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Öğe Acute patellar dislocation with multiple ligament injuries after knee dislocation and single session reconstruction(Pakistan Medical Assoc, 2016) Gormeli, Gokay; Gormeli, Cemile Ayse; Karakaplan, Mustafa; Gurbuz, Sukru; Ozdemir, Zeynep; Ozer, MustafaKnee dislocation is a relatively rare condition of all orthopaedic injuries. Accompanying multiple ligament injuries are common after knee dislocations. A 41-year-old male presented to the emergency department suffering from right knee dislocation in June 2013. The patient had anterior cruciate ligament, medial collateral ligament (MCL), medial patellofemoral ligament (MPFL) rupture, and lateral meniscal tear. A single-bundle anatomic reconstruction, medial collateral ligament reconstruction, medial patellofemoral ligament reconstruction and meniscus repair were performed in single session. At twelve months follow-up; there was 160 degrees flexion and 10 degrees extension knee range of motion. Lysholm knee score was 90. Extensive forces can cause both MCL and MPFL injury due to overload and the anatomical relationship between these two structures. Therefore, patients with valgus instability should be evaluated for both MPFL and MCL tears to facilitate successful treatment.Öğe Antibacterial azole derivatives: Antibacterial activity, cytotoxicity, and in silico mechanistic studies(Wiley, 2020) Sari, Suat; Avci, Ahmet; Kocak, Ebru; Kart, Didem; Sabuncuoglu, Suna; Dogan, Inci Selin; Ozdemir, ZeynepAzole antifungal drugs are commonly used in antifungal chemotherapy. Antibacterial effects of some topical antifungals, such as miconazole and econazole, have lately been revealed, which suggests a promising venue in antimicrobial chemotherapy. In this study, we tested an in-house azole collection with antifungal properties for their antibacterial activity to identify dual-acting hits using the broth microdilution method. The in vitro screen yielded a number of potent derivatives against gram-positive bacteria,Enterococcus faecalisandStaphylococcus aureus.Compound73's minimum inhibitory concentration (MIC) value less than 1 mu g/ml againstS. aureus; however, none of the compounds showed noteworthy activity against methicillin-resistantS. aureus(MRSA). All the active compounds were found safe at their MIC values against the healthy fibroblast cells in the in vitro cytotoxicity test. Molecular docking studies of the most active compounds using a set of docking programs with flavohemoglobin (flavoHb) structure, the proposed target of the azole antifungals with antibacterial activity, presented striking similarities regarding the binding modes and interactions between the tested compounds and the antifungal drugs with crystallographic data. In addition to being noncytotoxic, the library was predicted to be drug-like and free of pan-assay interference compounds (PAINS). As a result, the current study revealed several potential azole derivatives with both antifungal and antibacterial activities. Inhibition of bacterial flavoHb was suggested as a possible mechanism of action for the title compounds.Öğe Antifungal Azole Derivatives Featuring Naphthalene Prove Potent and Competitive Cholinesterase Inhibitors with Potential CNS Penetration According to the in Vitro and in Silico Studies(Wiley-V C H Verlag Gmbh, 2022) Sari, Suat; Akkaya, Didem; Zengin, Merve; Sabuncuoglu, Suna; Ozdemir, Zeynep; Alagoz, M. Abdullah; Karakurt, ArzuCholinesterase inhibition is of great importance in the fight against neurodegenerative disorders such as Alzheimer's disease. Azole antifungals have come under the spotlight with recent discoveries that underline the efficacy and potential of miconazole and its derivatives against cholinesterase enzymes. In this study, we evaluated a library of azoles against acetylcholinesterase and butyrylcholinesterase using in vitro and in silico methods to identify potent inhibitors. Low micromolar IC50 values were obtained for imidazole derivatives, which were further tested and found potent competitive cholinesterase inhibitors via enzyme kinetics study. The active derivatives showed negligible toxicity in in vitro cytotoxicity tests. Molecular modeling studies predicted that these derivatives were druglike, could penetrate blood-brain barrier, and tightly bind to cholinesterase active site making key interactions via the imidazole moiety at protonated state. Thus, current study identifies potent and competitive cholinesterase inhibitor azoles with minor toxicity and potential to pass into the central nervous system.