Design and synthesis of the ring-opened derivative of 3-n-butylphthalide-ferulic acid-glucose trihybrids as potential anti-ischemic agents

S2 is 30-fold more water-soluble, over 10-fold more potent in inhibition of platelet aggregation, and more effectively reduces ROS generation, protects primary neuronal cells from OGD/R-induced damage, as well as improves PK profile and active component distribution in rodent brain as compared to 3-n-butylphthalide (NBP), suggesting that S2 may be a potential anti-ischemia stroke agent. [Display omitted] To improve aqueous solubility and anti-ischemic activity of 3-n-butylphthalide (NBP), we designed and synthesized the ring-opened derivative of NBP-ferulic acid-glucose trihybrids (S1-S8). These hybrids inhibited adenosine diphosphate (ADP)- or arachidonic acid (AA)-induced platelet aggregation, among them, S2 was 30-fold more water-soluble, and over 10-fold more potent in inhibition of platelet aggregation, as well as reduced ROS generation and protected primary neuronal cells from OGD/R-induced damage, in comparison with NBP. Additionally, S2 was more active than its three moieties alone or in combination, suggesting that the activity of S2 may be attributed to the synergistic effects of these moieties. Importantly, in vivo studies indicated that S2 not only possessed good pharmacokinetic profile, but also improved NBP distribution in rodent brain, suggesting that the glucose moiety in S2 may be recognized by glucose transporter 1 (GLUT1) on blood-brain barrier (BBB), promoting it to penetrate through BBB. Our findings suggest that S2 may be a promising candidate for the intervention of ischemic stroke, warranting further study.