Dihydrobenzoxazinone derivatives as aldose reductase inhibitors with antioxidant activity

Abstract Dihydrobenzoxazinone based design and synthesis produced two series of compounds as aldose reductase (ALR2) inhibitor candidates. In particular, phenolic residues was 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 IC50 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 well-known antioxidant Trolox, confirming that the C8 p-hydroxystyryl substitution was determinative structure of alleviating oxidative stress. Therefore, these results provided an achievement of multifunctional ALR2 inhibitors possessing both capacities for ALR2 inhibition and as antioxidants.