Exploration of Some Bis-Sulfide and Bis-Sulfone Derivatives as Non-Classical Aldose Reductase Inhibitors

Abstract

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 K-I values ranging from 0.53 +/- 0.03 to 4.20 +/- 0.06 mu M. 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 K-I constants of 0.53 +/- 0.03 mu M, 0.65 +/- 0.04 mu M, and 0.71 +/- 0.05 mu M, respectively, against ALR2 and were found to be more potent than epalrestat (K-I=0.79 +/- 0.01 mu M) 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.