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- ArticleAçık Erişim2022Cytotoxic effect, enzyme inhibition, and in silico studies of some novel N-substituted sulfonyl amides incorporating 1,3,4-oxadiazol structural motif
Güleç, Özcan; Türkeş, Cüneyt; Arslan, Mustafa; Demir, Yeliz; Yeni, Yeşim; Hacımüftüoğlu, Ahmet; Ereminsoy, Ergün; Küfrevioğlu, Ömer İrfan; Beydemir, Şükrü
Abstract: The acetylcholinesterase and carbonic anhydrase inhibitors (AChEIs and hCAIs) remain key therapeutic agents for many bioactivities such as anti-Alzheimer and antiobesity antiepileptic, anticancer, antiinfective, antiglaucoma, and diuretic effects. Here, it has been attempted to discover novel multi-target AChEIs and hCAIs that are highly potent, orally bioavailable, may be brain penetrant, and have higher effectiveness at lower doses than tacrine and acetazolamide. After detailed investigations both in vitro and in silico, novel N-substituted sulfonyl amide derivatives (6a–j) were determined to be highly potent inhibitors for AChE and hCAs (KIs are in the range of 23.11–52.49 nM, 18.66–59.62 nM, and 9.33–120.80 nM for AChE, hCA I, and hCA II, respectively). Moreover, according to the cytotoxic effect studies, such as the ADME-Tox, cortex neuron cells, and neuroblastoma SH-SY5Y cell line, compounds 6a, 6d, and 6h, which are the most potent representative versus the target enzymes, were identified as orally bioavailable, highly selective, and brain preferentially distributed AChEIs and hCAIs. The docking studies revealed precise binding modes between 6a, 6d, and 6h and hCA II, hCA I, and AChE, respectively. The results presented here might provide a solid basis for further investigation into more potent AChEIs and hCAIs. Graphical abstract: [Figure not available: see fulltext.]
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2022Ophthalmic drugs: in vitro paraoxonase 1 inhibition and molecular docking studies
Çalışkan, Büşra; Demir, Yeliz; Türkeş, Cüneyt
Glaucoma is a neuropathy disorder and is generally treated by drugs. Allergic conjunctivitis is a common ophthalmologic disease. Paraoxonase 1 (PON1) is an organophosphate hydrolyzer and antiatherogenic enzyme. PON1 is known for preventing atherosclerosis through lipid-modifying features, as well as which has decisive actions of antiapoptosis, anti-inflammatory, antithrombosis, and antiadhesion antioxidant activity properties. Thus, reducing the enzyme levels in hyperthyroidism, chronic renal failure, glaucoma, diabetes mellitus, and cardiovascular diseases is a significant risk. This study was tested some ophthalmic drugs used to treat the diseases, such as glaucoma and allergic conjunctivitis, mentioned above, travoprost, latanoprost, ketotifen, emedastine, and olopatadine, for their inhibition activities against PON1. These drugs displayed the potent inhibition effect with IC50 values ranging between 14.95 ± 0.15 and 299.60 ± 4.07 μM and KI constants ranging from 9.71 ± 2.63 to 261.50 ± 59.98 μM. Besides, the molecular docking analyses of the competitive inhibitors, travoprost, emedastine, and olopatadine, were performed to understand the binding interactions on the enzyme's binding site. According to both in vitro and in silico analysis results, travoprost had the most potent effect on PON1 enzyme activity.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2022In Vitro Inhibitory Activity and Molecular Docking Study of Selected Natural Phenolic Compounds as AR and SDH Inhibitors**
Türkeş, Cüneyt; Demir, Yeliz; Beydemir, Şükrü
