Department of Chemistry, Allama Iqbal Open University, Islamabad, Pakistan.
Department is genetics and Inherited diseases, College of Medicine, Centre for Genetics and Inherited Diseases (CGID), Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia.
Drug Dev Res. 2019 Aug;80(5):646-654. doi: 10.1002/ddr.21542. Epub 2019 Apr 29.
A series of N-(5-(alkylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamides 6a-i were synthesized as alkaline phosphatase inhibitors. The intermediate 5-substituted 1,3,4-oxadiazole-2-thione 4 was synthesized starting with hippuric acid. Hippuric acid in the first step was converted into corresponding methyl ester 2 which upon reaction with hydrazine hydrate furnished the formation of hydrazide 3. The hippuric acid hydrazide was then cyclized into 5-substituted 1,3,4-oxadiazole-2-thione 4. The intermediate 4 was then reacted with alkyl or aryl halides 5a-5i to afford the title compounds N-(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamides 6a-i. The bioassay results showed that compounds 6a-i exhibited good to excellent alkaline phosphatase inhibitory activity. The most potent activity was exhibited by the compound 6i having IC value 0.420 μM, whereas IC value of standard (KH PO ) was 2.80 μM. Molecular docking studies was performed against alkaline phosphatase enzyme (PDBID 1EW2) to check binding affinity of the synthesized compounds 6a-i against target protein. The docking results showed that three compounds 6c, 6e, and 6i have maximum binding interactions with binding energy values of -8 kcal/mol. The compound 6i displayed the interactions of oxadiazole ring nitrogen with amino acid His265 having a binding distance 2.13 Ǻ. It was concluded from our results that synthesized compounds, especially compound 6i may serve as lead structure to design more potent inhibitors of human alkaline phosphatase.
一系列 N-(5-(烷基硫代)-1,3,4-恶二唑-2-基)甲基)苯甲酰胺 6a-i 被合成作为碱性磷酸酶抑制剂。中间产物 5-取代 1,3,4-恶二唑-2-硫酮 4 是从苯甲酰乙酸开始合成的。第一步中，苯甲酰乙酸转化为相应的甲酯 2，与水合肼反应生成酰肼 3。然后，苯甲酰肼环化成 5-取代 1,3,4-恶二唑-2-硫酮 4。然后，中间体 4 与烷基或芳基卤化物 5a-5i 反应，得到标题化合物 N-(5-(甲硫基)-1,3,4-恶二唑-2-基)甲基)苯甲酰胺 6a-i。生物测定结果表明，化合物 6a-i 表现出良好到优异的碱性磷酸酶抑制活性。活性最强的是化合物 6i，IC 值为 0.420 μM，而标准品 (KH PO )的 IC 值为 2.80 μM。进行了针对碱性磷酸酶酶 (PDBID 1EW2) 的分子对接研究，以检查合成化合物 6a-i 对靶蛋白的结合亲和力。对接结果表明，三种化合物 6c、6e 和 6i 与结合能值为-8 kcal/mol 的结合蛋白具有最大的结合相互作用。化合物 6i 显示出恶二唑环氮与具有结合距离 2.13 Ǻ的氨基酸 His265 的相互作用。从我们的结果可以得出结论，合成的化合物，特别是化合物 6i，可以作为设计更有效的人碱性磷酸酶抑制剂的先导结构。
