Sürdürülebilir Kalkınma Amaçları
Yayınlar
- ArticleAçık Erişim2024Dynamics of small molecule-enzyme interactions: Novel benzenesulfonamides as multi-target agents endowed with inhibitory effects against some metabolic enzymes
Güleç, Özcan; Türkeş, Cüneyt; Arslan, Mustafa; Işık, Mesut; Demir, Yeliz; Duran, Hatice Esra; Fırat, Muhammet; Küfrevioğlu, Ömer İrfan; Beydemir, Şükrü
In contemporary medicinal chemistry, employing a singular small molecule to concurrently multi-target disparate molecular entities is emerging as a potent strategy in the ongoing battle against metabolic disease. In this study, we present the meticulous design, synthesis, and comprehensive biological evaluation of a novel series of 1,2,3-triazolylmethylthio-1,3,4-oxadiazolylbenzenesulfonamide derivatives (8a-m) as potential multi-target inhibitors against human carbonic anhydrase (EC.4.2.1.1, hCA I/II), α-glycosidase (EC.3.2.1.20, α-GLY), and α-amylase (EC.3.2.1.1, α-AMY). Each synthesized sulfonamide underwent rigorous assessment for inhibitory effects against four distinct enzymes, revealing varying degrees of hCA I/II, a-GLY, and a-AMY inhibition across the tested compounds. hCA I was notably susceptible to inhibition by all compounds, demonstrating remarkably low inhibition constants (KI) ranging from 42.20 ± 3.90 nM to 217.90 ± 11.81 nM compared to the reference standard AAZ (KI of 439.17 ± 9.30 nM). The evaluation against hCA II showed that most of the synthesized compounds exhibited potent inhibition effects with KI values spanning the nanomolar range 16.44 ± 1.53–70.82 ± 4.51 nM, while three specific compounds, namely 8a-b and 8d, showcased lower inhibitory potency than other derivatives that did not exceed that of the reference drug AAZ (with a KI of 98.28 ± 1.69 nM). Moreover, across the spectrum of synthesized compounds, potent inhibition profiles were observed against diabetes mellitus-associated α-GLY (KI values spanning from 0.54 ± 0.06 μM to 5.48 ± 0.50 μM), while significant inhibition effects were noted against α-AMY, with IC50 values ranging between 0.16 ± 0.04 μM and 7.81 ± 0.51 μM) compared to reference standard ACR (KI of 23.53 ± 2.72 μM and IC50 of 48.17 ± 2.34 μM, respectively). Subsequently, these inhibitors were evaluated for their DPPH· and ABTS+· radical scavenging activity. Moreover, molecular docking investigations were meticulously conducted within the active sites of hCA I/II, α-GLY, and α-AMY to provide comprehensive elucidation and rationale for the observed inhibitory outcomes.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024Novel benzenesulfonamides containing a dual triazole moiety with selective carbonic anhydrase inhibition and anticancer activity
Buza, Aida; Türkeş, Cüneyt; Arslan, Mustafa; Demir, Yeliz; Dincer, Busra; Nixha, Arleta Rifati; Beydemir, Şükrü
A series of sulfonamides incorporating a 1,2,3-triazolyloxime substituted 1,2,3-triazolyl moiety were conceptualized and synthesized as human carbonic anhydrase (hCA) inhibitors. The synthesized small structures, denoted 7a through 7o, exhibited moderate inhibitory effects against the tumor-associated isoforms hCA IX and hCA XII compared to the well-known hCA inhibitor acetazolamide. In contrast, these molecules demonstrated higher potency and a diverse range of selectivity against the cytosolic isoforms hCA I and hCA II. Notably, the 4-hydroxyphenyl derivative (compound 7d versus cytosolic isoforms), the 4-acetylphenyl derivative (compound 7o), and the phenyl derivative (compound 7a) emerged as the most potent and selective inhibitors in this series, with inhibition constants (KI) of 47.1, 35.9, 170.0, and 149.9 nM, respectively, against hCA I, II, IX, and XII. Further cytotoxicity assays of compounds 7a–o against cancer cell lines Hep3B and A549, as well as normal cell line L929, were conducted to assess their selectivity towards malignant cells. Compounds 7d, 7g, and 7k exhibited selective cytotoxicity towards the Hep3B cell line, with reduced selectivity towards A549, whereas compound 7j demonstrated higher selectivity for the A549 cell line. Additionally, molecular docking studies were performed to elucidate the binding modes of these compounds within the active sites of hCAs, revealing crucial interactions that underpin their significant activity and selectivity for the tumor-specific isoforms.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2023Synthesis and Characterization of Novel 1,3-Diaryltriazene-Substituted Sulfaguanidine Derivatives as Selective Carbonic Anhydrase Inhibitors: Biological Evaluation, in Silico ADME/T and Molecular Docking Study