Polyol pathway enzymes, aldose reductase (EC 1.1.1.21; AR, ALR2), and sorbitol dehydrogenase (EC 1.1.1.14; SDH, SORD) have been widely investigated as the enzymes crucially involved in the pathogenesis of several chronic complications, including nephropathy, neuropathy, retinopathy, and cataracts associated with diabetes mellitus. Although phenolic compounds have been reported to possess many other biological activities, in continuation of our interest in designing and discovering potent inhibitors of AR and SDH, herein, we have evaluated these agents’ inhibitory potential against polyol pathway enzymes. Our in vitro studies revealed that all the derivatives show activity against recombinant human AR (rhAR) and SDH (rhSDH), with KI constants ranging from 9.37±0.16 μM to 77.22±2.49 μM and 2.51±0.10 μM to 42.16±1.03 μM, respectively. Among these agents, Prunetin and Phloridzin showed prominent inhibitory activity versus rhAR and rhSDH, while some were also determined to possess perfect dual activity. Moreover, in silico studies were also performed to rationalize binding site interactions of these agents with the target enzyme AR and SDH. According to ADME-Tox was also determined that these derivatives be agents exhibiting suitable drug-like properties. The compounds identified therapeutic potentials in this study may be promising for developing lead therapeutic agents to prevent polyol pathway complications.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2021A new series of 2,4-thiazolidinediones endowed with potent aldose reductase inhibitory activity
Sever, Belgin; Altlntop, Mehlika Dilek; Demir, Yeliz; Türkeş, Cüneyt; Özbaş, Kaan; Çiftçi, Gülşen Akalln; Beydemir, Sükrü; Özdemir, Ahmet
5-(2-Hydroxy-3-methylbenzylidene)thiazolidine-2,4-dione (3) was identified as the most potent AR inhibitor in this series, exerting uncompetitive inhibition with a Kivalue of 0.445 ± 0.013 μM. © 2021 De Gruyter. All rights reserved.; In an effort to identify potent aldose reductase (AR) inhibitors, 5-(arylidene)thiazolidine-2,4-diones (1-8), which were prepared by the solvent-free reaction of 2,4-thiazolidinedione with aromatic aldehydes in the presence of urea, were examined for their in vitro AR inhibitory activities and cytotoxicity. 5-(2-Hydroxy-3-methylbenzylidene)thiazolidine-2,4-dione (3) was the most potent AR inhibitor in this series, exerting uncompetitive inhibition with a Ki value of 0.445 ± 0.013 μM. The IC50 value of compound 3 for L929 mouse fibroblast cells was determined as 8.9 ± 0.66 μM, pointing out its safety as an AR inhibitor. Molecular docking studies suggested that compound 3 exhibited good affinity to the binding site of AR (PDB ID: 4JIR). Based upon in silico absorption, distribution, metabolism, and excretion data, the compound is predicted to have favorable pharmacokinetic features. Taking into account the in silico and in vitro data, compound 3 stands out as a potential orally bioavailable AR inhibitor for the management of diabetic complications as well as nondiabetic diseases.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2021Infection Medications: Assessment In-Vitro Glutathione S-Transferase Inhibition and Molecular Docking Study
Türkeş, Cüneyt; Demir, Yeliz; Beydemir, Şükrü
Glutathione S-transferases (EC 2.5.1.18, GSTs), consisting of at least seven subfamilies, such as alpha, kappa, mu, pi, theta, zeta, and omega, are the family of cytosolic proteins with many known functions and also are abundant in cells. Moreover, they play significant roles in influencing the efficacy and bioavailability of pharmaceutical agents in humans. It is also known that multiple types of cancer tissue frequently have high levels of GSTs compared to the corresponding healthy tissue. Herein, firstly, the GST was purified from human erythrocytes by rapid and straightforward chromatographic techniques. Subsequently, the active infection medications, the antimycotics (amphotericin B, anidulafungin, and caspofungin), antibacterials (daptomycin, ertapenem, and tigecycline), and antiviral (ganciclovir) were assessed for their inhibitory actions versus GST. All drugs demonstrated micromolar levels of potent inhibitory activity towards GST. Antifungal drugs had KI constants ranging between 20.60±0.05 μM and 50.43±0.12 μM, whilst antibacterial drugs exhibited KIs in the range of 20.92±0.09–114.80±0.41 μM. Daptomycin and ertapenem exhibited competitive inhibition, while other