Department of Biology, Damghan branch, Islamic Azad University, Damghan, Iran.
Department of Chemistry, Islamic Azad University, North Tehran Branch, Tehran, Iran.
Daru. 2020 Jun;28(1):109-117. doi: 10.1007/s40199-019-00322-y. Epub 2020 Jan 6.
One of the therapeutic approaches in the management of Type 2 diabetes is delaying the absorption of glucose through α-glucosidase enzymes inhibition, which can reduce the incidence of postprandial hyperglycemia. The existence of chronic postprandial hyperglycemia impaired the endogenous antioxidant defense due to inducing oxidative stress induced pancreatic β-cell destruction through uncontrolled free radicals generation such as ROS, which in turn, leads to various macrovascular and microvascular complications. This study aimed to synthesize 2-aryl-4,6-diarylpyrimidine derivatives, screen their α-glucosidase inhibitory activity, perform kinetic and molecular docking studies.
A series of 3,4,5-triphenyl-4,5-dihydro-1,2,4-oxadiazole derivatives were synthesized and their α-glucosidase inhibitory activity was screened in vitro. Compounds 6a-k were synthesized via a two-step reaction with a yield between 65 and 88%. The structural elucidation of the synthesized derivatives was performed by different spectroscopic techniques. α-Glucosidase inhibitory activity of the oxadiazole derivatives 6a-k was evaluated against Saccharomyces cerevisiae α-glucosidase.
Most of the synthesized compounds demonstrated α-glucosidase inhibitory action. Particularly compounds 6c, 6d and 6 k were the most active compounds with IC values 215 ± 3, 256 ± 3, and 295 ± 4 μM respectively. A kinetic study performed for compound 6c revealed that the compound is a competitive inhibitor of Saccharomyces cerevisiae α-glucosidase with K of 122 μM. The docking study also revealed that the two compounds, 6c and 6 k, have important binding interactions with the enzyme active site.
The overall results of our study reveal that the synthesized compounds could be a potential candidate in the search for novel α-glucosidase inhibitors to manage the postprandial hyperglycemia incidence. Graphical abstract.
2 型糖尿病治疗方法之一是通过抑制α-葡萄糖苷酶来延缓葡萄糖的吸收，从而降低餐后高血糖的发生率。慢性餐后高血糖会导致内源性抗氧化防御受损，因为自由基的产生会导致氧化应激，从而破坏胰腺β细胞，这些自由基如 ROS 不受控制地产生，进而导致各种大血管和微血管并发症。本研究旨在合成 2-芳基-4,6-二芳基嘧啶衍生物，筛选其α-葡萄糖苷酶抑制活性，并进行动力学和分子对接研究。
通过两步反应合成了一系列 3,4,5-三苯基-4,5-二氢-1,2,4-噁二唑衍生物，并在体外筛选其α-葡萄糖苷酶抑制活性。通过两步反应合成了 6a-k 化合物，产率在 65%至 88%之间。通过不同的光谱技术对合成衍生物的结构进行了阐明。用酿酒酵母α-葡萄糖苷酶评价噁二唑衍生物 6a-k 的α-葡萄糖苷酶抑制活性。
大多数合成化合物表现出α-葡萄糖苷酶抑制作用。特别是化合物 6c、6d 和 6k 是最具活性的化合物，IC 值分别为 215±3、256±3 和 295±4μM。对化合物 6c 的动力学研究表明，该化合物是酿酒酵母α-葡萄糖苷酶的竞争性抑制剂，K 值为 122μM。对接研究还表明，这两种化合物 6c 和 6k 与酶的活性位点有重要的结合相互作用。
我们的研究结果表明，所合成的化合物可能是寻找新型α-葡萄糖苷酶抑制剂以管理餐后高血糖发生率的潜在候选药物。