Akocak, Suleyman; Lolak, Nebih; Duran, Hatice Esra; Işık, Mesut; Türkeş, Cüneyt; Durgun, Mustafa; Beydemir, Şükrü
Sulfonamide compounds known as human carbonic anhydrase (hCA) inhibitors are used in the treatment of many diseases such as epilepsy, antibacterial, glaucoma, various diseases. 1,3-diaryl-substituted triazenes and sulfaguanidine are used for therapeutic purposes in many drug structures. Based on these two groups, the synthesis of new compounds is important. In the present study, the novel 1,3-diaryltriazene-substituted sulfaguanidine derivatives (SG1-13) were synthesized and fully characterized by spectroscopic and analytic methods. Inhibitory effect of these compounds on the hCA I and hCA II was screened as in vitro. All the series of synthesized compounds have been identified as potential hCA isoenzymes inhibitory with KI values in the range of 6.44±0.74-86.85±7.01 nM for hCA I and with KI values in the range of 8.16±0.40-77.29±9.56 nM for hCA II. Moreover, the new series of compounds showed a more effective inhibition effect than the acetazolamide used as a reference. The possible binding positions of the compounds with a binding affinity to the hCA I and hCA II was demonstrated by in silico studies. In conclusion, compounds with varying degrees of affinity for hCA isoenzymes have been designed and as selective hCA inhibitors. These compounds may be potential alternative agents that can be used to treat or prevent diseases associated with glaucoma and hCA inhibition.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2023Enzyme inhibition, molecular docking, and density functional theory studies of new thiosemicarbazones incorporating the 4-hydroxy-3,5-dimethoxy benzaldehyde motif
Demir, Yeliz; Türkeş, Cüneyt; Çavuş, Muhammet S.; Erdoğan, Musa; Muğlu, Halit; Yakan, Hasan; Beydemir, Şükrü
New Schiff base-bearing thiosemicarbazones (1–13) were obtained from 4-hydroxy-3,5-dimethoxy benzaldehyde and various isocyanates. The structures of the synthesized molecules were elucidated in detail. Density functional theory calculations were also performed to determine the spectroscopic properties of the compounds. Moreover, the enzyme inhibition activities of these compounds were investigated. They showed highly potent inhibition effects on acetylcholinesterase (AChE) and human carbonic anhydrases (hCAs) (KI values are in the range of 51.11 ± 6.01 to 278.10 ± 40.55 nM, 60.32 ± 9.78 to 300.00 ± 77.41 nM, and 64.21 ± 9.99 to 307.70 ± 61.35 nM for AChE, hCA I, and hCA II, respectively). In addition, molecular docking studies were performed, confirmed by binding affinities studies of the most potent derivatives.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2023Synthesis and characterization of novel acyl hydrazones derived from vanillin as potential aldose reductase inhibitors
Demir, Yeliz; Tokalı, Feyzi Sinan; Kalay, Erbay; Türkeş, Cüneyt; Tokalı, Pelin; Aslan, Osman Nuri; Şendil, Kıvılcım; Beydemir, Şükrü
In the polyol pathway, aldose reductase (AR) catalyzes the formation of sorbitol from glucose. In order to detoxify some dangerous aldehydes, AR is essential. However, due to the effects of the active polyol pathway, AR overexpression in the hyperglycemic state leads to microvascular and macrovascular diabetic problems. As a result, AR inhibition has been recognized as a potential treatment for issues linked to diabetes and has been studied by numerous researchers worldwide. In the present study, a series of acyl hydrazones were obtained from the reaction of vanillin derivatized with acyl groups and phenolic Mannich bases with hydrazides containing pharmacological groups such as morpholine, piperazine, and tetrahydroisoquinoline. The resulting 21 novel acyl hydrazone compounds were investigated as an inhibitor of the AR enzyme. All the novel acyl hydrazones derived from vanillin demonstrated activity in nanomolar levels as AR inhibitors with IC 50 and K I values in the range of 94.21 ± 2.33 to 430.00 ± 2.33 nM and 49.22 ± 3.64 to 897.20 ± 43.63 nM, respectively. Compounds 11c and 10b against AR enzyme activity were identified as highly potent inhibitors and showed 17.38 and 10.78-fold more effectiveness than standard drug epalrestat. The synthesized molecules’ absorption, distribution, metabolism, and excretion (ADME) effects were also assessed. The probable-binding mechanisms of these inhibitors against AR were investigated using molecular-docking simulations. Graphical abstract: [Figure not available: see fulltext.]
