Sürdürülebilir Kalkınma Amaçları
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- ArticleAçık Erişim20261,4-Naphthoquinone thiazole urea hybrids bearing morpholine/piperazine: synthesis, crystal structure, aldose reductase and α-glycosidase enzyme inhibition, molecular docking, and electrochemical interaction with dsDNA
Efeoglu, Cagla; Sadak, Selenay; Sahin, Ertan; Demir, Yeliz; Türkeş, Cüneyt; Uslu, Bengi; Nural, Yahya
In this study, new 1,4-naphthoquinone thiazole urea hybrids bearing morpholine (3a–d) or piperazine (3e–h) moiety were synthesized in 76–89 % yields and characterized by 1H NMR, 13C NMR, FT-IR, HRMS, and elemental analysis. The stereochemistry of 3d was determined by single crystal x-ray diffraction study. We evaluated the inhibitory potential of these compounds 3a–h on aldose reductase (ALR2) and α-glycosidase enzyme (α-GLY) activity. Our results indicate that these compounds substantially inhibit ALR2 at micromolar doses, with inhibition constants (KIs) between 0.79 and 2.20 μM and inhibit α-GLY KI between 0.67 and 2.82 μM. Molecular docking simulations were utilized to elucidate inhibitory effects and establish structure-activity relationships for the synthesized compounds. DNA interaction studies are of great importance for the synthesis of new drugs and for studying the behavior and mechanisms of action of synthesized drug molecules. Herein, the interaction of 3d selected as a model compound with ct-dsDNA was investigated in the solution phase by the electrochemical method of differential pulse voltammetry (DPV). The decrease in the peak current value of 3d after the addition of the DNA solution confirmed the interaction. Limits of detection (LOD) and quantification (LOQ) for the interaction were found to be 0.099 ppm and 0.327 ppm in the concentration range of 0.348 ppm to 0.739 ppm, respectively. To determine the binding constant, cyclic voltammetry (CV) was utilized and found to be 8.6 × 102 M−1. Additionally, the type of interaction between the 3D molecule and DNA was investigated and supported by molecular docking and Fourier transformed infrared spectroscopy (FTIR).
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2026Esculetin attenuates doxorubicin-induced cardiac toxicity: Evidence from gene expression, enzyme activity, and molecular docking analyses
Demir, Yeliz; Ceylan, Hamid; Yeşilkent, Esra Nur; Kizir, Duygu; Karaman, Melike; Türkeş, Cüneyt; Beydemir, Şükrü
Doxorubicin (DOX) is a potent chemotherapeutic agent whose dose-dependent cardiotoxicity is associated with oxidative stress, inflammation, and enzymatic dysfunction. This study evaluates the cardioprotective potential of esculetin, a natural coumarin derivative, against DOX-induced cardiac injury in rats. Forty-eight male Sprague-Dawley rats were divided into six groups, including control, DOX, esculetin (50 and 100 mg/kg), and combination treatments. DOX markedly altered the expression of oxidative stress-related genes (Ache, Ar, Sord upregulated; Pon1, Gst downregulated) and impaired enzyme activities, accompanied by increased malondialdehyde and depleted glutathione levels. Esculetin administration, particularly at 100 mg/kg, reversed these molecular and biochemical disturbances, restoring antioxidant defense and normalizing gene expression. Molecular docking revealed strong binding interactions of esculetin with the active sites of key enzymes including AR, SORD, AChE, GST, and PON1, supporting its regulatory role. These findings suggest that esculetin exerts multi-targeted protective effects and may serve as a promising candidate for mitigating chemotherapy-induced cardiotoxicity. Further research is warranted to explore its integration into clinical cardioprotective strategies.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2026Design, synthesis, in vitro and in silico evaluation of thiazole-hydrazine hybrids incorporating an isoindole-1,3-dione scaffold as potent α-glucosidase inhibitors
Aslan, Osman Nuri; Kalın, Şeyda Nur; Kalay, Erbay; Türkeş, Cüneyt; Demir, Yeliz
In this study, a series of novel hybrid molecules ( TR1–14 ) incorporating a thiazole-hydrazine pharmacophore with a bicyclic isoindole-1,3-dione core were designed and synthesized. All compounds were unambiguously characterized by 1H/ 13C NMR, FTIR, and high-resolution mass spectrometry, and their purities (˃95%) were confirmed by HPLC. The synthesized derivatives exhibited potent α-glucosidase inhibition, with K I values ranging from 0.452 to 1.788 μM. Notably, the most active compound, TR6 ( K I: 0.452 ± 0.093 μM), demonstrated approximately 15-fold greater potency compared to the reference drug acarbose ( K I: 6.748 ± 0.167 μM), highlighting the substantial enhancement achieved through the designed scaffold modification. Structure–activity relationship analysis