Sürdürülebilir Kalkınma Amaçları
Yayınlar
- 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 - ArticleAçık Erişim2026Isovanillin-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.
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 - ArticleYalnız künye2026Solution-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.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2026Marine 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.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2026Machine 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.
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 - ArticleYalnız künye2026The Effects of Apilarnil and Imatinib on GR/GST/TrxR1 Enzyme Activities and Pentose Phosphate Pathway Enzymes in Rats
Ayna, Adnan; Caglayan, Cuneyt; Türkeş, Cüneyt; Temel, Yusuf; Tahiroğlu, Veysel; Izol, Ebubekir; Inci, Hakan
Apilarnil, a relatively understudied bee-derived product from drone larvae, has recently gained attention due to its diverse chemical content and biological activities. Imatinib, a selective tyrosine kinase inhibitor widely used in cancer treatment, is recognized for its effectiveness but is also associated with off-target toxicities including disturbances in redox homeostasis. While previous studies have mainly focused on the roles of the key antioxidant enzymes glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), glutathione reductase (GR), glutathione-S transferase (GST) and thioredoxin reductase (TrxR1) in tumor resistance mechanisms, their inhibition in non-cancerous cells may contribute systemic toxicity. This study investigated whether co-administration of apilarnil could alleviate the inhibitory effects of imatinib on these enzymes in vivo. The secondary metabolite profile of apilarnil was characterized using liquid chromatography–high resolution mass spectrometry (LC-HRMS) revealing a richness in phenolic compounds, notably isorhamnetin, phenolidzin, ascorbic acid, liquiritigenin, leucoside, 3-(4-hydroxyphenyl) propionic acid and caffeic acid. Enzyme activity assays showed that imatinib significantly suppressed the activities of G6PD, 6PGD, GR, GST and TrxR1 compared to the control group. However, co-treatment with apilarnil particularly at a dose of 400 mg/kg, markedly restored activities of these enzymes. Furthermore, molecular docking analysis was performed to assess the binding affinities and interaction profiles of imatinib with target enzymes, confirming its potent inhibitory potential and revealing distinct but comparable binding interactions. These findings suggest that apilarnil may exert a protective effect against imatinib-induced toxicity by modulating disruptions in metabolic enzyme activities.
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 Erişim2026Mono- and Bis-Ureido Sulfapyridines as Nanomolar Dual Cholinesterase Inhibitors: Enzyme Kinetics, Molecular Docking, and ADME/Tox Insights
Yapar, Gönül; Akocak, Suleyman; Lolak, Nebih; Topal, Meryem; Türkeş, Cüneyt; Topal, Fevzi; Durgun, Mustafa; Koçyiğit, Ümit Muhammet; Işık, Mesut; Beydemir, Şükrü
A series of mono- and bis-ureido sulfapyridine derivatives (SP-1–SP-10) were synthesized and evaluated as dual cholinesterase inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). All compounds exhibited nanomolar inhibition. The most potent AChE inhibitors were SP-8 (Ki = 5.25 ± 0.73 nM), SP-9 (5.09 ± 0.44 nM), and SP-10 (5.74 ± 0.55 nM), significantly outperforming tacrine (Ki = 105.03 ± 8.85 nM) under identical conditions. For BChE, SP-9 showed the strongest inhibition (Ki = 26.38 ± 2.07 nM) compared with tacrine (172.03 ± 32.42 nM). Kinetic analyses revealed competitive inhibition toward AChE for all derivatives, whereas BChE inhibition displayed both competitive and noncompetitive patterns depending on structural features. Glide XP docking using AChE (PDB: 7XN1) and BChE (PDB: 4BDS), complemented by MM-GBSA binding free energy calculations, supported favorable ligand accommodation within the catalytic pockets and highlighted the importance of aromatic and hydrophobic interactions. In silico ADME/Tox analysis revealed a potency–drug-likeness trade-off: mono-ureido derivatives complied with Lipinski's rule of five and showed high predicted oral absorption, whereas bis-ureido derivatives, despite superior enzymatic potency, exhibited multiple drug-likeness violations. These findings identify the ureido–sulfapyridine scaffold as a potent enzymatic dual cholinesterase inhibitory framework, warranting further structural optimization to improve pharmacokinetic properties.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2026Design and Synthesis of 4-Arylazo Pyrazole Carboxamides as Dual AChE/BChE Inhibitors: Kinetic and In Silico Evaluation
Akocak, Suleyman; Lolak, Nebih; Duran, Hatice Esra; Demir Çetinkaya, Büşra; Hashem, Hamada; Bräse, Stefan; Türkeş, Cüneyt
