(5-Hydroxy-4-oxo-2-styryl-4<i>H</i>-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 detoxicatin...
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MDPI AG
2020-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/21/5135 |
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| author | Huan Chen Xin Zhang Xiaonan Zhang Wenchao Liu Yanqi Lei Changjin Zhu Bing Ma |
| author_facet | Huan Chen Xin Zhang Xiaonan Zhang Wenchao Liu Yanqi Lei Changjin Zhu Bing Ma |
| author_sort | Huan Chen |
| collection | DOAJ |
| description | 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-4<i>H</i>-pyridin-1-yl}-acetic acid (<b>7l</b>) was the most potent, with IC<sub>50</sub> values of 0.789 μM. Moreover, <b>7l</b> 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, <b>7l</b> performed powerful antioxidative action. At a concentration of 1 μM, phenolic compounds <b>7l</b> 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, <b>7l</b> 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. |
| first_indexed | 2024-03-10T15:05:01Z |
| format | Article |
| id | doaj.art-50ac2038c0fe43e3a30d86ea1d381f0f |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T15:05:01Z |
| publishDate | 2020-11-01 |
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| series | Molecules |
| spelling | doaj.art-50ac2038c0fe43e3a30d86ea1d381f0f2023-11-20T19:48:14ZengMDPI AGMolecules1420-30492020-11-012521513510.3390/molecules25215135(5-Hydroxy-4-oxo-2-styryl-4<i>H</i>-pyridin-1-yl)-acetic Acid Derivatives as Multifunctional Aldose Reductase InhibitorsHuan Chen0Xin Zhang1Xiaonan Zhang2Wenchao Liu3Yanqi Lei4Changjin Zhu5Bing Ma6School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, ChinaSchool of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, ChinaSchool of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, ChinaSchool of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, ChinaSchool of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, ChinaSchool of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, ChinaSchool of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, ChinaAs 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-4<i>H</i>-pyridin-1-yl}-acetic acid (<b>7l</b>) was the most potent, with IC<sub>50</sub> values of 0.789 μM. Moreover, <b>7l</b> 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, <b>7l</b> performed powerful antioxidative action. At a concentration of 1 μM, phenolic compounds <b>7l</b> 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, <b>7l</b> 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.https://www.mdpi.com/1420-3049/25/21/5135aldose reductase inhibitorsantioxidant activitypyridinones derivativesmolecular docking |
| spellingShingle | Huan Chen Xin Zhang Xiaonan Zhang Wenchao Liu Yanqi Lei Changjin Zhu Bing Ma (5-Hydroxy-4-oxo-2-styryl-4<i>H</i>-pyridin-1-yl)-acetic Acid Derivatives as Multifunctional Aldose Reductase Inhibitors Molecules aldose reductase inhibitors antioxidant activity pyridinones derivatives molecular docking |
| title | (5-Hydroxy-4-oxo-2-styryl-4<i>H</i>-pyridin-1-yl)-acetic Acid Derivatives as Multifunctional Aldose Reductase Inhibitors |
| title_full | (5-Hydroxy-4-oxo-2-styryl-4<i>H</i>-pyridin-1-yl)-acetic Acid Derivatives as Multifunctional Aldose Reductase Inhibitors |
| title_fullStr | (5-Hydroxy-4-oxo-2-styryl-4<i>H</i>-pyridin-1-yl)-acetic Acid Derivatives as Multifunctional Aldose Reductase Inhibitors |
| title_full_unstemmed | (5-Hydroxy-4-oxo-2-styryl-4<i>H</i>-pyridin-1-yl)-acetic Acid Derivatives as Multifunctional Aldose Reductase Inhibitors |
| title_short | (5-Hydroxy-4-oxo-2-styryl-4<i>H</i>-pyridin-1-yl)-acetic Acid Derivatives as Multifunctional Aldose Reductase Inhibitors |
| title_sort | 5 hydroxy 4 oxo 2 styryl 4 i h i pyridin 1 yl acetic acid derivatives as multifunctional aldose reductase inhibitors |
| topic | aldose reductase inhibitors antioxidant activity pyridinones derivatives molecular docking |
| url | https://www.mdpi.com/1420-3049/25/21/5135 |
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