demonstrated that halogen substitution, particularly with chlorine and bromine, significantly enhances inhibitory potency, presumably due to strengthened hydrophobic and electronic interactions within the enzyme active site. Molecular docking and molecular dynamics simulations supported the experimental findings by revealing a conserved binding mode involving key catalytic residues (Arg600, Asp518, and Met519), as well as stabilizing water-mediated interactions, thereby providing a mechanistic rationale for the observed inhibition. In silico ADME predictions indicated favorable drug-like properties for all compounds, with full compliance with Lipinski's and Jorgensen's rules and substantially improved permeability profiles compared to acarbose. Cytotoxicity analyses demonstrated that TR3 , TR6 , TR10 , and TR11 exhibited low cytotoxic effects at concentrations above 100 μM in non-cancerous human lung epithelial BEAS-2B cells. Especially, TR5 and TR9 did not cause significant cytotoxicity even at a concentration of 200 μM in BEAS-2B cells. Overall, this integrated experimental-computational study identifies thiazole-hydrazine-isoindole hybrids, particularly TR5 and TR6 , as promising lead candidates for further optimization toward the development of next-generation α-glucosidase inhibitors with improved efficacy and drug-likeness.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2026Rhodanine–Sulfonate hybrids targeting aldose reductase: Synthesis, in vitro inhibition, molecular docking, and cytotoxicity studies
Kalay, Erbay; Demir, Yeliz; Türkeş, Cüneyt; Aslan, Osman Nuri; Pezik, Esra; Şahin, Engin
Aldose reductase (ALR2), a key enzyme in the polyol pathway, plays a significant role in the onset and progression of diabetic complications, rendering it a critical pharmacological target. In this study, a novel series of twenty-four sulfonate ester-functionalized rhodanine derivatives (compounds 1–24) were rationally designed, synthesized via Knoevenagel condensation, and comprehensively evaluated for their inhibitory activity against ALR2. Spectroscopic and spectrometric methods confirmed the structural integrity of the synthesized compounds. In vitro enzyme inhibition assays revealed that all compounds acted as competitive inhibitors, with several analogues, particularly compounds 6 and 8, exhibiting stronger ALR2 inhibition (Ki = 0.43 µM and 0.48 µM, respectively) than the reference drug epalrestat (Ki = 0.98 µM). Structure–activity relationship (SAR) analysis highlighted the critical influence of para-substituted electron-donating (e.g., methyl) and electron-withdrawing (e.g., nitro, halogen) groups on binding potency. Molecular docking of the most potent inhibitor (compound 6) demonstrated a stable binding pose supported by key interactions, including hydrogen bonding with His110 and π–π stacking with Phe122. In silico ADME profiling confirmed favorable drug-likeness properties for all derivatives. Cytotoxicity studies on L929, A549, and RG-2 cell lines revealed that most compounds were less toxic than the reference drug at lower concentrations, with compound 8 showing a promising cytotoxic profile. These findings position rhodanine–sulfonate hybrids as promising scaffolds for the development of next-generation ALR2 inhibitors for the treatment of diabetic complications.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2026Synthesis, characterization, and lipoxygenase inhibition of salicylaldehyde-derived schiff base metal complexes: enzymatic and in silico evaluation using quinoa lipoxygenase
Ereminsoy, Ergün; Demir, Yeliz; Yıldırım, Sümeyra Tuna; Türkeş, Cüneyt; Küfrevioğlu, Ömer İrfan
In the present study, novel Schiff base ligands were synthesized via the condensation of salicylaldehyde derivatives with o-aminophenol, and their metal complexes with Co(II), Ni(II), Cu(II), Zn(II), Cd(II), and UO₂(VI) metal actetates were successfully prepared. The compounds were comprehensively characterized using FT-IR, 1H-NMR, 13C-NMR, UV–Vis spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), and magnetic susceptibility measurements. FT-IR spectra confirmed azomethine (C = N) coordination through characteristic bands at 1612–1630 cm−1, while 1H-NMR spectra exhibited diagnostic azomethine proton signals at δ 8.84–8.62 ppm. XRD analysis revealed a semi-crystalline nature with prominent reflections at 2θ = 18.02° and 20.87°, and SEM images demonstrated nanorod-like morphologies. Magnetic moment values supported the proposed coordination geometries of the paramagnetic complexes. The biological activity of the synthesized compounds was investigated through in vitro inhibition studies against lipoxygenase (LOX), a ~ 97 kDa enzyme purified from Chenopodium quinoa Willd. with 77.89% purity and 7.24% yield. All compounds exhibited competitive inhibition toward LOX, with inhibition constants (Ki) in the range of 0.014 ± 0.002 to 0.858 ± 0.194 μM, indicating remarkable inhibitory potency. Molecular docking studies further substantiated the experimental results by revealing key hydrogen-bonding and π-cation interactions between the most active compounds and essential amino acid residues within the LOX active site. Overall, the results demonstrate that these Schiff base metal complexes represent promising candidates for the development of potent LOX inhibitors.