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    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, Yusuf
    In 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.
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    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, Yusuf
    n 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.
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    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, Yusuf
    In 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.
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    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, Yusuf
    Background 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.