2. Academic Validation
  3. Proof of concept study for developing 1-thienyl-β-carboline derivatives as IDO1 and TDO dual inhibitors to treat Parkinson's disease complicating depression

Proof of concept study for developing 1-thienyl-β-carboline derivatives as IDO1 and TDO dual inhibitors to treat Parkinson's disease complicating depression

  • Eur J Med Chem. 2025 Jul 5:291:117597. doi: 10.1016/j.ejmech.2025.117597.
Xuan Chen 1,  Mengxiao Zhu 2,  Qingyuan Shi 2,  Zhenquan Huang 2,  Junjie Zhu 2,  Pingping Sun 2,  Hongzhen Zhang 2,  Lili Yang 2,  Xun Chen 2,  Yu Zhang 3,  Lili Feng 2,  Katsuhisa Horimoto 4,  Fei Li 5,  Feng Han 6,  Dongyin Chen 7
Affiliations

Affiliations

  • 1 Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, International Joint Laboratory for Drug Target of Critical Illnesses, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China; School of Pharmaceutical Engineering, Jiangsu Food and Pharmaceutical Science College, Huaian, 223003, China.
  • 2 Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, International Joint Laboratory for Drug Target of Critical Illnesses, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
  • 3 Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, International Joint Laboratory for Drug Target of Critical Illnesses, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China; Innovation Center of Suzhou Nanjing Medical University, Suzhou, 215000, Jiangsu, China; National Center of Technology Innovation for Biopharmaceuticals, Suzhou, 215000, Jiangsu, China.
  • 4 SOCIUM Inc., Koto-ku, Tokyo, 1350064, Japan.
  • 5 Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, International Joint Laboratory for Drug Target of Critical Illnesses, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China. Electronic address: kldlf@njmu.edu.cn.
  • 6 Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, International Joint Laboratory for Drug Target of Critical Illnesses, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China; Innovation Center of Suzhou Nanjing Medical University, Suzhou, 215000, Jiangsu, China; The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Northern Jiangsu Institute of Clinical Medicine, Huaian, 223300, China; Institute of Brain Science, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, 210029, China. Electronic address: fenghan169@njmu.edu.cn.
  • 7 Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, International Joint Laboratory for Drug Target of Critical Illnesses, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China; Innovation Center of Suzhou Nanjing Medical University, Suzhou, 215000, Jiangsu, China; National Center of Technology Innovation for Biopharmaceuticals, Suzhou, 215000, Jiangsu, China; The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Northern Jiangsu Institute of Clinical Medicine, Huaian, 223300, China. Electronic address: chendongyin@njmu.edu.cn.
PMID: 40215562 DOI: 10.1016/j.ejmech.2025.117597
Abstract

Depressive symptoms are the most common neuropsychiatric disorders at all stages of Parkinson's disease (PD). Imbalances of the kynurenine pathway of tryptophan metabolism have been closely linked to the pathogenesis of PD and depression. Herein, we designed and synthesized a series of 1-thienyl-β-carboline derivatives as IDO1 and TDO dual inhibitors; among them, compound CZ-17 manifested moderate inhibitory activities to IDO1 and TDO with IC50 values of 0.33 and 1.78 μM, respectively. CZ-17 inhibited the kynurenine pathway of tryptophan degradation at the cellular level, and remarkably reduced the kynurenine/tryptophan ratio. CZ-17 displayed directly neuroprotective effect in corticosterone-induced PC12 neural cell injury model. In vivo experiments demonstrated that CZ-17 significantly increased dopamine and serotonin levels, improved MPTP-induced motor disability and rescued LPS-induced depressive behavior in zebrafish model. Acute toxicity tests of CZ-17 in zebrafish embryos showed no toxicity within the effective dose range. Additionally, CZ-17 displayed the potential to cross the BBB via passive diffusion according to ADMET prediction and Caco-2 permeability assay. Thus, CZ-17 may be a promising drug candidate for PD complicating depression.

Keywords

Depression; IDO1; Parkinson's disease; TDO; β-carboline.

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