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2026Hydrazonylthiazole Derivatives as Dual EGFR and ALR2 Inhibitors: Design, Synthesis, and Comprehensive In Vitro and In Silico Evaluation for Potential Anticancer Activity
Sever, Belgin; Türkeş, Cüneyt; Demir, Yeliz; Elamin, Khaled M.; Osman, Wadah; Oral, Kübra; Akıncı Genç, Selenay; Cantürk, Zerrin; Masunaga, Takuya; Kishimoto, Naoki
Background/Objectives: Signaling imbalances involving epidermal growth factor receptor (EGFR) and aldose reductase (ALR2) are frequently associated with the biology of several solid tumors, including non-small-cell lung cancer (NSCLC) and breast cancer. This work sought to prepare and investigate a small set of hydrazonylthiazole derivatives as potential modulators of both targets with relevance to cancer therapy. Methods: Thirteen compounds (1–13) were synthesized and examined for their effects on A549 (NSCLC), MCF-7 (breast cancer), and Jurkat leukemia cells, together with peripheral blood mononuclear cells (PBMCs) to determine selectivity. The most active molecules were further analyzed through apoptosis studies, EGFR and ALR2 inhibition assays, docking calculations, and 200 ns molecular dynamics (MD) simulations. SwissADME was used to estimate pharmacokinetic and drug-likeness features. Results: Among all derivatives, compound 13, prepared here for the first time, showed the strongest activity on A549 and MCF-7 cells (IC50: 1.33 ± 0.41 µM; 1.74 ± 0.38 µM) and displayed a very high selectivity index (SI = 138.9). It also triggered apoptosis in A549 cells and reduced EGFR activity by 74% at 10 µM. In contrast, compound 5 acted as the most efficient ALR2 blocker (KI = 0.08 ± 0.01 µM). MD simulations showed that both compounds maintained stable contact patterns with essential residues in the EGFR and ALR2 binding pockets. SwissADME analysis suggested suitable oral absorption and drug-likeness for both molecules. Conclusions: Compound 13 behaves as a selective EGFR-directed agent capable of inducing apoptotic cell death in NSCLC, while compound 5 shows strong affinity toward ALR2. These outcomes indicate that both structures may serve as useful starting points for further development of small molecules acting on EGFR- and ALR2-related pathways.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025Structure-based inhibition of acetylcholinesterase and butyrylcholinesterase with 2-Aryl-6-carboxamide benzoxazole derivatives: synthesis, enzymatic assay, and in silico studies
Kuzu, Burak; Alagoz, M. Abdullah; Demir, Yeliz; Gulcin, Ilhami; Burmaoglu, Serdar; Algul, Oztekin
An important research topic is the discovery of multifunctional compounds targeting different disease-causing components. This research aimed to design and synthesize a series of 2-aryl-6-carboxamide benzoxazole derivatives that inhibit cholinesterases on both the peripheral anionic and catalytic anionic sides. Compounds (7–48) were prepared from 4-amino-3-hydroxybenzoic acid in three steps. The Ellman test, molecular docking with Maestro, and molecular dynamics simulation studies with Desmond were done (Schrodinger, 12.8.117). Compound 36, the most potent compound among the 42 new compounds synthesized, had an inhibitory concentration of IC50 12.62 nM for AChE and IC50 25.45 nM for BChE (whereas donepezil was 69.3 nM and 63.0 nM, respectively). Additionally, compound 36 had docking values of − 7.29 kcal/mol for AChE and − 6.71 kcal/mol for BChE (whereas donepezil was − 6.49 kcal/mol and − 5.057 kcal/mol, respectively). Furthermore, molecular dynamics simulations revealed that compound 36 is stable in the active gorges of both AChE (average RMSD: 1.98 Å) and BChE (average RMSD: 2.2 Å) (donepezil had average RMSD: 1.65 Å and 2.7 Å, respectively). The results show that compound 36 is a potent, selective, mixed-type dual inhibitor of both acetylcholinesterase and butyrylcholinesterase. It does this by binding to both the catalytically active and peripheral anionic sites of cholinesterases at the same time. These findings show that target compounds may be useful for establishing the structural basis for new anti-Alzheimer agents.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025New N-(1,3,4-thiadiazole-2-yl)acetamide derivatives as human carbonic anhydrase I and II and acetylcholinesterase inhibitors
