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- ArticleYalnız künye2022Pyridazinones containing the (4-methoxyphenyl)piperazine moiety as AChE/BChE inhibitors: design, synthesis, in silico and biological evaluation
Merde, İrem B.; Önel, Gülce T.; Türkmenoğlu, Burçin; Gürsoy, Şule; Dilek, Esra
Alzheimer’s disease is a progressive and fatal neurodegenerative disease affecting the elderly population accompanied by a decrease in cholinergic transmission, impairing cognitive functions. Acetylcholine deficiency is important in the development of disease symptoms. Inhibition of acetylcholinesterase, an important enzyme in acetylcholine hydrolysis, is one of the important drug targets to increase acetylcholine levels. In this study, we aimed to develop acetylcholinesterase inhibitor compounds. For this, we synthesized compounds 6(a–e) bearing 3(2H)-pyridazinone and 1,2,4-triazole ring structures. We determined the IC50, Ki and inhibition types of N-substituted-(p-methoxyphenyl)pyridazin-3(2H)-one derivatives that we synthesized and elucidated their structures. The compound with the best AChE activity was compound 6b (Ki = 3.73 ± 0.9 nM) with the p-methylphenyl group it carried and showed competitive inhibition. Kinetic study was also performed for the compounds with the highest BChE 6a (Ki = 0.95 ± 0.16 nM) inhibitory activities. Molecular docking studies have shown that the p-methylphenyl group is indeed active in the hinge region of the AChE crystal structure as a result of experimental activity. In addition, the best free binding energy (ΔGBind), docking score and Glide score values were determined by examining the interactions with AChE crystal structure for compound 6b and with BChE crystal structure for 6a in silico approaches. [Figure not available: see fulltext.]
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2020Relationship between zinc content and carbonic anhydrase activity in blood of anemic pregnant women in Turkey
Göktuğ Kadıoğlu, Berrin; Nalçakan, Aysel; Dilek, Esra
Aims: Carbonic anhydrase (CA) in pregnancy plays an important part in gaseous exchange across the placenta. The aim of our study was to determine the relationship between zinc content and the CA activity in blood of anemic and normal pregnant women in their third trimester, in Turkey. Methods: The patients with hemoglobin values below 11 g/dL were accepted as anemic. CA enzyme activity and zinc levels in erythrocyte of anemic and non-anemic pregnant women were carried out in 27 non-anemic pregnant women and 31 anemic pregnant women. Mean corpuscular volume (MCV) levels of the participants were also tested. Results: Zinc levels were lower in the anemic group compared to the non-anemic group (P = 0.049). Total CA enzyme activity was also lower in the anemic group (P = 0.044). MCV levels were found to be lower in the anemic group (P = 0.007). The decrease in these values was statistically significant (P < 0.05). Conclusion: This is the first study to evaluate the zinc content in red blood cells of anemic pregnant women in the third trimester and its relationship with carbonic anhydrase activity. CA isoenzymes to work healthily, providing iron and zinc supports is important for fetal development.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2020Synthesis, characterization and biological activity evaluation of novel naphthalenylmethylen hydrazine derivatives as carbonic anhydrase inhibitors
Shirinzadeh, Hanif; Dilek, Esra
In the current study some derivatives of naphthalenylmethylen hydrazine were synthesized and possible in vitro hCA I and II enzymes inhibition effects were investigated. The designed compounds were synthesized by condensation of phenylhydrazine with 1-naphthaldehyde or 6-methoxy-2-naphthaldehyde and eight compounds (1a-h) were obtained. The novel Schiff bases derivatives (compounds 1a-1h) were effective inhibitors of the cytosolic carbonic anhydrase I and II isoforms (hCA I and II) with Ki values in the range of 80.60 ± 17.90 to 492.53 ± 95.23 nM for hCA I, 102.88 ± 18.44 to 461.09 ± 102.50 nM for hCA II. 1f compound shows a remarkable inhibitory effect of hCA I and hCA II isoenzymes among the new synthesized compounds. The new derivatives of naphthalenylmethylen hydrazine can be a potent inhibitor of both cytosolic CA isoenzymes which are commonly used in the pharmaceutical industries and medical areas.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2019Antibiotics used in patients after surgery and effects of human serum paraoxonase-i (PON1) enzyme activity