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2023Exploration of 1,2,3-triazole linked benzenesulfonamide derivatives as isoform selective inhibitors of human carbonic anhydrase
Kakakhan, Chnar; Türkeş, Cüneyt; Güleç, Özcan; Demir, Yeliz; Arslan, Mustafa; Özkemahlı, Gizem; Beydemir, Şükrü
A novel series of 1,2,3-triazole benzenesulfonamide substituted 1,3-dioxoisoindolin-5-carboxylate (7a-l) inhibitors of human α-carbonic anhydrase (hCA) was designed using a tail approach. The design method relies on the hybridization of a benzenesulfonamide moiety with a tail of 1,3-dioxoisoindoline-5-carboxylate and a zinc-binding group on a 1,2,3-triazole scaffold. Among the synthesized analogues, 2‑iodophenyl (7f, KI of 105.00 nM and SI of 2.98) and 2‑naphthyl (7h, KI of 32.11 nM and SI of 3.48) analogues (over off-target hCA I) and phenyl (7a, KI of 50.13 nM and SI of 2.74) and 2,6‑dimethylphenyl (7d, KI of 50.60 nM and SI of 3.35) analogues (over off-target hCA II) exhibited a remarkable selectivity for tumor isoforms hCA IX and XII, respectively. Meanwhile, analogue 7a displayed a potent inhibitory effect against the tumor-associated isoform hCA IX (KI of 18.29 nM) compared with the reference drug acetazolamide (AAZ, KI of 437.20 nM), and analogue 7h showed higher potency (KI of 9.22 nM) than AAZ (KI of 338.90 nM) against another tumor-associated isoform hCA XII. However, adding the lipophilic large naphthyl tail to the 1,3-dioxoisoindolin-5-carboxylate analogues increased both the hCA inhibitory and selective activities against the target isoform, hCA XII. Additionally, these analogues (7a-l) showed IC50 values against the human lung (A549) adenocarcinoma cancer cell line ranging from 129.71 to 352.26 μM. The results of the molecular docking study suggested that the sulfonamide moiety fits snugly into the hCAs active sites and interacts with the Zn2+ ion. At the same time, the tail extension engages in various hydrophilic and hydrophobic interactions with the nearby amino acids, which affects the potency and selectivity of the hybrids.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2023A novel series of thiosemicarbazone hybrid scaffolds: Design, synthesis, DFT studies, metabolic enzyme inhibition properties, and molecular docking calculations
Yakan, Hasan; Muğlu, Halit; Türkeş, Cüneyt; Demir, Yeliz; Erdoğan, Musa; Çavuş, Muhammet Serdar; Beydemir, Şükrü
The fourteen new thiosemicarbazone derivatives of Schiff base were synthesized from the condensation reactions of two different aldehydes (3‑hydroxy-4-methoxhybenzaldehyde and 3-ethoxhy-4-hydroxybenzaldehyde) with various substituted-thiosemicarbazides. Structures of the compounds (1-14) were characterized by using FT-IR, 1H NMR, and 13C NMR spectroscopic techniques, and elemental analysis. Furthermore, the enzyme inhibitory effect of the obtained hybrid scaffolds was studied. They exhibited highly potent inhibition effect on acetylcholinesterase (AChE) and carbonic anhydrases (hCAs) (KI values are in the range of 111.00 ± 12.12 to 381.60 ± 38.10 nM, 120.60 ± 20.45 to 338.90 ± 42.18 nM, and 100.60 ± 11.31 to 285.30 ± 45.27 nM for AChE, hCA I, and hCA II, respectively). DFT analyzes were performed to demonstrate the usability of some electronic parameters and nucleophilic-electrophilic attack abilities of the compounds in predicting enzyme inhibition properties. A correlation was seen between the HOMO energy eigenvalues of the compounds and the inhibition reactivity, and revealing that QTAIM calculations could also be used to predict the probability of electrophilic and nucleophilic attacks. Findings supporting that hCA I and AChE enzyme inhibition reactions primarily proceed through electrophilic attack, while hCA II reactions tend to occur via nucleophilic attack have been obtained. Also, molecular docking studies were conducted to confirm the outcomes of studies on binding affinities and the most powerful derivatives. The obtained results showed that the novel thiosemicarbazone derivatives may lead to the development of novel types of pharmacological agents in the treatment of patients with Alzheimer's disease, idiopathic intracranial hypertension, glaucoma, and related conditions.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2023Exploration of Some Bis-Sulfide and Bis-Sulfone Derivatives as Non-Classical Aldose Reductase İnhibitors