Dawbaa, Sam; Türkeş, Cüneyt; Nuha, Demokrat; Demir, Yeliz; Evren, Asaf Evrim; Yurttaş, Leyla; Beydemir, Şükrü
Various carbonic anhydrase (CA) enzyme isoforms are known today. In addition to the use of CA inhibitors as diuretics, antiepileptics and antiglaucoma agents, the inhibition of other specific isoforms of CA was reported to have clinical benefits in cancers. In this study, two groups of 1,3,4-thiadiazole derivatives were designed and synthesized to act as human CA I and II (hCA I and hCA II) inhibitors. The activities of these compounds were tested in vitro and evaluated in silico studies. The activity of the synthesized compounds was also tested against acetylcholinesterase (AChE) to evaluate the relation of the newly designed structures to the activity against AChE. The synthesized compounds were analyzed by 1H NMR,13C NMR and high-resolution mass spectroscopy (HRMS). The results displayed a better activity of all the synthesized compounds against hCA I than that of the commonly used standard drug, Acetazolamide (AAZ). The compounds also showed better activity against hCA II, except for compounds 5b and 6b. Only compounds 6a and 6c showed superior activity against AChE compared to the standard agent, tacrine (THA). In silico studies, including absorption, distribution, metabolism and excretion (ADME) and drug-likeness evaluation, molecular docking, molecular dynamic simulations (MDSs) and density functional theory (DFT) calculations, were compatible with the in vitro results and presented details regarding the structure–activity relationship.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2025Design, Synthesis, and In Silico Analyses of Nitroimidazole Derivatives Targeting Cholinesterases
Biyik, Busra; Tarıkogulları, Ayse H.; Alagoz, Mehmet Abdullah; Demir, Yeliz; Gulcin, Ilhami; Burmaoglu, Serdar; Algul, Oztekin
The increasing incidence of diseases and the constraints of current treatments require expedited drug development. Drug repositioning presents an effective approach for discovering new therapeutic applications for drugs already in clinical use. This study examines the efficacy of metronidazole and secnidazole, which are presently utilized as antiprotozoal agents, in the treatment of Alzheimer's disease via ester modifications. The secondary alcohol group in nitroimidazole structures underwent esterification with acetyl, pivaloyl, cyclopropyl, and cyclohexyl carbonyl chlorides. The compounds exhibited significant inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with Ki values between 52.40 ± 6.99 nM and 240.80 ± 45.56 nM for AChE and 77.82 ± 18.01 nM and 323.70 ± 56.21 nM for BChE. Molecular docking studies demonstrated significant interactions of the most active compounds (MNZ 8 and MNZ 4) with essential residues, including Trp84 and Phe330 in AChE, as well as Trp82 and active-site water molecules in BChE. These findings corroborate their inhibitory potential, notwithstanding initial positional alterations observed during simulations. The synthesized compounds' absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties were also assessed in silico. All compounds demonstrated drug-like properties and did not exhibit undesirable toxic effects. The findings indicate that repositioned derivatives of metronidazole and secnidazole may serve as promising lead compounds for the development of cholinesterase inhibitors aimed at treating Alzheimer's disease.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025New 1,2,3-triazole derivatives as acetylcholinesterase and carbonic anhydrase inhibitors: Synthesis, molecular docking, and solubility
Efeoglu, Cagla; Demir, Yeliz; Türkeş, Cüneyt; Yabalak, Erdal; Seferoglu, Zeynel; Nural, Yahya
In this study, a series of new 1,2,3-triazole derivatives were synthesized in 84–93 % yield using copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry and characterized by 1H/13C NMR, FT-IR, and HRMS analyses. The synthesized compounds (4a–h) were evaluated for their inhibitory activities against human carbonic anhydrase isoforms I and II (hCA I and hCA II) and acetylcholinesterase (AChE), which are clinically relevant targets in neurological and metabolic disorders. Among them, compounds 4f and 4g exhibited the most potent dual inhibitory activities. Compound 4f showed KI values of 144.30 nM for hCA II and 205.10 nM for AChE, while compound 4g exhibited KI values of 239.10 nM for hCA II and 125.90 nM for AChE. These values demonstrate that 4f and 4g are more effective than the reference drugs acetazolamide (hCA II, KI = 381.44 nM) and tacrine (AChE, KI = 255.44 nM). Structure-activity relationship (SAR) analysis revealed that hydrophobicity, steric bulk, and aromaticity significantly influenced enzyme affinity. In silico docking confirmed strong interactions with key active site residues. Furthermore, ethanol solubility profiling revealed that polar and hydrogen-bonding groups significantly improved solubility, while bulky or aromatic hydrophobic substituents reduced it. The combined biological activity and solubility data emphasize the potential of these triazole derivatives particularly 4f and 4g as promising candidates for multitarget drug design and further preclinical development.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2025Esculetin Attenuates Doxorubicin-Induced Cardiotoxicity via Modulation of Apoptotic and Mitochondrial Gene Expression Networks