Background/Objectives: Pyrazole carboxamides are widely used as adaptable medicinal-chemistry scaffolds and have been explored as cholinesterase (ChE) inhibitor chemotypes. In this work, we prepared a new series of 4-arylazo-3,5-diamino-N-tosyl-1H-pyrazole-1-carboxamides 5(a–m) and evaluated their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), supported by structure-based computational analyses. Methods: Thirteen derivatives 5(a–m) were synthesized, fully characterized with analytical techniques (FT-IR, H NMR, and C NMR), and tested in vitro against AChE and BChE, with tacrine (THA) used as the reference inhibitor. Docking calculations were used to examine plausible binding modes. The top-ranked complexes (7XN1–5e and 4BDS–5i) were further examined by 100 ns explicit-solvent molecular dynamics (MD) simulations in Cresset Flare, followed by RMSD/RMSF analysis and contact-persistence profiling. Predicted ADME/Tox. properties were also assessed to identify potential developability issues. Results: The series showed strong ChE inhibition, and several compounds were more potent than THA. Compound 5e (4-nitro) was the most active AChE inhibitor (KI = 20.86 ± 1.61 nM) compared with THA (KI = 164.40 ± 20.84 nM). For BChE, the KI values ranged from 31.21 to 87.07 nM and exceeded the reference compound’s activity. MD trajectories supported stable binding in both systems (10–100 ns mean backbone RMSD: 2.21 ± 0.17 Å for 7XN1–5e; 1.89 ± 0.11 Å for 4BDS–5i). Most fluctuations were confined to flexible regions, while key contacts remained in place, consistent with the docking models. ADME/Tox. predictions suggested moderate lipophilicity but generally low aqueous solubility; all compounds were predicted as non-BBB permeant, and selected liabilities were flagged (e.g., carcinogenicity for 5e/5g/5h/5i; nephrotoxicity for 5f/5g). Conclusions: The 4-arylazo-3,5-diamino-N-tosyl-1H-pyrazole-1-carboxamide scaffold delivers low-nanomolar ChE inhibition, with docking and MD supporting stable binding modes. Future optimization should prioritize solubility improvement and mitigation of predicted toxicities and metabolic liabilities, especially given the predicted lack of BBB permeability for CNS-directed applications.
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 - ArticleAçık Erişim2025Molecular and structural characterization of ureido-benzenesulfonamides as dual inhibitors of aldose reductase and cholinesterases
Türkeş, Cüneyt; Lolak, Nebih; Duran, Hatice Esra; Yapar, Gönül; Akocak, Suleyman
The conformational and kinetic intricacies of enzyme-ligand interactions are critical for understanding molecular mechanisms underlying metabolic and neurodegenerative pathologies. Herein, we report a rationally designed series of ureido-benzenesulfonamides as dual-acting nanomolar inhibitors targeting aldose reductase (ALR2) and cholinesterases (AChE and BChE). Spectrophotometric inhibition assays revealed that compound 3SA-a displayed exceptional ALR2 affinity (KI = 7.00 ± 0.68 nM), surpassing epalrestat by over 30-fold. Likewise, 3SA-f selectively inhibited BChE with a KI of 24.20 ± 2.26 nM, outperforming tacrine by a factor of 7.8. Molecular docking simulations highlighted distinct dynamic binding modes: 3SA-a engaged ALR2's catalytic cleft through a hydrogen bond with Tyr48 and water-bridged interactions, whereas 3SA-f leveraged π-π stacking and halogen bonding within BChE's extended acyl pocket. These binding orientations were consistent with SAR findings, where meta-sulfonamide placement and halogen substitution optimized selectivity and conformational complementarity. Complementary in silico ADME-Tox predictions confirmed the drug-like nature of all compounds (0 Lipinski/PAINS violations), moderate oral permeability (QPPCaco: 79–85 nm/s), and low CNS exposure (CNS score = −2), aligning with a peripheral mechanism of action. Collectively, this study provides a detailed structural and dynamic framework for dual-target enzyme inhibition, offering a tunable scaffold for future therapeutics targeting the ALR2-ChE axis.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2025N-substituted phthalimide–carboxylic acid hybrids as dual-targeted aldose reductase inhibitors: Synthesis, mechanistic insights, and cancer-relevant profiling
Zognjani, Blinera; Nixha, Arleta Rifati; Duran, Hatice Esra; Arslan, Mustafa; Yıldıztekin, Gizem; Ece, Abdulilah; Türkeş, Cüneyt
