Novel Hydroxychalcone-Based Dual Inhibitors of Aldose Reductase and α-Glucosidase as Potential Therapeutic Agents against Diabetes Mellitus and Its Complications,Journal of Medicinal Chemistry

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Novel Hydroxychalcone-Based Dual Inhibitors of Aldose Reductase and α-Glucosidase as Potential Therapeutic Agents against Diabetes Mellitus and Its Complications
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-06-24 , DOI: 10.1021/acs.jmedchem.2c00380
Xiaonan Zhang ₁ , Long Xu ₁ , Huan Chen ₁ , Xin Zhang ₁ , Yanqi Lei ₁ , Wenchao Liu ₁ , Hulin Xu ₁ , Bing Ma ₁ , Changjin Zhu ₁

Affiliation

We designed a novel series of bifunctional inhibitors of α-glucosidase and aldose reductase (ALR2) based on the structure of hydroxychalcone. The two enzymes relate to blood glucose level and anomalously elevated polyol pathway of glucose metabolism under hyperglycemia, respectively. Most compounds in the series exhibited a potent inhibitory activity for both enzymes, and a significant antioxidant property was shown. Further in vivo studies of 11j and 14d using streptozotocin (STZ)-induced diabetic rats as a model found that 11j achieved not only good antihyperglycemic and glucose tolerance effect in a dose-dependent manner (p < 0.01) but also showed effective inhibition of polyol pathway. 14d significantly suppressed the maltose-induced postprandial glucose elevation. Additionally, they effectively improved lipid metabolisms and restored an antioxidant ability. Therefore, the two compounds may be promising agents for the prevention and treatment of diabetic complications.

中文翻译：

基于羟基查耳酮的醛糖还原酶和α-葡萄糖苷酶双重抑制剂作为糖尿病及其并发症的潜在治疗剂

我们基于羟基查耳酮的结构设计了一系列新型的α-葡萄糖苷酶和醛糖还原酶（ALR2）双功能抑制剂。这两种酶分别与血糖水平和高血糖下异常升高的葡萄糖代谢多元醇途径有关。该系列中的大多数化合物对这两种酶都表现出有效的抑制活性，并显示出显着的抗氧化特性。以链脲佐菌素（STZ）诱导的糖尿病大鼠为模型，进一步对11j和14d进行的体内研究发现， 11j不仅以剂量依赖性方式实现了良好的降血糖和葡萄糖耐量作用（p < 0.01），而且对多元醇有有效的抑制作用。途径。14天显着抑制麦芽糖引起的餐后血糖升高。此外，它们有效地改善了脂质代谢并恢复了抗氧化能力。因此，这两种化合物可能是预防和治疗糖尿病并发症的有前景的药物。

更新日期：2022-06-24

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