Unraveling the Alkaline Phosphatase Inhibition, Anticancer, and Antileishmanial Potential of Coumarin-Triazolothiadiazine Hybrids: Design, Synthesis, and Molecular Docking Analysis
Unraveling the Alkaline Phosphatase Inhibition, Anticancer, and Antileishmanial Potential of Coumarin-Triazolothiadiazine Hybrids: Design, Synthesis, and Molecular Docking Analysis
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DOI：
10.1002/ardp.201500392
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发表时间：
2016-07-01
影响因子：
5.1
通讯作者：
Saeed, Aamer
中科院分区：
文献类型：
--
作者：
Ibrar, Aliya;Zaib, Sumera;Saeed, Aamer
利用分子杂化的概念，设计合成了一系列新的香豆素-三唑并噻二嗪杂化化合物(5a-j)。环缩合反应涉及香豆素基4-氨基-1，2，4-三唑和一系列溴苯乙酮，以良好的产率提供了所需的产品。根据光谱分析数据确定了所合成化合物的结构。合成的化合物对碱性磷酸酶(ALP)的活性进行了评价，其中化合物5J在杂环的3-和6-位含有双香豆素基序，是一种有效的抑制剂，IC50值为1.15+/-1.0mU M。合成的化合物还对大利什曼原虫和5h进行了抗利什曼原虫活性测试，IC50值为0.89+/-0.08mU M。化合物5I对H-157细胞具有最强的细胞毒作用，其IC50值为1.01+/-0.12mU，与长春新碱和顺铂相比，其抑制作用有所提高。对合成的抗碱性磷酸酶香豆素-三唑并噻嗪杂化文库进行了分子对接研究。几乎所有的化合物都与受体活性部位的关键残基有很强的相互作用。在化合物5a-c、5h和5j的情况下，对接结果与实验筛选结果是积极的补充。这些结果为进一步开发这些化合物作为碱性磷酸酶的有效抑制剂提供了有力的证据。
A series of new coumarin-triazolothiadiazine hybrid compounds (5a-j) was designed and synthesized by using the molecular hybridization concept. The cyclocondensation reaction involves the coumarinyl 4-amino-1,2,4-triazole and a range of bromo-acetophenones, delivering the desired products in good yields. The structures of the synthesized compounds were established on the basis of spectro-analytical data. The prepared compounds were evaluated against alkaline phosphatase (ALP) where compound 5j incorporating bis-coumarinyl motifs at the 3- and 6-positions of the heteroaromatic core turned out to be a potent inhibitor with an IC50 value of 1.15 +/- 1.0 mu M. The synthesized compounds were also tested against Leishmania major and 5h was the lead member with an IC50 value of 0.89 +/- 0.08 mu M. Anticancer activity was also determined using kidney fibroblast (BHK-21) and lung carcinoma (H-157) cancer cell lines. Compound 5i showed highest cytotoxic potential against H-157 cells with an IC50 value of 1.01 +/- 0.12 mu M, which is an improved inhibition compared to the standards (vincristine and cisplatin) used in this assay. Molecular docking studies were carried out on the synthesized library of coumarin-triazolothiadiazine hybrids against ALP. Almost all of the compounds showed strong interactions with the key residues of the active site of the receptor. In case of compounds 5a-c, 5h, and 5j, docking results positively complemented the experimental screening. These results provided substantial evidence for the further development of these compounds as potent inhibitors of ALP.