Türkeş, Cüneyt; Demir, Yeliz; Biçer, Abdullah; Cin, Günseli Turgut; Gültekin, Mehmet Serdar; Beydemir, Şükrü
Aldose reductase (AR, ALR2; EC 1.1.1.21), an enzyme that converts glucose to fructose on the polyol pathway, is an important member of the Aldo-keto reductase superfamily. ALR2 is part of the rate-limiting step, which is associated with diabetic complications in this process, and plays a role in regulating reactive oxygen species induced by growth factors and cytokines. Despite the fact that sulfides and sulfones have been discovered to have a variety of other biological functions, in the current study, we assessed the ALR2 inhibitory potential of the derivatives of bis-sulfide (5 a–i) and bis-sulfone (6 a–i) in order to further our interest in designing and discovering powerful ALR2 inhibitors. The results of the biological investigations showed that all of the derivatives exhibit activity against ALR2, with KI values ranging from 0.53±0.03 to 4.20±0.06 μM. Among these agents, 2,6-bis((4-chlorophenyl)(phenylthio)methyl)cyclohexan-1-one (5 h), 2,6-bis((3-nitrophenyl)(phenylthio)methyl)cyclohexan-1-one (5 c), and 2,6-bis((3-chlorophenyl)(phenylthio)methyl)cyclohexan-1-one (5 g) exhibited prominent inhibitory activity with KI constants of 0.53±0.03 μM, 0.65±0.04 μM, and 0.71±0.05 μM, respectively, against ALR2 and were found to be more potent than epalrestat (KI=0.79±0.01 μM) is currently, the only ALR2 inhibitor (ALR2I) utilized in treatment. Additionally, in silico molecular docking experiments were carried out to explain how these bis-sulfides (5 a–i) and bis-sulfones (6 a–i) interacted with the target enzyme ALR2′s binding site. According to the ADME-Tox study, these compounds are predicted to be ALR2Is with appropriate drug-like characteristics. The study‘s findings on sulfides and sulfones could be exploited to create innovative therapeutics that prevent diabetes complications.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2023Novel acetic acid derivatives containing quinazolin-4(3H)-one ring: Synthesis, in vitro, and in silico evaluation of potent aldose reductase inhibitors
Tokalı, Feyzi Sinan; Demir, Yeliz; Türkeş, Cüneyt; Dinçer, Büşra; Beydemir, Şükrü
Aldose reductase (AR) is a crucial enzyme of the polyol pathway through which glucose is metabolized under conditions of hyperglycemia related to diabetes. A series of novel acetic acid derivatives containing quinazolin-4(3H)-one ring (1–22) was synthesized and tested for in vitro AR inhibitory effect. All the target compounds exhibited nanomolar activity against the target enzyme, and all compounds displayed higher activity as compared to the reference drug epalrestat. Among them, Compound 19, named 2-(4-[(2-[(4-methylpiperazin-1-yl)methyl]-4-oxoquinazolin-3(4H)-ylimino)methyl]phenoxy)acetic acid, displayed the strongest inhibitory effect with a KI value of 61.20 ± 10.18 nM. Additionally, these compounds were investigated for activity against L929, nontumoral fibroblast cells, and MCF-7, breast cancer cells using the MTT assay. Compounds 16 and 19 showed lower toxicity against the normal L929 cells. The synthesized compounds’ (1–22) absorption, distribution, metabolism, and excretion properties were also evaluated. Molecular docking simulations were used to look into the possible binding mechanisms of these inhibitors against AR.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2023Synthesis, characterization and docking studies of benzenesulfonamide derivatives containing 1,2,3-triazole as potential ınhibitor of carbonic anhydrase I-II enzymes
