He Min, Li Yuan-Jing, Shao Jiang, Li Ya-Sheng, Cui Zi-Ning
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, College of Plant Protection, South China Agricultural University, Guangzhou 510642, China.
Department of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Bioorg Med Chem Lett. 2023 Mar 1;83:129173. doi: 10.1016/j.bmcl.2023.129173. Epub 2023 Feb 9.
α-Glucosidase, which is involved in the hydrolysis of carbohydrates to glucose and directly mediates blood glucose elevation, is a crucial therapeutic target for type 2 diabetes. In this work, 2,5-disubstituted furan derivatives containing 1,3-thiazole-2-amino or 1,3-thiazole-2-thiol moiety (III-01 ∼ III-30) were synthesized and screened for their inhibitory activity against α-glucosidase. α-Glucosidase inhibition assay demonstrated that all compounds had IC in the range of 0.645-94.033 μM and more potent than standard inhibitor acarbose (IC = 452.243 ± 54.142 µM). The most promising inhibitors of the two series were compound III-10 (IC = 4.120 ± 0.764 μM) and III-24 (IC = 0.645 ± 0.052 μM), respectively. Kinetic study and molecular docking simulation revealed that compound III-10 (Ki = 2.04 ± 0.72 μM) is a competitive inhibitor and III-24 (Ki = 0.44 ± 0.53 μM) is a noncompetitive inhibitor against α-glucosidase. Significantly, these two compounds showed nontoxicity towards HEK293, RAW264.7 and HepG2 cells, suggesting that compounds may be considered as a class of potential candidates for further developing novel antidiabetic drugs.
α-葡萄糖苷酶参与碳水化合物水解为葡萄糖的过程，并直接介导血糖升高，是2型糖尿病的关键治疗靶点。在本研究中，合成了含有1,3-噻唑-2-氨基或1,3-噻唑-2-硫醇部分的2,5-二取代呋喃衍生物（III-01至III-30），并对其α-葡萄糖苷酶抑制活性进行了筛选。α-葡萄糖苷酶抑制试验表明，所有化合物的IC50在0.645 - 94.033 μM范围内，且比标准抑制剂阿卡波糖（IC50 = 452.243 ± 54.142 μM）更有效。这两个系列中最有前景的抑制剂分别是化合物III-10（IC50 = 4.120 ± 0.764 μM）和III-24（IC50 = 0.645 ± 0.052 μM）。动力学研究和分子对接模拟表明，化合物III-10（Ki = 2.04 ± 0.72 μM）是α-葡萄糖苷酶的竞争性抑制剂，III-24（Ki = 0.44 ± 0.53 μM）是非竞争性抑制剂。值得注意的是，这两种化合物对HEK293、RAW264.7和HepG2细胞均无毒性，表明这些化合物可被视为进一步开发新型抗糖尿病药物的一类潜在候选物。
