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A series of pyrido[2,3- b ]pyrazin-3(4 H )-one based derivatives were designed as inhibitors of aldose reductase (ALR2), the enzyme which plays a key role in the development of diabetes complications as well as in the oxidative stress processes associated with diabetes and other pathologies. Most of the derivatives, having a substituted C2 aromatic group and a N4 acetic acid group on the core structure, were found to be potent and selective aldose reductase inhibitors with submicromolar IC 50 values, and 9c was the most active with IC 50 value 0.009 μM. Particularly, a number of the designed compounds bearing phenolic hydroxyl substituted C2-styryl side chain showed excellent not only in ALR2 inhibition but also in antioxidant, and among these 11i was proved to be the top one with an antioxidant ability even comparable to that of the well-known antioxidant Trolox. Structure-activity relationship and molecular docking studies highlighted the importance of phenolic hydroxyl substituents and vinyl spacer in C2 side chain of the scaffold for the construction of efficient and multifunctional ALR2 inhibitors. [ABSTRACT FROM AUTHOR]

To enhance aldose reductase (ALR2) inhibition and add antioxidant ability, phenolic hydroxyl was introduced both to the quinoxalinone core and C3 side chain, resulting in a series of derivatives as ALR2 inhibitors. Biological activity tests suggested that most of the derivatives were potent and selective inhibitors with IC 50 values ranging from 0.059 to 6.825 μM, and 2-(3-(4-hydroxystyryl)-7-methoxy-2-oxoquinoxalin-1(2 H )-yl)acetic acid ( 6b ) was the most active. Particularly, it was encouraging to find that some derivatives endowed with obvious antioxidant activity, and among them the phenolic 3,4-dihydroxyl compound 6f with 7-hydroxyl in the quinoxalinone core showed the most potent activity, even comparable with the well-known antioxidant Trolox. Structure-activity relationship and docking studies highlighted the importance of phenolic hydroxyl both in C3 side chain and the core structure for constructing potent ALR2 inhibitors with antioxidant activity. [ABSTRACT FROM AUTHOR]

Dihydrobenzoxazinone derivatives revealed potent activities of aldose reductase inhibition and antioxidant against diabetic complications. 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 50 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. [ABSTRACT FROM AUTHOR]