Güngör, Seyit Ali; Köse, Muhammet; Tümer, Mehmet; Türkeş, Cüneyt; Beydemir, Şükrü
Carbonic Anhydrases (CAs) are an important family of metalloenzymes that contain zinc (Zn2+) ions in their active site and catalyze the conversion of carbon dioxide to bicarbonate and proton and found in all living organisms. Sulfonamides are well-known inhibitors of CAs isoenzymes. In this study, a series of benzenesulfonamide derivatives (9a–h) containing 1,2,3-triazole-moiety were designed, synthesized and their structures were characterized by spectroscopic methods. In addition, molecular structures of compounds 5a, 5 b, 9e and 9f were elucidated by X-ray diffraction technique. To investigate drug similarity of 9a–h compounds, Lipinski’s five rules (ADMET: absorption, distribution, metabolism, excretion and toxicity) were carried out by in silico studies. According to results, the compounds showed drug-like properties. Docking studies were applied to determine the scores, interactions and binding modes of compounds 9a–h against hCA I and hCA II enzymes. Compound 9c (-5.13 kcal/mol docking score) against hCA I enzyme and 9 h (-5.32 kcal/mol docking score) against hCA II enzyme showed potent inhibitory properties. The binding interactions of the compounds with the carbonic anhydrases were examined by docking studies. Communicated by Ramaswamy H. Sarma.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2023Novel bis-ureido-substituted sulfaguanidines and sulfisoxazoles as carbonic anhydrase and acetylcholinesterase inhibitors
Lolak, Nebih; Akocak, Süleyman; Durgun, Mustafa; Duran, Hatice Esra; Necip, Adem; Türkeş, Cüneyt; Işık, Mesut; Beydemir, Şükrü
Abstract: To discover alternative substances to compounds used to treat many diseases, especially treating Alzheimer’s disease (AD) and Parkinson’s disease targeting carbonic anhydrase (hCA) and acetylcholinesterase (AChE) enzymes, is important. For this purpose, a series of novel bis-ureido-substituted sulfaguanidine (SG1–4) and sulfisoxazole (SO1–4) derivatives were synthesized, and their inhibitory capacities were screened against hCA isoenzymes (hCA I and II) and AChE. Possible binding mechanisms of inhibitors to the active site were elucidated by in silico studies, and the results were supported by in vitro results. Moreover, the percent radical scavenging capacities of the derivatives were also evaluated. The derivatives (SG1–4 and SO1–4) were more effective against hCAs compared to standard drug acetazolamide (KI values of 98.28–439.17 nM for hCA I and II, respectively) and exhibited the highest inhibition with the KIs in the ranges of 2.54 ± 0.50–41.02 ± 7.52 nM for hCA I, 11.20 ± 2.97–67.14 ± 13.58 nM for hCA II, and 257.60 ± 27.84–442.60 ± 52.13 nM for AChE. Also, compounds SG1 and SO1 also showed ABTS radical scavenging activity at the rate of 70% and 78%, respectively. These results will contribute to the literature for the rational design and synthesis of new potent and selective inhibitors targeting hCAs and AChE with multifunctional effects such as radical scavenging as well as inhibition. Graphical abstract: This study focused on the synthesis and inhibitory effects of bis-ureido-substituted sulfaguanidine (SG1–4) andsulfisoxazole (SO1–4) derivatives against human hCA I and II isoforms and AChE. In order to test synthesizedderivatives’ free radical scavenging potentials were the DPPH and ABTS assays. In silico studies elucidatedpossible binding mechanisms of inhibitors to the active site.[Figure not available: see fulltext.].
