2. Academic Validation
  3. Identification of imidazo[1,2-a]pyridine-3-amine as a novel drug-like scaffold for efficious ferroptosis inhibition in vivo

Identification of imidazo[1,2-a]pyridine-3-amine as a novel drug-like scaffold for efficious ferroptosis inhibition in vivo

  • Eur J Med Chem. 2025 Jun 5:290:117516. doi: 10.1016/j.ejmech.2025.117516.
Jilei Wang 1,  Xuejing Fan 1,  Xinyu Han 1,  Huicong Liang 2,  Pei-Pei Xie 3,  Huimei Qian 1,  Luo Bao 1,  Qianer Zhang 1,  Qin Song 1,  Yao Ning 1,  Yicheng Wang 1,  Ximing Xu 2,  Xue Qiu 1,  Yong Wang 4
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, Shandong, PR China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, PR China.
  • 2 Marine Biomedical Research Institute of Qingdao, School of Medicine and Pharmacy, Key Laboratory of Marine Drugs, Chinese Ministry of Education, Ocean University of China, Qingdao, 266003, Shandong, PR China.
  • 3 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
  • 4 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, Shandong, PR China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, PR China. Electronic address: wangyong8866@ouc.edu.cn.
PMID: 40117856 DOI: 10.1016/j.ejmech.2025.117516
Abstract

Ferroptosis has emerged as a promising therapeutic approach for a wide range of diseases. However, limited chemical diversity and poor drug-like profiles have hindered the development of effective Ferroptosis inhibitors for clinical use. Herein, we identified drug-like imidazo[1,2-a]pyridine-3-amine derivatives as innovative Ferroptosis inhibitors for injury-related diseases by drug scaffold repositioning strategy. Our findings established that the selected compounds exhibited high radical scavenging and effective membrane retention, thereby leading to significant suppression of lipid peroxidation and Ferroptosis at nanomolar concentrations. Notably, compound C18, with low cytotoxicity and favorable pharmacokinetics properties, demonstrated remarkable in vivo neuroprotection against ischemic brain injury in mice. In conclusion, our investigations not only engender potent Ferroptosis inhibitors with novel structural characteristics that warrant further development, but also serve as a valuable case study for drug repurposing in the discovery of additional Ferroptosis inhibitors.

Keywords

Anti-ferroptosis; Drug repurposing; Ischemic injury; Multicomponent reaction; Radical-trapping antioxidants; Scaffold repurposing.

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