaluation of Novel Morpholine–Coumarin Derivatives for Inflammation-Associated Depression

The tryptophan–kynurenine 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–coumarin derivatives were designed and synthesized as dual IDO1/TDO inhibitors. Through in vitro enzyme screening, compound14dexhibited potent inhibitory activity with IC50values of 0.34 µM and 0.75 µM, respectively. In lipopolysaccharide (LPS)-stimulated BV2 microglial cells,14ddownregulated IDO1/TDO expression, suppressed pro-inflammatory cytokines (IL-1β, COX-2, iNOS, TNF-α), and upregulated the anti-inflammatory cytokine IL-10. In an LPS-induced acute depressive mouse model established in C57BL/6 mice, intraperitoneal administration of14d(20 mg/kg) significantly reduced immobility time in the forced swim and tail suspension tests, without affecting spontaneous locomotor activity. Mechanistic studies revealed that14dinhibited 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 of14dwith the active sites of IDO1 and TDO. These findings suggest that14drepresents a promising dual IDO1/TDO inhibitor lead compound for the treatment of inflammation-associated depression through modulation of the kynurenine pathway and neuroinflammatory responses.