Yilmaz, Aycan; Dilek, Esra
Background: Paraoxonase (PON; arilesterase, [EC 3.1.8.1]) is an enzyme from the group arilesterases (ARE). This enzyme is capable of hydrolyzing paraoxone which is the active metabolite of parathion, an organic phosphorus insecticide. PON activity was found to be low in individuals prone to development of atherosclerosis such as diabetes, familial hypercholesterolemia and kidney disorders. It was noted that PON enzyme activity decreases in relation to age increase in adults. PON enzyme activity is approximately half of that in newborns and premature babies. Approximately one year after birth, it reaches the adult level. It can be said that PON1 has significant role on living organisms. For this reason, many studies on interactions of PON-drugs are needed. Objective: In this article, our aim is to investigate in vitro effects of four pharmaceutically active agents (fosfomycin, cefuroxime axetil, cefaclor monohydrate, and cefixime) which are often used in patients after surgery on human serum paraoxanase-I (PON1) enzyme activity. Methods: In this article, we purify paraoxonase-I enzyme from human serum by using ammonium sulfate precipitation (in the range of 60-80%), ion exchange and gel filtration chromatography. We use electrophoresis to check the purity of the enzyme. We investigate the paraoxonase activity of the enzyme at 412 nm the inhibition effects of the active substances. Paraoxone is used as the substrate. Activity measurements arw made at different inhibitor concentrations related to inhibitor studies and % Activity- [I] graphs are drawn for drug active substances. Lineweaver-Burk graphics are used to determine the Ki constants. Finally, to determine the types of inhibition we interpret these graphs. Results: The active agents used after surgery decreased the PON1 enzyme activity. They showed different inhibition mechanism. The inhibition mechanism of fosfomycin and cefaclor monohydrate was noncompetitive, cefixime was uncompetitive and cefuroxime axetil was a competitive inhibitor. The IC50 values for fosfomycin, cefuroxime axetil, cefaclor monohydrate, and cefixime were calculated to be 31.5 mM, 1.03 mM, 4.18 mM and 0.781 mM, respectively, and the Ki constants were determined to be 27.98 ± 12.25 mM, 2.20 ± 0.22 mM, 4.81 ± 2.25 mM and 1.12 ± 0.32 mM, respectively. The IC50 and Ki values showed that cefixime active agent has the maximum inhibition. Conclusion: In this study, we have detected that cefuroxime axetil inhibited competitively in vitro paraoxonase activity of this enzyme. According to this information, we thought that cefuroxime axetil linked to the active site of the enzyme. Fosfomycin and cefaclor monohydrate can be attached with amino acids out of the active site of the enzyme because they inhibit enzyme noncompetitively. Cefixime can be attached only to the enzyme-substrate complex because it inhibits enzyme uncompetitively.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2019Synthesis, characterization, and in vitro effect of the Cu(II) complex with niflumic acid and 3-picoline on paraoxanase-I
Dilek, Esra; Caglar, Sema; Çardak, Seda; Karakoç, Barış; Caglar, Bülent; Sahin, Onur
