School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081 Beijing, China.
School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081 Beijing, China.
Bioorg Med Chem. 2020 Oct 15;28(20):115699. doi: 10.1016/j.bmc.2020.115699. Epub 2020 Aug 8.
Dihydrobenzoxazinone based design and synthesis produced two series of compounds as aldose reductase (ALR2) inhibitor candidates. In particular, phenolic residues were embodied into the compounds for the combination of strengthening the inhibitory acitvity and antioxidant ability to retard the progression of diabetic complications. Most of the derivatives with styryl side chains exhibited excellent activities on selective ALR2 inhibition with IC values ranging from 0.082 to 0.308 μM, and {8-[2-(4-hydroxy-phenyl)-vinyl]-2-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic acid (3a) was the most potent. More significantly, most of dihydrobenzoxazinone compounds revealed not only good inhibitory effect on ALR2, but also showed powerful antioxidant activity. Notably, phenolic compound 3a was even comparable to the well-known antioxidant Trolox, confirming that the C8 p-hydroxystyryl substitution was key structure of lowering oxidative stress. Therefore, these results provided an achievement of multifunctional ALR2 inhibitors possessing capacities for both ALR2 inhibition and as antioxidants.
基于二氢苯并恶嗪酮的设计和合成产生了两个系列的化合物，作为醛糖还原酶（ALR2）抑制剂候选物。特别是，酚类残基被融入到化合物中，以增强抑制活性和抗氧化能力，从而延缓糖尿病并发症的进展。大多数具有苯乙烯侧链的衍生物对选择性 ALR2 抑制具有优异的活性，IC 值范围为 0.082 至 0.308 μM，其中 {8-[2-(4-羟基-苯基)-乙烯基]-2-氧代-2,3-二氢-苯并[1,4]恶嗪-4-基}-乙酸（3a）的活性最强。更重要的是，大多数二氢苯并恶嗪酮化合物不仅对 ALR2 具有良好的抑制作用，而且还表现出强大的抗氧化活性。值得注意的是，酚类化合物 3a 甚至可与著名的抗氧化剂 Trolox 相媲美，证实了 C8 p-羟基苯乙烯取代基是降低氧化应激的关键结构。因此，这些结果提供了具有同时抑制 ALR2 和抗氧化能力的多功能 ALR2 抑制剂的成就。
