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

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 μM.Among these agents, 2,6-bis((4-chlorophenyl)(phenylthio)methyl)cyclohexan-1-one (5 h), 2,6bis((3-nitrophenyl)(phenylthio)methyl)cyclohexan-1-one (5 c), and 2,6-bis((3-chlorophenyl)(phenylthio)methyl)cyclohexan-1one (5 g) exhibited prominent inhibitory activity with K I 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 (K I = 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.

Screening of in Vitro Inhibition of Lactoperoxidase Enzyme by Methyl Benzoate Derivatives with Molecular Docking Studies

“…The Protein Data Bank (http://www.rcsb.org/) was utilized to acquire the crystal structure of LPO (PDB ID: 3UBA, Resolution: 2.65). The Protein Preparation Wizard [51,52] within the Maestro interface was utilized to facilitate the optimization of protein structure [53,54] . Using the ChemDraw program for Mac (PerkinElmer, Inc., Waltham, MA, USA), methyl benzoate derivatives ( 1 a – 16 a ) were created by the drawing tools [55,56] .…”

“…The Protein Preparation Wizard [51,52] within the Maestro interface was utilized to facilitate the optimization of protein structure. [53,54] Using the ChemDraw program for Mac (PerkinElmer, Inc., Waltham, MA, USA), methyl benzoate derivatives (1 a-16 a) were created by the drawing tools. [55,56] The LigPrep application [57,58] was employed to generate the most probable ionization state in the OPLS4 force field at pH 7.4 � 0.5 utilizing Epik.…”

The effects of morin and methotrexate on pentose phosphate pathway enzymes and GR/GST/TrxR enzyme activities: An in vivo and in silico study

“…[57] The SiteMap algorithm [58] was used to predict the active sites of proteins. [59][60][61] The most likely ionization states in the OPLS4 force field [62] at pH 7.4 ± 0.5 were generated using Epik [63] and the LigPrep program. [64] Energy grids were built using the Receptor Grid Generation application with its default settings.…”

Rapid identification of chemical components in Xuelian granule by UHPLC-Q-orbitrap-HRMS based on enzyme activity in vitro

“…To date, a wide range of synthetic and natural AR inhibitors have been developed. Such as bis-sulfide and its derivatives [ 12 ], acylthiourea derivatives [ 13 ], N-substituted phthalazine sulfonamide derivatives [ 14 ], these synthetic compounds and its derivatives showed AR enzyme inhibitory activity in vitro at different degrees. Furthermore, natural phenolic compounds, including acteoside, echinacoside, danshensu and vanillic acid, displayed inhibition effects against AR as well [ 15 , 16 ].…”