Niflumic acid is used to treat inflammatory rheumatoid diseases, pain, and fever. The present study reports the experimental, spectroscopic, thermal, structural analyses, and biological activities of this complex. The nonsteroidal anti-inflammatory drug niflumic acid, 3-picoline, and copper(II) chloride were utilized to synthesize a new complex: [Cu2Cl 2(nif) 2(3-pic) 4]. The crystal structure of [Cu 2Cl 2(nif) 2(3-pic) 4] was determined by X-ray crystallography. The complex crystallizes in the triclinic space group P-1 and each Cu(II) center displayed six-coordinated distorted octahedral geometry. Two Cu(II) centers are connected by a chloro-bridge to form the binuclear metal core. Finally, the in vitro effects of the synthesized new complex and free niflumic acid were evaluated on the human serum paraoxonase 1 enzyme. At low doses, both the new complex and free niflumic acid showed very good inhibition activity with different inhibition mechanisms. In addition, the results showed that the new complex has more inhibition activity than free niflumic acid.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2018Synthesis and characterization of four novel palladium(II) and platinum(II) complexes with 1-(2-aminoethyl)pyrrolidine, diclofenac and mefenamic acid: In vitro effect of these complexes on human serum paraoxanase1 activity
Dilek, Esra; Caglar, Sema; Erdogan, Kübra; Caglar, Bülent; Sahin, Onur
In this study, the effects of four novel mononuclear palladium(II) and platinum(II) complexes on the activity of human serum paraoxanase1 were examined. First, four novel mononuclear palladium(II) and platinum(II) complexes were synthesized with a nitrogen donor ligand 1-(2-aminoethyl)pyrrolidine and nonsteroidal anti-inflammatory drugs diclofenac, mefenamic acid. These complexes were characterized by spectroscopic, thermal, and elemental analyses. The crystal structures of complex [Pd(2-amepyr)2](dicl)2 1 and [Pd(2-amepyr)2](mef)2 3 were determined by X-ray crystallography. Then, paraoxonase1 enzyme was purified from human serum. The effects of these complexes on enzyme were evaluated in vitro. The complexes consist of the cationic unit and the counterions. The diclofenac and mefenamic acid acted as a counterion in the complexes. It was observed that all the complexes were stable up to high temperatures. These complexes, even at low doses, inhibited the activity of the enzyme with different inhibition mechanisms.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2017Investigation in vitro Effects of Rivastigmine and Galantamine Used to Treatment of Alzheimer's Disease on CA Isozymes I and II
Çankaya, Murat; Çoban, T. Abdülkadir; Dilek, Esra; Sunar, Mukadder; Ezmeci, Talat
The carbonic anhydrases (CA, EC. 4.2.1.1) are an expanding family of zinc-containing enzymes catalyzing the reversible hydration of CO2 in a two-step reaction to yield HCO3-and H+. These enzymes play important roles in several physiological/pathological processes. The aim of this study is to evaluate in vitro the effects of these drug active substances which use which use for treatment of Alzheimer disease on CA I and II isoenzyme. CA I and II isoenzymes from human blood have been purified using Sepharose-4B-l-tyrosine-sulfanilamide affinity chromatography method. The CA I isoenzyme was purified ~122.2-fold with a yield of 61.7%. The CA II isoenzyme was purified ~807.5-fold with a yield of 60%. rivastigmine was showed competitive inhibition and galantamine was showed uncompetitive inhibition for CAI. Both of these drug active substances were showed uncompetitive inhibition for CAII. Ki values were determined for rivastigmine CA I: 0.79 µM; CA II: 1.08 µM and for galantamine CA I: 0.41µM; CA II: 0.40 µM. The results obtained in this study galantamine was identified as the most potent inhibitor.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2017Investigation Effects of Some Heart Disorder Drugs on Human Carbonic Anhydrase I
Kuzucu, Mehmet; Çankaya, Murat; Tuğral Kaplan, Sibel; Çoban, Taha Abdullkadir; Dilek, Esra; Aktaş, Nurdagül