drugs in noncompetitive inhibition. Moreover, amphotericin B exhibited the most potent inhibitory activity (KI=20.60±0.05 μM), and in contrast, antiviral drug ganciclovir had the highest inhibition constant (KI=463.10±1.28 μM). Studying both in-vitro inhibitory activity and molecular docking interactions in silico activities of these infection medications in complex with the GST, an enzyme biologically important, demonstrates was caused significant associations between these drugs and GST were detected. The results here might provide structural guidance to design more potent GST inhibitors.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2021Novel benzoic acid derivatives: Synthesis and biological evaluation as multitarget acetylcholinesterase and carbonic anhydrase inhibitors
Kalaycı, Muharrem; Türkeş, Cüneyt; Arslan, Mustafa; Demir, Yeliz; Beydemir, Şükrü
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia, memory impairment, cognitive dysfunction, and speech impairment. The utility of cholinergic replacement by acetylcholinesterase (AChE) inhibitors in AD treatment has been well documented so far. Recently, studies have also evidenced that human carbonic anhydrases (hCAs) serve as an important target for AD treatment. In this direction, the improvement of new multitarget drugs, which can simultaneously modulate several mechanisms or targets included in the AD pathway, may be a potent strategy to treat AD. In light of these data for understanding and developing AD-related multitarget AChE and hCAs inhibitors, in this study, novel methylene-aminobenzoic acid and tetrahydroisoquinolynyl-benzoic acid derivatives (4a–g and 6a–g) were designed. The synthesized analogs were experimentally validated for their effects by in vitro and direct enzymatic tests. Also, the compounds were subjected to in silico monitoring with Schrödinger Suite software to assign binding affinities of potential derivatives based on Glide XP scoring, molecular mechanics-generalized Born surface area computing, and validation by molecular docking. The results revealed that 6c (1,3-dimethyldihydropyrimidine-2,4-(1H,3H)-dione-substituted, KI value of 33.00 ± 0.29 nM), 6e (cyclohexanone-substituted, KI value of 18.78 ± 0.09 nM), and 6f (2,2-dimethyl-1,3-dioxan-4-one-substituted, KI value of 13.62 ± 0.21 nM) from the benzoic acid derivatives in this series were the most promising derivatives, as they exhibited a good multifunctional inhibition at all experimental levels and in the in silico validation against hCA I, hCA II, and AChE, respectively, for the treatment of AD.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2021Design, synthesis, characterization, in vitro and in silico evaluation of novel imidazo[2,1-b][1,3,4]thiadiazoles as highly potent acetylcholinesterase and non-classical carbonic anhydrase inhibitors
Askin, Sercan; Tahtaci, Hakan; Türkeş, Cüneyt; Demir, Yeliz; Ece, Abdulilah; Akalın Çiftçi, Gülşen; Beydemir, Şükrü
Imidazole and thiadiazole derivatives display an extensive application in pharmaceutical chemistry, and they have been investigated as bioactive molecules for medicinal chemistry purposes. Classical carbonic anhydrase (CA) inhibitors are based on sulfonamide groups, but inhibiting all CA isoforms nonspecifically, thereby causing undesired side effects, is the main drawback of these types of inhibitors. Here we reported an investigation of novel 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives (9a-k, 10a, and 11a) and 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives (12a-20a) that do not possess the zinc-binding sulfonamide group for the inhibition of human carbonic anhydrase (hCA, EC 4.2.1.1) I and II isoforms and also of acetylcholinesterase (AChE, EC 3.1.1.7). Imidazo[2,1-b][1,3,4]thiadiazoles demonstrated low nanomolar inhibitory activity against hCA I, hCA II, and AChE (KIs are in the range of 23.44–105.50 nM, 10.32–104.70 nM, and 20.52–54.06 nM, respectively). Besides, compound 9b inhibit hCA I up to 18-fold compared to acetazolamide, while compound 10a has a 5-fold selectivity towards hCA II. The synthesized compounds were also evaluated for their cytotoxic effects on the L929 mouse fibroblast cell line. Molecular docking simulations were performed to elucidate these inhibitors’ potential binding modes against hCA I and II isoforms and AChE. The novel compounds reported here can represent interesting lead compounds, and the results presented here might provide further structural guidance to discover and design more potent hCA and AChE inhibitors.