Department of Applied Chemistry, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081 Beijing, China.
Bioorg Med Chem. 2011 Dec 1;19(23):7262-9. doi: 10.1016/j.bmc.2011.07.051. Epub 2011 Jul 30.
Due to the importance of aldose reductase (ALR2) as a potential drug target in the treatment of diabetic complications, there are increasing interests in design and synthesis of ALR2 inhibitors. Here, we prepared 1,2-benzothiazine 1,1-dioxide acetic acid derivatives and investigated their inhibition activity. Most of these derivatives were found to be active with IC(50) values ranging from 0.11 μM to 10.42 μM, and compound 8d, 2-[2-(4-bromo-2-fluorobenzyl)-1,1-dioxido-2H-1,2-benzothiazin-4(3H)-ylidene]acetic acid, showed the most potent inhibition activity. Further, SAR and docking studies suggest that in comparison with the α,β-unsaturated derivatives, the saturated carboxylic acid derivatives had a greater binding affinity with the enzyme and thus an enhanced inhibition activity. Therefore, development of more powerful ARIs based on benzothiazine 1,1-dioxide by stereo-controlled synthesis could be expected.
由于醛糖还原酶 (ALR2) 作为治疗糖尿病并发症的潜在药物靶点非常重要，因此人们越来越关注 ALR2 抑制剂的设计和合成。在这里，我们制备了 1,2-苯并噻嗪 1,1-二氧化物乙酸衍生物，并研究了它们的抑制活性。这些衍生物大多数具有活性，IC50值范围为 0.11 μM 至 10.42 μM，化合物 8d，2-[2-(4-溴-2-氟苄基)-1,1-二氧代-2H-1,2-苯并噻嗪-4(3H)-亚基]乙酸，表现出最强的抑制活性。此外，SAR 和对接研究表明，与α,β-不饱和衍生物相比，饱和羧酸衍生物与酶具有更大的结合亲和力，因此具有增强的抑制活性。因此，通过立体控制合成，基于苯并噻嗪 1,1-二氧化物开发更有效的 ARIs 是可以预期的。