In the treatment of heart disorders, metoprolol tartrates and digoxin drugs which act by way of blood are used widely. Being vital of using these drug substances, investigation of inhibitory effect on the activities of enzymes in the blood reveals the importance of this work. Aim of this study to investigate effects of metoprolol tartrate and digoxin on human erythrocyte carbonic anhydrase I isoenzyme in vitro conditions. CA-I isoenzyme from human blood has been purified using Sepharose-4B-l-tyrosine-sulfanilamide affinity chromatography method. The enzyme was purified ~116-fold with a yield of 62%. At the end of inhibition studies two substances were showed uncompetitive inhibition. Ki values were determined metoprolol tartrate 5.49±1.86 mM and digoxin 0.0914±0.0062 mM.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2017Activation of Two Different Drugs Used in Alzheimer's Disease Treatment on Human Carbonic Anhydrase Isozymes I and II Activity: an In Vitro Study
Dilek, Esra
Objectives: Human carbonic anhydrase I and II (hCAI, II) isoenzymes were purified from human erythrocyte. Kinetic interactions between the enzymes and memantine and donepezil, two different drugs used in Alzheimer's disease (AD) treatment, were investigated. Materials and Methods: The purification procedure was composed of preparation of homogenate (or hemolysate) and affinity chromatography on Sepharose 4B-L-tyrosine-sulfanilamide. Results: Both drug exhibited in vitro activator effects on hCAI and II enzymes activity. Strong activations were found for these compounds: The CA values of memantine and donepezil against hCAI were 0.013 ?M and 1.8 ?M, respectively. The KA values of memantine and donepezil against hCAII were 0.045 ?M and 3.7 ?M, respectively.Conclusion: Since the levels of CA isoenzymes are low in patients with AD or in the older population, increasing activities of these isoenzymes are important for these patients. The effect of these drugs used in AD treatment was thought to be caused by positive changes in the levels of carbonic anhydrase isoenzymes.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2017Synthesis, crystal structure, spectroscopy, thermal properties and carbonic anhydrase activities of new metal(II) complexes with mefenamic acid and picoline derivatives
Dilek, Esra; Caglar, Sema; Dogancay, Nesrin; Caglar, Bulent; Sahin, Onur; Tabak, Ahmet
The mononuclear six metal(II) complexes ([Co(mef)2(3-pic)2(CH3OH)2] (1), [Ni(mef)2(3-pic)2(CH3OH)2] (2), [Cu(mef)2(3-pic)2] (3), [Co(mef)2(4-pic)2] (4), [Ni(mef)2(4-pic)2] (5), and [Cu(mef)2(4-pic)2] (6) with mefenamic acid and picoline ligands were synthesized, characterized, and their carbonic anhydrase inhibitory activities were evaluated. The six complexes were characterized by elemental analysis, FT-IR spectroscopy, and thermal analyses. The crystal structures of 1, 3, and 6 were determined by X-ray crystallography. The complexes have octahedral geometry. In 1, the mefenamato ligand behaved as monodentate whereas in 3 and 6, the mefenamato ligand acted as a bidentate ligand. Complexes 3 and 6 consist of the mefenamate and 4-picoline ligands. In 1, unlike the other complexes, methanol acted as a ligand and was involved in the coordination. Carbonic anhydrase I and II isoenzymes were purified from human erythrocytes. The in vitro effects of mefenamic acid, 3-picoline, 4-picoline, and the six metal(II) complexes on these isoenzymes were evaluated.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2017Investigation on the effects of pomiferin from Maclura pomifera on indomethacin-induced gastric ulcer: An experimental study in rats
Bozkurt, İlyas; Dilek, Esra; Erol, Hüseyin Serkan; Çakir, Ahmet; Hamzaoğlu, Ergin; Koç, Murat; Keleş, Osman Nuri; Halici, Mesut Bünyami
Previously, water extract of Maclura pomifera plant has been found effective on gastric damage. In this study, pomiferin product was purified from this plant by thin-layer chromatography method and its structure was elucidated by nuclear magnetic resonance methods. Its antiulcer effect was investigated on indomethacin-induced gastric damage in rats. For this study, a total of 36 Sprague Dawley female rats were divided into six groups such as healthy, control, reference, and three treatment groups (n = 6 each). Ranitidine (Ulcuran® 25 mg/ml vial) was used as reference. Biochemically, lipid peroxidation, and glutathione levels as well as