Araştırmacılar(7)

• Dilek, Esra
• Elmastas, Mahfuz
• Gursoy, Sule
• Gülaboğlu, Mine
• Karakoç, Barış
• Türkeş, Cüneyt
• Yılmaz, Ali Osman

• ArticleYayıncıda açık erişim2026/r/ebyu/11347
  1,4-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).

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• ArticleYayıncıda açık erişim2026/r/ebyu/11134
  Isovanillin-derived bis-hydrazones as dual cholinesterase and carbonic anhydrase inhibitors: synthesis, enzymatic profiling, and computational insights from molecular docking and dynamics

  Türkeş, Cüneyt; Yapar, Gönül; Duran, Hatice Esra; Lolak, Nebih; Akocak, Suleyman

  Aims: To develop isovanillin-based bis-hydrazones as multitarget inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase I/II (hCA I/II). Materials & methods: Twelve bis-hydrazones (4a–4l) were synthesized in two steps and evaluated by spectrophotometric enzyme assays, Lineweaver–Burk kinetics, molecular docking, MM-GBSA, molecular dynamics simulations, and in silico ADME/Tox profiling. Results: All compounds showed nanomolar inhibition. Compound 4d was the most potent AChE/BChE inhibitor (KI = 10.46 and 3.56 nM), while 4a and 4j led the hCA I/II panel (KI = 3.46 and 16.12 nM). Docking, MM-GBSA, and molecular dynamics supported dual-site cholinesterase engagement and non-zinc, peripherally anchored hCA inhibition. Conclusions: Isovanillin-based bis-hydrazones, particularly 4d, 4a, and 4j, represent promising multitarget leads for cholinergic and hCA-linked disorders.

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• ArticleYayıncıda açık erişim2026/r/ebyu/10825
  Synergistic effects of luteolin and Lactobacillus rhamnosus on methicillin-resistant Staphylococcus aureus biofilm inhibition: in vitro and in silico molecular deployment studies

  Baser, Sumeyye; Celebi, Demet; Celebi, Ozgur; Kara, Adem; Turkes, Cuneyt

  Methicillin-resistant Staphylococcus aureus (MRSA) remains one of the leading causes of healthcare-associated infections due to its remarkable biofilm-forming ability and multidrug resistance, highlighting the urgent need for alternative antimicrobial strategies. The present study investigated the antibacterial, antibiofilm, antivirulence, and cytotoxic effects of luteolin alone and in combination with Lactobacillus rhamnosus bacterial suspension natant against MRSA. Antibacterial activity was evaluated using minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), disk diffusion, and fractional inhibitory concentration (FIC) assays. Biofilm inhibition was quantified using the crystal violet method, while the expression levels of biofilm-associated genes (icaA, icaB, icaC, icaD, clfA, clfB, fnbA, and fnbB) were determined by quantitative real-time PCR. Molecular docking analysis was performed to investigate the interaction between luteolin and S. aureus Sortase A (SrtA), and the cytotoxic potential of the treatments was evaluated in human dermal fibroblast (HDF) cells using the WST-8 assay. Luteolin exhibited MIC and MBC values of 128 and 256 µg/mL, respectively, whereas L. rhamnosus bacterial suspension natant also demonstrated antibacterial activity against MRSA. Combination treatment significantly increased the inhibition zone diameter and produced a synergistic interaction with an FIC index of 0.50. Moreover, the combination inhibited biofilm formation by approximately 75%, markedly exceeding the inhibitory effects of either treatment alone. Gene expression analysis revealed dose-dependent modulation of several biofilm-associated genes, particularly suppression of fnbA, suggesting interference with bacterial adhesion mechanisms. Molecular docking demonstrated favorable binding of luteolin to the active site of Sortase A with a predicted binding energy of − 9.220 kcal/mol, supporting its potential antivirulence mechanism. No significant cytotoxicity was observed in HDF cells within the tested concentration range. Collectively, these results demonstrate that luteolin combined with L. rhamnosus bacterial suspension natant represents a promising natural therapeutic strategy for controlling MRSA infections by simultaneously targeting bacterial growth, biofilm formation, and virulence while maintaining acceptable biocompatibility.

