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

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.