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In this study, a series of phenyl β-aldehyde ketones were designed and synthesized as novel dual inhibitors of aldose reductase (ALR2) and α-glucosidase. The results showed substantial inhibition of ALR2 and α-glucosidase by the synthetic compounds and also demonstrated the antioxidant activity of these inhibitors. Among them, compound 5l had the most potent inhibitory effect on both enzymes, with non-competitive inhibition patterns, and was the most effective antioxidant in tests for 2,2-diphenyl-1-picrylhydrazyl radical scavenging and lipid peroxidation suppression. High lipophilicity and negligible cytotoxicity were also observed for this compound. Analysis indicated that the β-aldehyde ketone moiety might play a vital role in the inhibitory effect on the enzymes and that the phenolic hydroxy group was the key structure for intensifying the inhibitory and antioxidant activities. Overall, the results confirmed the successful synthesis of potent ALR2 and α-glucosidase inhibitors with antioxidant activity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]