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Öğe Antifungal screening and in silico mechanistic studies of an in-house azole library(Wiley, 2019) Sari, Suat; Kart, Didem; Sabuncuoglu, Suna; Dogan, Inci Selin; Ozdemir, Zeynep; Bozbey, Irem; Gencel, MelisSystemic Candida infections pose a serious public health problem with high morbidity and mortality. C. albicans is the major pathogen identified in candidiasis; however, non-albicans Candida spp. with antifungal resistance are now more prevalent. Azoles are first-choice antifungal drugs for candidiasis; however, they are ineffective for certain infections caused by the resistant strains. Azoles block ergosterol synthesis by inhibiting fungal CYP51, which leads to disruption of fungal membrane permeability. In this study, we screened for antifungal activity of an in-house azole library of 65 compounds to identify hit matter followed by a molecular modeling study for their CYP51 inhibition mechanism. Antifungal susceptibility tests against standard Candida spp. including C. albicans revealed derivatives 12 and 13 as highly active. Furthermore, they showed potent antibiofilm activity as well as neglectable cytotoxicity in a mouse fibroblast assay. According to molecular docking studies, 12 and 13 have the necessary binding characteristics for effective inhibition of CYP51. Finally, molecular dynamics simulations of the C. albicans CYP51 (CACYP51) homology model's catalytic site complexed with 13 were stable demonstrating excellent binding.Öğe Conventional and microwave prompted synthesis of aryl(alkyl)azole oximes, 1H-NMR spectroscopic determination of E/Z isomer ratio and HOMO-LUMO analysis(Elsevier, 2022) Bozbey, Irem; Uslu, Harun; Turkmenoglu, Burcin; Ozdemir, Zeynep; Karakurt, Arzu; Levent, SerkanIn this study, 12 oxime derivatives were synthesized by using with conventional method and microwave irradiation method. It was aimed to compare the effectiveness of the conventional method and microwave method. Their yields were determined for both methods, and the yields increased when the microwave method was used. The compounds which have oxime show geometric isomerism because they have carbon-nitrogen double bonds. Therefore, we have also aimed to evaluate their E/Z isomer ratios in this study. While the synthesized pyrazole derivative compounds were mostly obtained in Z isomer in both synthesis methods, it was observed that some of the title compounds were almost completely obtained as E isomers when the conventional synthesis method was used in the synthesized imidazole derivative compounds. The structures of synthesized compounds were confirmed by IR, H-1-NMR, C-13-NMR and HRMS spectra. Additionally, in this study, the HOMO-LUMO energies and thermodynamic properties of the E/Z isomers of 12 oxime derivatives were performed using the 6-31 * G basis set and the Density Functional Theory (DFT) calculation using the B3LYP method three different environments (water, ethanol, vacuum). In addition, geometric parameters such as chemical hardness (eta), chemical potential (mu), electrophilicity index (omega), chemical softness (sigma) were calculated depending on the calculated HOMO-LUMO energies. (C) 2021 Elsevier B.V. All rights reserved.Öğe p-Trifluoroacetophenone Oxime Ester Derivatives: Synthesis, Antimicrobial and Cytotoxic Evaluation and Molecular Modeling Studies(Bentham Science Publ Ltd, 2020) Bozbey, Irem; Sari, Suat; Salva, Emine; Kart, Didem; Karakurt, ArzuBackground: Azole antifungals are among the first-line drugs clinically used for the treatment of systemic candidiasis, a deadly type of fungal infection that threatens mostly immune-compromised and hospitalized patients. Some azole derivatives were also reported to have antiproliferative effects on cancer cells. Objective: In this study, 1-(4-trifluoromethylphenyl)-2-(1H-imidazol-1-yl)ethanone (3), its oxime (4), and a series of its novel oxime ester derivatives (5a-v) were synthesized and tested for their in vitro antimicrobial activities against certain ATCC standard strains of Candida sp. fungi and bacteria. The compounds were also tested for their cytotoxic effects against mouse fibroblast and human neuroblastoma cell lines. Molecular modeling studies were performed to provide insights into their possible mechanisms for antifungal and antibacterial actions. Methods: The compounds were synthesized by the reaction of various oximes with acyl chlorides. Antimicrobial activity of the compounds was determined according to the broth microdilution method. For the determination of cytotoxic effect, we used MTS assay. Molecular docking and QM/MM studies were performed to predict the binding mechanisms of the active compounds in the catalytic site of C. albicans CYP51 (CACYP51) and S. aureus flavohemoglobin (SAFH), the latter of which was created via homology modeling. Results: 5d, 5l, and 5t showed moderate antifungal activity against C. albicans, while 3, 5c, and 5r showed significant antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. Most of the compounds showed approximately 40-50% inhibition against the human neuroblastoma cells at 100 mu M. In this line, 3 was the most potent with an IC50 value of 82.18 mu M followed by 5a, 5o, and 5t. 3 and 5a were highly selective to the neuroblastoma cells. Molecular modelling results supported the hypothesis that our compounds were inhibitors of CAYP51 and SAFH. Conclusion: This study supports that oxime ester derivatives may be used for the development of new antimicrobial and cytotoxic agents.