superoxide dismutase, catalase, myeloperoxidase, and cyclooxygenase isoenzymes activities were measured in stomach tissues. Comparing with healthy group, ulcerative area was observed in control group (only administered to indomethacin group). However, Ulcerative area in stomach tissues of rats administered of all doses of pomiferin and ranitidine showed significant decrease (p < 0.05). Also, there were significant changes at the antioxidant levels (lipid peroxidation, glutathione, superoxide dismutase, and catalase) and some important enzyme activities (myeloperoxidase, cyclooxygenase isoenzymes). We found that pomiferin was effective on gastric damage induced by indomethacin. This effect was thought to be caused by positive changes in the antioxidant system.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2017Natural product inhibitors of carbonic anhydrase I and II isoenzymes: osajin and pomiferin
Dilek, Esra; Erol, Hüseyin Serkan; Cakir, Ahmet; Koc, Murat; Halici, Mesut Bünyami
The aim of this study is to purify carbonic anhydrase I and II isoenzymes from human erythrocyte, isolate two natural products osajin (OSJ) and pomiferin (PMF) from Maclura pomifera fruits, and evaluate the in vitro effect of these natural metabolites on these isoenzymes. These natural products may be used as starting points for drug discovery (like drugs used in several therapeutic applications, including antiglaucoma activity). For the purification procedure, the Sepharose-4B-l-tyrosine-sulphonamide affinity chromatography was used. Column chromatography and thin layer chromatography methods were used for isolation of OSJ and PMF from M. pomifera fruits and their chemical structures were elucidated by IR, 1D, and 2D NMR methods. We compared inhibitory effects of these natural products with inhibitory effects of phenolic compounds and found that these products demonstrated average inhibition effects. We thought that this study will give inspiration to scientists interested in this issue.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2017Activation of two different drugs used in alzheimer’s disease treatment on human carbonic anhydrase isozymes I and II activity: An in vitro study; [Alzheimer hastalığının tedavisinde kullanılan iki farklı ilacın insan karbonik anhidraz I ve II izoenzim aktiviteleri üzerindeki aktivasyonu: İn vitro çalışma]
Dilek, Esra
Objectives: Human carbonic anhydrase I and II (hCAI, II) isoenzymes were purified from human erythrocyte. Kinetic interactions between the enzymes and memantine and donepezil, two different drugs used in Alzheimer’s disease (AD) treatment, were investigated. Materials and Methods: The purification procedure was composed of preparation of homogenate (or hemolysate) and affinity chromatography on Sepharose 4B-L-tyrosine-sulfanilamide. Results: Both drug exhibited in vitro activator effects on hCAI and II enzymes activity. Strong activations were found for these compounds: The CA values of memantine and donepezil against hCAI were 0.013 M and 1.8 µM, respectively. The KA values of memantine and donepezil against hCAII were 0.045 M and 3.7 µM, respectively. Conclusion: Since the levels of CA isoenzymes are low in patients with AD or in the older population, increasing activities of these isoenzymes are important for these patients. The effect of these drugs used in AD treatment was thought to be caused by positive changes in the levels of carbonic anhydrase isoenzymes.
RDL Kalıcı Kaydıİncele - Proje2016Maclura Pomifera Bitki Ekstreleri İle Bu Bitkiden İzole Edilen Pomiferin Maddesinin Ratlarda İndometazin İle Oluşturulan Gastrik Hasar Üzerine Etkilerinin Araştırılması
Halıcı, Mesut Bünyami; Küfrevioğlu, Ömer İrfan; Dilek, Esra; Bozkurt, İlyas
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RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2016Synthesis of two phloroglucinol derivatives with cinnamyl moieties as inhibitors of the carbonic anhydrase isozymes I and II: an in vitro study
Burmaoğlu, Serdar; Dilek, Esra; Yılmaz, Ali Osman; Supuran, Claudiu T.