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 Azole derivatives with naphthalene showing potent antifungal effects against planktonic and biofilm forms ofCandidaspp.: an in vitro and in silico study(Springer, 2021) Sari, Suat; Kocak, Ebru; Kart, Didem; Ozdemir, Zeynep; Acar, M. Fahir; Sayoglu, Burcu; Karakurt, ArzuCandidainfections pose a serious public health threat due to increasing drug resistance. Azoles are first-line antifungal drugs for fungal infections. In this study, we tested an in-house azole collection incorporating naphthalene ring to find hits against planktonic and biofilm forms of resistantCandidaspp. In the collection, potent derivatives were identified against the susceptible strains ofCandidawith minimum inhibitory concentration (MIC) values lower than those of the reference drug, fluconazole. MIC values of 0.125 mu g/ml againstC. albicans, 0.0625 mu g/ml againstC. parapsilosis, and 2 mu g/ml againstC. krusei, an intrinsically azole-resistant non-albicans Candida, were obtained. Some of the derivatives were highly active against fluconazole-resistant clinical isolate ofC. tropicalis. Inhibition ofC. albicansbiofilms was also observed at 4 mu g/ml similar as amphotericin B, the reference drug known for its antibiofilm activity. Through molecular docking studies, affinities and key interactions of the compounds with fungal lanosterol 14 alpha-demethylase (CYP51), the target enzyme of azoles, were predicted. The interactions of imidazole with heme cofactor and of the naphthalene with Tyr118 were highlighted in line with the literature data. As a result, this study proves the importance of naphthalene for the antifungal activity of azoles againstCandidaspp. in both planktonic and biofilm forms.Öğe Azoles containing naphthalene with activity against Gram-positive bacteria: in vitro studies and in silico predictions for flavohemoglobin inhibition(Taylor & Francis Inc, 2022) Sari, Suat; Sabuncuoglu, Suna; Aslan, Ebru Kocak; Avci, Ahmet; Kart, Didem; Ozdemir, Zeynep; Acar, M. FahirAzoles are first-line drugs used in fungal infections. Topical antifungals, such as miconazole and econazole, are known to be active against Gram-positive bacteria, which was reported to result from bacterial flavohemoglobin (flavoHb) inhibition. Dual antibacterial/antifungal action is believed to have benefits for antimicrobial chemotherapy. In this study, we tested antibacterial effects of an in-house library of naphthalene-bearing azoles, some of which were reported as potent antifungals, in an attempt to find dual-acting hits. Several potent derivatives were obtained against the Gram-positive bacteria, Enterococcus faecalis and Staphylococcus aureus. 9 was active at a minimum inhibitor concentration (MIC) less than 1 mg/ml against E. faecalis and S. aureus, and 10 against S. aureus. 16 was also potent against E. faecalis and S. aureus (MIC = 1 and 2 mg/ml, respectively). Six more were active against S. aureus with MIC <= 4 mg/ml. In vitro cytotoxicity studies showed that the active compounds were safe for healthy cells within their MIC ranges. According to the calculated descriptors, the library was found within the drug-like chemical space and free of pan-assay interference compounds (PAINS). Molecular docking studies suggested that the compounds might be bacterial flavohemoglobin (flavoHb) inhibitors and the azole and naphthalene rings were important pharmacophores, which was further supported by pharmacophore modeling study. As a result, the current study presents several non-toxic azole derivatives with antibacterial effects. In addition to their previously reported antifungal properties, they could set a promising starting point for the future design of dual acting antimicrobials.