School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, China.
Bioorg Med Chem Lett. 2021 Nov 15;52:128413. doi: 10.1016/j.bmcl.2021.128413. Epub 2021 Oct 8.
In this present study, a series of novel (E)-2-benzylidene-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)hydrazine-1-carboxamide derivatives against α-glucosidase were designed and synthesized, and their biological activities were evaluated in vitro and in vivo. Most of the designed analogues exhibited better inhibitory activity than the marketed acarbose, especially the most potent compound 7 with an IC value of 9.26 ± 1.84 μM. The direct binding of 7 and 8 with α-glucosidase was confirmed by fluorescence quenching experiments, and the kinetic and molecular docking studies revealed that 7 and 8 inhibited α-glucosidase in a non-competitive manner. Cytotoxicity bioassay indicated compounds 7 and 8 were non-toxic towards LO2 and HepG2 at 100 μM. Furthermore, both compounds were demonstrated to have in vivo hypoglycemic activity by reducing the blood glucose levels in sucrose-treated rats.
在本研究中，设计并合成了一系列新型的（E）-2-苄亚基-N-（3-氰基-4,5,6,7-四氢苯并[b]噻吩-2-基）肼-1-甲酰胺衍生物，用于抑制α-葡萄糖苷酶，并对其进行了体外和体内的生物活性评价。大多数设计的类似物的抑制活性均优于市售的阿卡波糖，特别是最有效的化合物 7，其 IC 值为 9.26±1.84μM。荧光猝灭实验证实了 7 和 8 与 α-葡萄糖苷酶的直接结合，动力学和分子对接研究表明 7 和 8 以非竞争性方式抑制α-葡萄糖苷酶。细胞毒性测定表明，化合物 7 和 8 在 100μM 时对 LO2 和 HepG2 无毒性。此外，这两种化合物在蔗糖处理的大鼠中均表现出体内降血糖活性，能够降低血糖水平。
