5-芳亚甲基噻唑烷-2,4-二酮衍生物的设计合成及抗糖尿病活性研究

发布时间：2018-10-17 19:44

【摘要】：以本研究室发现的高活性噻唑烷-2,4-二酮类(TZDs)化合物为先导物,对其TZD母核的3位氨基修饰,设计并合成了目标分子TM1和TM2;利用生物电子等排和拼合原理,设计并合成了含绕丹宁结构单元的目标分子TM3~TM6;将含酚羟基的目标分子与Linker和咔唑连接,设计并合成了与传统TZDs结构类似的目标分子TM7。体外过氧化物酶体增殖物激活受体反应元件(PPRE)激动活性、α-葡萄糖苷酶抑制活性与蛋白质酪氨酸磷酸酶-1B(PTP-1B)抑制活性测定结果显示,多数目标化合物的活性均较弱,但化合物TM2-6、TM7b-2和TM7b-4的PTP-1B抑制活性很好,其中TM2-6抑制活性高达96.71%、IC50低至1.48 mg·L~(-1),优于阳性对照物。构效关系表明,TZD环改变,PPAR激动活性变弱。毒性预测显示,高活性化合物几乎无毒性。这些结果对新型抗糖尿病药物的研制具有一定的借鉴意义。
[Abstract]:The target molecules TM1 and TM2; were designed and synthesized by using the highly active thiazolidine-2azolidine-4-diketone compounds as the lead, and the 3-position amino modification of their TZD parent nuclei. The target molecules TM1 and TM2; were designed and synthesized by using the principle of equal arrangement and assembly of biological electrons. The target molecule TM3~TM6; with the structure unit around tannin is designed and synthesized. The target molecule containing phenolic hydroxyl groups is connected with Linker and carbazole. The target molecule TM7., which is similar to the traditional TZDs structure, is designed and synthesized. The activity of peroxisome proliferator activated receptor (PPRE), 伪 -glucosidase inhibitory activity and protein tyrosine phosphatase 1B (PTP-1B) inhibitory activity were measured in vitro. But the PTP-1B inhibitory activity of compound TM2-6,TM7b-2 and TM7b-4 was very good, and the inhibitory activity of TM2-6 was as high as 96.71% and the IC50 was as low as 1.48 mg L ~ (-1), which was superior to the positive control. The structure-activity relationship showed that the TZD ring changed and the activation activity of PPAR became weaker. Toxicity prediction showed that highly active compounds were almost nontoxic. These results are useful for the development of new anti-diabetic drugs.
【作者单位】：西南大学化学化工学院重庆市高校应用化学重点实验室生物有机与药物化学研究所;
【基金】：国家自然科学基金应急项目资助(21542003)
【分类号】：R914;R96

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