Demir, Yeliz; Ceylan, Hamid; Karağaç, Medine Sibel; Türkeş, Cüneyt; Karaman, Melike; Beydemir, Şükrü
Doxorubicin (DOX), although widely used as a potent chemotherapeutic agent, is limited by its dose-dependent cardiotoxicity. Esculetin (E), a naturally occurring coumarin derivative, has been reported to exert antioxidant and anti-apoptotic effects in various tissues. This study aimed to evaluate the cardioprotective effects of esculetin against DOX-induced cardiac injury in rats by examining changes in the expression of genes related to apoptosis, oxidative stress, and mitochondrial function. Male Wistar rats were randomly assigned into six groups (Control, DOX, E50, E100, DOX + E50, DOX + E100). Cardiotoxicity was induced by administering DOX was administered as six intraperitoneal injections of 5 mg/kg each over 14 days (cumulative dose = 30 mg/kg). Serum cardiac markers (CK-MB, LDH, and cTn-I) were measured, and cardiac tissues were subjected to histopathological examination and RT-qPCR analysis for target gene expression. In addition, hierarchical clustering heatmap was employed to evaluate multidimensional gene expression patterns across groups. DOX treatment significantly elevated serum cardiac injury markers and upregulated pro-apoptotic genes (Casp3, Casp9, Anf, Bnp, β-Mhc), while downregulating genes associated with mitochondrial biogenesis (Pgc1α) and antioxidant response (Foxo1, Cox2). These findings suggest esculetin as a potential adjunctive candidate for cardioprotection during DOX chemotherapy. However, given the absence of protein-level validation, further studies are warranted to confirm whether the observed gene expression changes translate into corresponding alterations at the protein level.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025Novel Schiff Base Sulfonate Derivatives as Carbonic Anhydrase and Acetylcholinesterase Inhibitors: Synthesis, Biological Activity, and Molecular Docking Insights
Yaşar, Ümit; Demir, Yeliz; Gönül, İlyas; Özaslan, Muhammet Serhat; Çelik, Gizem Gümüşgöz; Türkeş, Cüneyt; Beydemir, Şükrü
Sulfonate derivatives are an essential class of compounds with diverse pharmacological applications. This study presents the synthesis and detailed characterization of six novel Schiff base sulfonate derivatives (L1–L6) through spectroscopic techniques (FT-IR and NMR). Their inhibitory potential was evaluated against human carbonic anhydrase isoenzymes (hCA I and hCA II) and acetylcholinesterase (AChE), which are crucial therapeutic targets for diseases such as glaucoma, epilepsy, and Alzheimer's disease. The KI values for the compounds concerning AChE, hCA I, and hCA II enzymes were in the ranges of 106.10 ± 14.73 to 422.80 ± 17.64 nM (THA: 159.61 ± 8.41 nM), 116.90 ± 24.40 to 268.00 ± 35.84 nM (AAZ: 439.17 ± 9.30 nM), and 177.00 ± 35.03 to 435.20 ± 75.98 nM (AAZ: 98.28 ± 1.69 nM), respectively. Molecular docking analyses revealed key interactions within the active sites of the enzymes, including hydrogen bonding with critical residues and π–π stacking interactions. Notably, L3 demonstrated superior inhibition against hCA I (KI: 116.90 ± 24.40 nM) and AChE (KI: 106.10 ± 14.73 nM), positioning it as a promising lead compound. This comprehensive investigation contributes to the development of isoform-specific inhibitors for therapeutic use and provides valuable insights into their binding mechanisms. The findings underscore the potential of Schiff base sulfonates as scaffolds in drug discovery for neurodegenerative and metabolic disorders.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2025A new series of naphthyl-thiosemicarbazone and thio/carbohydrazone derivatives: Synthesis, spectroscopic elucidation, dual enzyme inhibition targeting carbonic anhydrase/ acetylcholinesterase and molecular docking studies
Yakan, Hasan; Muğlu, Halit; Erdoğan, Musa; Türkeş, Cüneyt; Demir, Yeliz
