2. Academic Validation
  3. Discovery of Trolox amide derivatives as potent membrane-targeted ferroptosis inhibitors for corneal injury therapy

Discovery of Trolox amide derivatives as potent membrane-targeted ferroptosis inhibitors for corneal injury therapy

  • Eur J Med Chem. 2026 Sep 5:313:118880. doi: 10.1016/j.ejmech.2026.118880.
Jingyi Wang 1,  Cheng Liu 1,  Huiying Huang 2,  Silvio Osella 3,  Shuhuan Ai 1,  Yu Zhang 1,  Jiasheng Yang 4,  Jiang-Fan Chen 5,  Feng He 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; Oujiang Laboratory (Zhejiang Laboratory for Regenerative Medicine, Vision and Brain Health), School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 2 National Engineering Research Center of Ophthalmology and Optometry, School of Biomedical Engineering, School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; Materials and Processes Simulation Lab, Centre of New Technologies, University of Warsaw, Banacha 2C, Warsaw, 02-097, Poland.
  • 3 Materials and Processes Simulation Lab, Centre of New Technologies, University of Warsaw, Banacha 2C, Warsaw, 02-097, Poland.
  • 4 Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 5 State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; Oujiang Laboratory (Zhejiang Laboratory for Regenerative Medicine, Vision and Brain Health), School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: chenjf555@gmail.com.
  • 6 State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; Oujiang Laboratory (Zhejiang Laboratory for Regenerative Medicine, Vision and Brain Health), School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: fenghe@wmu.edu.cn.
PMID: 42060968 DOI: 10.1016/j.ejmech.2026.118880
Abstract

Vitamin E and its water-soluble analogue Trolox are potent radical scavengers but require high concentrations to inhibit Ferroptosis effectively. The discovery of a Trolox amide derivative 1 showing 95-fold greater potency inspired the systematic synthesis of a focused library. Most amide derivatives demonstrated significantly enhanced potency, with IC50 values in the sub-micromolar range. Notably, compound 20, which features an indazole moiety, emerged as the most potent inhibitor, exhibiting a 556-fold improvement in activity (IC50 = 0.036 μM) over Trolox and a favorable safety index. Mechanistically, compound 20 selectively inhibits Ferroptosis (not Apoptosis or Necroptosis) by scavenging ROS and suppressing lipid peroxidation independently of glutathione. Molecular dynamics simulations reveal its preferential membrane localization within the peroxidation-active mid-chain region, exhibiting confined lateral motion and local enrichment, and adopting a preferred orientation of the phenolic hydroxyl toward the hydrophobic core with low structural fluctuation, facilitated by indazole-lipid headgroup hydrogen bonding. In a murine model of corneal alkali burn, topical administration of compound 20 significantly ameliorate corneal neovascularization and edema. These findings highlight Trolox amide derivatives as promising anti-ferroptosis agents with translational prospects for treating ocular surface diseases.

Keywords

Corneal injury; Ferroptosis; Trolox; Vitamin E.

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