Although multivalent glucosidase inhibitors based on iminosugars have shown enhanced inhibition activity, an effective way to improve their hypoglycemic effect in vivo, is still in infancy and needs further development. In this paper, PBI-5DNJ and PBI-6DNJ, with three or four DNJ moieties respectively conjugated at the bay position were synthesized. PBI-6DNJ evidenced stronger π-π stacking interactions and, when self-assembled, a smaller size than that of PBI-5DNJ. It was found that PBI-6DNJ exhibited superior α-glucosidases (from mice) inhibition activity (K_i = 0.14 ± 0.007 μM) in vitro than that (K_i = 0.31 ± 0.01) of PBI-5DNJ and in vivo hypoglycemic effects in mice models. PBI-6DNJ possessed good hypoglycemic effects with the percentages of PBG levels of 40.40 ± 3.33% and 39.23 ± 4.84% at a dose of 2.0 mg/kg after 15 min and 30 min of administration, respectively. In terms of measuring percentage decrease of PBG level per DNJ unit, PBI-6DNJ displayed a 2.1-fold enhancement than miglitol, demonstrating a consistency between in vitro and in vivo experiments. This paves the way to the connection between in vivo hypoglycemic potency and in vitro glucosidase inhibition assay, leading to reliable and simplified assessment of hypoglycemic potency determination, and opening a basic understanding of the design of multivalent glucosidase inhibitors.

虽然基于亚氨基糖的多价葡萄糖苷酶抑制剂已显示出增强的抑制活性，但提高其体内降血糖作用的有效途径仍处于起步阶段，需要进一步开发。在本文中，合成了 PBI-5DNJ和PBI-6DNJ，它们分别在bay位置缀合了三个或四个DNJ部分。PBI-6DNJ证明了更强的 π-π 堆叠相互作用，并且当自组装时，其尺寸小于PBI-5DNJ。发现PBI-6DNJ在体外表现出优于（ K _i =  0.14 ± 0.007 μM）的α-葡萄糖苷酶（来自小鼠）抑制活性_i  = 0.31 ± 0.01) PBI-5DNJ和小鼠模型的体内降血糖作用。PBI-6DNJ在2.0 mg/kg剂量下给药15 min和30 min后，PBG水平百分比分别为40.40±3.33%和39.23±4.84%，具有良好的降血糖作用。在测量每 DNJ 单位的 PBG 水平下降百分比方面，PBI-6DNJ显示出比米格列醇增强 2.1 倍，证明了体外和体内实验之间的一致性。这为体内降血糖效力与体外之间的联系铺平了道路葡萄糖苷酶抑制测定，导致对低血糖效力测定的可靠和简化评估，并开启对多价葡萄糖苷酶抑制剂设计的基本了解。