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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 New benzimidazole derivatives containing hydrazone group as anticancer agents: Inhibition of carbonic anhydrase IX and molecular docking studies(Wiley-V C H Verlag Gmbh, 2025) Bostanci, Hayrani Eren; Yildiz, Mehmet Taha; Kapancik, Serkan; Inan, Zeynep Deniz Sahin; Kilic, Haci Ahmet; Guler, Ozen Ozensoy; Cevik, Ulviye AcarIn this study, we propose identifying potential novel compounds targeting carbonic anhydrase (CA) IX and anticancer activity. To study the impact of these synthesized compounds on CA IX and anticancer activity, we have developed and synthesized novel benzimidazole-hydrazone derivatives (3a-3j). The target compounds' H-1 NMR (nuclear magnetic resonance), C-13 NMR, and high resolution mass spectrometry spectra were used to confirm their chemical structures. L929 (healthy mouse fibroblast cell line) used as control healthy cell line and MCF-7 (breast cancer), C6 (rat glioblastoma), HT-29 (colon cancer), cells were used in cell culture studies. As a result of cell culture studies, it was determined that the newly synthesized compounds 3d and 3j had cytotoxic effects on colon cancer. Again, it was determined that the compound 3d had a more toxic effect than cisplatin on both breast cancer and glioma cells. According to the CA IX activity results, compounds 3d and 3j were found to have the highest activity. Compounds 3d and 3j are essential for having anti-cancer properties and inhibiting the carbonic anhydrase IX enzyme. Molecular docking of these compounds was carried out in the active site of CA IX. Flow cytometry and immunofluorescence microscope analyses also confirmed that these compounds had cytotoxic effects on cancer cells.Öğe New benzimidazole-oxadiazole derivatives as potent VEGFR-2 inhibitors: Synthesis, anticancer evaluation, and docking study(Wiley, 2024) Cevik, Ulviye Acar; Celik, Ismail; Gorgulu, Sennur; Inan, Zeynep Deniz Sahin; Bostanci, Hayrani Eren; Ozkay, Yusuf; Kaplacikli, Zafer AsimWe report herein, the design and synthesis of benzimidazole-oxadiazole derivatives as new inhibitors for vascular endothelial growth factor receptor-2 (VEGFR-2). The designed members were assessed for their in vitro anticancer activity against three cancer cell lines and two normal cell lines; A549, MCF-7, PANC-1, hTERT-HPNE and CCD-19Lu. Compounds 4c and 4d were found to be the most effective compounds against three cancer cell lines. Compounds 4c and 4d were then tested for their in vitro VEGFR-2 inhibitory activity, safety profiles, and selectivity indices using the normal hTERT-HPNE and CCD-19Lu cell lines. It was determined that compound 4c was the most effective and safe member of the produced chemical family. Vascular endothelial growth factor A (VEGFA) immunolocalizations of compounds 4c and 4d were evaluated relative to control by VEGFA immunofluorescence staining. Compounds 4c and 4d inhibited VEGFR-2 enzyme with half-maximal inhibitory concentration values of 0.475 +/- 0.021 and 0.618 +/- 0.028 mu M, respectively. Molecular docking of the target compounds was carried out in the active site of VEGFR-2 (Protein Data Bank: 4ASD).Öğe New hydrazone derivatives: synthesis, characterization, carbonic anhydrase I-II enzyme inhibition, anticancer activity and in silico studies(Walter De Gruyter Gmbh, 2025) Cevik, Ulviye Acar; Unver, Hakan; Bostanci, Hayrani Eren; Tuzun, Burak; Gedik, Nurten Irem; Kocyigit, Umit M.A new series of hydrazone derivatives (1a-1l) were prepared from a condensation reaction between different hydrazide derivatives and 3-formylbenzoic acid. Through the use of several spectral techniques, such as 1H-NMR, 13C-NMR, and elemental analysis, the structures of the compounds were clarified. The crystal structure of compound 1d was obtained by single-crystal X-ray crystallography. They were found to have inhibitory effects on the anticancer potentials and human carbonic anhydrase isoforms I and II. Compound 1d was found to be the strongest inhibitor, with IC50 values of 0.133 mu M against hCA I. Also, compound 1l showed the highest inhibitory activity with IC50 values of 3.244 mu M against hCA II. Moreover, their cytotoxic effects on rat glioma cell and colon adeno carcinoma cell lines were evaluated. According to the cytotoxicity results, compounds 1j and 1l exhibited the highest cytotoxicity on the HT29 cell, while compounds 1e, 1g, and 1l showed the strongest cytotoxic effect on C6 cell line. Compound 1l, which carries the methoxy substituent at the 3rd position on the phenyl ring, was effective against both cancer cells and showed the highest inhibitory effect on hCA II. The ADME/T properties and molecular docking of the molecules with the highest activity were examined.