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    Comprehensive experimental and computational evaluation of novel linagliptin-analogues: Synthesis, DFT calculations, molecular modeling, and in vitro anticancer/antioxidant activities
    (Elsevier Sci Ltd, 2026) Dilek, Omer; Bahar, Dilek; Yesil, Tolga Acar; Ozkara, Yagmur; Tilki, Tahir
    Recent evidence suggests that linagliptin and its structural derivatives exhibit biological activities beyond glycemic control, highlighting the linagliptin scaffold as a promising platform for multifunctional drug design. In this study, eight novel linagliptin-based azo-imine derivatives (3a-h) were designed, synthesized, and structurally characterized, with the stereochemistry of representative compound 3e confirmed by 2D NMR. Computational analyses (DFT, molecular docking, and molecular dynamics simulations) were employed to support electronic structure elucidation and ligand-protein interaction stability. Specifically, 250 ns molecular dynamics simulations confirmed that the 6XFP-3h complex maintains high structural stability and thermodynamic equilibration throughout the trajectory. All derivatives displayed moderate antioxidant activity (TEAC = 0.46-0.84). Antiproliferative effects were evaluated against A549 and DLD1 cancer cell lines, with WI-38 fibroblasts used to assess selectivity. Compound 3h exhibited the highest potency, with IC50 values of 0.66 & micro;M (A549) and 0.29 & micro;M (DLD1), while compounds 3d and 3e showed cytotoxicity comparable to cisplatin. Selectivity index analysis revealed moderate but discernible cancer cell preference, with compound 3h demonstrating the most favorable selectivity toward DLD1 cells (SI = 3.62). These results suggest that compound 3h represents a prioritized candidate within this series and support linagliptin-based azo-imine derivatives as a tractable framework for further structure-activity relationship optimization.
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    Computational and experimental insights into azo-containing Aroylhydrazones: A promising class of CDK2 inhibitors
    (Elsevier, 2025) Yesil, Tolga Acar; Dilek, Omer; Tilki, Tahir
    The discovery of novel small-molecule inhibitors targeting cyclin-dependent kinase 2 (CDK2) remains a critical area of research in drug development. Herein, five new azo-based aroylhydrazones (3a-e) were synthesized with high yields and thoroughly characterized using spectroscopic techniques. DFT calculations with the B3LYP functional and 6-311++G(d,p) basis set demonstrated a strong correlation between theoretical and experimental spectral data. Global reactivity assessments via HOMO-LUMO calculations identified 3e as the most electrophilic compound, while 3b displayed the highest hardness. ADMET evaluations confirmed that all synthesized compounds adhered to Lipinski's Rule of Five, suggesting favorable pharmacokinetic properties. Molecular docking studies against CDK2 revealed strong binding affinities, with the 3PXY-3c complex achieving an outstanding docking score of-10.7 kcal/mol and an MM/PBSA binding energy of-131.812 kJ/mol. To further explore its dynamic stability, a 100 ns MD simulation was performed for the 3PXY-3c complex. The results confirmed that 3c maintained stable interactions throughout the simulation, reinforcing its potential as a promising CDK2 inhibitor.
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    Coumarin-Based Azo Derivatives With Trifluoromethyl Substituents: A Combined Experimental and Computational Approach Toward Novel Anticancer Agents
    (Wiley-V C H Verlag Gmbh, 2026) Dilek, Omer; Yesil, Tolga Acar; Tilki, Tahir
    Cancer's global prevalence demands novel therapeutic agents with improved efficacy and selectivity. In this study, six azo-containing derivatives featuring trifluoromethyl (& horbar;CF3) groups and a coumarin scaffold were comprehensively examined, five of which were newly synthesized. Their chemical structures were confirmed using FTIR, UV-Vis, and NMR (1H and 13C) spectroscopy. DFT calculations (B3LYP/6-311++G(d,p)) supported the experimental data, showing strong agreement between theoretical and observed spectra. All compounds fulfilled Lipinski's rule of five, according to ADMEt studies; however, compounds 4b and 4c showed the lowest projected toxicity (LD50: 6480 mg/kg). High binding affinities toward cancer-related VEGFR2 protein targets (PDB IDs: 3VO3, 6GQO, 3VHE, and 3WZD) were found via molecular docking. The compound that interacted with 3VHE the most was compound 5a (-11.2 kcal/mol). The 6GQO-4a complex was shown to be the most stable (-120.099 kJ/mol) by MM/PBSA analysis. This finding was confirmed by 100 ns molecular dynamics simulations that showed constant hydrogen bonding and stable RMSD values. These results point to compound 4a as a promising lead molecule for the development of anticancer drugs, which calls for additional in vitro and in vivo research.
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    Design, synthesis, and quantum chemical calculations of triazole-based aroylhydrazone molecules: Dual assessment of antioxidant properties via in vitro and in silico approaches
    (Elsevier, 2025) Dilek, Omer; Yesil, Tolga Acar; Tilki, Tahir; Dede, Bulent
    In this study, five novel Triazole-Based Aroylhydrazone compounds (6a-e) were synthesized in high yields (87-79 %), starting from deferasirox which has known iron chelator, and characterized with NMR, FTIR, Mass, and UV-vis spectroscopic methods. Quantum chemical calculations of all synthesized molecules were performed at the DFT/B3LYP/6-311G(d,p) level. It was observed that both theoretical and experimental spectral values were compatible. Optimized molecular geometries were acquired from DFT calculations and used in molecular docking studies. Tyrosinase (PDB ID: 3NM8) protein was utilized in molecular docking studies. 6d-3NM8 complex had the highest docking score with the -10.1 kcal/mol. Stabilization of the 6d-3NM8 complex during 100 ns was determined via molecular dynamics simulation. Intramolecular interactions of all molecules were also examined by NCI-RDG analysis. The frequently used cupric ion reducing antioxidant capacity method (CUPRAC) was used to determine the antioxidant activity of synthesized compounds and Trolox which is unknown in the literature on its activity in DMSO. The highest TEAC value was 1.76 (6d) while the lowest one was 1.34 (6e). It is possible to say that the synthesized molecule 6d has the potential to be an antioxidant reagent based on the results of in vitro and in silico antioxidant activity.