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 Conventional and microwave prompted synthesis, antioxidant, anticholinesterase activity screening and molecular docking studies of new quinolone-triazole hybrids(Academic Press Inc Elsevier Science, 2018) Mermer, Arif; Demirbas, Neslihan; Sirin, Yakup; Uslu, Harun; Ozdemir, Zeynep; Demirbas, AhmetThe synthesis of ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylates (4, 5) was performed via the reaction of corresponding anilines with diethyl ethoxymethylenemalonate under conventional and also microwave promoted conditions. The treatment of 4 and 5 afforded the corresponding hydrazides (6 and 7). These hydrazides were converted to the corresponding carbo(thio) amides (9a-f and 10a-e) which were then subjected to an intramolecular cyclisation leading to the formation of quinolone-triazole hybrids (11a-f and 12a-e). The newly synthesized compounds were screened for their biological activities such as antioxidant capacity (AC) and acetylcholinesterase Activity. Inhibition of cholinesterases is an effective method to curb Alzheimer's disease, a progressive and fatal neurological disorder. A series of some novel quinolone derivatives were designed, synthesized, and their inhibitory effects on AChE were evaluated. We obtained our compounds and determined their anticholinesterase activities according to the Ellman's method. 9b and 10c showed the best AChE inhibition with 0.48 +/- 0.02 and 0.52 +/- 0.07, respectively. Docking studies were performed for the most active compounds (9b, 10c) and interaction modes with enzyme active sites were determined. As a result of these studies, a strong interaction between these compounds and the active sites of AChE enzyme was revealed. (C) 2018 Elsevier Inc. All rights reserved.Öğe 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, ArafaTwelve 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.Öğe 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, TijenIn 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.Öğe 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, MehtapInhibition 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.Öğe Development of a Novel Class of Pyridazinone Derivatives as Selective MAO-B Inhibitors(Mdpi, 2022) Alagoz, Mehmet Abdullah; Oh, Jong Min; Zenni, Yaren Nur; Ozdemir, Zeynep; Abdelgawad, Mohamed A.; Naguib, Ibrahim A.; Ghoneim, Mohammed M.Sixteen compounds (TR1-TR16) were synthesized and evaluated for their inhibitory activities against monoamine oxidase A and B (MAOs). Most of the derivatives showed potent and highly selective MAO-B inhibition. Compound TR16 was the most potent inhibitor against MAO-B with an IC50 value of 0.17 mu M, followed by TR2 (IC50 = 0.27 mu M). TR2 and TR16 selectivity index (SI) values for MAO-B versus MAO-A were 84.96 and higher than 235.29, respectively. Compared to the basic structures, the para-chloro substituent in TR2 and TR16 increased the inhibitory activity of MAO-B. TR2 and TR16 were reversible MAO-B inhibitors that were competitive, with K-i values of 0.230 +/- 0.004 and 0.149 +/- 0.016 mu M, respectively. The PAMPA method indicated that compounds TR2 and TR16 had the tendency to traverse the blood-brain barrier. Docking investigations revealed that lead compounds were beneficial for MAO-B inhibition via association with key as well as selective E84 or Y326 residues, but not for MAO-A inhibition via interaction primarily driven by hydrophobic contacts. In conclusion, TR2 and TR16 are therapeutic prospects for the management of multiple neurodegenerative diseases.