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- 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 künye2020Inhibition of Human Serum Paraoxonase-I with Antimycotic Drugs: In Vitro and In Silico Studies
Türkeş, Cüneyt; Beydemir, Şükrü
Drugs show their pharmacological effects by inhibiting or activating enzymes. Therefore, enzyme inhibitors have an essential place in the drug design for numerous different sorts of diseases, i.e., cardiovascular, cancer, metabolic, and neurological. The purpose of the current study was to contribute to the growing drug discovery and development area by analyzing functions and drug interactions of paraoxonase-I. For this purpose, the PON1 enzyme was purified from fresh human serum using simple, rapid, and different chromatographic techniques. Then, it was tested for the inhibitory effects of some antimycotic drugs on the PON1. Also, molecular docking analyses of each drug were carried out to determine the binding interactions on the active site of the PON1 enzyme. It was identified that the purified enzyme had the specific activity of 3880.83 EU/mg proteins and the molecular weight of 43 kDa by SDS-PAGE. IC50 values for PON1 were in the range of 0.037 ± 0.001–5.728 ± 0.043 mM. Ki constants for caspofungin acetate, amphotericin B, anidulafungin, and fluconazole were determined to be 0.0105 ± 0.0015 mM, 0.3206 ± 0.0196 mM, 0.1674 ± 0.0233 mM, and 2.5464 ± 0.1655 mM, respectively. The inhibition mechanism of amphotericin B was non-competitive, whereas anidulafungin was mixed type, and the others were competitive.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2020Synthesis, characterization, biological evaluation, and in silico studies of novel 1,3-diaryltriazene-substituted sulfathiazole derivatives
Işık, Mesut; Akocak, Süleyman; Lolak, Nabih; Taslimi, Parham; Türkeş, Cüneyt; Gülçin, İlhami; Durgun, Mustafa; Beydemir, Şükrü
In the present study, a series of eleven novel 1,3-diaryltriazene-substituted sulfathiazole moieties (ST1–11) was synthesized by the reaction of diazonium salt of sulfathiazole with substituted aromatic amines and their chemical structures were characterized by Fourier transform infrared, 1H-NMR (nuclear magnetic resonance), 13C-NMR, and high-resolution mass spectroscopy methods. These synthesized novel derivatives were found to be effective inhibitor molecules for α-glycosidase (α-GLY), human carbonic anhydrase (hCA), and acetylcholinesterase (AChE), with KI values in the range of 426.84 ± 58.42–708.61 ± 122.67 nM for α-GLY, 450.37 ± 50.35–1,094.34 ± 111.37 nM for hCA I, 504.37 ± 57.22–1,205.36 ± 195.47 nM for hCA II, and 68.28 ± 10.26–193.74 ± 19.75 nM for AChE. Among the synthesized novel compounds, several lead compounds were investigated against the tested metabolic enzymes. More specifically, ST11 (4-[3-(perfluorophenyl)triaz-1-en-1-yl]-N-(thiazol-2-yl)benzenesulfonamide) showed a highly efficient inhibition profile against hCA I, hCA II, and AChE, with KI values of 450.37 ± 50.35, 504.37 ± 57.22, and 68.28 ± 10.26 nM, respectively. Due to its significant biological inhibitory potency, this derivative may be considered as an interesting lead compound against these enzymes.
