Design, synthesis and anti-Parkinson's disease bioactivity evaluation of isoquinoline derivatives as potent IDO1/TDO dual inhibitors.

Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) are potential targets for the development of PD according to current research; nevertheless, reports on dual hIDO1/hTDO inhibitors against PD are still lacking. In this study, a series of isoquinoline derivatives were designed, synthesized, and evaluated as novel IDO1/TDO dual inhibitors. Among them, Y-13 showed potent inhibitory activities against both IDO1 (IC50 = 2.87 ± 0.93 μM) and TDO (IC50 = 0.08 ± 0.01 μM). The neuroprotective efficiency of Y-13 against PD was explored in vitro and in vivo. It was found that Y-13 could protect BV2 cells from neuroinflammation by inhibiting NO and ROS generation and improve cognitive function, learning ability, and motor performance in a MPTP-induced PD rat model. In general, our study has demonstrated that Y-13 has significant efficacy against PD in vitro and in vivo experiments, which can provide guidance for the development of IDO1/TDO dual inhibitors to treat PD.