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    Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors
    (Mdpi, 2020) Cecen, Muhammed; Oh, Jong Min; Ozdemir, Zeynep; Buyuktuncel, Saliha Ebru; Uysal, Mehtap; Abdelgawad, Mohamed A.; Musa, Arafa
    Twelve pyridazinones (T1-T12) containing the (2-fluorophenyl) piperazine moiety were designed, synthesized, and evaluated for monoamine oxidase (MAO) -A and -B inhibitory activities. T6 was found to be the most potent MAO-B inhibitor with an IC50 value of 0.013 mu M, followed by T3 (IC50 = 0.039 mu M). Inhibitory potency for MAO-B was more enhanced by meta bromo substitution (T6) than by para bromo substitution (T7). For para substitution, inhibitory potencies for MAO-B were as follows: -Cl (T3) > -N(CH3)(2) (T12) > -OCH3 (T9) > Br (T7) > F (T5) > -CH3 (T11) > -H (T1). T6 and T3 efficiently inhibited MAO-A with IC50 values of 1.57 and 4.19 mu M and had the highest selectivity indices (SIs) for MAO-B (120.8 and 107.4, respectively). T3 and T6 were found to be reversible and competitive inhibitors of MAO-B with K-i values of 0.014 and 0.0071, respectively. Moreover, T6 was less toxic to healthy fibroblast cells (L929) than T3. Molecular docking simulations with MAO binding sites returned higher docking scores for T6 and T3 with MAO-B than with MAO-A. These results suggest that T3 and T6 are selective, reversible, and competitive inhibitors of MAO-B and should be considered lead candidates for the treatment of neurodegenerative disorders like Alzheimer's disease.
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    Design, synthesis, and molecular modeling of new 3(2H)-pyridazinone derivatives as acetylcholinesterase/butyrylcholinesterase inhibitors
    (Springer Birkhauser, 2017) Ozdemir, Zeynep; Yilmaz, Hayriye; Sari, Suat; Karakurt, Arzu; Senol, Fatma Sezer; Uysal, Mehtap
    Inhibition of cholinesterases is an effective method to curb Alzheimer's disease, a progressive and fatal neurological disorder. A series of 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(p-substituted benzalhidrazone) derivatives were designed, synthesized, and their inhibitory effects on acetylcholinesterase and butyrylcholinesterase were evaluated in pursuit of potent dual inhibitors. We obtained our compounds by the reaction of various substituted/nonsubstituted benzaldehydes with 6-[4-(3,4-dichlorophenyl)piperazine-1-yl]-3(2H)-pyridazinone-2-yl acetohydrazide and determined their anticholinesterase activities according to the Ellman's method. 5f and 5i showed 75.52 and 71.72% acetylcholinesterase inhibition at 100 A mu g/ml, respectively. 5h and 5f, on the other hand, were the best butyrylcholinesterase inhibitors with 67.16 and 62.03% inhibition at the same concentration, respectively. 5f emerged as a potent dual cholinesterase inhibitor. Through molecular docking studies we predicted the inhibition mechanism of 5f for both enzymes in comparison with our previous derivatives, which differ in inhibition potency, and tried to get insights into the factors that affect receptor affinity in molecular level.
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    A new series of pyridazinone derivatives as cholinesterases inhibitors: Synthesis, in vitro activity and molecular modeling studies
    (Springer Heidelberg, 2019) Ozcelik, Azime Berna; Ozdemir, Zeynep; Sari, Suat; Utku, Semra; Uysal, Mehtap
    Background: The pyridazinone nucleus has been incorporated into a wide variety of therapeutically interesting molecules to transform them into better drugs. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are known to be serine hydrolase enzymes responsible for the hydrolysis of acetylcholine (ACh). Inhibition of cholinesterases is an effective method to curb Alzheimer's disease. Here, we prepared 12 new 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(nonsubstituted/4-substituted benzenesulfonohydrazide) derivatives and evaluated their inhibitory effects on AChE/BChE in pursuit of potent dual inhibitors for Alzheirmer's Disease. 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. Method: We obtained our compounds by the reaction of various substituted/nonsubstituted benzenesulfonic acid derivatives with 6-substitutedphenyl-3(2H)-pyridazinone-2-yl acetohydrazide and determined their anticholinesterase activities according to the Ellman's method. Molecular docking studies were done using Glide and the results were evaluated on Maestro (Schrodinger, LLC, New York, NY, 2019). Results: The title compounds showed moderate inhibition at 100 mg/ml against both enzymes, yet with better activity against BChE. Compound VI2a emerged as a dual inhibitor with 25.02% and 51.70% inhibition against AChE and BChE, respectively. Conclusion: This study supports that novel pyridazinone derivates may be used for the development of new BChE inhibitory agents. It was less potent than the reference drugs, yet promising for further modifications as a lead. The ability of the compounds to adopt energetically more favourable conformations and to engage in more key interactions in the ECBChE active gorge explains their better activity profile against ECBChE. (C) 2019 Maj Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.