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    New Azo-Azomethine Compounds: Comprehensive Evaluation of In Silico Biological Activities, ADMEt Profiling, and In Vitro Antioxidant Properties
    (Wiley-V C H Verlag Gmbh, 2025) Yesil, Tolga Acar
    The discovery of novel azo-azomethine compounds and the exploration of their biological activities are critical for expanding the pool of potential drug candidates. In this study, four new fluorine-substituted azo-azomethines (4a-d), containing groups such as & horbar;CF3 and & horbar;OCF3, were successfully synthesized in high yields. Their in vitro antioxidant activities were evaluated using the CUPRAC method, and the results indicate that all compounds demonstrated higher TEAC values compared to the standard antioxidant Trolox. Notably, compound 4d exhibited the highest value of 2.22. A comparative analysis indicated that the antioxidant activity was influenced not only by the presence of fluorine-based substituents but also by the number of hydroxyl (& horbar;OH) groups in their structures. The ADMEt properties were also assessed, revealing that the synthesized compounds adhered to Lipinski's rule of five. Additionally, molecular docking studies were performed to examine various biological activities, targeting specific proteins involved in disease mechanisms. The findings revealed that; Among the compounds, the 4b-2XIR complex displayed the highest docking score of -11.0 kcal/mol, indicating strong binding affinity. These findings suggest that the synthesized azo-azomethine compounds have significant potential as drug candidates for the treatment of specified diseases.
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    Polyphenols containing new azo-aroylhydrazone hybrids: theoretical insights and evaluation of antioxidant potential via CUPRAC and DPPH assays
    (Academic Press Inc Elsevier Science, 2026) Yesil, Tolga Acar
    The growing interest in multifunctional antioxidants has drawn attention to hybrid scaffolds that unify distinct redox-active pharmacophores. Azo groups, aroylhydrazones, and gallic acid derivatives are individually recognized for their notable antioxidant potential, yet molecular hybrids integrating all three remain scarce. To address this gap, a new series of compounds (5a-j) combining azo, aroylhydrazone, and polyhydroxyphenyl moieties was designed and synthesized to enhance antioxidant activity through structural synergy. The synthesized molecules were thoroughly characterized by FTIR, 1H, 13C NMR, 2D NOESY/COSY, UV-Vis, and mass spectrometry. Their electronic and structural properties were further evaluated using DFT calculations at the B3LYP/6-311++G(d,p) level. In silico ADMEt predictions and molecular docking studies revealed favorable pharmacokinetic profiles and strong binding affinities toward key antioxidant-related enzymes-glutathione reductase (PDB: 1XAN), myeloperoxidase (PDB: 3F9P), and NAD(P)H oxidase (PDB: 2CDU). In vitro antioxidant activity was assessed using CUPRAC and DPPH assays, with Trolox serving as the standard. Remarkably, this is the first study to report the combined use of DMF in the CUPRAC and DMSO in the DPPH assays, offering a novel solvent strategy that enhanced compound solubility and assay compatibility. Among the tested compounds, 5b and 5e showed the highest antioxidant activities, surpassing Trolox in both methods. These results suggest that the azo-aroylhydrazone-polyphenol hybrid structure holds strong promise as a platform for developing nextgeneration antioxidant agents.
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    Promising Novel Heterocyclic Drug Candidates: Synthesis, Characterization, DFT Calculations and In Silico Investigations of Anticancer Behaviors
    (Taylor & Francis Ltd, 2024) Dilek, Omer; Yesil, Tolga Acar; Tilki, Tahir
    In recent years, the inadequacy and high costs of current cancer treatment drugs have led to an increase in research focused on the design and synthesis of new compounds with potential applications in this field and the evaluation of their anticancer properties using in silico methods. For this purpose, four novel heterocyclic compounds (6-9) were synthesized and characterized using spectroscopic techniques. The DFT approach and B3LYP/6-311G(d,p) basis set were used to compare theoretical data with experimental ones and to obtain optimized geometries. It was observed that experimental and theoretical data were in harmony. In silico techniques were used to investigate the potential of synthesized compounds as drug candidates. ADMEt results have shown that all synthesized compounds have Lipinski's rule of five which has searched criteria in drug candidates. Molecular docking studies were also performed against cancer-related proteins. The highest docking score between 2XIR protein and compound 8 was found to be -11.7 kcal/mol, while the lowest was -8.2 kcal/mol between 1MP8 protein and compound 9. To do meaningful comparisons standard drugs were also used in Molecular Docking studies. It was observed that all synthesized molecules had higher docking scores than standard drugs except ifebemtinib. It can be suggested that based on ADMET and molecular docking studies compound 8 has the potential to be a drug candidate after further investigations such as in vitro, in silico, etc., have been performed in this area.