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Öğe Design, synthesis and biological evaluation of novel ketone derivatives containing benzimidazole and 1,3,4-triazole as CA inhibitors(Elsevier, 2024) Cevik, Ulviye Acar; Isik, Aysen; Kapavarapu, Ravikumar; Kucukoglu, Kaan; Nadaroglu, Hayrunnisa; Bostanci, Hayrani Eren; Ozkay, YusufIn this study, we synthesized a series of new benzimidazole-triazole (6a-6k) derivatives and characterized them by 1H NMR, 13C NMR, and HRMS. These compounds were evaluated for their inhibitory activity against hCA-I and hCA-II. All the compounds exhibited good hCA-I and hCA-II inhibitory activities with IC50 values in the range of 1.158 mu M to 3.48 mu M. Among all these compounds, compound 6j, with an IC50 value of 1.288 mu M and 1.6197 mu M, is the most active against hCA-I and hCA-II, respectively. Compounds 6a-6k were also evaluated for their cytotoxic effects on the L929 mouse fibroblast (normal) cell line. Enzyme inhibition kinetics showed all compounds 6a-6k to inhibit the enzyme by non-competitive. The most active compound 6j was subjected to molecular docking, which revealed their binding interactions with the enzyme's active site, confirming the experimental findings.Öğe Design, synthesis, and molecular docking studies of benzimidazole-1,3,4-triazole hybrids as carbonic anhydrase I and II inhibitors(Wiley, 2024) Celik, Ismail; Cevik, Ulviye Acar; Kucukoglu, Kaan; Nadaroglu, Hayrunnisa; Bostanci, Hayrani Eren; Isik, Aysen; Ozkay, Yusufn this study, with an aim to develop novel heterocyclic hybrids as potent enzyme inhibitors, we synthesized a series of 10 novel 2-(4-(4-ethyl-5-(2-(substitutedphenyl)-2-oxo-ethylthio)-4H-1,2,4-triazol-3-yl)-phenyl)-5,6-dimethyl-1H-benzimidazole (5a-5j) derivatives and characterized by H-1-NMR, C-13-NMR, and HRMS. These compounds were evaluated for their inhibitory activity against hCA I and hCA II. All the compounds exhibited good hCA I and hCA II inhibitory activities with IC50 values in range of 1.288 mu M-3.122 mu M. Among all these compounds, compound 5e, with an IC50 value of 1.288 mu M is the most active against carbonic hCA I. Compound 5h with an IC50 value of 1.532 mu M is the most active against carbonic hCA-II. Compounds 5a-5j were also evaluated for their cytotoxic effects on the L929 mouse fibroblast (normal) cell line. The compounds were also analyzed for their antioxidant capacity by TAS, FRAP, and DPPH activity. Enzyme inhibition kinetics showed all compounds 5a-5j to inhibit the enzyme by non-competitive. The most active compound 5e for hCA I and compound 5h for hCA-II were subjected to molecular docking, which revealed their binding interactions with the enzyme's active site, confirming the experimental findings.Öğe Novel Hydrazide-Hydrazones Bearing a Benzimidazole Ring: Design, Synthesis, and Evaluation of Inhibitor Properties Against CA I and CA II Isozymes(Wiley, 2024) Isik, Aysen; Cevik, Ulviye Acar; Celik, Ismail; Kucukoglu, Kaan; Nadaroglu, Hayrunnisa; Bostanci, Hayrani Eren; Ozkay, YusufIn this study, we propose identifying potential novel compounds targeting carbonic anhydrase I and II. Herein, we have designed and synthesized new benzimidazole-hydrazide-hydrazones derivatives (4a-4r) to investigate the effects of these synthesized compounds on CA isoenzymes. The compounds' 1H NMR, 13C NMR, and HRMS spectra were used to confirm their chemical structures. The synthetic derivatives were screened for their inhibitory potential against carbonic anhydrase I and II by in vitro assay. These compounds have IC50 values of 3.727-1.493 mu M (hCA I) and 3.892-1.547 mu M (hCA II). Inhibition types and Ki values of the compounds were determined. The Ki values of the compounds were 3.006 +/- 0.17 mu M-0.356 +/- 0.0 mu M (hCA I) and 2.923 +/- 0.15 mu M-0.346 +/- 0.0 mu M (hCA II). Acetazolamide (AAZ) was used as the reference in the study. The most potent derivatives, a 4-methoxy derivative (compound 4k) and 4-(trifluoromethyl) derivative (compound 4g), than AAZ (IC50 = 2.26 mu M) and their IC50 values were found as 1.493 mu M and 1.675 mu M, respectively. Compared to AAZ, the other derivatives having more effect on hCA I were compounds 4b, 4e, 4l, 4m, 4n, and 4o. The compounds gave IC50 values of 1.743, 1.789, 1.933, 1.966, 1.983, and 1.986 mu M, respectively. Compounds 4a-4r found no more effective inhibitory activity against hCA II isozyme than AAZ (IC50 = 1.17 mu M). According to the in vitro test results, detailed protein-ligand interactions of the compounds 4b and 4k exhibited considerably low binding energies, suggesting strong interaction affinities against hCA I. In addition, the cytotoxic effects of the compounds on the L929 healthy cell line were evaluated.Öğe Synthesis and Molecular Docking of New N-Acyl Hydrazones-Benzimidazole as hCA I and II Inhibitors(Bentham Science Publ Ltd, 2023) Kucukoglu, Kaan; Cevik, Ulviye Acar; Nadaroglu, Hayrunnisa; Celik, Ismail; Isik, Aysen; Bostanci, Hayrani Eren; Ozkay, YusufBackground The carbonic anhydrases (CAs) which are found in most living organisms is a member of the zinc-containing metalloenzyme family. The abnormal levels and activities are frequently associated with various diseases therefore CAs have become an attractive target for the design of inhibitors or activators that can be used in the treatment of those diseases. Methods Herein, we have designed and synthesized new benzimidazole-hydrazone derivatives to investigate the effects of these synthesized compounds on CA isoenzymes. Chemical structures of synthesized compounds were confirmed by H-1 NMR, C-13 NMR, and HRMS. The synthetic derivatives were screened for their inhibitory potential against carbonic anhydrase I and II by in vitro assay. Results These compounds have IC50 values of 5.156-1.684 mu M (hCA I) and 4.334-2.188 mu M (hCA II). Inhibition types and Ki values of the compounds were determined. The Ki values of the compounds were 5.44 +/- 0.14 mu M-0.299 +/- 0.01 mu M (hCA I) and 3.699 +/- 0.041 mu M-1.507 +/- 0.01 mu M (hCA II). The synthetic compounds displayed inhibitory action comparable to that of the clinically utilized reference substance, acetazolamide. According to this, compound 3p was the most effective molecule with an IC50 value of 1.684 mu M. Accordingly, the type of inhibition was noncompetitive and the Ki value was 0.299 +/- 0.01 mu M. Conclusion According to the in vitro test results, detailed protein-ligand interactions of the compound 3p, which is more active against hCA I than standard azithromycin (AZM), were analyzed. In addition, the cytotoxic effects of the compounds on the L929 healthy cell line were evaluated.Öğe Synthesis of Thiazole-methylsulfonyl Derivatives, X-ray Study, and Investigation of Their Carbonic Anhydrase Activities: In Vitro and In Silico Potentials(Amer Chemical Soc, 2025) Maryam, Zahra; Isik, Aysen; Bagci, Emine Rana; Yildiz, Maksut; Unver, Hakan; Kocyigit, U''mit M.; Kirilmaz, BurakThis study focused on the design, synthesis, chemical characterization, and potential inhibitory study of thiazole-methylsulfonyl derivatives against carbonic anhydrase enzymes. The synthesized compounds, with the characteristics of both the thiazole ring and methyl sulfonyl group, were synthesized through a two-step scheme, and their structures were confirmed through NMR spectroscopy and HRMS. Additionally, the structure of compound 2b was elucidated by an X-ray study. An enzyme inhibition assay was performed to assess their biological activity against carbonic anhydrases, and the compounds showed promising results against carbonic anhydrases I and II, highlighting their potential for specificity and targeted therapy. The effects of these molecules on in vitro enzyme activities were investigated by spectrophotometric methods. For this purpose, the concentrations (IC50 values) of compounds that inhibited the biological activities of carbonic anhydrase isoenzymes (hCA I and hCA II) by 50% were