Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Central Research Laboratory, Shiraz University of Medical Sciences, Shiraz, Iran.
Sci Rep. 2022 May 23;12(1):8647. doi: 10.1038/s41598-022-11771-y.
In this work, a novel series of cyanoacetohydrazide linked to 1,2,3-triazoles (9a-n) were designed and synthesized to be evaluated for their anti-α-glucosidase activity, focusing on the fact that α-glucosidase inhibitors have played a significant role in the management of type 2 diabetes mellitus. All synthesized compounds except 9a exhibited excellent inhibitory potential, with IC values ranging from 1.00 ± 0.01 to 271.17 ± 0.30 μM when compared to the standard drug acarbose (IC = 754.1 ± 0.5 μM). The kinetic binding study indicated that the most active derivatives 9b (IC = 1.50 ± 0.01 μM) and 9e (IC = 1.00 ± 0.01 μM) behaved as the uncompetitive inhibitors of α-glucosidase with K = 0.43 and 0.24 μM, respectively. Moreover, fluorescence measurements were conducted to show conformational changes of the enzyme after binding of the most potent inhibitor (9e). Calculation of standard enthalpy (ΔH°) and entropy (ΔS°) values confirmed the construction of hydrophobic interactions between 9e and the enzyme. Also, docking studies indicated desired interactions with important residues of the enzyme which rationalized the in vitro results.
在这项工作中，设计并合成了一系列新型的氰基乙酰胺连接到 1,2,3-三唑（9a-n），以评估它们的抗α-葡萄糖苷酶活性，这主要是因为α-葡萄糖苷酶抑制剂在 2 型糖尿病的治疗中发挥了重要作用。除了 9a 之外，所有合成的化合物都表现出了优异的抑制潜力，与标准药物阿卡波糖（IC=754.1±0.5μM）相比，其 IC 值范围为 1.00±0.01 至 271.17±0.30μM。动力学结合研究表明，最活跃的衍生物 9b（IC=1.50±0.01μM）和 9e（IC=1.00±0.01μM）表现为α-葡萄糖苷酶的非竞争性抑制剂，K值分别为 0.43 和 0.24μM。此外，荧光测量表明，最有效抑制剂（9e）结合后，酶的构象发生变化。标准焓（ΔH°）和熵（ΔS°）值的计算证实了 9e 与酶之间形成了疏水相互作用。此外，对接研究表明，与酶的重要残基存在所需的相互作用，这合理地解释了体外结果。
