Novel 1,3,4-oxadiazole hybrids of 3-n-butylphthalide derivatives as potential anti-ischemic stroke agents

In continuation of our program to search for novel potential anti-ischemic stroke agents, a series of 1,3,4-oxadiazole and sulfoxide hybrids of phthalide derivatives was designed and synthesized in this study to evaluate their anti-ischemic stroke activity. Among them, compounds 5b, 5d, 5 l, and 5 m exhibited excellent inhibitory effects on platelet aggregation induced by adenosine diphosphate (ADP) and arachidonic acid (AA). In particular, compound 5b possessed considerable antithrombotic activity in animal models, as demonstrated by the effective alleviation of carrageenan-induced and FeCl3-induced thrombosis in tail and carotid arteries, respectively. Notably, intraperitoneal administration of compound 5b could better protect the brain from injury caused by ischemia/reperfusion in rats compared with precursor 3-n-butylphthalide. Further pharmacokinetics, liver microsomal stability, and PAMPA-BBB assays also indicated that compound 5b had relatively high bioavailability, metabolic stability, and BBB permeability. Moreover, compound 5b showed a safety profile that was superior to the clinical drugs clopidogrel, aspirin, and 3-n-butylphthalide in the mouse-tail bleeding assay. Finally, molecular docking predicted that the potential target of the antiplatelet aggregation activity of compound 5b was P2Y12 receptor. This research provides a novel candidate compound for the treatment of ischemic stroke.