Synthesis and characterization of novel acyl hydrazones derived from vanillin as potential aldose reductase inhibitors

Demir, Yeliz; Tokalı, Feyzi Sinan; Kalay, Erbay; Türkeş, Cüneyt; Tokalı, Pelin; Aslan, Osman Nuri; Şendil, Kıvılcim; Beydemır, Şükrü

doi:10.1007/s11030-022-10526-1

Cited by 34 publications

(18 citation statements)

References 116 publications

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“…In the final reaction mixture, DMSO was present at a concentration of around 1 % [89] . To investigate the in vitro inhibitory mechanisms of these bis‐sulfides ( 5 a – i ) and bis‐sulfones ( 6 a – i ) against ALR2 [90–92] , the kinetic tests were conducted using Cerelli's method [93] at 340 nm, spectrophotometrically, and the DL‐glyceraldehyde (PubChem CID: 79014) was used as the substrate [94–97] . All the samples were measured three times.…”

Section: Methodsmentioning

confidence: 99%

“…[89] To investigate the in vitro inhibitory mechanisms of these bis-sulfides (5 a-i) and bis-sulfones (6 a-i) against ALR2 [90][91][92] , the kinetic tests were conducted using Cerelli's method [93] at 340 nm, spectrophotometrically, and the DL-glyceraldehyde (PubChem CID: 79014) was used as the substrate. [94][95][96][97] All the samples were measured three times. In accordance with our earlier research, IC 50 plots and Lineweaver-Burk curves [98] were made, and K I constants, their coefficient of determination (R 2 ), and inhibition types were determined based on the observed data.…”

Section: Biological Activity Studymentioning

confidence: 99%

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

et al. 2023

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Biological Activity Studymentioning

confidence: 99%

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

et al. 2023

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“…[51] The Receptor Grid Generation panel was used to construct the docking grid box. [52] As in our earlier investigations, [53][54][55] molecular docking simulations were run using the extreme precision (XP) method. [56][57][58] The VSGB energy model and the OPLS4 force field [20] were utilized in the computation of the MM-GBSA binding energies, [59] which forecast relative binding affinities for these tetrazole-based hydrazones.…”

Section: In Silico Pharmacokinetic Studiesmentioning

confidence: 99%

A new series of hydrazones as small‐molecule aldose reductase inhibitors

Altıntop

Demir

Türkeş

et al. 2023

Archiv der Pharmazie

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In the search for small-molecule aldose reductase (AR) inhibitors, new tetrazolehydrazone hybrids (1-15) were designed. An efficient procedure was employed for the synthesis of compounds 1-15. All hydrazones were subjected to an in vitro assay to assess their AR inhibitory profiles. Compounds 1-15 caused AR inhibition with K i values ranging between 0.177 and 6.322 µM and IC 50 values ranging between 0.210 and 0.676 µM. 2-[(1-(4-Hydroxyphenyl)-1H-tetrazol-5-yl)thio]-N'-(4-fluorobenzylidene) acetohydrazide ( 4) was the most potent inhibitor of AR in this series. Compound 4 markedly inhibited AR (IC 50 = 0.297 µM) in a competitive manner (K i = 0.177 µM) compared to epalrestat (K i = 0.857 µM, IC 50 = 0.267 µM). Based on the in vitro data obtained by applying the MTT test, compound 4 showed no cytotoxic activity toward normal (NIH/3T3) cells at the tested concentrations, indicating its safety as an AR inhibitor. Compound 4 exhibited proper interactions with crucial amino acid residues within the active site of AR. In silico QikProp data of all hydrazones (1-15) were also determined to assess their pharmacokinetic profiles. Taken together, compound 4 stands out as a promising inhibitor of AR for further in vivo studies.

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“…[74,75] In ChemDraw program V19.1 for Mac, the novel synthesized thiosemicarbazones (1-13) and reference drugs AAZ and THA were created using drawing tools (PerkinElmer, Inc.). [76] Using Epik, the LigPrep application was used to generate the most likely ionization states in the OPLS4 force field [77,78] at pH 7.4 ± 2.0. [79] The Receptor Grid Generation program [80] was utilized to create energy grids with default parameters.…”

Section: Computational Studymentioning

confidence: 99%

Enzyme inhibition, molecular docking, and density functional theory studies of new thiosemicarbazones incorporating the 4‐hydroxy‐3,5‐dimethoxy benzaldehyde motif

Demir

Türkeş

Çavuş

et al. 2022

Archiv der Pharmazie

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New Schiff base-bearing thiosemicarbazones (1-13) were obtained from 4-hydroxy-3, 5-dimethoxy benzaldehyde and various isocyanates. The structures of the synthesized molecules were elucidated in detail. Density functional theory calculations were also performed to determine the spectroscopic properties of the compounds. Moreover, the enzyme inhibition activities of these compounds were investigated. They showed highly potent inhibition effects on acetylcholinesterase (AChE) and human carbonic anhydrases (hCAs) (K I values are in the range of 51.11 ± 6.01 to 278.10 ± 40.55 nM, 60.32 ± 9.78 to 300.00 ± 77.41 nM, and 64.21 ± 9.99 to 307.70 ± 61.35 nM for AChE, hCA I, and hCA II, respectively). In addition, molecular docking studies were performed, confirmed by binding affinities studies of the most potent derivatives.

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Synthesis and characterization of novel acyl hydrazones derived from vanillin as potential aldose reductase inhibitors

Cited by 34 publications

References 116 publications

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

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

A new series of hydrazones as small‐molecule aldose reductase inhibitors

Enzyme inhibition, molecular docking, and density functional theory studies of new thiosemicarbazones incorporating the 4‐hydroxy‐3,5‐dimethoxy benzaldehyde motif

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