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2021Calcium channel blockers: molecular docking and inhibition studies on carbonic anhydrase I and II isoenzymes
Türkeş, Cüneyt; Demir, Yeliz; Beydemir, Şükrü
Carbonic anhydrases (CAs) are potent dehydration of carbonic acid and catalyst of the reversible hydration of carbon dioxide. Here, CA I and CA II was purified from human erythrocytes using the simple chromatographic method and determined the interactions between some calcium channel blockers and the enzymes. Molecular docking studies were performed these compounds. It was found that calcium channel blockers (nimodipine, nilvadipine, nitrendipine, isradipine, and nifedipine) exhibit potential inhibitor properties for hCA I and hCA II. IC 50 values of hCA I were in the range of 9.24-58.00 μM, and K i constants were in the range of 7.60 ± 2.68-35.92 ± 16.01 μM. IC 50 values of hCA II were in the range of 70.00-138.60 μM, and K i constants were in the range of 48.30 ± 9.81-162.35 ± 20.47 μM. Nimodipine presented the highest docking score and had competitive inhibition, the benzene and pyridine rings were found to enter the cavity for hCA I. Nifedipine and isradipine did not affect hCA II. Among these drugs, nitrendipine was found to be the most potent inhibitor for hCA I and nimodipine for hCA II. These compounds may be useful for CA inhibitors. Communicated by Ramaswamy H. Sarma.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2021Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds
Sever, Belgin; Türkeş, Cüneyt; Altıntop, Mehlika D.; Demir, Yeliz; Akalın Çiftçi, Gülşen; Beydemir, Şükrü
New hybrid thiazolyl–pyrazoline derivatives (4a–k) were obtained through a facile and versatile synthetic procedure, and their inhibitory effects on the human carbonic anhydrase (hCA) isoforms I and II as well as on acetylcholinesterase (AChE) were determined. All new thiazolyl–pyrazolines showed activity at nanomolar levels as hCA I, hCA II, and AChE inhibitors, with KI values in the range of 13.35–63.79, 7.01–115.80, and 17.89–48.05 nM, respectively. 1-[4-(4-Cyanophenyl)thiazol-2-yl]-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (4f) and 1-(4-phenylthiazol-2-yl)-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (4a) against hCAs and 1-[4-(4-chlorophenyl)thiazol-2-yl]-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (4d) and 1-[4-(4-nitrophenyl)thiazol-2-yl]-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (4b) against AChE were identified as highly potent inhibitors, superior to the standard drugs, acetazolamide and tacrine, respectively. Compounds 4a–k were also evaluated for their cytotoxic effects on the L929 mouse fibroblast (normal) cell line. Moreover, a comprehensive ligand–receptor interaction prediction was performed using the ADME-Tox, Glide XP, and MM-GBSA modules of the Schrödinger Small-Molecule Drug Discovery Suite to elucidate the potential binding modes of the new hybrid inhibitors against these metabolic enzymes.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2021Transition-Metal Complexes of Bidentate Schiff-Base Ligands: In Vitro and In Silico Evaluation as Non-Classical Carbonic Anhydrase and Potential Acetylcholinesterase Inhibitors
Yaşar, Ümit; Gönül, İlyas; Türkeş, Cüneyt; Demir, Yeliz; Beydemir, Şükrü
