摘要Ischemic stroke(IS)presents a major threat to human life and health due to its high disability and mortality rates.3-n-Butylphthalide(NBP),derived from celery seeds of the Apiaceae fam-ily native to the Mediterranean region,was first introduced in China for acute IS treatment in 2004.NBP demonstrates multiple therapeutic actions,including reconstruction of microcircu-lation in the cerebral ischemia area,inhibition of platelet aggregation,reduction of cerebral infarction volume,maintenance of blood-brain barrier(BBB)integrity,and enhancement of cerebral blood perfusion.However,its overall efficacy remains moderate,limited by poor wa-ter solubility and low bioavailability,which constrains its clinical application.To address these limitations,researchers have actively pursued the development of NBP derivatives and analogs,achieving notable progress.These efforts,including substituent introduction,ring opening derivatization,esterification,and atom substitution,have generated diverse NBP de-rivatives.Several of these derivatives have advanced to clinical studies.Specifically,potassi-um 2-(1-hydroxypentyl)-benzoate(PHPB),brozopentyl sodium(BZP),and XY-03-EA(ZONK1103)have reached phase Ⅱ clinical trials,while(S)-2-(1-acetoxypentyl)benzoic acid L-arginine salt(AAPB)has received clinical trial approval for 2024.This review examines the structural modification and optimization of NBP over the past two decades from a medicinal chemistry perspective,aiming to facilitate the development of superior derivatives and ad-vance cerebral ischemia treatment.