Design, Synthesis, and Biological Evaluation of Dual Functional Inhibitors Targeting Indoleamine 2,3-dioxygenase 1 (IDO1) and Tryptophan 2,3-dioxygenase (TDO)

Tryptophan metabolism via the kynurenine pathway plays a critical role in immune regulation and neurobiology. Dysregulation of this pathway, particularly through overactivation of indoleamine 2,3-dioxygenases (IDOs) and tryptophan 2,3-dioxygenase (TDO), has been implicated in various pathological conditions, including Cancer, depression, chronic pain, and neurodegenerative diseases. Here, we report the design and synthesis of a novel class of dual IDO1/TDO inhibitors featuring a 5,6-dihydroimidazothiazole core linked to a urea motif via an alkyl spacer. These compounds were evaluated for their inhibitory activity against IDO1 and TDO using cellular-based enzymatic activity assays. Most compounds demonstrated higher potency toward IDO1, as indicated by EC₅₀ values below 5 μM, and showed moderate potency against TDO, with EC₅₀ values ranging from 10 to 20 μM. Furthermore, at a concentration of 5 μM, the compounds significantly suppressed the lipopolysaccharide-induced proinflammatory cytokines production in macrophages. These findings identify a novel chemical scaffold with dual inhibitory activity against IDO1/TDO and anti-inflammatory effects, suggesting potential for therapeutic application in Cancer and inflammatory diseases.

IDO1; SAR; TDO; antiinflammation; imidazothiazole.