含 1,3,4-噻二唑的 2,5-二取代呋喃衍生物作为有效的α-葡萄糖苷酶和 E. coliβ-葡萄糖醛酸酶抑制剂。
2,5-Disubstituted furan derivatives containing 1,3,4-thiadiazole moiety as potent α-glucosidase and E. coli β-glucuronidase inhibitors.
机构信息
College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou, 310014, China.
State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou, 510642, China.
出版信息
Eur J Med Chem. 2021 Apr 15;216:113322. doi: 10.1016/j.ejmech.2021.113322. Epub 2021 Feb 23.
In this paper, the 2,5-disubstituted furan derivatives containing 1,3,4-thiadiazole were synthesized and screened for their inhibitory activity against α-glucosidase and β-glucuronidases to obtain potent α-glucosidase inhibitor 9 (IC = 0.186 μM) and E. coli β-glucuronidase inhibitor 26 (IC = 0.082 μM), respectively. The mechanisms of the compounds were studied. The kinetic study revealed that compound 9 is a competitive inhibitor against α-glucosidase (Ki = 0.05 ± 0.003 μM) and molecular docking simulation showed several key interactions between 9 and the target including hydrogen bond and p-π stacking interaction. Derivative 26 (Ki = 0.06 ± 0.005 μM) displayed uncompetitive inhibition behavior against EcGUS. Furthermore, the result of docking revealed the furan ring of 26 may be a key moiety in obstructing the active domain of EcGUS. In addition, compound 15 exhibited significant inhibitory activity against these two enzymes, with potential therapeutic effects against diabetes and against CPT-11-induced diarrhea. At the same time, their low toxicity against normal liver tissue LO2 cells lays the foundation for in vivo studies and the development of bifunctional drug.
在本文中，合成了含有 1,3,4-噻二唑的 2,5-取代呋喃衍生物，并对其抑制α-葡萄糖苷酶和β-葡萄糖醛酸酶的活性进行了筛选，分别得到了具有较强α-葡萄糖苷酶抑制活性的化合物 9（IC50=0.186 μM）和大肠杆菌β-葡萄糖醛酸酶抑制剂 26（IC50=0.082 μM）。研究了这些化合物的作用机制。动力学研究表明，化合物 9 是一种竞争性的α-葡萄糖苷酶抑制剂（Ki=0.05±0.003 μM），分子对接模拟表明化合物 9 与靶标之间存在几个关键相互作用，包括氢键和 p-π 堆积相互作用。衍生物 26（Ki=0.06±0.005 μM）对 EcGUS 表现出非竞争性抑制作用。此外，对接结果表明，26 的呋喃环可能是阻碍 EcGUS 活性域的关键部分。此外，化合物 15 对这两种酶表现出显著的抑制活性，具有治疗糖尿病和伊立替康诱导性腹泻的潜力。同时，它们对正常肝组织 LO2 细胞的低毒性为体内研究和双功能药物的开发奠定了基础。
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