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2023Molecular Docking Studies and the Effect of Fluorophenylthiourea Derivatives on Glutathione-Dependent Enzymes
Demir, Yeliz; Türkeş, Cüneyt; Küfrevioğlu, Ömer İrfan; Beydemir, Şükrü
Cancer is a serious problem affecting the health of all human societies. Chemotherapy refers to the use of drugs to kill cancer or the origin of cancer. In the past three decades, researchers have studied about proteins and their roles in the production of cancer cells. Glutathione S-transferases (GSTs) are a superfamily of enzymes that play a key role in cellular detoxification, protecting against reactive electrophiles attacks, including chemotherapeutic agents. Glutathione reductase (GR) is an important antioxidant enzyme involved in protecting the cell against oxidative stress. In this current study, GST and GR enzymes were purified from human erythrocytes using affinity chromatography. GR was obtained with a specific activity of 5.95 EU/mg protein and a 52.38 % yield. GST was obtained with a specific activity of 4.88 EU/mg protein and a 74.88 % yield. The effect of fluorophenylthiourea derivatives on the purified enzymes was investigated. Afterward, KI values were found to range from 23.04±4.37 μM–59.97±13.45 μM for GR and 7.22±1.64 μM–41.24±2.55 μM for GST. 1-(2,6-difluorophenyl)thiourea was showed the best inhibition effect for both GST and GR enzymes. The relationships of inhibitors with 3D structures of GST and GR were explained by molecular docking studies.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2023A new series of hydrazones as small-molecule aldose reductase inhibitors
Altıntop, Mehlika D.; Demir, Yeliz; Türkeş, Cüneyt; Öztürk, Remzi B.; Cantürk, Zerrin; Beydemir, Şükrü; Özdemir, Ahmet
In the search for small-molecule aldose reductase (AR) inhibitors, new tetrazole-hydrazone hybrids (1–15) were designed. An efficient procedure was employed for the synthesis of compounds 1–15. All hydrazones were subjected to an in vitro assay to assess their AR inhibitory profiles. Compounds 1–15 caused AR inhibition with Ki values ranging between 0.177 and 6.322 µM and IC50 values ranging between 0.210 and 0.676 µM. 2-[(1-(4-Hydroxyphenyl)-1H-tetrazol-5-yl)thio]-N’-(4-fluorobenzylidene)acetohydrazide (4) was the most potent inhibitor of AR in this series. Compound 4 markedly inhibited AR (IC50 = 0.297 µM) in a competitive manner (Ki = 0.177 µM) compared to epalrestat (Ki = 0.857 µM, IC50 = 0.267 µM). Based on the in vitro data obtained by applying the MTT test, compound 4 showed no cytotoxic activity toward normal (NIH/3T3) cells at the tested concentrations, indicating its safety as an AR inhibitor. Compound 4 exhibited proper interactions with crucial amino acid residues within the active site of AR. In silico QikProp data of all hydrazones (1–15) were also determined to assess their pharmacokinetic profiles. Taken together, compound 4 stands out as a promising inhibitor of AR for further in vivo studies.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2023Synthesis, Theoretical, in Silico and in Vitro Biological Evaluation Studies of New Thiosemicarbazones as Enzyme Inhibitors
Erdoğan, Musa; Serdar Çavuş, M.; Muğlu, Halit; Yakan, Hasan; Türkeş, Cüneyt; Demir, Yeliz; Beydemir, Şükrü
Eleven new thiosemicarbazone derivatives (1–11) were designed from nine different biologically and pharmacologically important isothiocyanate derivatives containing functional groups such as fluorine, chlorine, methoxy, methyl, and nitro at various positions of the phenyl ring, in addition to the benzyl unit in the molecular skeletal structure. First, their substituted-thiosemicarbazide derivatives were synthesized from the treatment of isothiocyanate with hydrazine to synthesize the designed compounds. Through a one-step easy synthesis and an eco-friendly process, the designed compounds were synthesized with yields of up to 95 % from the treatment of the thiosemicarbazides with aldehyde derivatives having methoxy and hydroxy groups. The structures of the synthesized molecules were elucidated with elemental analysis and FT–IR, 1H-NMR, and 13C-NMR spectroscopic methods. The electronic and spectroscopic properties of the compounds were determined by the DFT calculations performed at the B3LYP/6-311++G(2d,2p) level of theory, and the experimental findings were supported. The effects of some global reactivity parameters and nucleophilic-electrophilic attack abilities of the compounds on the enzyme inhibition properties were also investigated. They exhibited a highly potent inhibition effect on acetylcholinesterase (AChE) and carbonic anhydrases (hCAs) (KI values are in the range of 23.54±4.34 to 185.90±26.16 nM, 103.90±23.49 to 325.90±77.99 nM, and 86.15±18.58 to 287.70±43.09 nM for AChE, hCA I, and hCA II, respectively). Furthermore, molecular docking simulations were performed to explain each enzyme-ligand complex's interaction.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2022N-substituted phthalazine sulfonamide derivatives as non-classical aldose reductase inhibitors
