Exploration of Some Bis‐Sulfide and Bis‐Sulfone Derivatives as Non‐Classical Aldose Reductase İnhibitors

Aldose reductase (AR, ALR2; EC 1.1.1.21), an enzyme that converts glucose to fructose on the polyol pathway, is an important member of the Aldo‐keto reductase superfamily. ALR2 is part of the rate‐limiting step, which is associated with diabetic complications in this process, and plays a role in regulating reactive oxygen species induced by growth factors and cytokines. Despite the fact that sulfides and sulfones have been discovered to have a variety of other biological functions, in the current study, we assessed the ALR2 inhibitory potential of the derivatives of bis‐sulfide (5 a–i) and bis‐sulfone (6 a–i) in order to further our interest in designing and discovering powerful ALR2 inhibitors. The results of the biological investigations showed that all of the derivatives exhibit activity against ALR2, with KI values ranging from 0.53±0.03 to 4.20±0.06 μM. Among these agents, 2,6‐bis((4‐chlorophenyl)(phenylthio)methyl)cyclohexan‐1‐one (5 h), 2,6‐bis((3‐nitrophenyl)(phenylthio)methyl)cyclohexan‐1‐one (5 c), and 2,6‐bis((3‐chlorophenyl)(phenylthio)methyl)cyclohexan‐1‐one (5 g) exhibited prominent inhibitory activity with KI constants of 0.53±0.03 μM, 0.65±0.04 μM, and 0.71±0.05 μM, respectively, against ALR2 and were found to be more potent than epalrestat (KI=0.79±0.01 μM) is currently, the only ALR2 inhibitor (ALR2I) utilized in treatment. Additionally, in silico molecular docking experiments were carried out to explain how these bis‐sulfides (5 a–i) and bis‐sulfones (6 a–i) interacted with the target enzyme ALR2′s binding site. According to the ADME‐Tox study, these compounds are predicted to be ALR2Is with appropriate drug‐like characteristics. The study‘s findings on sulfides and sulfones could be exploited to create innovative therapeutics that prevent diabetes complications. The aldo‐keto reductase superfamily includes aldose reductase (EC 1.1.1.21; AR, ALR2), an important enzyme that uses the polyol route to convert glucose to fructose. The rate‐limiting step connected to diabetes problems includes ALR2. It controls the reactive oxygen species brought on by cytokines and growth hormones. In this study, we assessed the ALR2 inhibitory potential of bis‐sulfide derivatives (5 a–i) and bis‐sulfone (6 a–i) to further our interest in designing and discovering potent ALR2 inhibitors.