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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。
The target compounds TM1 and TM2 were designed and synthesized based on the 3-amino-modification of the TZD nucleus in this study. The target compounds TM1 and TM2 were designed and synthesized by using bioactive thiazolidine-2,4-dione (TZDs) The target molecules TM3 ~ TM6 with rhodanine units were designed and synthesized. The target molecules with phenolic hydroxyl groups were linked with Linker and carbazole, and the target molecule TM7 with similar structure as TZDs was designed and synthesized . In vitro activity of peroxisome proliferator activated receptor response element (PPRE), α-glucosidase inhibitory activity and protein tyrosine phosphatase-1B (PTP-1B) inhibitory activity assay showed that most of the target compounds The activities of PTP-1B of TM2-6, TM7b-2 and TM7b-4 were very good. The inhibitory activity of TM2-6 was up to 96.71%, the IC50 was as low as 1.48 mg · L -1, Outperform positive control. The structure-activity relationship shows that the TZD loop changes and the PPAR activation activity becomes weaker. Toxicity prediction shows that highly active compounds are almost non-toxic. These results have some reference to the development of new anti-diabetic drugs.