Öğe The effect of the intercondylar notch width index on anterior cruciate ligament injuries : A study on groups with unilateral and bilateral ACL injury(Acta Medica Belgica, 2015) Gormeli, Cemile Ayse; Gormeli, Gokay; Ozturk, Burak Yagmur; Ozdemir, Zeynep; Kahraman, Aysegul Sagir; Yildirim, Okan; Gozukara, HarikaBackground : To evaluate the relationship of the intercondylar notch width with unilateral and bilateral ACL injury by using MR images. Materials and Methods : The intercondylar notch width index was measured on the MR images of 18 patients with a bilateral ACL injury, 38 patients with a unilateral ACL injury and 53 healthy subjects with a normal ACL and the results of all groups were compared with each other. Results : The mean NWI values were 0,227 (+/- 0.008) in bilateral injured; 0,245 (+/- 0.009) in unilateral injured and 0,272 (+/- 0.01) in control groups and 0,251(+/- 0.01) in unaffected side of the unilateral group. There were statistically significant differences in intercondylar notch width index (NWI) values between all groups and there was a significant difference between the affected and the unaffected sides in group with unilateral ACL injury. A cutoff value of 0.25 for NWI gave an odds ratio of 26.5 for bilateral and 3.23 for unilateral ACL injuries. Conclusions : The finding that NWI is significantly narrowed in patients with bilateral and unilateral ACL tears compared with the healthy controls suggest a relationship between a narrow NWI and an increased risk of ACL injury. The patients with a narrow NWI should also be screened contralaterally for assessment of ACL injury risk on the other knee. So, specialized training programmes for the people with narrow NWI can be prepared for preventing ACL injuries.Öğe Elucidating the antimicrobial and anticarcinogenic potential of methanolic and water extracts of edible Tragopogon coelesyriacus Boiss.(Wiley, 2024) Unver, Tuba; Uzuner, Ugur; Celik-Uzuner, Selcen; Gurhan, Ismet; Sivri, Nur Sena; Ozdemir, ZeynepTragopogon coelesyriacus is a pharmacotherapeutic herbaceous plant belonging to the Asteraceae family and consumed as a vegetable. Here, the methanolic and water extracts of T. coelesyriacus were obtained from its aboveground parts (stem, leaves, and flowers), and the phytochemical potentials were investigated by LC-HRMS (liquid chromatography-high resolution mass spectrometry) analysis for the first time. The antibacterial, antifungal, and anticarcinogenic activities of T. coelesyriacus extracts were investigated using experimental and in silico methods. T. coelesyriacus methanol extract revealed remarkable inhibitory activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumonia (MICs = 0.83, 1.67, and 1.67 mg/mL, respectively) compared to Escherichia coli and Enterobacter aerogenes (MIC = 53.3 mg/mL). Inhibitory effects of T. coelesyriacus methanolic extracts were also observed in all Candida species tested, with the highest inhibition on Candida krusei (MIC = 0.83 mg/mL), whereas no inhibitory effect was identified from the water extract. Additionally, both T. coelesyriacus methanolic (IC50 = 86 mu g/mL) and water (IC50 = 92 mu g/mL) extracts revealed significant selective anticarcinogenic effects on AR42J pancreatic cancer cells. HeLa and MDA-MB-231 cells were, however, more resilient to methanol and water extract, respectively. In silico analyses further elucidated the noteworthy antibacterial potential of keracyanin chloride on S. aureus MurB enzyme and the remarkable inhibitory potential of naringin on FYN kinase specific for pancreatic cancer (AR42J) development. In conclusion, T. coelesyriacus phytochemicals with antibacterial, antifungal, and anticancer properties were revealed for the first time, and molecular docking studies on potential targets confirmed good agreement with experimental findings. Therefore, the current studies on T. coelesyriacus provide the basis for investigating new pharmaceutical potentials of other Tragopogon members.Öğe Histological assessment of liver and stomach damage caused by pyridazinone derivative antidepressant agents(Taylor & Francis Ltd, 2022) Ozdemir, Zeynep; Karakurt, Arzu; Taslidere, Elif; Vardi, Nigar; Alagoz, Mehmet Abdullah; Parlakpinar, Hakan; Uslu, HarunDepression is a serious psychological disorder that affects a significant population. We investigated the antidepressant activities of four pyridazinone derivatives that contain the hydrazide moiety using the forced swimming test (FST). The compounds tested exhibited good antidepressant activity compared to duloxetine. The most promising compound was compound 2, which reduced the duration of immobility during FST. The toxic effects of the four compounds on the histomorphology of the liver and stomach tissue also was evaluated.