Identification of 9H‐purin‐6‐amine derivatives as novel aldose reductase inhibitors for the treatment of diabetic complications

Abstract A series of 9 H ‐purin‐6‐amine derivatives as aldose reductase (ALR) inhibitors were designed and synthesized. Most of these derivatives, having a C6‐substituted benzylamine side chain and N9 carboxylic acid on the core structure, were found to be potent and selective ALR inhibitors, with submicromolar IC 50 values against ALR2. Particularly, compound 4e was the most active with an IC 50 value of 0.038 μM, and it was also proved to be endowed with excellent inhibitory selectivity. The structure–activity relationship and molecular docking studies highlighted the importance of the carboxylic acid head group along with different halogen substituents on the C6 benzylamine side chain of the 9 H ‐purin‐6‐amine scaffold for the construction of strong and selective ALR inhibitors.