Schiff bases display superior features for many areas, such as significant intermediates in industrial biological, pharmacological, catalytic and optical properties, organic synthesis, and coordination chemistry. The pre-synthesized two Schiff base ligands (HL1 and HL2) and their bidentate metal complexes (Co(L1)2, Cu(L1)2, Ni(L1)2, Co(L2)2, Cu(L2)2, and Ni(L2)2) were tested for their inhibition activities on acetylcholinesterase (AChE) and human carbonic anhydrase (hCA I and hCA II) isoforms. The transition metal complexes of bidentate Schiff base ligands displayed the potent inhibition effect with KI constants ranging from 16.39±0.15 to 88.63±0.27 nM and 9.32±0.13 to 33.66±0.57 nM for hCA isoenzymes and AChE, respectively. The compound Cu(L1)2 for hCA I and Ni(L2)2 for AChE and hCA II had the highest inhibitory effect. Besides, the molecular docking analyses of the most active complexes (Cu(L1)2 and Ni(L2)2) were performed to understand the binding interactions on the enzymes’ binding sites. According to both in vitro and in silico analysis results, all the compounds were potential inhibitors of AChE and hCA I, II isoenzymes.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2021Calcium Channel Blockers: The Effect of Glutathione S-Transferase Enzyme Activity and Molecular Docking Studies
Türkeş, Cüneyt; Kesebir, Arzu Öztürk; Demir, Yeliz; Küfrevioğlu, Ömer İrfan; Beydemir, Şükrü
Recently, as a drug target in cancer treatment, the superfamily of glutathione S-transferase (GSTs, EC 2.5.1.18) have been invited considerable interest by scientists. In particular, as they are overexpressed in many human cancer cell lines, GSTs can catalyze the conjugation of the cellular nucleophile glutathione (GSH) with a wide range of electrophilic carcinogens toxins and drugs, meanwhile producing oxidative stress. For this purpose, the GST was purified by GSH-agarose affinity chromatography, and some calcium channel blockers (CCBs), such as amlodipine, cinnarizine, isradipine, nifedipine, and nilvadipine, were assessed for their inhibitory actions against GST. The CCBs demonstrated micromolar levels inhibitory activity towards GST (KIs spanning within the 98.84±0.53 μM–502.70±2.53 μM range). The best GST inhibitory activity was observed for the isradipine. Additionally, molecular docking study was performed for competitive inhibitor nilvadipine on GST to describe the possible interaction with the active site to confirm the inhibitory activity.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2020The Influence of Some Nonsteroidal Anti-inflammatory Drugs on Metabolic Enzymes of Aldose Reductase, Sorbitol Dehydrogenase, and α-Glycosidase: a Perspective for Metabolic Disorders
Demir, Yeliz; Duran, Hatice Esra; Durmaz, Lokman; Taslimi, Parham; Beydemir, Şükrü; Gulçin, İlhami
Pain, as a sensible alarm signal of living organisms to avoid tissue damage, is a common and debilitating consequence of a lot of disorders and diseases. The management of chronic pain is particularly challenging. For pain treatment, many analgesic drugs are used for their therapeutic effects. In this study, some nonsteroidal anti-inflammatory drugs including etofenamate, meloxicam, diclofenac, and tenoxicam were tested against α-glycosidase from Saccharomyces cerevisiae, sorbitol dehydrogenase (SDH), and aldose reductase (AR) enzymes from sheep liver. Nonsteroidal anti-inflammatory drugs demonstrated useful inhibition properties against α-glycosidase, AR, and SDH enzymes. Ki values were found in the range of 11.93 ± 3.77–364.88 ± 40.01 μM for α-glycosidase, 3.36 ± 1.08μM–17.68 ± 3.39 mM for AR, and 1.68 ± 0.02 μM–30.98 ± 14.31 mM for SDH. They can be selective drugs as antidiabetic agents, because of their inhibitory properties against SDH, α-glycosidase, and AR enzymes.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2020Synthesis, characterisation, biological evaluation and in silico studies of sulphonamide Schiff bases
Durgun, Mustafa; Türkeş, Cüneyt; Işık, Mesut; Demir, Yeliz; Saklı, Ali; Kuru, Ali; Güzel, Abdussamat; Beydemir, Şükrü; Akocak, Suleyman; Osman, Sameh M.