New naphthyl-thiosemicarbazone derivatives (1–9) were obtained from 1-naphthaldehyde and numerous thiosemicarbazides. New naphthyl-thio/carbohydrazones (10–12) were prepared from 1-naphthaldehyde and various thio/carbohydrazides. FT-IR, 1H NMR, 13C NMR, and elemental analysis were used to elucidate the structures of the newly obtained compounds. The inhibitory effects of these compounds against human carbonic anhydrase isoforms I and II (hCA I and hCA II) and acetylcholinesterase (AChE) were systematically evaluated. Several compounds exhibited potent inhibition, particularly derivatives bearing halogenated and electron-donating aromatic substituents. Among them, compound 11 demonstrated the strongest inhibition for all three enzymes, with KI values of 52.42 nM (hCA I), 59.23 nM (hCA II), and 40.16 nM (AChE), surpassing the reference standards acetazolamide and tacrine. Structure–activity relationship (SAR) analysis highlighted the critical influence of substituent type and position on enzymatic activity. In addition, molecular docking simulations were conducted to elucidate the binding interactions of the most potent compound with hCA I, hCA II, and AChE enzymes. The docking results supported the in vitro findings, revealing favorable binding energies and key interactions such as π–π stacking and hydrogen bonding, especially for compound 11.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024Protective effects of esculetin against doxorubicin-induced toxicity correlated with oxidative stress in rat liver: In vivo and in silico studies
Köroğlu, Zeynep; Kizir, Duygu; Karaman, Melike; Demir, Yeliz; Türkeş, Cüneyt; Beydemir, Şükrü
Doxorubicin (DOX) is widely used in cancer treatment but the dose-related toxicity of DOX on organs including the liver limit its use. Therefore, there is great interest in combining DOX with natural compounds with antioxidant properties to reduce toxicity and increase drug efficacy. Esculetin is a natural coumarin derivative with biological properties encompassing anti-inflammatory and antioxidant activities. In light of these properties, this study was meticulously crafted to investigate the potential of esculetin in preventing doxorubicin (DOX)-induced hepatotoxicity in Sprague-Dawley rats. The rats were divided into a total of six groups: control group, DOX group (administered DOX at a cumulative dose of 5 mg/kg intraperitoneally every other day for 2 weeks), E50 group (administered 50 mg/kg of esculetin intraperitoneally every day), E100 group (administered 100 mg/kg of esculetin intraperitoneally every day) and combined groups (DOX + E50 and DOX + E100) in which esculetin was administered together with DOX. The treatments, both with DOX alone and in combination with E50, manifested a reduction in catalase (CAT mRNA) levels in comparison to the control group. Notably, the enzymatic activities of superoxide dismutase (SOD), CAT, and glutathione peroxidase (GPx) witnessed significant decreases in the liver of rats treated with DOX. Moreover, DOX treatment induced a statistically significant elevation in malondialdehyde (MDA) levels, coupled with a concurrent decrease in glutathione (GSH) levels. Additionally, molecular docking studies were conducted. However, further studies are needed to confirm the hepatoprotective properties of esculetin and to precisely elucidate its mechanisms of action.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024New naphthoquinone thiazole hybrids as carbonic anhydrase and cholinesterase inhibitors: Synthesis, crystal structure, molecular docking, and acid dissociation constant
Efeoglu, Cagla; Selcuk, Ozge; Demir, Bunyamin; Sahin, Ertan; Sari, Hayati; Türkeş, Cüneyt; Demir, Yeliz; Nural, Yahya; Beydemir, Şükrü
In this study, N-[3-(3-amino-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-R-thiazol-2(3H)-ylidene]-2,6-difluorobenzamide derivatives as new 1,4-naphthoquinone thiazole hybrids were synthesized by reacting of N-[(3-amino-1,4-dioxo-1,4-dihydronaphthalen-2-yl)carbamothioyl]-2,6-difluorobenzamide with various α-bromoketones in 76–92% yields. Their molecular structures were characterized by 1H NMR, 13C NMR, 19F NMR, FT-IR, and HRMS, and the stereochemistry of one of the hybrids was determined by single crystal x-ray diffraction study. These synthesized new compounds (3a–e) were found to be effective inhibitor molecules for cholinesterases (butyrylcholinesterase (BChE) and acetylcholinesterase (AChE)), and carbonic anhydrase I and II (hCA I and hCA II) enzymes. KI values were found to be in the range of 45.03–84.43 nM for BChE, 26.12–98.42 nM for AChE, 67.86–161.60 nM for hCA I, and 55.27–87.48 nM for hCA II. The acid dissociation constants (pKa) of 1,4-naphthoquinone thiazole hybrids were determined in 25% (v/v) DMSO:water (25.0 ± 0.1 °C, I = 0.1 M by NaCl). Three pKa values for each hybrid were calculated with the HYPERQUAD program from the data obtained as a result of potentiometric titrations. The results obtained from molecular docking studies indicate that the compounds in question favorably fit within the active sites of hCAs and ChEs. Additionally, the acceptability of these compounds, as determined by Lipinski's and Jorgensen's rules, was estimated using the ADME/T results. Based on these estimations, it can be concluded that the synthesized molecules have the potential to be developed as effective and safe inhibitors of hCAs and ChEs, thus making them suitable lead agents for glaucoma and Alzheimer's disease.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024Novel beta-lactam substituted benzenesulfonamides: in vitro enzyme inhibition, cytotoxic activity and in silico interactions