Öğe Inhibition of Cholinesterases by Benzothiazolone Derivatives(Mdpi, 2022) Alagoz, Mehmet Abdullah; Kim, Seong-Min; Oh, Jong Min; Arslan, Gulnur; Ozdemir, Zeynep; Sari, Suat; Ozcelik, Azime BernaThirteen benzothiazolone derivatives (M1-M13) were synthesized and evaluated for their inhibitory activity against cholinesterases (ChEs) and monoamine oxidases (MAOs). All the compounds inhibited ChEs more effectively than MAOs. In addition, most of the compounds showed higher inhibitory activities against butyrylcholinesterase (BChE) than acetylcholinesterase (AChE). Compound M13 most potently inhibited BChE with an IC50 value of 1.21 mu M, followed by M2 (IC50 = 1.38 mu M). Compound M2 had a higher selectivity index (SI) value for BChE over AChE (28.99) than M13 (4.16). The 6-methoxy indole group of M13 was expected to have a greater effect on BChE inhibitory activity than the other groups. Kinetics and reversibility tests showed that M13 was a reversible noncompetitive BChE inhibitor with a K-i value of 1.14 +/- 0.21 mu M. In a docking simulation, M13 is predicted to form a hydrogen bond with the backbone carbonyl group of Ser287 of BChE through its methoxy indole moiety and pi-pi interactions between its benzothiazolone group and the side chain of Trp82 with the five-membered pyrrole ring and with the six-membered benzene ring. From these results, it is suggested that M13 is a BChE inhibitor and a potential candidate agent for the treatment of Alzheimer's disease.Öğe Inhibition of Monoamine Oxidases by Pyridazinobenzylpiperidine Derivatives(Mdpi, 2024) Oh, Jong Min; Zenni, Yaren Nur; Ozdemir, Zeynep; Kumar, Sunil; Kilic, Semanur; Akdag, Mevlut; Ozcelik, Azime BernaMonoamine oxidase inhibitors (MAOIs) have been crucial in the search for anti-neurodegenerative medications and continued to be a vital source of molecular and mechanistic diversity. Therefore, the search for selective MAOIs is one of the main areas of current drug development. To increase the effectiveness and safety of treating Parkinson's disease, new scaffolds for reversible MAO-B inhibitors are being developed. A total of 24 pyridazinobenzylpiperidine derivatives were synthesized and evaluated for MAO. Most of the compounds showed a higher inhibition of MAO-B than of MAO-A. Compound S5 most potently inhibited MAO-B with an IC50 value of 0.203 mu M, followed by S16 (IC50 = 0.979 mu M). In contrast, all compounds showed weak MAO-A inhibition. Among them, S15 most potently inhibited MAO-A with an IC50 value of 3.691 mu M, followed by S5 (IC50 = 3.857 mu M). Compound S5 had the highest selectivity index (SI) value of 19.04 for MAO-B compared with MAO-A. Compound S5 (3-Cl) showed greater MAO-B inhibition than the other derivatives with substituents of -Cl > -OCH3 > -F > -CN > -CH3 > -Br at the 3-position. However, the 2- and 4-position showed low MAO-B inhibition, except S16 (2-CN). In addition, compounds containing two or more substituents exhibited low MAO-B inhibition. In the kinetic study, the K-i values of S5 and S16 for MAO-B were 0.155 +/- 0.050 and 0.721 +/- 0.074 mu M, respectively, with competitive reversible-type inhibition. Additionally, in the PAMPA, both lead compounds demonstrated blood-brain barrier penetration. Furthermore, stability was demonstrated by the 2V5Z-S5 complex by pi-pi stacking with Tyr398 and Tyr326. These results suggest that S5 and S16 are potent, reversible, selective MAO-B inhibitors that can be used as potential agents for the treatment of neurological disorders.