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    Studies on a novel series of 3(2H)-pyridazinones: Synthesis, molecular modelling, antimicrobial activity
    (2019) Özdemir, Zeynep; Alagöz, Mehmet; Akdemir, Alp; Özçelik, Azime; Özçelik, Berrin; Uysal, Mehtap
    Abstract: Efforts to develop new potent and effective antimicrobial compounds with lower side effects are important not only for controlling serious infections but also for cancer, surgical operations, and preventing possible infections which are related to other threats. Therefore, it is getting more important to develop new antibacterial and antifungal compounds with wide spectrum, systemic effect and lower side effects. In this study eight new 3(2H)- pyridazinone derivatives were synthesized and their antimicrobial activities were evaluated by using broth microdilution method agains two Gr (+) (Staphylococcus aureus, Enterococcus faecalis), two Gr (-) bacteria (Pseudomonas aeruginosa, Escherichia coli) and three yeasts like fungi (Candida albicans, Candida krusei). Compound D2a had the best antibacterial activity among the synthesized compounds. All compounds were more effective against the fungus than the bacteria. In this study, we performed molecular modelling studies to provide in depth understanding of their CYP51 inhibition. Antifungal susceptibility tests against standard Candida spp. including C. albicans revealed D2aas highly active compound. The molecular docking studies showed similarities in binding interactions in active site gorges of the enzymes with known inhibitors, such as VT1, fluconazole.
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    SYNTHESIS OF NEW 6-[4-(2-FLUOROPHENYLPIPERAZINE-1-YL)]-3(2H)-PYRIDAZINONE-2-ACETHYL-2-(SUBSTITUTEDBENZAL)HYDRAZONE DERIVATIVES AND EVULATION OF THEIR CYTOTOXIC EFFECTS IN LIVER AND COLON CANCER CELL LINES
    (Springer, 2019) Ozdemir, Zeynep; Basak-Turkmen, Nese; Ayhan, Idris; Ciftci, Osman; Uysal, Mehtap
    In this study, seven new 3(2H)-pyridazinone derivatives expected to show cytotoxic activity in liver and colon cancer cell lines were synthesized. Their structures were confirmed by the IR, H-1-NMR, C-13-NMR spectra and elementary analyses. Compunds V-1-V-7 were tested on HEP3B (liver cancer) and HTC116 (colon cancer) cell lines for cytotoxicity by using MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] proliferation assay. Human fibroblast cells were used as safety control in these tests. 6-[4-(2-Fluorophenyl)piperazine-1-yl]-3(2H)-pyridazinone-2-acetyl-2-(2-chlorobenzal) hydrazone (compound V-3) was the most active agent with respect to HEP3B and HTC116 cell lines.
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    Synthesis, Cytotoxicity and Anti-Proliferative Activity against AGS Cells of New 3(2H)-Pyridazinone Derivatives Endowed with a Piperazinyl Linker
    (Mdpi, 2021) Alagoz, Mehmet Abdullah; Ozdemir, Zeynep; Uysal, Mehtap; Carradori, Simone; Gallorini, Marialucia; Ricci, Alessia; Zara, Susi
    Novel twenty-three 3(2H)-pyridazinone derivatives were designed and synthesized based on the chemical requirements related to the anti-proliferative effects previously demonstrated within this scaffold. The introduction of a piperazinyl linker between the pyridazinone nucleus and the additional (un)substituted phenyl group led to some compounds endowed with a limited cytotoxicity against human gingival fibroblasts (HGFs) and good anti-proliferative effects against gastric adenocarcinoma cells (AGS) as evaluated by MTT and LDH assays, using doxorubicin as a positive control. Successive analyses revealed that the two most promising representative compounds (12 and 22) could exert their effects by inducing oxidative stress as demonstrated by the hydrogen peroxide release and the morphological changes (cell blebbing) revealed by light microscopy analysis after the haematoxylin-eosin staining. Moreover, to further assess the apoptotic process induced by compounds 12 and 22, Bax expression was measured by flow cytometry. These findings enlarged our knowledge of the structural requirements in this scaffold to display valuable biological effects against cancerous cell lines.
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    Synthesis, molecular modelling and biological activity of some pyridazinone derivatives as selective human monoamine oxidase-B inhibitors
    (Springer Heidelberg, 2020) Ozdemir, Zeynep; Alagoz, Mehmet Abdullah; Uslu, Harun; Karakurt, Arzu; Erikci, Acelya; Ucar, Gulberk; Uysal, Mehtap
    Background Since brain neurotransmitter levels are associated with the pathology of various neurodegenerative diseases like Parkinson and Alzheimer, monoamineoxidase (MAO) plays a critical role in balancing these neurotransmitters in the brain. MAO isoforms appear as promising drug targets for the development of central nervous system agents. Pyridazinones have a broad array of biological activities. Here, six pyridazinone derivatives were synthesized and their human monoamine oxidase inhibitory activities were evaluated by molecular docking studies, in silico ADME prediction and in vitro biological screening tests. Methods The compounds were synthesized by the reaction of different piperazine derivatives with 3 (2H)-pyridazinone ring and MAO-inhibitory effects were investigated. Docking studies were conducted with Maestro11.8 software. Results Most of the synthesized compounds inhibited hMAO-B selectively except compound 4f. Compounds 4a-4e inhibited hMAO-B selectively and reversibly in a competitive mode. Compound 4b was found as the most potent (k(i)=0.0220.001 mu M) and selective (SI (Ki (hMAO-A/hMAO-B))=206.82) hMAO-B inhibitor in this series. The results of docking studies were found to be consistent with the results of the in vivo activity studies. Compounds 4a-4e were found to be non-toxic to HepG2 cells at 25 mu M concentration. In silico calculations of ADME properties indicated that the compounds have good pharmacokinetic profiles. Conclusion It was concluded that 4b is possibly recommended as a promising nominee for the design and development of new pyridazinones which can be used in the treatment of neurological diseases.