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Abstract: A series of pyrido[2,3-e]-[1,2,4]-thiadiazine 1,1-dioxide acetic acid derivatives were synthesized and tested for their inhibitory activity against aldose reductase (ALR2). These derivatives were found to be potent aldose reductase inhibitors with IC50 values ranging from 0.038μM to 11.29μM. Most but not all of them showed a strong ALR2 inhibition activity and significant selectivity, which were further supported by docking studies. Of these inhibitors, compound 7d exhibited highest inhibition activity. Structure–activity relationship studies indicate the requirement of N2-benzyl group with electron-withdrawing substituents and N4-acetic acid group in the pyridothiadiazine scaffold. [Copyright &y& Elsevier]

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]