Sulphonamides are biologically important compounds with low toxicity, many bioactivities and cost-effectiveness. Eight sulphonamide derivatives were synthesised and characterised by FT-IR, 13C NMR, 1H NMR, LC-MS and elemental analysis. Their inhibitory effect on AChE, and carbonic anhydrase I and II enzyme activities was investigated. Their antioxidant activity was determined using different bioanalytical assays such as radical scavenging tests with ABTS•+, and DPPH•+ as well as metal-reducing abilities with CUPRAC, and FRAP assays. All compounds showed satisfactory enzyme inhibitory potency in nanomolar concentrations against AChE and CA isoforms with KI values ranging from 10.14 ± 0.03 to 100.58 ± 1.90 nM. Amine group containing derivatives showed high metal reduction activity and about 70% ABTS radical scavenging activity. Due to their antioxidant activity and AChE inhibition, these novel compounds may be considered as leads for investigations in neurodegenerative diseases.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2020Molecular docking studies and inhibition properties of some antineoplastic agents against paraoxonase-I
Demir, Yeliz; Türkeş, Cüneyt; Beydemir, Şükrü
Background: Currently, most of the drugs used in clinical applications show their pharmacological influences by inhibiting or activating enzymes. Therefore, enzyme inhibitors have an essential place in the drug design for many diseases. Objective: The current study aimed to contribute to this growing drug design field (i.e., medicine discovery and development) by analyzing enzyme-drug interactions. Methods: For this reason, Paraoxonase-I (PON1) enzyme was purified from fresh human serum by using rapid chromatographic techniques. Additionally, the inhibition effects of some antineoplastic agents were researched on the PON1. Results: The enzyme was obtained with a specific activity of 2603.57 EU/mg protein. IC50 values for pemetrexed disodium, irinotecan hydrochloride, dacarbazine, and azacitidine were determined to be 9.63µM, 30.13µM, 53.31µM, and 21.00mM, respectively. These agents found to strongly inhibit PON1, with Ki constants ranging from 8.29±1.47µM to 23.34±2.71mM. Dacarbazine and azacitidine showed non-competitive inhibition, while other drugs showed competitive inhibition. Furthermore, molecular docking was performed using maestro for these agents. Among these, irinotecan hydrochloride and pemetrexed disodium possess the binding energy of-5.46 and-8.43 kcal/mol, respectively. Conclusion: The interaction studies indicated that these agents with the PON1 possess binding affinity.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2020Molecular docking and investigation of 4-(benzylideneamino)- and 4-(benzylamino)-benzenesulfonamide derivatives as potent AChE inhibitors
Işık, Mesut; Demir, Yeliz; Durgun, Mustafa; Türkeş, Cüneyt; Necip, Adem; Beydemir, Şükrü
The discovery of acetylcholinesterase inhibitors is important for the treatment of Alzheimer’s disease (AD), known as the most common type of dementia. Due to the side effects of commonly used acetylcholinesterase inhibitors, studies for the detection of new inhibitors are increasing day by day. In this study, we investigated the effects of some sulfonamide derivatives (S1–S4 and S1i–S4i) on AChE enzymes. The best pose of the active compounds to understand the mechanism of possible inhibition in interaction of enzyme-sulfonamide derivative were performed docking studies after in vitro experimental results. ADME-related physicochemical and pharmacokinetic properties of the synthesized 4-aminobenzenesulfonamide derivatives were the compatibility with Lipinski’s rule of five. We found that the synthesized derivatives of sulfonamides show potential inhibitor properties for AChE with Ki constants in the range of 2.54 ± 0.22–299.60 ± 8.73 µM. The derivatives of sulfonamides exhibited different inhibition type. We determined that the derivatives (S1, S1i, S3, and S3i) showed a competitive inhibition effect, whereas others (S2, S2i, S4, and S4i) showed mixed-type inhibition. As a result, the sulfonamide derivatives can be used as an alternative acetylcholinesterase inhibitor due to this effect. Inhibitors with fewer side effects, are thought to be important in the treatment of AD.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2020Sulfonamides incorporating ketene N,S-acetal bioisosteres as potent carbonic anhydrase and acetylcholinesterase inhibitors
Istrefi, Qëndresa; Türkeş, Cüneyt; Arslan, Mustafa; Demir, Yeliz; Nixha, Arleta R.; Beydemir, Şükrü; Küfrevioğlu, Ömer İ.
