Novel 3-n-butylphthalide derivatives as potent multi-functional anti-IS agents with BBB protective function

  • Bioorg Chem. 2025 Dec:167:109237. doi: 10.1016/j.bioorg.2025.109237.
Li Shao  1 ,  Gaofeng Lin  1 ,  Zhaoxing Chu  2 ,  Jiajia Mo  2 ,  Qinlong Xu  2 ,  Yan Zhao  2 ,  Qihua Zhu  3 ,  Shiqi Wu  3 ,  Shaoyun Yue  2 ,  Xiaodong Ma  4 ,  Guangwei He  5 ,  Jiaming Li  6
Affiliations
  • 1. College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China; Hefei Institute of Pharmaceutical Industry Co.,Ltd., Hefei 230088, China.
  • 2. Hefei Institute of Pharmaceutical Industry Co.,Ltd., Hefei 230088, China.
  • 3. Department of Medicinal Chemistry, College of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 4. College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China; Institute of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei 230012, China; Anhui Province Key Laboratory of Bioactive Natural Products, Hefei 230012, China. Electronic address: [email protected].
  • 5. Hefei Institute of Pharmaceutical Industry Co.,Ltd., Hefei 230088, China. Electronic address: [email protected].
  • 6. College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China; Institute of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei 230012, China; Anhui Province Key Laboratory of Bioactive Natural Products, Hefei 230012, China. Electronic address: [email protected].
PMID: 41270613 DOI: 10.1016/j.bioorg.2025.109237
Abstract

The discovery of multi-functional small-molecule compounds with potent blood-brain barrier (BBB) protective effect for treating ischemic stroke (IS) is a relatively unexplored area. Herein, a series of 33 novel hybrid molecules were rationally designed and synthesized via incorporating 4-methoxybenzyl alcohol-mimicking pharmacophore (With potential BBB protective activity) into 3-n-butylphthalide (NBP) scaffold. Among them, the representative compound 30 exhibited enhanced neuroprotective, anti-inflammatory, anti-oxidative, and BBB protective activities than those of NBP. After the chiral resolution, the neuroprotective potency of R-enantiomer (R-30) was identified to be more potent than the S-enantiomer. In vivo, R-30 significantly reduced infarct volume and markedly preserved BBB integrity. Furthermore, it displayed a good safety profile in acute toxicity study. These findings support the potential of R-30 as a multi-functional anti-IS candidate that deserves further development.

Keywords
BBB protective; Chiral resolution; Ischemic stroke; Multi-functional; Neuroprotection.
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