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 - ArticleAçık Erişim2020Mannich reaction derived novel boron complexes with amine-bis(phenolate) ligands: Synthesis, spectroscopy and in vitro/in silico biological studies
Kilic, Ahmet; Beyazsakal, Levent; Işık, Mesut; Türkeş, Cüneyt; Necip, Adem; Takım, Kasım; Beydemir, Şükrü
The amine-bis(phenolate) ligands was prepared through a Mannich reaction utilizing two equivalents of 2,4-di-tert-butylphenol or 4-tert-butylphenol, two equivalents of formaldehyde and a single equivalent of 2-aminoethyl diphenylborinate as primary amine. This work deals with the synthesis and evaluation of new (B←N) and (B-O) units containing amine-bis(phenolate) boron complexes designed by combination of amine-bis(phenolate) ligands and various boronic acids in toluene reflux using a Dean-Stark apparatus to remove water formed as a by-product. The newly synthesized amine-bis(phenolate) ligands and their boron complexes were characterized using elemental analysis, and their probable structures were proposed based on 1H and 13C NMR, FT-IR, UV-Vis spectroscopy and LC-MS/MS spectrometry. The inhibition effects of the synthesized compounds on acetylcholinesterase (AChE) activity in vitro and their radical scavenging activities were evaluated. The AChE was effectively inhibited by compounds, with KI values in the range from 5.48 ± 0.65 to 40.56 ± 4.42 µM. The (L1B4) has more inhibition effect on AChE with KI value (6.37 ± 1.50 µM) in (L2) series, while (L2B4) has an inhibition effect with KI (5.48 ± 0.65 µM) in (L2) series. Also, the compounds showed about 18-45% DPPH and 26-85% ABTS radical scavenging activity. On the other hand, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT) and Trolox showed about 72-96% DPPH and 94-96% ABTS radical scavenging activity, respectively in the same concentration (25-30 µg/mL). Besides, the (L1B4), (L1B5), and (L2B4) determined as the most active inhibitors were docked into the binding site of AChE to find the binding interactions of the boron complexes with the protein.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2019Inhibition Effects of Phenolic Compounds on Human Serum Paraoxonase-1 Enzyme
Türkeş, Cüneyt
Metabolic processes in living organisms are closely related to the catalytic activity of enzymes. Inhibition or induction of enzymes leads to toxicities and metabolic interactions. This study aims to contribute to the growing drug design field by studying PON1-phenolic compound interactions. For this purpose, the paraoxonase-1 enzyme was purified from fresh human serum by using rapid and different chromatographic techniques. Additionally, it was investigated the inhibitory effects of some phenolic substances on the PON1 and was found that the purified enzyme had the molecular weight of 43 kDa and the specific activity of 3945.15 EU mg-1. These compounds showed potent inhibition against PON1, especially homovanillic acid exhibited a significant inhibition profile against PON1 with an IC50 value of 13.84±0.08 mM. Ki constants were 6.10±0.26 mM for homovanillic acid and 16.96±0.76 mM for phloridzin dihydrate. Homovanillic acid had competitive inhibition while the phloridzin dihydrate inhibited the PON1 as non-competitive. Also, molecular docking computations were performed by using the Glide XP mode. Glide energy of the homovanillic acid determined to be -23.95 kcal mol-1.
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.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2019Anti-diabetic Properties of Calcium Channel Blockers: Inhibition Effects on Aldose Reductase Enzyme Activity
Türkeş, Cüneyt; Demir, Yeliz; Beydemir, Şükrü
Aldose reductase (AR) belongs to NADPH-dependent oxidoreductases and converts glucose to sorbitol in the polyol pathway. AR inhibition is essential to prevent diabetic complications. Here, AR was purified from sheep kidney using simple methods and determined the interactions between some calcium channel blockers and the enzyme. It was found that calcium channel blockers (cinnarizine, nilvadipine, amlodipine besylate, nifedipine, isradipine, and nitrendipine) exhibit potential inhibitor properties for sheep kidney AR with IC50 values in the range of 5.87–8.77 μM and Ki constants in the range of 2.07 ± 0.72–5.62 ± 1.53 μM. The calcium channel blockers showed different inhibition mechanisms. It was determined that all studied compounds showed competitive inhibition effect except for isradipine and nitrendipine. They showed non-competitive inhibition. Among these drugs, cinnarizine was found to be the most potent AR inhibitor (Ki: 2.07 ± 0.72 μM). They may be useful in the treatment and/or prevention of diabetic complications.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2019In Vitro and In Silico Studies on the Toxic Effects of Antibacterial Drugs as Human Serum Paraoxonase 1 Inhibitor
