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  3. Discovery of 8-hydroxy-tetrahydroquinoline ferroptosis inhibitors for the treatment of acute kidney injury

Discovery of 8-hydroxy-tetrahydroquinoline ferroptosis inhibitors for the treatment of acute kidney injury

  • Bioorg Chem. 2025 Sep:164:108874. doi: 10.1016/j.bioorg.2025.108874.
Xie-Huang Sheng 1,  Lin-Song Teng 2,  Xiang-Shuai Meng 1,  Yuan-Hao Song 1,  Zhao-Hua Liu 3,  Jing-Wen Sun 1,  Deng-Feng Wu 4,  Jian-Ping Ma 5,  Lei Zhang 6
Affiliations

Affiliations

  • 1 College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan 250014, China.
  • 2 Second Clinical Medical College of Shandong University of Traditional Chinese Medicine, Jinan 250001, China.
  • 3 The Model Animal Research Center, Cheeloo College of medicine, Shandong University, Jinan 250014, China.
  • 4 School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
  • 5 College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan 250014, China. Electronic address: xxgk123@163.com.
  • 6 Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Tissue Engineering Laboratory, Department of Radiology, Shandong First Medical University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan 250014, China. Electronic address: qygkzl1818@163.com.
PMID: 40834455 DOI: 10.1016/j.bioorg.2025.108874
Abstract

Acute kidney injury (AKI) is a severe public health challenge, characterized by high incidence and mortality rates, alongside a lack of effective therapeutic interventions. Emerging evidence highlights kidney tubular Ferroptosis as a key driver of AKI pathogenesis. While α-tocopherol, a natural lipid antioxidant, exhibits potent anti-ferroptotic activity, its therapeutic potential remains limited by a lack of structural optimization. Here, we present the discovery of 8-hydroxy-tetrahydroquinoline (compound 6), a rationally designed derivative inspired by α-tocopherol's simplified core structure (6-chromanol), which effectively protects against renal ischemia/reperfusion (I/R) injury by suppressing Ferroptosis. Quantum chemistry and reaction kinetics analyses reveal that enhancing p-π conjugation and introducing hydrogen bond donors significantly improve radical trapping activity (RTA), thereby strengthening Ferroptosis inhibition. Compound 6 displayed broad-spectrum anti-ferroptotic efficacy across multiple inducers in renal tubular epithelial cells, with nanomolar potency and robust suppression of lipid ROS. Mechanistically, compound 6 neither chelated iron nor altered GPX4 expression, indicating its protection arises via direct peroxyl radical scavenging. In vivo, compound 6 significantly ameliorated renal I/R injury in mice, reducing histological damage, functional impairment, and inflammatory cytokine expression, while decreasing lipid peroxidation biomarkers such as 4-hydroxynonenal. Collectively, this work identifies compound 6 as a promising ferroptosis-targeted therapeutic scaffold for AKI and provides a framework for rational antioxidant design based on natural phenolic structures.

Keywords

8-hydroxy-tetrahydroquinoline; Acute kidney injury; Antioxidants; Ferroptosis; H-bond donor; Α-Tocopherol.

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