Novel indole-based indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors: design, synthesis, and antidepressant evaluation

Indoleamine 2,3-dioxygenase-1 (IDO1) has emerged as a promising therapeutic target for antidepressant development. The present study performed scaffold hopping-based structural optimization of a known benzimidazole-derived IDO1 inhibitor C-0 (20.20 ± 2.27 nM), which yielded a series of novel indole-based IDO1 inhibitors. Among these, the 6-fluoroindole/indole-2-carboxamide hybrid 9f and the 6-fluoroindole/4-bromopyrrole-2-carboxamide hybrid 10f exhibited the most improved IDO1 inhibitory activity, achieving IC₅₀ values of 9.18 ± 0.84 and 6.57 ± 0.61 nM, respectively. In addition, compound 10f demonstrated anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Further study revealed that compounds 9f and 10f had improved in vitro and in vivo pharmacokinetic properties compared to the controls, and rescued LPS-induced depressive-like behavior in mice. The present study provides indole-based IDO1 inhibitors as a promising lead compound for the development of novel and effective IDO1-targeted antidepressants.