Türkeş, Cüneyt; Arslan, Mustafa; Demir, Yeliz; Çoçaj, Liridon; Nixha, Arleta Rifati; Beydemir, Şükrü
Aldose reductase (AR, AKR1B1; EC 1.1.1.21) is an aldo-keto reductase that has been widely investigated as an enzyme crucially involved in the pathogenesis of several chronic complications, including nephropathy, neuropathy, retinopathy, and cataracts associated with diabetes mellitus. Although sulfonamides have been reported to possess many other biological activities, in continuation of our interest in designing and discovering potent inhibitors of AR, herein, we have evaluated the AR inhibitory potential of N-substituted phthalazine sulfonamide derivatives 5a-l. The biological studies revealed that all the derivatives show excellent activity against AR, with KI constants ranging from 67.73 to 495.20 nM. Among these agents, 4-(6-nitro-1,4-dioxo-1,2,3,4-tetrahydrophthalazine-2-carbonyl)benzenesulfonamide (5e) and 1,4-dioxo-3-(4-sulfamoylbenzoyl)-1,2,3,4-tetrahydrophthalazine-6-carboxylic acid (5f) showed prominent inhibitory activity with KI values of 67.73 and 148.20 nM, respectively, vs AR and were found to be more potent than epalrestat (KI = 852.50 nM), the only AR inhibitor currently used in the therapy. Moreover, molecular docking studies were also performed to rationalize binding site interactions of these sulfonamides (5a-l) with the target enzyme AR. According to ADME-Tox, predicts were also determined that these derivatives be ARIs displaying suitable drug-like properties. The sulfonamides identified in this study may be used to develop lead therapeutic agents inhibiting diabetic complications.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2022Design, synthesis, and biological activity of novel dithiocarbamate-methylsulfonyl hybrids as carbonic anhydrase inhibitors
Osmaniye, Derya; Türkeş, Cüneyt; Demir, Yeliz; Özkay, Yusuf; Beydemir, Şükrü; Kaplancıklı, Zafer A.
Carbonic anhydrase (CA) enzymes are involved in many physiological events. These enzymes, which contain Zn2+ in their structure, can be easily inhibited by dithiocarbamate compounds. In addition, CA enzyme inhibitory activities are known in groups such as sulfonamide and methylsulfonyl. For this purpose, in this study, a series of 23 new dithiocarbamate-methylsulfonyl derivatives were synthesized and their CA enzyme inhibitory activities were investigated. The inhibition potentials of the obtained compounds against the human CA I and CA II enzymes were investigated by the in vitro enzyme isolation method. It is seen that the compounds show activity at the nanomolar level. Molecular docking studies of the compounds were carried out by in silico methods. The poses of compounds 2a, 2e, 2o, and 2t are presented.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2022Synthesis, biological evaluation, and in silico study of novel library sulfonates containing quinazolin-4(3H)-one derivatives as potential aldose reductase inhibitors
Tokalı, Feyzi Sinan; Demir, Yeliz; Demircioğlu, İbrahim Hakkı; Türkeş, Cüneyt; Kalay, Erbay; Şendil, Kıvılcım; Beydemir, Şükrü
A series of novel sulfonates containing quinazolin-4(3H)-one ring derivatives was designed to inhibit aldose reductase (ALR2, EC 1.1.1.21). Novel quinazolinone derivatives (1–21) were synthesized from the reaction of sulfonated aldehydes with 3-amino-2-alkylquinazolin-4(3H)-ones in glacial acetic acid with good yields (85%–94%). The structures of the novel molecules were characterized using IR, 1H-NMR, 13C-NMR, and HRMS. All the novel quinazolinones (1–21) demonstrated nanomolar levels of inhibitory activity against ALR2 (KIs are in the range of 101.50–2066.00 nM). Besides, 4-[(2-isopropyl-4-oxoquinazolin-3[4H]-ylimino)methyl]phenyl benzenesulfonate (15) showed higher inhibitor activity inhibited ALR2 up to 7.7-fold compared to epalrestat, a standard inhibitor. Binding interactions between ALR2 and quinazolinones have been investigated using Schrödinger Small-Molecule Drug Discovery Suite 2021–1, reported possible inhibitor-ALR2 interactions. Both in vitro and in silico study results suggest that these quinazolin-4(3H)-one ring derivatives (1–21) require further molecular modification to improve their drug nominee potency as an ALR2 inhibitor.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2022Methyl benzoate derivatives: in vitro Paraoxonase 1 inhibition and in silico studies