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• ArticleYalnız künye2026/r/ebyu/10788
  In Vitro Cholinesterase Inhibition and Computational Investigation of some 1,2,3-triazole Derivatives as Dual AChE/BuChE Inhibitors

  Tan, Ayse; Dilek, Esra

  In vitro anticholinesterase activities of a series of 1,2,3-triazole derivatives, 9(a-e) and 10(f-l), were evaluated against electric eel acetylcholinesterase (eeAChE) and equine serum butyrylcholinesterase (eqBuChE), using donepezil as a reference inhibitor. Enzyme inhibitory activities were characterized by IC50, inhibition constants (Ki), and inhibition mechanisms. All target compounds exhibited potent inhibitory activity against both enzymes. 9e demonstrated the highest activity against eeAChE (Ki = 7.69 ± 1.24 nM), outperforming donepezil (Ki = 25.28 ± 5.79 nM). 9b showed the strongest inhibition against eqBuChE (Ki = 3.36 ± 0.67 nM), whereas donepezil displayed comparatively weak activity (Ki = 43.48 ± 10.36 nM). To further elucidate ligand–enzyme interactions, molecular docking, molecular dynamics simulation (MDS), MM/GBSA, and structure–activity relationship studies were performed. Docking results indicated that all target compounds exhibited higher binding affinities for both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE than for BuChE. MDS and MM/GBSA analyses confirmed the stability of the selected complexes, without significant fluctuations over 50 ns, and showed that while 9e was selective for hAChE-CAS, 9b bound similarly to both hBuChE sites. Taken together, all target compounds, particularly 9e and 9b, may serve as novel dual AChE/BuChE inhibitor candidates.

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• ArticleYalnız künye2026/r/ebyu/10748
  Synthesis and characterization of novel 5-fluoroindolylmethylene hydrazone derivatives as schiff base compounds: In vitro and in silico evaluation as potential cholinesterase (AChE and BChE) inhibitors

  Koprulu, Cigdem; Faydali, Nagihan; Muhammed, Muhammed Tilahun; Dilek, Esra; Kucukoglu, Kaan; Sirinzade, Hanif

  This study analyzes the inhibitory effects of newly synthesized compounds of the K1–12 series on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes comparatively using IC50 and Kᵢ parameters. Initially, a series of novel 5-fluoroindolylmethylene hydrazone derivatives (K1–12) were designed and synthesized. The structures of the synthesized compounds were elucidated using 1H and 13C NMR spectroscopy as well as mass spectrometric analyses. Subsequently, their inhibitory effects on AChE and BChE were evaluated in vitro . Molecular docking studies performed for all compounds with AChE and BChE enzymes, and pi interactions and conventional hydrogen bonds were involved in protein-ligand interactions. The molecular dynamics (MD) simulation study of the compound with the highest binding potential to the AChE and BChE structures, K10, disclosed that the complexes obtained from docking would be stable. Moreover, the compound is predicted to have a greater tendency to remain within the binding site of the BChE structure. The density functional theory (DFT) study resulted in similar levels of chemical stability and reactivity for the relatively active compounds. The findings revealed that, especially, the K5 and K10 compounds exhibited higher inhibitory activity than donepezil against BChE and AChE, respectively. The results indicate that these compounds could be potential agents for the treatment of neurodegenerative diseases in the future.

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• ArticleYalnız künye2026/r/ebyu/10747
  Esculetin 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.

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• ArticleYalnız künye2026/r/ebyu/10735
  Design, 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.

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• ArticleYalnız künye2026/r/ebyu/10728
  Solution-phase multifunctional modulation of cholinesterases and carbonic anhydrases by thiourea–pyrimidine benzenesulfonamides: Kinetics and explicit-solvent molecular dynamics

  Tok, Fatih; Dumani, Alessia; Güney, Sultan; Abas, Burçin İrem; Kozan, Bensu; Türkeş, Cüneyt; Duran, Hatice Esra; Başoğlu, Faika; Çevik, Özge; Ece, Abdulilah

  In aqueous media, enzyme–ligand recognition is shaped not only by direct contacts but also by solvent-mediated interaction networks that persist across time scales. Here, cholinesterases (AChE and BChE) and cytosolic human carbonic anhydrases ( h CA I and h CA II) were investigated as two disease-relevant enzyme systems in solution, and twelve thiourea–pyrimidine benzenesulfonamide derivatives were synthesized and structurally characterized. Enzyme inhibition was quantified by steady-state kinetics; inhibition constants ( K I) were obtained by nonlinear global fitting of untransformed rate data, with Lineweaver–Burk plots used only for visualization. To connect solution-phase inhibition with molecular recognition, docking was validated by redocking (heavy-atom RMSD <2.0 Å across targets), and representative complexes were examined by 500 ns explicit-solvent MD simulations (TIP3P, 0.15 M NaCl, NPT), revealing stable binding modes and persistent, frequently water-mediated interaction patterns consistent with experimental trends. Cellular relevance was assessed in MKN-28 gastric cancer cells with L929 fibroblasts as a non-malignant control. Compounds with improved cytotoxic selectivity toward MKN-28 were identified, and the lead compound ( 11 ) was further evaluated by Annexin V/PI flow cytometry, showing a shift from viable cells toward apoptotic populations under the tested conditions. In silico ADMET profiling suggested moderate lipophilicity across the series, while highlighting elevated polar surface area and compound-dependent toxicity flags as parameters to monitor during optimization. Overall, thiourea–pyrimidine benzenesulfonamides emerge as multifunctional modulators of ChEs and cytosolic h CAs within the applied biochemical and cellular assays.

