Browsing by Author "Manap, Sevda"

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Novel Schiff Bases: Synthesis, Characterization, Bioactivity, Cytotoxicity, and Computational Evaluations
(Taylor & Francis Ltd, 2025) Medetalibeyoglu, Hilal; Manap, Sevda; Alkan, Muzaffer; Beytur, Murat; Barlak, Neslisah; Karatas, Omer Faruk; Taslimi, Parham
Hypopharyngeal cancer is rare subtype of head and neck cancers with relatively poor prognosis. Current therapeutic modalities lack the potential to provide patients with better clinical outcome and quality of life. This study was conducted on the synthesis of 2-methoxy-4-((3-alkyl(aryl)-5-oxo-1H-1,2,4-triazol-4(5H)-ylimino)-methyl)-phenyl-4-(2-methoxy-4-((3-alkyl(aryl)-5-oxo-1H-1,2,4-triazol-4(5H)-ylimino)-methyl)-phenyl)-4-oxobutanoates (3) using biologically important 1,2,4-triazole. The condensation of 3-alkyl(aryl)-4-amino-4,5-dihydro-1H-1,2,4-triazol-5-ones (1) with 4-formyl-2-methoxyphenyl-4-(4-formyl-2-methoxyphenyl)-4-oxobutanoate yielded the biologically active 2-methoxy-4-((3-alkyl(aryl)-5-oxo-1H-1,2,4-triazol-4(5H)-ylimino)-methyl)-phenyl-4-(2-methoxy-4-((3-alkyl(aryl)-5-oxo-1H-1,2,4-triazol-4(5H)-ylimino)-methyl)-phenyl)-4-oxobutanoates (3). The compounds obtained were analyzed via FT-IR,1H-/13C-NMR spectrometers, elemental analysis, and HRMS spectroscopic techniques. Furthermore, we aimed at investigating the potential of compounds 3a-g against FaDu hypopharyngeal cancer cells. We demonstrated that compounds 3c, 3e, and 3 g had relatively lower IC50 values compared to the remaining tested compounds and more importantly their IC50 values were comparable to 5-FU, which suggests them as important therapeutic agent candidates. These newly synthesized compounds were assessed for their inhibitory activities toward two human carbonic anhydrase isoforms I and II (hCA I and II). Then, molecular docking calculations were made to compare the biological activities of studied molecules against cancer proteins. Compound 3c has a docking score of -7.15 against squamous cell carcinoma protein with ID: 2DO4 and -5.49 docking score against squamous cell carcinoma protein with ID:5PJZ. ADME/T analysis was performed to examine the drug properties of studied molecules. [GRAPHICAL ABSTRACT]
Synthesis and Computational Evaluation of N-Acetyl Schiff Bases Incorporating 1,2,4-Triazoles for Dual Inhibition of Prostate Cancer Cells and Carbonic Anhydrases
(Amer Chemical Soc, 2025) Medetalibeyoglu, Hilal; Aytatli, Abdulmelik; Manap, Sevda; Atalay, Abdurrahman; Ortaakarsu, Ahmet Bugra; Tuzun, Burak; Yuksek, Haydar
In this study, we synthesized a series of novel N-acetyl Schiff bases (6a-e) containing 1,2,4-triazole moiety and evaluated their potential as anticancer agents through both experimental and computational approaches. Cytotoxicity assays on prostate cancer (PC) (DU145) and normal epithelial cells (PNT1a) demonstrated selective inhibition, particularly for compounds 6a, 6d, and 6e, with IC50 values of 73.25, 49.80, and 111.73 mu M, respectively, in DU145 cells. Notably, 6d exhibited a 10-fold selectivity toward cancer cells over normal cells. Enzyme inhibition studies demonstrated that compound 6d exhibited the most potent inhibitory activity against the carbonic anhydrase isoforms hCAI and hCAII, with the lowest recorded IC50 and K i values (7.12 and 9.26 mu M for hCAI, and 10.62 and 11.72 mu M for hCA II, respectively), suggesting strong potential for antiglaucoma therapeutic application. To elucidate molecular interactions, QM/MM molecular docking highlighted the strong affinity of compound 6d for the active sites of CYP17A1, hCAI, and hCAII enzymes. The coordination of functional groups with key residues, particularly the Zn2+ ion and HEM group, was confirmed by detailed binding analyses. Molecular dynamics simulations further validated the stability of these interactions over a 100 ns trajectory, with 6d maintaining robust engagement with the protein targets. This stability was reflected in consistent RMSD and RMSF profiles, with minimal fluctuations, particularly in CYP17A1 complexes, suggesting a stable binding conformation. The Markov State Model (MSM) analysis, integrated with TICA-FES and MM-GBSA calculations, revealed rapid conformational stabilization of 6d, especially in CYP17A1 complexes. The observed deeper energy wells in diffusion maps indicate stronger binding affinities and reduced conformational transitions compared to reference inhibitors, such as abiraterone and acetazolamide. These computational insights align with experimental findings, suggesting that 6d holds significant promise as a potent dual-target inhibitor with applications in prostate cancer therapy and glaucoma treatment.
Synthesis, Molecular Modeling Investigation, Molecular Dynamic and ADME Prediction of Some Novel Mannich Bases Derived from 1,2,4-Triazole, and Assessment of Their Anticancer Activity
(Taylor & Francis Inc, 2024) Manap, Sevda; Medetalibeyoglu, Hilal; Kilic, Ahsen; Karatas, Omer Faruk; Tuzun, Burak; Alkan, Muzaffer; Yuksek, Haydar
A series of biologically active novel Mannich bases containing with a 1H-1,2,4-triazole-5-one ring were developed to evaluate the cytotoxic activity. For this purpose, the synthesized Schiff Bases (S1-5) were reacted with formaldehyde and morpholine, which is a secondary amine to yield novel N-Mannich bases (M1-5) via the Mannich reaction. The structures of the compounds (M1-5) were determined structurally employing 1H/13C-NMR, IR and elemental analysis. In this study, we evaluated the cytotoxic potential of the compounds (M1-5) on the human hypopharyngeal carcinoma FaDu cells. We found that the compound (M3) possesses a significant anticancer feature against FaDu cells that might be evaluated with further in vitro and in vivo studies to understand its anticancer potential better. Lastly, comparisons were made using molecular docking calculations to find the theoretical activities of the compounds (M1-5). The docking score parameter of the compound (M3) against the 2DO4 protein is -5.67, the docking score parameter against the 5JPZ protein is -5.72, and finally, the docking score parameter against the 2H80 protein is -5.50. Molecular dynamic calculations are made for 0-100 ns. The ADME/T calculations were performed to find the drug potential of the compounds (M1-5). The results suggest that our drug candidate compound exhibits strong potential for co-administration with the antigen structures, owing to the low rate of interactions that decreased over time.Communicated by Ramaswamy H. Sarma