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    Design, Synthesis, and Biological Evaluation of Some Benzothiazolone Derivatives as Cholinesterase Inhibitors
    (Wiley-V C H Verlag Gmbh, 2022) Alagoz, Mehmet Abdullah; Akkaya, Didem; Arslan, Gulnur; Uludag, Berk; Ozdemir, Zeynep; Barut, Burak; Onkol, Tijen
    In this study, nine new benzothiazolone derivatives (6 a-i) were designed and synthesized to identify potent cholinesterase inhibitors. The compounds were tested in vitro against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and found to be selective to BChE. Compound 6 f proved the most potent derivative (IC50=12.25 +/- 0.23 mu M) against BChE and was identified as a mixed-type inhibitor with a K-i value of 4.45 +/- 0.35 mu M according to the kinetic studies. Molecular modelling suggested that the derivatives were druglike and non-PAINS. Compound 6 f showed good fit in BChE active site interacting with the key sites important for enzyme activity according to the molecular docking study.
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    QSAR and pharmacophore analysis on pyridazinone derivatives as acetylcholinesterase inhibitors
    (2020) Ozdemir, Zeynep; Alagoz, Mehmet Abdullah; Yilmaz, Tuba; Zenni, Yaren Nur; Onkol, Tijen
    Aim: The aim of this study is to provide a qualitative and quantitative explanation of the structure activity relationships with pharmacophore analysis and Quantitative Structure Activity Relationship (QSAR) studies of the compounds synthesized as acetylcholinesterase enzyme inhibitor by our research group.Material and Methods: Maestro 11.9 (Schrödinger, New York) was used for pharmacophore model studies. Pharmacophore analysis was performed for all compounds showing acetylcholine esterase inhibitory effect. For QSAR studies, various physicochemical parameters of these compounds were calculated using GaussView 5.0 and ChemDraw 15.0 programs. Regression analysis was performed by using these parameters and QSAR equation was obtained.Results: All compounds overlapped and hypotheses generated. The most appropriate pharmacophore model was created by comparing the hypothesis and activity results of the compounds. The analyses were performed using 8 different parameters for all compounds. R2 value of equation was found 1. Conclusion: The pharmacophore analysis and the QSAR equation are applicable for all compounds synthesized as acetylcholinasterase inhibitory and containing pyridazinon-2-ylacetohydrazide structure. Also, the estimated IC50 values can be calculated before the compounds are synthesized using the QSAR equation.
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    Synthesis and in silico studies of Novel Ru(II) complexes of Schiff base derivatives of 3-[(4-amino-5-thioxo-1,2,4-triazole-3-yl)methyl]-2(3H)-benzoxazolone compounds as potent Glutathione S-transferase and Cholinesterases Inhibitor
    (Elsevier, 2021) Adiguzel, Ragip; Turkan, Fikret; Yildiko, Umit; Aras, Abdulmelik; Evren, Enes; Onkol, Tijen
    Novel Ru(II) complexes of Shiff base derivatives of 3-[(4-amino-5-thioxo-1,2,4-triazole-3-yl)methyl]-2(3H)benzoxazolone were synthesized. The ligands (1a-e) were confirmed by IR, H-1 NMR, and C-13 NMR spectra (only 1b and 1c). Structures of the synthesized Ru(II) complexes (2a-e) were illuminated by elemental analysis, IR, H-1 NMR, C-13 NMR, and mass spectra. As the biological studies, the inhibitory potency of the ligands and the novel synthesized complexes were evaluated against the glutathione S-transferase (GST), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes in vitro conditions. Ki values in the range of 26.87-47.63 mu M for AChE, 23.51-42.81 mu M for BChE, and 33.14-51.73 mu M for GST, respectively. The free binding energy of most active inhibitors against AChE, BChE, and GST enzymes were detected as-10.183 kcal/mol, -9.111 kcal/mol, and -6.097 kcal/mol, respectively. All compounds docked were observed to bind in the active site of the enzymes with similar binding orientation and binding interactions with the surrounding amino acids. (C) 2021 Published by Elsevier B.V.
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    Synthesis of New 1-Aryl-2-(3,5-dimethylpyrazol-1-yl)ethanone Oxime Ether Derivatives and Investigation of Their Cytotoxic Effects
    (Mdpi, 2021) Alagoz, Mehmet Abdullah; Karakurt, Arzu; Hepokur, Ceylan; Salva, Emine; Onkol, Tijen; Ghoneim, Mohammed M.; Abdelgawad, Mohamed A.
    In this study, 12 new 1-aryl-2-(3,5-dimethylpyrazol-1-yl)ethanone oxime ether derivatives were designed and synthesized to investigate their cytotoxic effects. The in vitro cytotoxic activities of the compounds were evaluated against cervix, colon, breast, glioma, neuroblastoma, and lung cancer cell lines, as well as a healthy cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazo-lium bromide (MTT) assays with 5-fluorouracil (5-FU) as the reference compound. Compound 5f (IC50 = 5.13 mu M) was found to be more effective than 5-FU (IC50 = 8.34 mu M) in the C6 cancer cell line, and it had no cytotoxic effect on the L929 healthy cell line. Flow cytometry was used to investigate the mechanism of action of compound 5f on the cell cycle of the C6 cell line. The analysis showed that cell death was significantly due to apoptosis. These results indicate that compound 5f induces cell cycle arrest, and may be effective in treating glioma.