Öğe Monoamine Oxidase-B (MAO-B) Inhibitors in the Treatment of Alzheimer's and Parkinson's Disease(Bentham Science Publ Ltd, 2021) Ozdemir, Zeynep; Alagoz, Mehmet Abdullah; Bahcecioglu, Omer Faruk; Gok, SelimBackground: The MAO enzyme is presented in the brain and peripheral tissues and is a significant enzyme that is responsible for the deamination of biogenic amines and thus the regulation of neurotransmitter levels. The reaction of these neurotransmitters with the MAO enzyme produces aldehyde and free amine. MAO enzyme consists of two isoforms, MAO-A and MAO-B, which are characterized by amino acid sequence, three-dimensional structure, substrate preference, and inhibitor selectivity. Dopamine, tyramine, and tryptamine are substrates of both MAO isoforms and MAO inhibitors such as clorgiline and selegiline, which are used as medications in neurodegenerative and neurological diseases. In particular, MAO-A inhibitors are used in the treatment of depression, while MAO-B inhibitors are used in the treatment of Parkinson's disease. It is also investigated whether MAO-B inhibitors are effective in the treatment of Alzheimer's disease. Nowadays, life expectancy has increased, as a result, neurodegenerative diseases such as Parkinson's and Alzheimer's disease have started to occur more frequently. The elderly population is increasing day by day. As a result of these common diseases in elderly people, these people are unable to do their jobs and need care. Therefore, these diseases have become a significant health problem in society. Methods: In this study, review, inclusion, and exclusion criteria were used. Peer -reviewed research articles were searched. The quality of the examined articles was evaluated with standard tools. The information obtained was analyzed conceptually by using qualitative content analysis methodology. Results: One hundred and five papers were included in the review. The current MAO-B inhibitors and their usage areas are discussed together with the structures of the drugs; also, their possible effects in Alzheimer's and Parkinson's treatment are evaluated. In addition, different articles have been compiled in which structures such as arylalkylamines, chalcones, benzoquinone, benzoxazinone, and chromen are substituted with various functional groups and aromatic rings, along with thestructures of 44 different compounds that have recently been developed and their inhibitory effects on MAO-B enzyme. As a result, the structure required for MAO-B inhibition and SAR studies is discussed. Conclusion: Many studies demonstrate that MAO-B activity increases with age in brain tissue, cerebrospinal fluid (CSF), and platelets in Alzheimer's patients. This suggests that MAO-B inhibitor drugs, which may be effective in the treatment of Parkinson's disease, may also be effective in the treatment of Alzheimer's disease. This article was written to explain the multifaceted MAO-B inhibitor molecules.Öğe 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, MehtapBackground: 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.Öğe The Novel Synthesized Pyridazinone Derivates Had the Antiproliferative and Apoptotic Effects in SHSY5Y and HEP3B Cancer Cell Line(Bentham Science Publ Ltd, 2018) Ciftci, Osman; Ozdemir, Zeynep; Acar, Ceren; Sozen, Mert; Basak-Turkmen, Nese; Ayhan, Idris; Gozukara, HarikaBackground: Brain cancer (neuroblastoma) and liver cancer (hepatocellular carcinoma) are common cancer types among others worldwide which do not have a radical treatment and cure. Objective: In the current study, five novel pyridazinone derivates bearing benzelhydrazone moiety at second position were synthesized and evaluated for their cytotoxic activity against neuroblastoma and hepatocellular carcinoma (SHSY5Y and HEP3B) and human fibroblast (HF) cell lines. The aim of the current study is to identify antiproliferative activity of five novel pyridazinone derivates against neuroblastoma and hepatocellular carcinoma (SHSY5Y and HEP3B) and human fibroblast (HF) cell lines. Method: The compounds were synthesized by the reacting 6-[4-(phenyl/4-chlorophenyl)piperazine-1yl]-3(2H)-pyridazinone-2-yl acetohydrazide with benzaldehyde in ethanol. The in vitro antiproliferative activities were determined with MTT assay. Bax, Bcl-2 and Casp3 gene expression levels were detected with RT-PCR analyses. Results: The lowest IC50 was observed for compound 4 in SHSY5Y and HEP3B cells. Apoptosis increased in cancer cells which was shown by changes inBax, Bcl-2 and Casp3 gene expression levels with 1-5 compound therapy. Conclusion: Novel pyridazinone derivates might be promising agents as new chemotherapeutic candidates in brain and liver cancer.