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• ArticleYalnız künye2026/r/ebyu/10717
  Marine algae-derived polyamines and phlorotannins as cholinesterase inhibitors: In vitro and in silico analysis

  Necip, Adem; Işık, Mesut; Türkeş, Cüneyt; Ünal, Dilek; Kırboğa, Kevser Kübra; Beydemir, Şükrü; Rudrapal, Mithun

  The limitations of conventional cholinesterase inhibitors in Alzheimer's disease (AD) therapy namely, their short half-lives and adverse side effects—necessitate the exploration of natural alternatives. This investigation examined the inhibitory potential of selected polyamines (putrescine and spermidine) and a phlorotannin derivative (phloroglucinol), naturally present in the macroalgae species Cystoseira crinita and Stypopodium schimperi, against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using in vitro and in silico approaches. Additionally, radical scavenging potentials of each sample were determined. Enzyme activity assays employing the Ellman method revealed that putrescine and spermidine reached similar inhibition levels (approximately 32 %), while Cystoseira crinita acetone extract demonstrated superior potency with an IC50 of 0.085 mg/mL, indicating robust enzyme modulation. Complementary molecular docking studies conducted with Schrödinger Maestro 2020 elucidated the formation of stable enzyme-ligand complexes through hydrogen bonding and π-π interactions with critical residues including HIS447, TYR337, and TRP86 within the AChE active site. Moreover, crude macroalgal extracts, particularly those derived from C. crinita and S. schimperi, exhibited marked AChE inhibition, further substantiating the therapeutic potential of these marine-derived compounds. Collectively, these findings demonstrate that the polyamines and phlorotannin derivative studied not only effectively regulate cholinesterase activity but also offer naturally derived structural frameworks for the development of novel AD treatments. Phloroglucinol showed a high scavenging of DPPH (85%) and ABTS (98%) radicals, close to the activity of the reference compound trolox (96% for DPPH and 94% for ABTS). Further pharmacokinetic and toxicological evaluations are warranted to ascertain their clinical viability in AD management.

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• ArticleYalnız künye2026/r/ebyu/10706
  Machine learning-guided repurposing of FDA-approved quinolones as dual cholinesterase inhibitors: A multi-level docking, molecular dynamics, DFT, and SHAP-based analysis

  Türkeş, Cüneyt

  Alzheimer's disease (AD) involves progressive cholinergic degeneration, with acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) playing key enzymatic roles in its pathology. In this study, we computationally repurposed four FDA-approved quinolone antibiotics, Norfloxacin, Sparfloxacin, Gatifloxacin, and Nalidixic acid, as potential dual-site cholinesterase (ChE) inhibitors using a hybrid in vitro/in silico workflow. Enzyme inhibition assays identified Norfloxacin as the most potent AChE inhibitor (KI = 1.08 μM), while all compounds displayed non-competitive inhibition toward BChE. Molecular docking and MM-GBSA binding free energy analyses revealed key interactions within the catalytic gorge of AChE, supported by hydrogen bonding with Phe295 and Arg296, as well as π–π contacts with Tyr124. Density functional theory computations highlighted the influence of frontier orbital distribution on binding affinity, particularly for Norfloxacin and Sparfloxacin. An explicit-solvent molecular dynamics simulation of the AChE–Norfloxacin complex further confirmed the stability of the docking-derived binding mode over 100 ns. In an exploratory fashion, SHAP-based machine learning models were applied to a descriptor set derived from QikProp, SwissADME, and Jaguar outputs, suggesting that BBB-related indices and HOMO energy contribute to AChE inhibition, whereas the energy gap is more relevant for BChE; these trends, however, are constrained by the small four-compound dataset and should be regarded as hypothesis-generating. In silico ADME/Tox profiling indicated favorable oral drug-like properties, low predicted CYP450 inhibition liabilities, and physicochemical profiles compatible with CNS-oriented optimization, although passive BBB permeability was not predicted to be high. Finally, systems-level enrichment (STRING, GeneCards) provided a qualitative network context linking ACHE and BCHE to neurodegeneration. Together, these data position Norfloxacin and Sparfloxacin as computationally prioritised candidates whose ChE-related repurposing potential warrants further validation in dedicated cellular and in vivo models.

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