title: Novel hybrids of optically active ring-opened 3-n-butylphthalide derivative and isosorbide as potential anti-ischemic stroke agents.
abstract: In search of novel anti-ischemic stroke agents with higher potency than a known drug 3-n-butylphthalide (NBP), a series of hybrids ((S)- and (R)-5a-f) from optically active ring-opened NBP derivative and isosorbide were synthesized for evaluating their anti-ischemic stroke activity. Compound (S)-5e displayed the strongest activity in inhibiting the adenosine diphosphate (ADP) and arachidonic acid (AA)-induced platelet aggregation in vitro, with 10.0- and 8.4-fold more effectiveness than (S)-NBP, respectively. Furthermore, (S)-5e was stable in artificial gastrointestinal fluids and could penetrate the blood-brain barrier (BBB) with an appreciate lipid/water partition coefficient relative to (S)-NBP. More importantly, oral treatment with (S)-5e protected from acute thrombosis and inhibited the ischemia/reperfusion-related brain injury in animals. Our findings suggest that (S)-5e may be promising for further evaluation for the intervention of ischemic stroke.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.forename: Linna
authors.initials: L
authors.lastname: Wang
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.forename: Zhangjian
authors.initials: Z
authors.lastname: Huang
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Lai
authors.forename: Hui
authors.initials: H
authors.lastname: Ji
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Wan
authors.forename: Jinyi
authors.initials: J
authors.lastname: Xu
authors.forename: Jide
authors.initials: J
authors.lastname: Tian
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001812:Blood-Brain Barrier; D007547:Isosorbide / Q000737:chemistry*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D013237:Stereoisomerism; D020521:Stroke / Q000188:drug therapy*
chemical_list: D001572:Benzofurans; D010975:Platelet Aggregation Inhibitors; C027125:3-n-butylphthalide; D007547:Isosorbide