In this study, 15 novel compounds in a series of sulfonamide-based ketenes (7a–o) were synthesized and characterized using Fourier-transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectrometry. All compounds were tested for their ability to inhibit the human carbonic anhydrase (hCA) isoforms I and II, and acetylcholinesterase (AChE). The halogen-appended compounds, 7g, 7o, and 7i, exhibited the highest hCA I/II and AChE inhibition, with the KI values in the low nanomolar range (KI = 9.01 ± 0.08, 7.41 ± 0.03, and 7.37 ± 0.31 nM, respectively), as compared with their corresponding parent 2-[2,2-dicyano-1-(phenylamino)vinylthio]-N-(4-sulfamoylphenyl)acetamide analogs 7a–o. Besides, derivatives 7c and 7e selectively inhibited the isoform hCA I, whereas compounds 7m and 7n selectively inhibited isoform hCA II. These findings indicated that all compounds can inhibit metabolic dysfunctions, such as edema, epilepsy, glaucoma, and Alzheimer's disease, by specifically targeting both the hCA isoforms and AChE expression. Herein, also the interactions between ligands and receptors were highlighted through in silico molecular docking studies. The molecular mechanics–generalized Born surface area method was utilized to compute the binding free energy and the energy contribution of the critical residues in the active site was estimated. All these results would help us to perfectly understand the relationship between activity and structural characteristics of derivatives and to further improve newly and highly effective analogs targeting hCA and AChE.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2020Benzenesulfonamide derivatives containing imine and amine groups: Inhibition on human paraoxonase and molecular docking studies
Işık, Mesut; Beydemir, Şükrü; Demir, Yeliz; Durgun, Mustafa; Türkeş, Cüneyt; Nasır, Abdul; Necip, Adem; Akkuş, Musa
Sulfonamides known as inhibitors of many metabolic enzymes have been widely used as antimicrobial drugs for a long time. In the present study, we investigated in vitro inhibitory activities of benzenesulfonamide derivatives on human paraoxonase-I (hPON1). For this aim, PON1 was purified from human serum with a specific activity of 2603.57 EU/mg and 8.34% yield using simple chromatographic methods. The various concentrations of early-synthesized sixteen sulfonamide derivatives were tested on the paraoxonase activity. Ki values of compounds were found in the range of 0.28–357.70 µM. Compound H4 had the highest inhibitory activity on hPON1 as competitive. Estimated structure–activity relationship (SAR) for compounds was done based on different substituents and their positions in the compounds. Besides, the molecular docking analysis of compound H4 was performed to understand the binding interactions on the active site of the enzyme. According to these experimental results, compound H4 was a potential inhibitor of PON1.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2020Thiazolyl-pyrazoline derivatives: In vitro and in silico evaluation as potential acetylcholinesterase and carbonic anhydrase inhibitors
Sever, Belgin; Türkeş, Cüneyt; Altıntop, Mehlika Dilek; Demir, Yeliz; Beydemir, Şükrü
