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

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

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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