Department of Applied Chemistry, School of Chemical Engineering and Environment, Beijing Institute of Technology, Zhongguancun South Street, 100081 Beijing, China.
J Med Chem. 2010 Dec 9;53(23):8330-44. doi: 10.1021/jm100962a. Epub 2010 Nov 9.
A series of novel benzothiadiazine 1,1-dioxide derivatives were synthesized and tested for their inhibitory activity against aldose reductase. Of these derivatives, 17 compounds, having a substituted N2-benzyl group and a N4-acetic acid group on the benzothiadiazine, were found to be potent and selective aldose reductase inhibitors in vitro with IC50 values ranging from 0.032 to 0.975 μM. 9m proved to be the most active in vitro. The eight top-scoring compounds coming from the in vitro test for ALR2 inhibition activity were then tested in vivo, whereby three derivatives, 9i, 9j, and 9m, demonstrated a significantly preventive effect on sorbitol accumulation in the sciatic nerve in the 5-day streptozotocin-induced diabetic rats in vivo. Structure-activity relationship and molecular docking studies highlighted the importance of substitution features of N4-acetic acid group and halogen-substituted N2-benzyl group in the benzothiadiazine scaffold and indicated that substitution with hallogen at C-7 had a remarkably strong effect on ALR2 inhibition potency.
一系列新型苯并噻二嗪 1,1-二氧化物衍生物被合成并测试其对醛糖还原酶的抑制活性。在这些衍生物中，有 17 种化合物，苯并噻二嗪上的 N2-苄基和 N4-乙酸基团被取代，被发现是体外具有强效和选择性的醛糖还原酶抑制剂，IC50 值范围为 0.032 到 0.975 μM。9m 在体外表现出最强的活性。然后，从 ALR2 抑制活性的体外测试中选出的 8 种评分最高的化合物在体内进行测试，其中 3 种衍生物 9i、9j 和 9m，在体内 5 天链脲佐菌素诱导的糖尿病大鼠坐骨神经中，对山梨醇积累表现出显著的预防作用。构效关系和分子对接研究强调了 N4-乙酸基团和卤素取代的 N2-苄基取代特征在苯并噻二嗪骨架中的重要性，并表明 C-7 上的卤素取代对 ALR2 抑制活性有很强的影响。