Alzheimer's disease (AD) is a complex, predominant, and progressive form of dementia. The treatment of AD alters depending on the cognitive and behavioral symptoms. The utility of cholinergic replacement by acetylcholinesterase (AChE) inhibitors in AD treatment has been well-documented so far. Recent studies have also demonstrated that human carbonic anhydrases (hCAs) serve as important targets for AD treatment. In an attempt to identify potent AChE and hCA inhibitors, new thiazolyl-pyrazolines (3a-k) were designed based on the molecular hybridization of thiazole and pyrazoline scaffolds. A facile and versatile synthetic route consisting of three steps, namely Claisen-Schmidt reaction, the formation of the 2-pyrazoline ring system, and Hantzsch thiazole synthesis was used to prepare compounds 3a-k. The synthesized derivatives were experimentally validated for efficacy by in vitro and direct enzymatic assays. Furthermore, the compounds were subjected to in silico screening using Schrödinger Suite software to identify the binding affinities of potential compounds based on Glide XP scoring, MM-GBSA calculating, and validation. The results of in vitro and in silico studies revealed that compounds 3a, 3f, and 3d were the most promising derivatives in this series due to their significant effects on AChE, hCA I, and hCA II, respectively.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2019Antidiabetic properties of dietary phenolic compounds: Inhibition effects on α-amylase, aldose reductase, and α-glycosidase
Demir, Yeliz; Durmaz, Lokman; Taslimi, Parham; Gulçin, İlhami
Aldose reductase (AR), α-amylase, and α-glycosidase are vital enzymes to prevent diabetic complications. Here, AR was purified from sheep kidney using elementary methods with 111.11-purification fold and with 0.85% purification yield. The interactions between some phenolic compounds and the AR, α-glycosidase, and α-amylase enzyme were determined. It was found that phenolic compounds exhibit potential inhibitor properties for these enzymes. For α-amylase, studied phenolic compounds showed IC50 values in the range of 601.56–2,067.78 nM. For α-glycosidase, Ki values were found in the range of 169.25 ± 27.22–572.88 ± 106.76 nM. For AR, Ki values in the range of 8.48 ± 0.56–43.26 ± 7.63 µM. However, genistein showed the best inhibition effect toward AR and α-glycosidase, but delphinidin chloride exhibited the best inhibition effect against α-amylase enzyme. We determined that all compounds showed noncompetitive inhibition effect against AR and α-glycosidase. Also, studied phenolic compounds may be useful in the prevention or treatment of diabetic complications.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2019New Isoindole-1,3-dione Substituted Sulfonamides as Potent Inhibitors of Carbonic Anhydrase and Acetylcholinesterase: Design, Synthesis, and Biological Evaluation
Gündoğdu, Saliha; Türkeş, Cüneyt; Arslan, Mustafa; Demir, Yeliz; Beydemir, Şükrü
Herein, a series of isoindole-1,3-dione substituted sulfonamide derivatives (3, 4 a–k) were designed, synthesized, and biologically evaluated, as inhibitors of carbonic anhydrase (CA) and acetylcholinesterase (AChE). CA and AChE inhibitory activities of newly synthesized isoindole-1,3-dione substituted sulfonamides compounds (3, 4 a–k) towards the hCA I, II, and AChE were evaluated utilizing the Verpoorte's and Ellman's assays and checked against that of standard inhibitors, acetazolamide (AAZ) and tacrine (TAC). The developed compounds (3, 4 a–k) showed the potent hCA isoenzyme inhibitory effect with Ki constants ranging from 7.96 to 48.34 nM, compared to AAZ (Kis; 436.20 nM for hCA I and 93.53 nM for hCA II). Among these derivatives; 1,3-dioxo-1,3-dihydroisobenzofuran-5-carbocyclic acid (3) and benzyl-1,3-dioxo-2-(4-sulfomophenyl)isoindoline-5-carboxylate (4 i) determined to be effective AChE inhibitors (Kis, 103.51 and 108.92 nM, respectively); these compounds were almost as potent to TAC (Ki, 109.75 nM). Furthermore, molecular docking studies of derivatives 3 and 4 i were carried out utilizing the crystal structures of hCA I (PDB Code: 4WR7), II (PDB Code: 4HT0) isozymes and AChE (PDB Code: 4EY7) receptors to study their binding interactions.
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