基于 3-aminopyridin-2(1H)-one 的新型单硫代草胺和 1,3,4-thiadiazoles 的设计、合成、光谱表征、计算分析和体外 α-淀粉酶和 α-葡萄糖苷酶评价,Organic & Biomolecular Chemistry

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基于 3-aminopyridin-2(1H)-one 的新型单硫代草胺和 1,3,4-thiadiazoles 的设计、合成、光谱表征、计算分析和体外 α-淀粉酶和 α-葡萄糖苷酶评价
Organic & Biomolecular Chemistry ( IF 2.9 ) Pub Date : 2022-10-26 , DOI: 10.1039/d2ob01772e
Irina V Palamarchuk ₁ , Zarina T Shulgau ₂ , Adilet Y Dautov ₂ , Shynggys D Sergazy ₂ , Ivan V Kulakov ₁

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由于全世界糖尿病发病率的增加，寻找新的安全有效的α-淀粉酶和α-葡萄糖苷酶抑制剂的紧迫性越来越大。在本工作中，我们尝试开展单硫代草酰胺新衍生物的合成、修饰及综合计算机和生物学研究。结果表明，基于 3-氨基吡啶-2(1 H ) 的单硫代草酰胺)-ones 与水合肼发生转酰胺基反应，形成相应的硫代酰肼。此外，在氯乙酰氯和琥珀酸酐的作用下，这些硫代酰肼环化成共轭的1,3,4-噻二唑衍生物。使用AutoDock Vina程序通过分子对接评估所得产物可能的生物活性。与已知的抗糖尿病药物阿卡波糖和 TAK-875 相比，化合物7a和8b对选定的靶蛋白显示出更高的结合亲和力。获得的 1,3,4-噻二唑新衍生物在体外试验中对 α-淀粉酶和 α-葡萄糖苷酶具有足够高的抑制活性值以及足够低的 IC ₅₀值（8b 122.2 μM），比参考药物阿卡波糖的值（998.3 μM）小 8 倍。在人类新生儿真皮成纤维细胞的 MTT 测试中，所有单硫代草酰胺5-8(a-c) 的合成衍生物在生理浓度下均未显示出细胞毒性。此外，一些化合物（6a–c、7a–c、8b、c）显示出显着的细胞保护活性。因此，根据计算机计算和体外生物筛选的结果，我们合成的化合物5-8(a-c)显示出潜在的抗糖尿病活性和进一步深入研究包括体内研究的良好前景。

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Design, synthesis, spectroscopic characterization, computational analysis, and in vitro α-amylase and α-glucosidase evaluation of 3-aminopyridin-2(1H)-one based novel monothiooxamides and 1,3,4-thiadiazoles

Due to the growth in the incidence of diabetes mellitus throughout the world, the urgency in the search for new safe and effective inhibitors of α-amylase and α-glucosidase is increasing. In this work, we attempted to carry out studies on the synthesis, modification and comprehensive computer and biological research of new derivatives of monothiooxamides. It was shown that monothiooxamides based on 3-aminopyridin-2(1H)-ones enter into transamidation reactions with hydrazine hydrate to form the corresponding thiohydrazides. Furthermore, under the action of chloroacetyl chloride and succinic anhydride, these thiohydrazides are cyclized into conjugated 1,3,4-thiadiazole derivatives. The possible biological activity of the obtained products was evaluated by molecular docking using the AutoDock Vina program. Compounds 7a and 8b showed higher binding affinities for selected target proteins compared to the known anti-diabetic drugs acarbose and TAK-875. The obtained new derivatives of 1,3,4-thiadiazole showed sufficiently high values of inhibitory activity in the in vitro test against the enzymes α-amylase and α-glucosidase as well as sufficiently low IC₅₀ values (for 8b 122.2 μM), which is 8 times less than the value for the reference drug acarbose (998.3 μM). All synthesized derivatives of monothiooxamides 5–8(a–c) showed no cytotoxic properties at physiological concentrations in the MTT test in human neonatal dermal fibroblasts. Moreover, some compounds (6a–c, 7a–c, 8b,c) showed pronounced cytoprotective activity. Thus, the compounds 5–8(a–c) synthesized by us, both according to the results of computer calculations and in vitro biological screening, showed their potential antidiabetic activity and high prospects for further in-depth studies, including in vivo studies.

更新日期：2022-10-26

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