Novel Pyrazolo[3,4-d]pyrimidine-Containing Amide Derivatives: Synthesis, Molecular Docking, In Vitro and In Vivo Antidiabetic Activity
Novel Pyrazolo[3,4-d]pyrimidine-Containing Amide Derivatives: Synthesis, Molecular Docking, In Vitro and In Vivo Antidiabetic Activity
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DOI：
10.1002/slct.201900208
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发表时间：
2019-09-13
期刊：
影响因子：
2.1
通讯作者：
Reddy, Anreddy Rama Narsimha
中科院分区：
文献类型：
--
作者：
Reddy, Bijivemula N.;Ruddarraju, Radhakrishnam Raju;Reddy, Anreddy Rama Narsimha
设计、合成了一系列新的含吡唑并[3，4-d]嘧啶的酰胺衍生物（8a-l），并评价了它们的体外α-淀粉酶抑制活性。目标化合物的IC 50值范围为1.60 +/- 0.48 - 2.04 +/- 1.20 μ M，而标准阿卡波糖为1.73 +/- 0.05 μ M。所有的吡唑并[3，4-d]嘧啶酰胺衍生物均表现出较好的抑制活性，（8 d、8 f、8 g、8 h、8 i、8 j和8 k）显示出或多或少的等效活性，IC 50值为1.77 +/- 2.84、1.65 +/- 0.45、1.66 +/- 2.24、1.73 +/- 0.37、1.74 +/-0.37、1.75 +/- 0.45、1.66 +/- 0.37、1.73 +/- 0.37、1.75 +/-0.分别为1.60 ± 0.48、1.75 ± 0.36和1.64 ± 0.03 μ M。此外，还筛选了最有效的α-淀粉酶抑制剂8 d和8 k在25和50 mg/kg剂量下对四氧嘧啶诱导的糖尿病大鼠模型的体内抗糖尿病活性。这些测试化合物的口服给药以剂量依赖性方式显著降低空腹血糖水平。这些化合物的降血糖作用在测试化合物给药后3小时和5小时更明显，这与阳性对照显示的作用相似。此外，从与α-淀粉酶（PDB ID：1HNY）的对接研究计算的结合能和生物活性表明，在苯基上含有硝基部分的化合物显著地有助于抗糖尿病活性。
A new series of Pyrazolo[3,4-d]pyrimidine containing amide derivatives (8 a-l) were designed, synthesized, and evaluated for their in vitro alpha-amylase inhibitory activity. The IC50 values of the target compounds ranged from 1.60 +/- 0.48 to 2.04 +/- 1.20 mu M as compared to the standard acarbose 1.73 +/- 0.05 mu M. All the Pyrazolo[3,4-d]pyrimidine amide derivatives displayed good inhibitory activities, while seven analogs (8 d, 8 f, 8 g, 8 h, 8 i, 8 j and 8 k) exhibited more or less equipotent activity with IC50 values 1.77 +/- 2.84, 1.65 +/- 0.45, 1.66 +/- 2.24, 1.73 +/- 0.37, 1.60 +/- 0.48, 1.75 +/- 0.36 and 1.64 +/- 0.03 mu M respectively. Further, the most potent alpha-amylase inhibitors 8 d and 8 k were also screened for their in vivo antidiabetic activity against alloxan induced diabetic rat model at the dose of 25 and 50 mg/kg. Oral administration of these tested compounds significantly reduced the fasting blood glucose levels in dose dependent manner. The hypoglycemic effects of these compounds were more evident at 3 h and 5 h after administration of tested compounds which was similar to the effect displayed by the positive control. In addition, the binding energies calculated from the docking studies with the alpha-amylase enzyme (PDB ID: 1HNY) and biological activities indicate that the compounds containing nitro moiety on the phenyl group contributed significantly towards the antidiabetic activity.