Two cinnamyl-substituted phloroglucinols, 4-p-methoxycinnamyl phloroglucinol (9) and 4,6-bis-p-methoxycinnamyl phloroglucinol (10) were synthesized. Two carbonic anhydrases, human carbonic anhydrase I and II (hCA I and II), were purified. Kinetic interactions between these isozymes with 9 and 10 were investigated. These new compounds exhibited inhibitory effects on the hCA I and II enzymes’ activity in vitro. The combination of the inhibitory effects of both phloroglucinol and p-coumaric acid groups in a single compound was explored. However, relative to the inhibitory effects of the two groups separately, compounds 9 and 10 demonstrated comparable inhibitory effects. More effective inhibitors of CAs could be created by testing these compounds on other CA isozymes.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2016New metal complexes with diclofenac containing 2-pyridineethanol or 2-pyridinepropanol: synthesis, structural, spectroscopic, thermal properties, catechol oxidase and carbonic anhydrase activities
Caglar, Sema; Dilek, Esra; Caglar, Bulent; Adiguzel, Ekrem; Temel, Ersin; Buyukgungor, Orhan; Tabak, Ahmet
Four new neutral diclofenac-based complexes, [Co(dicl)2(2-pyet)2] 1, [Ni(dicl)2(2-pyet)2] 2, [Cu2(dicl)2(2-pyet)2] 3, and [Cu2(dicl)2(2-pypr)2] 4 have been synthesized and characterized by elemental analysis, FT-IR, thermal analysis. Complexes 1, 3, and 4 have also been characterized by X-ray single-crystal structural analysis. The compounds of Co(II) and Ni(II) have octahedral geometry with two diclofenac and two 2-pyridineethanol ligands in the coordination sphere. The compounds of Cu(II) have square-pyramidal geometry and Cu(II) ions are linked via oxygens to the bridging 2-pyridineethanol or 2-pyridinepropanol ligands. The Δν values acquired by FT-IR are in agreement with the single XRD data. Studies on the thermal properties are reported and the complexes are stable to 196, 216, 215, and 201 °C in air, respectively. Two dinuclear Cu(II) complexes have demonstrated catalytic activity on oxidation of 3,5-di-tert-butylcatechol to 3,5-di-tert-butylquinone showing saturation kinetics at high substrate concentrations. The diclofenac complexes are investigated as inhibitors of the human cytosolic isoforms hCA I and II. The complexes are good as hCA I inhibitors (Kis of 1.52–55.06 μM) but only moderately efficient as hCA II inhibitors (Kis of 0.23–5.61 μM).
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2016New copper(II) complexes including pyridine-2,5-dicarboxylic acid: synthesis, spectroscopic, thermal properties, crystal structure and how these complexes interact with purified PON 1 enzyme
Caglar, Sema; Dilek, Esra; Hamamci Alisir, Sevim; Caglar, Bulent
We report the synthesis of two square-pyramidal copper(II) complexes, [Cu(2,5-pydc)(2-aepy)(H2O)]·H2O, 1, and [Cu(2,5-pydc)(2-ampy)(H2O)]·H2O, 2 (2-aepy = 2-(aminoethyl)pyridine, 2-ampy = 2-(aminomethyl)pyridine, 2,5-pydc = pyridine-2,5-dicarboxylic acid or isocinchomeronic acid). The synthesized complexes have been characterized by X-ray diffraction, FT-IR, elemental, and thermal analysis techniques. The crystal structure of 1 was established by X-ray analysis. Powder X-ray diffraction analysis showed that the complexes are pure. The inhibition of human serum paraoxonase 1 (PON 1, EC 3.1.8.1) enzyme with these complexes were investigated. We used diethyl 4-nitrophenyl phosphate as a substrate to measure the paraoxonase activity of PON 1 enzyme spectrophotometrically. Complexes 1 and 2 decreased the in vitro PON 1 activity with different inhibition mechanisms. Complexes 1 and 2 inhibited paraoxonase activity of this enzyme as competitively and noncompetitively, respectively.
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