Öğe A Series of New Hydrazone Derivatives: Synthesis, Molecular Docking and Anticholinesterase Activity Studies(Bentham Science Publ Ltd, 2020) Bozbey, Irem; Ozdemir, Zeynep; Uslu, Harun; Ozcelik, Azime Berna; Senol, Fatma Sezer; Orhan, Ilkay Erdogan; Uysal, MchtapBackground: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are known to be serine hydrolase enzymes responsible for the hydrolysis of acetylcholine (ACh), which is a significant neurotransmitter for regulation of cognition in animals. Inhibition of cholinesterases is an effective method to curb Alzheimer's disease, a progressive and fatal neurological disorder. Objective: In this study, 30 new hydrazone derivatives were synthesized. Then we evaluated their anticholinesterase activity of compounds. We also tried to get insights into binding interactions of the synthesized compounds in the active site of both enzymes by using molecular docking approach. Methods: The compounds were synthesized by the reaction of various substituted/nonsubstituted benzaldehydes with 6-(substitute/nonsubstituephenyl)-3(2H)-pyridazinone-2-yl propiyohydrazide. Anticholinesterase activity of the compounds was determined using Ellman's method. Molecular docking studies were done by using the ADT package version 1.5.6rc3 and showed by Maestro. RMSD values were obtained using Lamarckian Genetic Algorithm and scoring function of AutoDock 4.2 release 4.2.5.1 software. Results: The activities of the compounds were compared with galantamine as cholinesterase enzyme inhibitor, where some of the compounds showed higher BChE inhibitory activity than galantamine. Compound F1(11) was shown to be the best BChE inhibitor effective in 50 mu M dose, providing 89.43% inhibition of BChE (IC50=4.27 +/- 0.36 mu M). Conclusion: This study supports that novel hydrazone derivates may be used for the development of new BChE inhibitory agents.Öğe Synthesis and cytotoxicity studies on new pyrazole-containing oxime ester derivatives(Pharmacotherapy Group, 2019) Karakurt, Arzu; Bozbey, Irem; Uslu, Harun; Sari, Suat; Ozdemir, Zeynep; Salva, EminePurpose: To synthesize a series of new 1-(2-naphthyl)-2-(1H-pyrazol-1-yl)ethanone oxime ester derivatives (5-12) with potential anticancer properties, and to determine their cytotoxic effects in mouse fibroblast and human neuroblastoma cell lines. Methods: The title compounds were obtained through sodium salt reaction of 1-(naphthalene-2-yl)-2(1H-pyrazol-1-yl)etanone oxime (4) with various acyl chlorides. The cytotoxic effects were evaluated by MTS colorimetric assay, while physicochemical descriptors were calculated using QikProp software. Results: Most of the compounds showed approximately 50 - 60 % inhibition against SH-SY5Y neuroblastoma cells at 100 mu M. Of these, compound 7a was the most active combination with an IC50 value of 85.94 mu M. The toxic effect of the compounds on mouse fibroblast cell line was insignificant (p < 0.05) even when the dose was increased. The calculated physicochemical properties of the compounds were within drug-like chemical space. Conclusion: The synthesized oxime ester derivatives with pyrazole ring exhibit selective toxicity to neuroblastoma cells without affecting healthy mouse fibroblast cells. The compounds proved to be drug-like while their pharmacokinetic features were also encouraging, and were in line with in silico predictions.Öğe Synthesis, anticonvulsant activity, and molecular modeling studies of novel 1-phenyl/1-(4-chlorophenyl)-2-(1H-triazol-1-yl)ethanol ester derivatives(Springer Birkhauser, 2018) Dogan, Inci Selin; Ozdemir, Zeynep; Sari, Suat; Bozbey, Irem; Karakurt, Arzu; Sarac, SelmaA series of new ester derivatives were synthesized by the reaction of various acids with 1-phenyl/1-(4-chlorophenyl)-2-(1H-triazol-1-yl)ethanol and in vivo screened for their anticonvulsant activity. The title compounds were screened against MES and ScM seizure tests according to a modified version of the Epilepsy Therapy Screening Program (ETSP) protocol of the National Institutes of Health (NIH). Their neurotoxic effects were evaluated by the rotarod test. All the compounds showed protection against MES and/or ScM-induced seizures at 30 mg/kg without neurotoxicity. More compounds were found active in the ScM test and at lower dose than the MES test. Physicochemical and pharmacokinetic profiles of the compounds were predicted by QikProp. Using molecular docking approach we tried to get insights into their possible anticonvulsant mechanisms.
