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

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. (C) 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.