Öğe New imidazole derivatives as aromatase inhibitor: Design, synthesis, biological activity, molecular docking, and computational ADME-Tox studies(Elsevier, 2023) Cetiner, Gokay; Cevik, Ulviye Acar; Celik, Ismail; Bostanci, Hayrani Eren; Ozkay, Yusuf; Kaplancikli, Zafer AsimIn this study, a series of imidazole derivatives was designed, synthesized, and evaluated for in vitro bi-ological activity on the human breast cancer cell line MCF7 by MTT assay. To determine the selectivity of the compounds, their cytotoxic effects on the L929 (healthy mouse fibroblast) cell line were also in-vestigated. Compounds 1a, 1b, and 1d were found to be more effective than the reference drug cisplatin against the MCF7 cell line. It is seen that the cytotoxic effects of the compounds on the L929 cell line are quite low, and the compounds are found to be highly selective. The inhibition potentials of the com-pounds 1a, 1b, 1d, and 1k which were effective on the MCF7 cell line, and on the aromatase enzyme were evaluated and it was found that the compounds had similar effects to the reference drug letro-zole. Further, the interactions between the best active compounds and the human aromatase cytochrome P450 (CYP) enzyme were analyzed through a molecular docking study. The findings suggest that these compounds could be a promising candidate for the creation of a new family of non-steroidal aromatase inhibitors. Finally, computational ADME-Tox studies of compounds 1a, 1b, 1d, and 1k were performed and found to have the appropriate profile.(c) 2023 Elsevier B.V. All rights reserved.Öğe New Thiazole Derivatives: Carbonic Anhydrase I-II and Cholinesterase Inhibition Profiles, Molecular Docking Studies(Wiley-V C H Verlag Gmbh, 2024) Karakaya, Abdullatif; Ercetin, Tugba; Yildirim, Suheda; Kocyigit, Umit M.; Rudrapal, Mithun; Rakshit, Gourav; Cevik, Ulviye AcarThiosemicarbazone derivative was obtained by the addition of thiosemicarbazide to 5-nitro-thiophene-2-carbaldehyde. The addition-cyclization of the 2-bromoacetophenone derivative to thiosemicarbazone derivative gave the new thiazole derivatives (2 a-k). Acetylcholinesterase (AChE), butyrylcholinesterase (BChE), antioxidant, and human carbonic anhydrase (hCA) I and II isoform inhibitory activities of the thiazole derivatives 2 a-k were investigated. The effects of thiazole derivatives on carbonic anhydrase I and II (hCA I-II) isoenzymes were examined in vitro using the esterase method. IC50 values for enzyme inhibition were found to be 2.661-22.712 mu M for hCA I and 5.372-26.813 mu M for hCA II. All derivatives reduced the activities of carbonic anhydrase I and II isoenzymes and were new potential inhibitor molecule candidates. These compounds were found to have minimal effects on AChE and BChE. The antioxidant properties of the target compounds were determined using DPPH and ferric ion-chelating assays. In particular, compounds 2 k and 2 h had the highest antioxidant effect in the series with IC50 values of 30.11 +/- 0.008 mu M and 30.21 +/- 0.006 mu M, respectively. ADMET properties of the compounds found to be effective were evaluated and their interactions with the enzyme were determined by molecular docking.Öğe Novel Benzimidazole-Oxadiazole Derivatives as Anticancer Agents with VEGFR2 Inhibitory Activity: Design, Synthesis, In Vitro Anticancer Evaluation, and In Silico Studies(Amer Chemical Soc, 2025) Cevik, Ulviye Acar; Celik, Ismail; Gorgulu, Sennur; Inan, Zeynep Deniz Sahin; Bostanci, Hayrani Eren; Karayel, Arzu; Ozkay, YusufThe aim of this research is the synthesis of benzimidazole-1,3,4-oxadiazole derivatives that could be potential anticancer leads inhibiting VEGFR2. The compounds were evaluated for their cytotoxicity against cancer cell lines PANC-1, MCF-7, and A549 using the MTT assay. Two different normal cell lines (hTERT-HPNE and CCD-19Lu) were used to calculate the selectivity indices of the compounds. Compound 4r showed the highest anticancer activities, with IC50 = 5.5, 0.3, and 0.5 mu M against the PANC-1, A549, and MCF-7 cell lines, respectively. Also, compounds 4r and 4s were further evaluated for their inhibitory activity against VEGFR2. VGFRA immunolocalizations of compounds 4r and 4s were visualized by the VEGFA immunofluorescent staining method. Molecular docking studies have proven that, as in sorafenib, compounds 4r and 4s show hydrogen bond formation with Asp1046 