School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081 Beijing, China.
ME Genomics Inc., Software Industry Base, Shenzhen 518061, China.
Bioorg Med Chem. 2019 Apr 15;27(8):1658-1669. doi: 10.1016/j.bmc.2019.03.015. Epub 2019 Mar 7.
A series of quinoxalinone scaffold-based acyl sulfonamides were designed as aldose reductase inhibitors and evaluated for aldose reductase (ALR2)/aldehyde reductase (ALR1) inhibition and antioxidation. Compounds 9b-g containing styryl side chains at C3-side exhibited good ALR2 inhibitory activity and selectivity. Of them, 9g demonstrated the most potent inhibitory activity with an IC value of 0.100 μM, and also exhibited excellent antioxidant activity, even comparable to the typical antioxidant Trolox. Compounds 9 had higher lipid-water partition coefficients relative to the carboxylic acid compounds 8, indicating that they may have better lipophilicity and membrane permeability. Structure-activity relationship (SAR) studies found that acyl trifluoromethanesulfonamide group at N1 and the C3-dihydroxystyryl side chain were the key structure for improving the aldose reductase inhibitory activity and antioxidant activity.
一系列基于喹喔啉酮骨架的酰基磺酰胺类化合物被设计为醛糖还原酶抑制剂，并对其醛糖还原酶 (ALR2)/醛还原酶 (ALR1) 抑制作用和抗氧化活性进行了评估。在 C3-位含有苯乙烯侧链的化合物 9b-g 表现出良好的 ALR2 抑制活性和选择性。其中，化合物 9g 表现出最有效的抑制活性，IC 值为 0.100 μM，同时还表现出优异的抗氧化活性，甚至可与典型的抗氧化剂 Trolox 相媲美。与羧酸化合物 8 相比，化合物 9 具有更高的油水分配系数，这表明它们可能具有更好的亲脂性和膜通透性。构效关系 (SAR) 研究发现，N1 上的酰基三氟甲磺酸酰胺基团和 C3-二羟基苯乙烯侧链是提高醛糖还原酶抑制活性和抗氧化活性的关键结构。