calculated. The IC50 values were found between 39.38-198.04 mu M (AAZ IC50 = 18.11 mu M) for hCA I and 39.16-86.64 mu M (AAZ IC50 = 20.65 mu M). Molecular docking studies have shown that compounds 2a and 2h exhibit stable interaction networks with targeted enzymes. The combinations of both studies, enzyme inhibition assay and molecular docking studies, thus enlighten the significance of these compounds for further optimization for pharmacological profiling and for developing therapeutic agents against carbonic anhydrase. Moreover, the study provides insight for future research on the synthesis of heterocyclic compounds against carbonic anhydrase for therapeutic applications.Öğe Synthesis, characterization, antimicrobial, antioxidant, and anti-cancer activity of new hybrid structures based on benzimidazole and thiadiazole(Univ Sao Paulo, Conjunto Quimicas, 2025) Bostanci, Hayrani Eren; Cevik, Ulviye Acar; Isik, Aysen; Maryam, Zahra; Ince, Ufuk; Ozkay, Yusuf; Kaplancikli, Zafer AsimHybrid structures containing multiple pharmacophore units with known activity have attracted attention due to their promising outcomes. In this study, several new hybrid structures containing benzimidazole and thiadiazole units were synthesized. The newly synthesized compounds were structurally analyzed using 1H-NMR, 13C-NMR, HRMS, and elemental analysis. The antimicrobial, in vitro anti-cancer, and antioxidant activities of all compounds were investigated. In vitro antimicrobial activities of the compounds were determined against Gram-positive (S. aureus ATCC 29213, E. faecalis ATCC 29212), Gram-negative (E. coli ATCC 25922, P. aeruginosa ATCC 27853) bacteria and fungi (C. albicans ATCC 10231) by using broth microdilution method. The compound 5g bearing 4-methoxyphenyl derivative showed the best activity with 32 mu g/mL against S. aureus ATCC 29213 and P. aeruginosa ATCC 27853. The MTT test was used to determine the cytotoxicity of the produced compounds on the MCF-7 (human breast cancer) and L-929 (fibroblast) cell lines. FRAP method was used to determine the antioxidant properties of synthesized compounds. The Ferric Reducing Antioxidant Power of the compounds 5a, 5b, and 5c showed more antioxidant properties than vitamin E. The compound 5g stands out in the series in that it is not toxic on the healthy cell line and has promising antimicrobial activity.Öğe Synthesis, DFT Calculations, In Silico Studies, and Antimicrobial Evaluation of Benzimidazole-Thiadiazole Derivatives(Amer Chemical Soc, 2024) Isik, Aysen; Acar Cevik, Ulviye; Karayel, Arzu; Ahmad, Iqrar; Patel, Harun; Celik, Ismail; Gul, Ulkuye DuduIn this study, a series of new benzimidazole-thiadiazole hybrids were synthesized, and the synthesized compounds were screened for their antimicrobial activities against eight species of pathogenic bacteria and three fungal species. Azithromycin, voriconazole, and fluconazole were used as reference drugs in the mtt assay. Among them, compounds 5f and 5h showed potent antifungal activity against C. albicans with a MIC of 3.90 mu g/mL. Further, the results of the antimicrobial assay for compounds 5a, 5b, 5f, and 5h proved to be potent against E. faecalis (ATCC 2942) on the basis of an acceptable MIC value of 3.90 mu g/mL. The cytotoxic effects of compounds that are effective as a result of their antimicrobial activity on healthy mouse fibroblast cells (L929) were evaluated. According to HOMO-LUMO analysis, compound 5h (with the lower Delta E = 3.417 eV) is chemically more reactive than the other molecules, which is compatible with the highest antibacterial and antifungal activity results. A molecular docking study was performed to understand their binding modes within the sterol 14-alpha demethylase active site and to interpret their promising fungal inhibitory activities. Molecular dynamics (MD) simulations of the most potent compounds 5f and 5h were found to be quite stable in the active site of the 14-alpha demethylase (5TZ1) protein.