Korkmaz, Işıl Nihan; Türkeş, Cüneyt; Demir, Yeliz; Özdemir, Hasan; Beydemir, Şükrü
Paraoxonase 1 (PON1) can metabolize some compounds such as aromatic carboxylic acid and unsaturated aliphatic esters, arylesters, cyclic carbonate, plucuronide drugs, some carbamate insecticide classes, nerve gases, and lactone compounds. Methyl benzoate has recently been shown to display potent toxicity against several insect species. In the current study, we aimed to investigate the effect of the methyl benzoate compounds (1–17) on PON1 activity. Methyl benzoate compounds inhibited PON1 with KI values ranging from 25.10 ± 4.73 to 502.10 ± 64.72 μM. Compound 10 (methyl 4-amino-2-bromo benzoate) showed the best inhibition (KI = 25.10 ± 4.73 μM). Furthermore, using the ADME-Tox, Glide XP, and MM-GBSA tools of the Schrödinger Suite 2021-4, a complete ligand–receptor interaction prediction was performed to characterize the methyl benzoates (1–17), probable binding modalities versus the PON1.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2022Some calcium-channel blockers: kinetic and in silico studies on paraoxonase-I
Türkeş, Cüneyt; Demir, Yeliz; Beydemir, Şükrü
Many drugs, which are used in clinical treatments, show pharmacological effects on enzyme activity with an essential role in the pathogenesis of various diseases. Paraoxonase-I (PON1) is a member of the mammalian lactonase enzyme family, serves to the prevention of blood vessel plaque formation by protecting high-density lipoprotein and low-density lipoprotein against oxidation. In the current study, we aimed to contribute to drug discovery and to determine the interaction of some calcium channel blockers (CCBs) with PON1. For this purpose, first, the PON1 enzyme was purified from fresh human serum by using different chromatographic techniques. Then, the various concentrations of CCBs were tested on the paraoxonase activity of PON1. IC 50 values were found as 41.00, 48.00, and 180 µM for nimodipine, cinnarizine, and nilvadipine, respectively. PON1 was effectively inhibited by these drugs (K is ranging between 22.13 ± 1.13 and 174.12 ± 20.52 µM). Of these drugs, only the inhibition mechanism of cinnarizine was competitive on PON1. Besides, the molecular docking analysis of cinnarizine was applied to detailed the binding interactions on the active site of PON1. The docking scores for the Glide standard-precision (SP), and Glide extra-precision (XP) modes for 1V04 receptor monitored to be −5.001, and −6.079, respectively. We determined that the CCBs reduced PON1 enzyme activity both in vitro and in silico conditions, significantly. Therefore, further biological studies such as gene expression and in vivo experiments should be done for these drugs. Communicated by Ramaswamy H. Sarma.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2022Molecular docking and inhibition studies of vulpinic, carnosic and usnic acids on polyol pathway enzymes
Demir, Yeliz; Ceylan, Hamid; Türkeş, Cüneyt; Beydemir, Şükrü
Aldose reductase (AR) and sorbitol dehydrogenase (SDH) are important enzymes of the polyol pathway. In the current study, inhibitory effects of vulpinic acid (VA) carnosic acid (CA) and usnic acid (UA) on purified AR and SDH enzymes were determined. These enzymes inhibition could be essential to prevent diabetic complications. AR and SDH enzymes were purified from sheep kidney. Then, VA, CA and UA were tested in various concentrations against these enzymes activity in vitro. K I values were found to be as 1.46 ± 0.04, 5.13 ± 0.25 and 11.71 ± 0.27 μΜ for VA, CA and UA, respectively, for AR. K I constants were found to be as 15.32 ± 0.34, 145.60 ± 2.17 and 213.40 ± 2.64 μΜ VA, CA and UA, respectively, for SDH. These findings indicate that VA, CA and UA could be useful in the treatment of diabetic complications. Communicated by Ramaswamy H. Sarma.
RDL Kalıcı Kaydıİncele