Synthesis, Characterization, and Inhibition Study of Novel Substituted Phenylureido Sulfaguanidine Derivatives as α‐Glycosidase and Cholinesterase Inhibitors

Akocak, Süleyman; Taslimi, Parham; Lolak, Nabih; Işık, Mesut; Durgun, Mustafa; Budak, Yakup; Türkeş, Cüneyt; Gülçın, İlhami; Beydemır, Şükrü

doi:10.1002/cbdv.202000958

Cited by 72 publications

(56 citation statements)

References 68 publications

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“…To begin with, the X-ray crystal structures of the hCA I (PDB code: 4WUQ, species Homo sapiens), [71] hCA II (PDB code: 4FU5, species H. sapiens), and AChE (PDB code: 4EY7, species H. sapiens), [72] which have resolutions of 1.55, 0.98, and 2.35 Å, respectively, were retrieved from the RCSB Protein Data Bank. [73] These were prepared by adding hydrogen atoms, bond orders, and missing side chains by proper ionization at pH 7.0 ± 2.0 [74] using the Protein Preparation Wizard panel [75,76] integrated into the Schrödinger Small-Molecule Drug Discovery Suite [77] 2021-2 for Mac (Schrödinger, LLC). Thereupon, the 2D structures of the new hybrid thiazolyl-pyrazoline derivatives (4a-k) were drawn utilizing the ChemDraw version 19.1 for Mac (PerkinElmer, Inc.) [78] and suitably optimized for docking by the LigPrep tool [79] using the OPLS4 force field [80] at a pH range of 7.0 ± 2.0 using Epik.…”

Section: In Vitro Cytotoxicity Assaymentioning

confidence: 99%

Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds

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New hybrid thiazolyl-pyrazoline derivatives (4a-k) were obtained through a facile and versatile synthetic procedure, and their inhibitory effects on the human carbonic anhydrase (hCA) isoforms I and II as well as on acetylcholinesterase (AChE) were determined.All new thiazolyl-pyrazolines showed activity at nanomolar levels as hCA I, hCA II, and AChE inhibitors, with K I values in the range of 13.35-63.79, 7.01-115.80, and 17.89-48.05 were identified as highly potent inhibitors, superior to the standard drugs, acetazolamide and tacrine, respectively. Compounds 4a-k were also evaluated for their cytotoxic effects on the L929 mouse fibroblast (normal) cell line. Moreover, a comprehensive ligand-receptor interaction prediction was performed using the ADME-Tox, Glide XP, and MM-GBSA modules of the Schrödinger Small-Molecule Drug Discovery Suite to elucidate the potential binding modes of the new hybrid inhibitors against these metabolic enzymes.

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Section: In Vitro Cytotoxicity Assaymentioning

confidence: 99%

Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds

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Türkeş

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et al. 2021

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“…In this study, the procedures applied in synthesis, biological assay, and in silico analyses were provided in the Supporting Information [25–64] …”

Section: Resultsmentioning

confidence: 99%

Transition‐Metal Complexes of Bidentate Schiff‐Base Ligands: In Vitro and In Silico Evaluation as Non‐Classical Carbonic Anhydrase and Potential Acetylcholinesterase Inhibitors

et al. 2021

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Schiff bases display superior features for many areas, such as significant intermediates in industrial biological, pharmacological, catalytic and optical properties, organic synthesis, and coordination chemistry. The pre‐synthesized two Schiff base ligands (HL1 and HL2) and their bidentate metal complexes (Co(L1)2, Cu(L1)2, Ni(L1)2, Co(L2)2, Cu(L2)2, and Ni(L2)2) were tested for their inhibition activities on acetylcholinesterase (AChE) and human carbonic anhydrase (hCA I and hCA II) isoforms. The transition metal complexes of bidentate Schiff base ligands displayed the potent inhibition effect with KI constants ranging from 16.39±0.15 to 88.63±0.27 nM and 9.32±0.13 to 33.66±0.57 nM for hCA isoenzymes and AChE, respectively. The compound Cu(L1)2 for hCA I and Ni(L2)2 for AChE and hCA II had the highest inhibitory effect. Besides, the molecular docking analyses of the most active complexes (Cu(L1)2 and Ni(L2)2) were performed to understand the binding interactions on the enzymes’ binding sites. According to both in vitro and in silico analysis results, all the compounds were potential inhibitors of AChE and hCA I, II isoenzymes.

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“…Finally, molecular docking was carried out against the binding site of the molecular surface of the P‐gpAchain [68] (PDB ID: 4XWK, mus musculus, 3.5 Å), in complex with 2,4‐dibromophenyl 2,4,6‐tribromophenyl ether (4C8, C 12 H 5 Br 5 O). For 4XWK docking, process validation [69–71] was performed identically by re‐docking the inhibitor (4C8) that had co‐crystallized with the P‐gp. The Glide Ligand Docking software reproduced the experimentally determined conformation of the co‐crystallized inhibitor with RMSD of 0.74Å.…”

Section: Resultsmentioning

confidence: 99%

The Effects of P‐glycoprotein Modulators on the Transition of Levofloxacin to Rat Brain, Testicle, and Plasma: In Vivo and In Silico Studies

2021

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P‐glycoprotein (P‐gp), a transporter membrane protein, plays an important role in various physiological and physiopathological conditions, drug‐drug and drug‐food interactions, and multi‐drug resistance. Nowadays, P‐gp modulators are used consciously to treat some specific diseases, such as cancer and poisoning. Levofloxacin (LVX), a P‐gp substrate, may cause the stimulation of the central nervous system. The aim of this study was to determine the effects of fexofenadine (FEX) and dexamethasone (DEX) with P‐gp modulators on the distribution of LVX in rat brain, testicle, and plasma. In the in vivo section of the study, LVX concentrations in tissue and plasma samples were detected by high‐performance liquid chromatography. In addition, in silico molecular docking studies were conducted to elucidate interactions between P‐gp and drugs. The administration of DEX at a low dose and minute 30 reduced the LVX passage to the brain, while the administration of DEX at a high dose and hour 2 increased the LVX passage to the brain, testicle tissue, and plasma. MM‐GBSA ΔG values of FEX, DEX, and LVX were calculated to be−80.95,−57.74, and−52.12 kcal/mol, respectively. The results of this study reported that DEX, known as a P‐gp inductor, may show inhibitory activity based on dose, tissue, and time of application.

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Synthesis, Characterization, and Inhibition Study of Novel Substituted Phenylureido Sulfaguanidine Derivatives as α‐Glycosidase and Cholinesterase Inhibitors

Cited by 72 publications

References 68 publications

Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds

Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds

Transition‐Metal Complexes of Bidentate Schiff‐Base Ligands: In Vitro and In Silico Evaluation as Non‐Classical Carbonic Anhydrase and Potential Acetylcholinesterase Inhibitors

The Effects of P‐glycoprotein Modulators on the Transition of Levofloxacin to Rat Brain, Testicle, and Plasma: In Vivo and In Silico Studies

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