Research progress of 3-n-butylphthalide and its derivatives in combating cerebral ischemia

Ischemic stroke (IS) poses a significant threat to human life and health due to its high disability and mortality rates. 3-n-butylphthalide (NBP) is derived from celery seeds, a plant indigenous to the Mediterranean and belonging to the Apiaceae family, and first launched in China for the treatment of acute IS in 2004. NBP exhibits multiple target actions, including reconstructing the microcirculation in the cerebral ischemia area, inhibiting platelet aggregation, reducing the volume of cerebral infarction, maintaining the integrity of the blood-brain barrier (BBB), and enhancing cerebral blood perfusion. Nevertheless, its overall efficacy is moderate, hindered by poor water solubility and low bioavailability, which restricts its clinical application. To overcome this limitation, researchers have been diligently engaged in the development of NBP derivatives and analogs, and have made some progress. These endeavors, encompassing various strategies such as substituent introduction, ring opening derivatization, esterification, and atom substitution, have significantly diversified the NBP derivatives. Encouragingly, several NBP derivatives have currently entered clinical studies. Among them, PHPB, BZP, and ZONK1103 have all entered phase II clinical trials, and AAPB has received approval for clinical trial in 2024. From the perspective of medicinal chemistry, this review focuses on the structural modification and optimization of NBP in the recent two decades, with the aim of exerting positive influences on the development of more excellent derivatives and the advancement of the cerebral ischemia treatment field.