Güleç, Özcan; Türkeş, Cüneyt; Arslan, Mustafa; Demir, Yeliz; Dincer, Busra; Ece, Abdulilah; Beydemir, Şükrü
In this study, a library of twelve beta-lactam-substituted benzenesulfonamides (5a–l) was synthesized using the tail-approach method. The compounds were characterized using IR, 1H NMR, 13C NMR and elemental analysis techniques. These newly synthesized compounds were tested for their ability to inhibit the activity of two carbonic anhydrases (hCA) isoforms, I and II, and acetylcholinesterase (AChE) in vitro. The results showed that the synthesized compounds were potent inhibitors of hCA I, with K Is in the low nanomolar range (66.60–278.40 nM) than the reference drug acetazolamide (AAZ), which had a K I of 439.17 nM. The hCA II was potently inhibited by compounds 5a, 5d–g and 5l, with K Is of 69.56, 39.64, 79.63, 74.76, 78.93 and 74.94 nM, respectively (AAZ, K I of 98.28 nM). Notably, compound 5a selectively inhibited hCA II with a selectivity of > 4-fold over hCA I. In terms of inhibition of AChE, the synthesized compounds had K Is ranging from 30.95 to 154.50 nM, compared to the reference drug tacrine, which had a K I of 159.61 nM. Compounds 5f, 5h and 5l were also evaluated for their ability to inhibit the MCF-7 cancer cell line proliferation and were found to have promising anticancer activity, more potent than 5-fluorouracil and cisplatin. Molecular docking studies suggested that the sulfonamide moiety of these compounds fits snugly into the active sites of hCAs and interacts with the Zn2+ ion. Furthermore, molecular dynamics simulations were performed for 200 ns to assess the stability and dynamics of each enzyme-ligand complex. The acceptability of the compounds based on Lipinski’s and Jorgensen’s rules was also estimated from the ADME/T results. These results indicate that the synthesized molecules have the potential to be developed into effective and safe inhibitors of hCAs and AChE and could be lead agents. Communicated by Ramaswamy H. Sarma.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2024Investigation of Some Metabolic Enzyme Inhibition Properties of Novel Chalcone-Cu Complexes
Ebiri, Rustem; Turgut, Muhammet; Aktas Anil, Derya; Demir, Yeliz; Saglamtas, Ruya; Abdullah Alagoz, M.; Algul, Oztekin; Burmaoglu, Serdar
Fourteen novel Chalcone-Cu complexes were effectively synthesized in this work. The newly synthesized Chalcone-Cu complexes were assessed for their effects on human carbonic anhydrase isoenzymes I and II, acetylcholinesterase enzymes, and antioxidant activity. The intricate compounds exhibited Ki values ranging from 41.65–190.42 nM against hCA I, 15.79–259.07 nM against hCA II, and 14.36–175.73 nM against AChE enzymes. These complexes demonstrated potent inhibitory profiles against the specified metabolic enzymes, surpassing the inhibitory effects of acetazolamide (for hCA I and II) and tacrine (for AChE). The antioxidant properties of the compounds were assessed using DPPH and ABTS radical scavenging assays, revealing that the complexes had moderate to high efficacy in neutralizing free radicals. All complexes underwent molecular docking experiments. Compounds 14, 22, and 23 yielded the highest docking scores. Compound 14 demonstrated a docking score of −6.414 kcal/mol against hCAI, whereas compound 23 attained a docking score of −6.697 kcal/mol against hCA II. Compound 22 exhibited the most favorable docking score of −9.645 kcal/mol against AChE. The acquired results have the potential to help towards the development of new drugs containing Cu complex structures for the treatment of prevalent ailments such as glaucoma and Alzheimer's diseases.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024Novel spiroindoline derivatives targeting aldose reductase against diabetic complications: Bioactivity, cytotoxicity, and molecular modeling studies
Güleç, Özcan; Türkeş, Cüneyt; Arslan, Mustafa; Demir, Yeliz; Dincer, Busra; Ece, Abdulilah; İrfan Küfrevioğlu, Ömer; Beydemir, Şükrü
