Discovery of novel tert-butylhydroquinone derivatives as potential anti-endothelial injury agents: Synthesis, in vitro, and in vivo evaluation

  • Bioorg Chem. 2026 Jul 15:176:109865. doi: 10.1016/j.bioorg.2026.109865.
Juan Zhang  1 ,  Meng-Qi Ma  2 ,  Ming-Zhu Shao  2 ,  Jin-He Zhang  3 ,  Nai-Yu Zhang  2 ,  Kong-Kai Zhu  4 ,  Chao Liu  5 ,  Cheng-Shi Jiang  6 ,  Ning Meng  7 ,  Jia-Hong Wang  8
Affiliations
  • 1. Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou 310013, Zhejiang, China; School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
  • 2. School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
  • 3. School of Traditional Chinese Medicine, Zhanjiang University of Science and Technology, Zhanjiang 524094, China.
  • 4. Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
  • 5. Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs/Key Laboratory of Agro-Products Processing Technology of Shandong Province, Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, Jinan 250100, China.. Electronic address: [email protected].
  • 6. School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: [email protected].
  • 7. School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: [email protected].
  • 8. Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou 310013, Zhejiang, China. Electronic address: [email protected].
PMID: 42000455 DOI: 10.1016/j.bioorg.2026.109865
Abstract

Tert-butyl hydroquinone (tBHQ) is widely used as a food additive due to its superior protective properties, making it a valuable component in the food, cosmetic, and pharmaceutical industries. This study focused on the discovery of novel tBHQ derivatives as potential vascular endothelial cell (VEC) protective agents by evaluating their potential in mitigating VEC injury, including Apoptosis and Ferroptosis induced by ox-LDL, HG, or CoCl2 in vitro, as well as endothelial dysfunction in diabetic mice induced by STZ. Notably, compound 3 h demonstrated robust efficacy in protecting VECs against injury induced by these stimuli. Additionally, compound 3 h attenuated vascular fibrosis in diabetic mice. The protective mechanisms of compound 3 h were associated with the stimulation of the Nrf2 signaling pathway, which resulted in the dissociation of Nrf2 from Keap1, Nrf2 nuclear translocation, and an increase in the production of downstream antioxidant Enzymes such as HO-1 and GPX4, ultimately preventing damage to HUVECs. The present results suggest that compound 3 h could be a promising lead compound in the treatment of cardiovascular diseases associated with VEC injury.

Keywords
Nrf2 activator; Nrf2-Keap1 PPI; Vascular endothelial cells; tBHQ derivatives.
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