Türkeş, Cüneyt; Beydemir, Şükrü; Küfrevioğlu, Ömer İrfan
The core purpose of the current study was to investigate the interactions of widely used broad-spectrum antibacterial drugs developed in response to the increasing rate of antibiotic-resistant various bacteria and to contribute to the field of drug design. Also, it is to broaden the current knowledge of paraoxonase 1 enzyme (EC: 3.1.8.1; PON1) which is a crucial drug-target enzyme. For this aim, first, we purified PON1 from human serum using rapid chromatographic techniques including, enzyme precipitation, IEX (ion-exchange) chromatography, and SEC (size exclusion chromatography), quickly. Following this, we researched the inhibitory effects of some antibacterial drugs. Finally, molecular docking tests were performed and analyzed in silico data. PON1 was found to be effectively inhibited by tigecycline, linezolid, ciprofloxacin lactate, and ertapenem sodium (Kis in the ranging from 0.018 to 125.540 mM). Drugs showed two different inhibition mechanisms: Linezolid was competitive; others were non-competitive. While Glide GScore of the linezolid for 1 V04 and 3SRE receptors were detected to be –4.442 and –4.915 kcal/mol in the SP mode, monitored as –3.548 and –3.791 kcal/mol in the XP mode, respectively.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2019Synthesis, biological evaluation and in silico studies of novel N-substituted phthalazine sulfonamide compounds as potent carbonic anhydrase and acetylcholinesterase inhibitors
Türkeş, Cüneyt; Arslan, Mustafa; Demir, Yeliz; Çoçaj, Liridon; Rifati Nixha, Arleta; Beydemir, Şükrü
The synthesis, characterization and biological evaluation of a series of novel N-substituted phthalazine sulfonamide (5a-l) are disclosed. Phthalazines which are nitrogen-containing heterocyclic compounds are biologically preferential scaffolds, endowed with versatile pharmacological activity, such as anti-inflammatory, cardiotonic vasorelaxant, anticonvulsant, antihypertensive, antibacterial, anti-cancer action. The compounds were investigated for the inhibition against the cytosolic hCA I, II and AChE. Most screened sulfonamides showed high potency in inhibiting hCA II, widely involved in glaucoma, epilepsy, edema, and other pathologies (Kis in the ranging from 6.32 ± 0.06 to 128.93 ± 23.11 nM). hCA I was inhibited with Kis in the range of 6.80 ± 0.10–85.91 ± 7.57 nM, whereas AChE in the range of 60.79 ± 3.51–249.55 ± 7.89 nM. ADME prediction study of the designed N-substituted phthalazine sulfonamides showed that they are not only with carbonic anhydrase and acetylcholinesterase inhibitory activities but also with appropriate pharmacokinetic, physicochemical parameters and drug-likeness properties. Also, in silico docking studies were investigated the binding modes of selected compounds, to hCA I, II, and AChE.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2019A potential risk factor for paraoxonase 1: in silico and in-vitro analysis of the biological activity of proton-pump inhibitors
Türkeş, Cüneyt
Objectives: Proton-pump inhibitors (PPIs) are drugs commonly utilized by about 7% of adults in the world. Recent researches have shown that there are countless and severe side effects of these drugs. This situation has raised concern among clinicians and patients alike. The purpose of this study is to contribute the novel drug discovery and development technology and toxicology field by researching interactions of PPIs on paraoxonase 1. Methods: In this study, the paraoxonase 1 enzyme was purified from human serum by using rapid and straightforward chromatographic techniques. Subsequently, the inhibition effects of pantoprazole, omeprazole, and esomeprazole, PPIs, were investigated on paraoxonase 1. Besides, molecular docking studies were performed to unravel the binding mechanism between the enzyme and drugs. Key findings: All drugs showed potent inhibitory activities. IC50 of the drugs values were 54.780 ± 0.524, 86.470 ± 0.818 and 93.390 ± 0.885 mm and Ki constants were found as 39.895 ± 0.005 mm, 70.112 ± 0.010 mm and 78.868 ± 0.008 mm, respectively. The binding scores observed in silico studies were found to agree with the obtained from in-vitro experimental results. Conclusions: We observed that the drugs decreased PON1 activity at low concentrations. The results show that adjusting the dosages of these medications is a crucial case for each patient. The physicians should more carefully interpret whether there is an essential indication before prescribing PPIs and, if there is, to approve the proper dosing for the situation.
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