<br>(5-羟基-4-氧代-2-苯乙烯基-4H-吡啶-1-基)-乙酸衍生物作为多功能醛糖还原酶抑制剂,Molecules

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(5-羟基-4-氧代-2-苯乙烯基-4H-吡啶-1-基)-乙酸衍生物作为多功能醛糖还原酶抑制剂
Molecules ( IF 4.2 ) Pub Date : 2020-11-04 , DOI: 10.3390/molecules25215135
Huan Chen ₁ , Xin Zhang ₁ , Xiaonan Zhang ₁ , Wenchao Liu ₁ , Yanqi Lei ₁ , Changjin Zhu ₁ , Bing Ma ₁

Affiliation

醛糖还原酶（ALR2）作为多元醇途径的限速酶，是缓解糖尿病并发症的关键抑制靶点之一。为了减少抑制剂的毒副作用并降低氧化应激水平，多功能ALR2抑制剂的设计包括对ALR2对解毒醛还原酶(ALR1)的抑制选择性和抗氧化活性。设计、合成羟基吡啶酮衍生物并评估其抑制行为和抗氧化活性。值得注意的是，{2-[2-(3,4-二羟基-苯基)-乙烯基]-5-羟基-4-氧代-4H-吡啶-1-基}-乙酸 (7l) 是最有效的，IC50值为 0.789 μM。此外，7l对ALR2表现出优异的选择性，选择性指数为25.23，远高于阳性对照eparlestat（17.37）。更重要的是，7l 具有强大的抗氧化作用。在1 μM浓度下，酚类化合物7l清除DPPH自由基的抑制率为41.48%，远高于著名抗氧化剂Trolox的11.89%。此外，7l在100 μM浓度下显着抑制脂质过氧化，抑制率为88.76%。分子对接得出的结合模式证明衍生物与激活位点紧密结合，表明衍生物对ALR2具有强烈的抑制作用。因此，这些结果提供了多功能 ALR2 抑制剂的成就，其能够选择性抑制 ALR2 并作为抗氧化剂。

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(5-Hydroxy-4-oxo-2-styryl-4H-pyridin-1-yl)-acetic Acid Derivatives as Multifunctional Aldose Reductase Inhibitors

As rate-limited enzyme of polyol pathway, aldose reductase (ALR2) is one of the key inhibitory targets for alleviating diabetic complications. To reduce the toxic side effects of the inhibitors and to decrease the level of oxidative stress, the inhibitory selectivity towards ALR2 against detoxicating aldehyde reductase (ALR1) and antioxidant activity are included in the design of multifunctional ALR2 inhibitors. Hydroxypyridinone derivatives were designed, synthesized and evaluated their inhibitory behavior and antioxidant activity. Notably, {2-[2-(3,4-dihydroxy-phenyl)-vinyl]-5-hydroxy-4-oxo-4H-pyridin-1-yl}-acetic acid (7l) was the most potent, with IC50 values of 0.789 μM. Moreover, 7l showed excellent selectivity towards ALR2 with selectivity index 25.23, which was much higher than that of eparlestat (17.37), the positive control. More significantly, 7l performed powerful antioxidative action. At a concentration of 1 μM, phenolic compounds 7l scavenged DPPH radical with an inhibitory rate of 41.48%, which was much higher than that of the well-known antioxidant Trolox, at 11.89%. Besides, 7l remarkably suppressed lipid peroxidation with a rate of 88.76% at a concentration of 100 μM. The binding mode derived from molecular docking proved that the derivatives were tightly bound to the activate site, suggesting strongly inhibitory action of derivatives against ALR2. Therefore, these results provided an achievement of multifunctional ALR2 inhibitors capable with potency for both selective ALR2 inhibition and as antioxidants.

更新日期：2020-11-04

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