Design of Benzothiazolone-Based Carboxylic Acid Aldose Reductase Inhibitors

Aldose Reductase (AR, ALR2) is a member of the aldo-keto reductase superfamily that plays a critical role in diabetic complications. In this work, benzothiazolone was employed as the scaffold, and the C6 position was modified with aryl and heterocyclic groups to design potent inhibitor against ALR2. 2-(6-(4-hydroxystyryl)-2-oxobenzothiazol-3(2H)-yl)acetic acid (6 c) was identified the most active with IC₅₀ value of 18.8 nM. 2-(6-(3,4-dihydroxyphenyl)-2-oxobenzothiazol-3(2H)-yl)acetic acid (4 c) and 2-(6-(4-hydroxy-3-methoxystyryl)-2-oxobenzothiazol-3(2H)-yl)acetic acid (6 b) were also strong in the ALR2 inhibition, and even exhibited good antioxidant activity by tests of DPPH radical scavenging and lipid peroxidation suppression. 6 b having C6-hydroxymethoxystyryl sidechain is suggested as a promising candidate for further structure optimizations.