Despite significant developments in therapeutic strategies, Diabetes Mellitus remains an increasing concern, leading to various complications, e.g., cataracts, neuropathy, retinopathy, nephropathy, and several cardiovascular diseases. The polyol pathway, which involves Aldose reductase (AR) as a critical enzyme, has been focused on by many researchers as a target for intervention. On the other hand, spiroindoline-based compounds possess remarkable biological properties. This guided us to synthesize novel spiroindoline oxadiazolyl-based acetate derivatives and investigate their biological activities. The synthesized molecules' structures were confirmed herein, using IR, NMR (1H and 13C), and Mass spectroscopy. All compounds were potent inhibitors with KI constants spanning from 0.186 ± 0.020 μM to 0.662 ± 0.042 μM versus AR and appeared as better inhibitors than the clinically used drug, Epalrestat (EPR, KI: 0.841 ± 0.051 μM). Besides its remarkable inhibitory profile compared to EPR, compound 6k (KI: 0.186 ± 0.020 μM) was also determined to have an unusual pharmacokinetic profile. The results showed that 6k had less cytotoxic effect on normal mouse fibroblast (L929) cells (IC50 of 569.58 ± 0.80 μM) and reduced the viability of human breast adenocarcinoma (MCF-7) cells (IC50 of 110.87 ± 0.42 μM) more than the reference drug Doxorubicin (IC50s of 98.26 ± 0.45 μM and 158.49 ± 2.73 μM, respectively), thus exhibiting more potent anticancer activity. Moreover, molecular dynamic simulations for 200 ns were conducted to predict the docked complex's stability and reveal significant amino acid residues that 6k interacts with throughout the simulation.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024Synthesis of N-substituted 4-phenyl-2-aminothiazole derivatives and investigation of their inhibition properties against hCA I, II, and AChE enzymes
Biçer, Abdullah; Çağlayan, Cüneyt; Demir, Yeliz; Türkeş, Cüneyt; Altundaş, Ramazan; Akyıldız, Hasan; Beydemir, Şükrü
In this study, thiazole derivatives containing sulphonamide, amide, and phenyl amino groups were synthesized to protect the free amino groups of 5-methyl-4-phenyl-2-aminothiazole and 4-phenyl-2-aminothiazole. Halogenated reactions of N-protected thiazole derivatives have been investigated. LCMS, FT-IR, 1H NMR, and 13C NMR spectroscopy techniques were used to elucidate the structures of the synthesized compounds. Inhibition effects of the N-protected thiazole derivatives against human carbonic anhydrase I, II (hCA I, hCA II), and acetylcholinesterase (AChE) were investigated. The best results among the synthesized N-protected thiazole derivatives showed Ki values in the range of 46.85–587.53 nM against hCA I, 35.01–578.06 nM against hCA II, and in the range of 19.58–226.18 nM against AChE. Furthermore, in silico studies with the target enzyme of the thiazole derivatives (9 and 11), which showed the best results experimentally, have examined the binding interactions of the related compounds at the enzyme active site.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2024Bioactivity, cytotoxicity, and molecular modeling studies of novel sulfonamides as dual inhibitors of carbonic anhydrases and acetylcholinesterase
Güleç, Özcan; Türkeş, Cüneyt; Arslan, Mustafa; Demir, Yeliz; Dincer, Busra; Ece, Abdulilah; Küfrevioğlu, Ömer İrfan; Beydemir, Şükrü
In the present medical epoch, the prevailing approach of drug discovery, which focuses on inhibiting a single target, has been superseded by the concept of designing drugs that target more than one specific site. Herein, we present the design and synthesis of a novel series of 1-oxo-3,4-dihydronaphthalene substituted sulfonamides (5a-j) with human carbonic anhydrase (hCA) and acetylcholinesterase (AChE) inhibitory activities as potential dual-target agents. The design of target compounds 5a-j incorporated two key elements: i) The sulfonamide group, which is widely recognized for its high affinity for the active site of hCAs, and ii) the effectiveness of 2-benzylidene-1-tetralone class compounds in some neurodegenerative disorders. All reported sulfonamides were evaluated for their inhibitory effect against hCA I, II isoforms, and AChE. Both hCAs, and AChE were potently inhibited by 5a-j with KI constants in the nanomolar range; 47.71–113.20 nM, 28.05–206.60 nM, and 87.38–136.60 nM, respectively, compared to standard inhibitors, acetazolamide (KIs of 439.17 and 98.28 nM for hCA I and hCA II, respectively) and tacrine (KI of 159.61 nM). 5i exhibited the best multi-target inhibitory activity against hCA I (KI of 47.71 nM), hCA II (KI of 30.75 nM), and AChE (KI of 88.97 nM), while 5b showed a selectivity index (hCA I/II) of 3.61. Moreover, a cytotoxic activity assay for sulfonamides 5a-j was applied on the human breast adenocarcinoma MCF-7 cell line as well as on the non-tumoral mouse fibroblast L929 cell. Thereafter, extensive molecular dynamics simulations revealed the dynamic behavior of ligand/enzyme complex and predicted vital ligand contacts in the binding pocket.
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