Biological evaluation and in silico study of benzohydrazide derivatives as paraoxonase 1 inhibitors

Korkmaz, Işıl Nihan; Türkeş, Cüneyt; Demir, Yeliz; Öztekіn, Aykut; Özdemir, Haşan; Beydemır, Şükrü

doi:10.1002/jbt.23180

Cited by 26 publications

(21 citation statements)

References 75 publications

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“…ADME calculations and molecular docking studies were conducted employing Small‐Molecule Drug Discovery Suite 2022‐2 for Mac (Schrödinger, LLC, NY), including the Maestro 58 V13.2, QikProp 59 V7.2, Protein Preparation Wizard, 60 SiteMap, 61,62 LigPrep, 63 Receptor Grid Generation, 64 Ligand Docking, 65 and Prime MM‐GBSA 66 V3.0 tools as previously reported 67‐69 . Crystal structure of AR (PDB ID: 4JIR; Resolution: 2.00 Å; Species: Homo sapiens ) 70 was downloaded from Protein Data Bank (http://www.rcsb.org/).…”

Section: Methodsmentioning

confidence: 99%

N‐substituted phthalazine sulfonamide derivatives as non‐classical aldose reductase inhibitors

Türkeş

Arslan

Demir

et al. 2022

J of Molecular Recognition

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Aldose reductase (AR, AKR1B1; EC 1.1.1.21) is an aldo‐keto reductase that has been widely investigated as an enzyme crucially involved in the pathogenesis of several chronic complications, including nephropathy, neuropathy, retinopathy, and cataracts associated with diabetes mellitus. Although sulfonamides have been reported to possess many other biological activities, in continuation of our interest in designing and discovering potent inhibitors of AR, herein, we have evaluated the AR inhibitory potential of N‐substituted phthalazine sulfonamide derivatives 5a‐l. The biological studies revealed that all the derivatives show excellent activity against AR, with KI constants ranging from 67.73 to 495.20 nM. Among these agents, 4‐(6‐nitro‐1,4‐dioxo‐1,2,3,4‐tetrahydrophthalazine‐2‐carbonyl)benzenesulfonamide (5e) and 1,4‐dioxo‐3‐(4‐sulfamoylbenzoyl)‐1,2,3,4‐tetrahydrophthalazine‐6‐carboxylic acid (5f) showed prominent inhibitory activity with KI values of 67.73 and 148.20 nM, respectively, vs AR and were found to be more potent than epalrestat (KI = 852.50 nM), the only AR inhibitor currently used in the therapy. Moreover, molecular docking studies were also performed to rationalize binding site interactions of these sulfonamides (5a‐l) with the target enzyme AR. According to ADME‐Tox, predicts were also determined that these derivatives be ARIs displaying suitable drug‐like properties. The sulfonamides identified in this study may be used to develop lead therapeutic agents inhibiting diabetic complications.

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Section: Methodsmentioning

confidence: 99%

N‐substituted phthalazine sulfonamide derivatives as non‐classical aldose reductase inhibitors

Türkeş

Arslan

Demir

et al. 2022

J of Molecular Recognition

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“…Firstly, the ADME‐Tox profile screening of fluorophenylthiourea derivatives pertaining to pre‐clinical agent discovery stages was performed using the QikProp module [62,63] in Maestro (Schrödinger, LLC, NY, USA). Afterward, the X‐ray structures of the human GR complexed, solved by Kasozi et al [64] .…”

Section: Methodsmentioning

confidence: 99%

Molecular Docking Studies and the Effect of Fluorophenylthiourea Derivatives on Glutathione‐Dependent Enzymes

Demir

Türkeş

Küfrevioğlu

et al. 2022

Chemistry & Biodiversity

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Cancer is a serious problem affecting the health of all human societies. Chemotherapy refers to the use of drugs to kill cancer or the origin of cancer. In the past three decades, researchers have studied about proteins and their roles in the production of cancer cells. Glutathione S-transferases (GSTs) are a superfamily of enzymes that play a key role in cellular detoxification, protecting against reactive electrophiles attacks, including chemotherapeutic agents. Glutathione reductase (GR) is an important antioxidant enzyme involved in protecting the cell against oxidative stress. In this current study, GST and GR enzymes were purified from human erythrocytes using affinity chromatography. GR was obtained with a specific activity of 5.95 EU/mg protein and a 52.38 % yield. GST was obtained with a specific activity of 4.88 EU/mg protein and a 74.88 % yield. The effect of fluorophenylthiourea derivatives on the purified enzymes was investigated. Afterward, K I values were found to range from 23.04 � 4.37 μM-59.97 � 13.45 μM for GR and 7.22 � 1.64 μM -41.24 � 2.55 μM for GST. 1-(2,6difluorophenyl)thiourea was showed the best inhibition effect for both GST and GR enzymes. The relationships of inhibitors with 3D structures of GST and GR were explained by molecular docking studies.

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“…The resulting molecules were submitted to the LigPrep application for generating the most probable ionization state in the OPLS4 force field [101] at pH 7.0±2.0 with Epik [102] . Energy grids were defined using the Receptor Grid Generation tool [103] with the default values. Glide docking calculations were conducted using the scoring function XP [104–106] .…”

Section: Methodsmentioning

confidence: 99%

In Vitro Inhibitory Activity and Molecular Docking Study of Selected Natural Phenolic Compounds as AR and SDH Inhibitors**

2022

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Polyol pathway enzymes, aldose reductase (EC 1.1.1.21; AR, ALR2), and sorbitol dehydrogenase (EC 1.1.1.14; SDH, SORD) have been widely investigated as the enzymes crucially involved in the pathogenesis of several chronic complications, including nephropathy, neuropathy, retinopathy, and cataracts associated with diabetes mellitus. Although phenolic compounds have been reported to possess many other biological activities, in continuation of our interest in designing and discovering potent inhibitors of AR and SDH, herein, we have evaluated these agents’ inhibitory potential against polyol pathway enzymes. Our in vitro studies revealed that all the derivatives show activity against recombinant human AR (rhAR) and SDH (rhSDH), with KI constants ranging from 9.37±0.16 μM to 77.22±2.49 μM and 2.51±0.10 μM to 42.16±1.03 μM, respectively. Among these agents, Prunetin and Phloridzin showed prominent inhibitory activity versus rhAR and rhSDH, while some were also determined to possess perfect dual activity. Moreover, in silico studies were also performed to rationalize binding site interactions of these agents with the target enzyme AR and SDH. According to ADME‐Tox was also determined that these derivatives be agents exhibiting suitable drug‐like properties. The compounds identified therapeutic potentials in this study may be promising for developing lead therapeutic agents to prevent polyol pathway complications.

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Biological evaluation and in silico study of benzohydrazide derivatives as paraoxonase 1 inhibitors

Cited by 26 publications

References 75 publications

N‐substituted phthalazine sulfonamide derivatives as non‐classical aldose reductase inhibitors

N‐substituted phthalazine sulfonamide derivatives as non‐classical aldose reductase inhibitors

Molecular Docking Studies and the Effect of Fluorophenylthiourea Derivatives on Glutathione‐Dependent Enzymes

In Vitro Inhibitory Activity and Molecular Docking Study of Selected Natural Phenolic Compounds as AR and SDH Inhibitors**

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