Aldose reductase (ALR2; AKR1B1), a NADPH-dependent cytosolic oxidoreductase, plays a central role in the polyol pathway and is implicated in hyperglycemia-induced tissue injury. Beyond its metabolic function, elevated ALR2 expression has been reported in several malignancies, including hepatocellular and pulmonary carcinomas, highlighting its potential as a therapeutic target in metabolic-oncologic interface. In this study, a novel set of eleven N-substituted phthalimide–carboxylic acid derivatives (5a–5k) was synthesized and evaluated for ALR2 inhibition, pharmacokinetic characteristics, and cancer-selective safety. Among the series, compound 5f demonstrated the highest inhibitory potency (KI = 7.34 nM), outperforming epalrestat (KI = 232.1 nM). Glide docking positioned 5f within the ALR2 active site (GlideScore: −6.71 kcal/mol), stabilized via key contacts with Tyr48, His110, and Cys298, along with π–π stacking at Trp219. MM-GBSA analysis corroborated strong binding affinity (ΔG = −64.86 kcal/mol). DFT-derived quantum descriptors, logP, TPSA, and solvation energies supported its favorable interaction profile. ADME/Tox predictions indicated high GI absorption, no P-gp or CYP liabilities, and acceptable bioavailability. In vitro cytotoxicity assays showed negligible activity of 5f against A549 and Hep3B cancer cell lines (IC₅₀ > 160 μM) and no toxicity toward L929 fibroblasts, reflecting safety for long-term use. Transcriptomic data from CCLE and DepMap confirmed AKR1B1 overexpression in these cancer models. Network analysis linked ALR2 to redox imbalance and inflammation, suggesting its broader role in tumorigenesis.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2025Phthalimide–benzoic acid hybrids as potent aldose reductase inhibitors: Synthesis, enzymatic kinetics, and in silico characterization
Hoti, Dafina; Nixha, Arleta Rifati; Duran, Hatice Esra; Arslan, Mustafa; Yıldıztekin, Gizem; Ece, Abdulilah; Türkeş, Cüneyt
Aldose reductase (ALR2; AKR1B1) is implicated in hyperglycemia-driven tissue injury and remains a tractable enzymatic target. We developed a concise, chromatography-free two-step route to phthalimide–benzoic acid hybrids ( 5a–5m) and profiled their biochemical activity against human ALR2. Across the series, halogenated analogs were most active, with the para-bromophenyl derivative5demerging as the top hit (KI = 7.56 nM). Steady-state kinetic analysis indicated a competitive inhibition mechanism. Molecular docking to the ALR2 active site (PDB4JIR), supported by MM-GBSA rescoring, yielded a catalytically consistent binding mode featuring hydrogen-bonding within the anion-binding region (Tyr48, His110) and complementary hydrophobic contacts (Trp111, Trp219), with Cys298 contributing as a proximal hydrophobic contact. In cell-based assays (A549, Hep3B, L929), the compounds generally showed low intrinsic cytotoxicity at the tested concentrations, suggesting a favorable preliminary safety margin aligned with their ALR2-directed pharmacology. In silico ADME/Tox assessments further supported oral drug-likeness. Overall, these results identify phthalimide–benzoic acid hybrids as tractable ALR2 inhibitor scaffolds that combine potent biochemical inhibition with a competitive kinetic profile and encouraging early safety signals, warranting in vivo evaluation and SAR-guided optimization.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2025Fluorenyl-phthalimide hybrids as potent aldose reductase inhibitors with selective anticancer activity: Rational design, synthesis, and molecular insights
Gundogdu, Saliha; Duran, Hatice Esra; Arslan, Mustafa; Çetinkaya, Büşra Demir; Türkeş, Cüneyt
Metabolic reprogramming in cancer cells creates actionable vulnerabilities for precision oncology. Aldose reductase (ALR2, AKR1B1; EC 1.1.1.21), a cytosolic NADPH-dependent oxidoreductase, has emerged as a multifunctional player in tumor progression, drug resistance, and oxidative stress modulation, yet remains underexploited as a cancer target. In this study, we report the rational design, synthesis, and biological evaluation of a focused series of fluorenyl-phthalimide carboxylic-acid hybrids (5a-5l) as dual-acting agents with selective anticancer potential and potent ALR2 inhibition. Among them, compound 5a exhibited the strongest ALR2 inhibition with a KI of 8.71 ± 0.81 nM, far surpassing the clinical comparator epalrestat (KI = 232.10 ± 14.42 nM). In MCF-7 and A549 carcinoma cells, 5a demonstrated moderate antiproliferative activity (IC50 = 52.04 μM and 192.91 μM, respectively) while sparing normal bronchial epithelial cells, indicating tumor selectivity. Molecular docking and MM-GBSA calculations (ΔGbind = −44.02 kcal/mol) revealed a consistent bidentate hydrogen bonding network supporting high-affinity binding involving Tyr48, His110, and Trp111, further stabilized by crystallographic water molecules. To explore structure-activity relationships, a Random Forest regression model was developed using 24 descriptors derived from QikProp. The model achieved strong predictive performance (Q2CV = 0.71), and SHAP analysis identified water/gas partition coefficient, skin permeability, and human oral absorption as the most influential features shaping inhibitory potency. In silico ADME/Tox profiling supported the drug-like nature of compound 5a, with no major CYP or hERG liabilities predicted. Collectively, these findings position 5a as a first-in-class ALR2-targeted anticancer lead, introducing a chemically novel and mechanistically validated chemotype for further development within the framework of metabolically targeted precision therapies.
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