Design, Synthesis of 3-n-Butylphthalide-Hydrazine/Hydrazide Derivatives as Potential Anti-Ischemic Stroke Agents.

To identify novel therapeutic candidates for ischemic stroke, a series of hydrazine- and hydrazide-derived analogs based on 3-n-butylphthalide (NBP) were designed and synthesized in this study, and their anti-ischemic stroke activities were systematically assessed. Among all synthesized derivatives, the compound NBP-HY exerted potent antiplatelet aggregation and antioxidant activities in vitro. Consistent in vivo results revealed that NBP-HY significantly alleviated thrombus formation in both carrageenan-induced tail thrombosis and FeCl3-induced carotid artery thrombosis models. In a rat middle cerebral artery occlusion/reperfusion (MCAO/R) injury model, NBP-HY markedly reduced cerebral infarct volume, improved cerebral blood perfusion, and protected hippocampal CA1 and cortical neurons, exhibiting superior therapeutic efficacy compared with the lead compound NBP. Further pharmacological experiments showed that NBP-HY exhibits moderate metabolic stability in liver microsomes, good blood-brain barrier permeability in the PAMPA-BBB model, and minimal impact on mice's physiological hemostatic function. Collectively, this work indicates that NBP‑HY has potential as a therapeutic candidate for ischemic stroke and warrants further in‑depth investigation.