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

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

  • Bioorg Med Chem Lett. 2026 Feb 22:136:130596. doi: 10.1016/j.bmcl.2026.130596.
Zhongzhen Yang 1,  Zhiqian Lin 2,  Chunyan Yang 2,  Runxin Lu 3,  Yong Wu 4
Affiliations

Affiliations

  • 1 Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
  • 2 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
  • 3 Department of Pharmacy/Evidence-Based Pharmacy Center, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Children's Medicine Key Laboratory of Sichuan Province, NMPA Key Laboratory for Technical Research on Drug Products In Vitro and In Vivo Correlation, West China Second University Hospital, Sichuan University, Chengdu 610041, PR China. Electronic address: [email protected].
  • 4 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China. Electronic address: [email protected].
PMID: 41734858 DOI: 10.1016/j.bmcl.2026.130596
Abstract

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.

Keywords

Anti-inflammatory effects; Isoquinoline derivatives; Neuroprotective effects; Parkinson's disease; Tryptophan-kynurenine pathway.

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