and Cys919 and hydrophobic interactions with other active site amino acids. Molecular dynamics simulations were carried out for compounds 4r and 4s to examine the stability and behavior of the protein-ligand complex obtained from molecular docking under in silico physiological conditions. An in silico ADME investigation was undertaken to confirm the druglikeness of the synthesized compounds. Furthermore, the stable geometries of the ligands were determined through the application of density functional theory (DFT). The optimized geometries were confirmed to correspond to true minima, as no imaginary frequencies were observed in the vibration frequency survey. The rotations of the thio and benzimidazole groups with respect to the 1,3,4-oxadiazole rings are 180 deg, and the molecules are planar.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 Benzimidazole-1,2,4-triazole Derivatives as Potential Antifungal Agents Targeting 14α-Demethylase(Amer Chemical Soc, 2023) Guzel, Emir; Cevik, Ulviye Acar; Evren, Asaf Evrim; Bostanci, Hayrani Eren; Gul, Ulkuye Dudu; Kayis, Ugur; Ozkay, YusufInvasive fungal infections (IFIs) are increasing as major infectious diseases around the world, and the limited efficacy of existing medications has resulted in substantial morbidity and death in patients due to the lack of effective antifungal agents and serious drug resistance. In this study, a series of benzimidazole-1,2,4-triazole derivatives (6a-6l) were synthesized and characterized by 1H NMR, 13C NMR, and HR-MS spectral analysis. All the target compounds were screened for their in vitro antifungal activity against four fungal strains, namely, C. albicans, C. glabrata, C. krusei, and C. parapsilopsis. The synthesized compounds exhibited significant antifungal potential, especially against C. glabrata. Three compounds (6b, 6i, and 6j) showed higher antifungal activity with their MIC values (0.97 mu g/mL) compared with voriconazole and fluconazole. Molecular docking provided a possible binding mode of compounds 6b, 6i, and 6j in the 14 alpha-demethylase active site. Our studies suggested that the benzimidazole-1,2,4-triazole derivatives can be used as a new fungicidal lead targeting 14 alpha-demethylase for further structural optimization. In addition, their effects on the L929 cell line were also investigated to evaluate the cytotoxic effects of the compounds. SEM analyses were performed to examine the effects of compounds 6a, 6i, and 6j on C. glabrata cells under in vivo experimental conditions.Öğe Synthesis, antibacterial, anti-urease, DFT and molecular docking studies of novel bis-1,3,4-thiadiazoles(Elsevier, 2025) Kaya, Betul; Cevik, Ulviye Acar; Behcet, Mustafa; Karayel, Arzu; Daoud, Nour El-Huda; Bostanci, Hayrani Eren; Kaplancikli, Zafer AsimA series of 2-substitutedamino-1,3,4-thiadiazoles (4a-4j) were synthesized starting from various isothiocyanate derivatives. The newly synthesized compounds were characterized by H-1 NMR, C-13 NMR, and elemental analysis. All compounds were tested for antibacterial activity against Proteus vulgaris (ATCC 7829) via the microbroth dilution technique. Among them, compound 4h emerged as the most potent antibacterial agent with MIC value of 4.1 mu M. All synthetic compounds were additionally evaluated for their urease inhibitory activity and exhibited good inhibitory potential against urease with IC50 values in the range of 1.732 +/- 0.186 - 3.786 +/- 0.300 mu M as compared to the standard thiourea (IC50 = 11.008 +/- 0.932 mu M). Compounds 4d, 4h and 4i showed significant inhibitory effects with IC50 values of 1.981 +/- 0.265, 1.732 +/- 0.186 and 1.937 +/- 0.173 mu M, respectively. In silico molecular docking study showed the critical interactions of compound 4h with the active site of the urease. According to DFT, compounds 4j and 4d (with low Delta E=4.536 eV and 4.629 eV values, respectively) are more chemically reactive than the other molecules, in which consistent with their inhibitory potentials against the urease enzyme. Molecular Dynamics simulations also were performed to assess the energetic features of the urease in complex with compound 4h. Furthermore, the predicted ADMET characteristics of the compound 4h was calculated using QikProp to gain insights into its pharmacokinetic properties. These newly identified inhibitors of the urease enzyme can serve as leads for further antibacterial drug research and development.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, α-Glucosidase, α-Amylase, and Aldol Reductase Inhibitory Activity with Molecular Docking Study of Novel Imidazo[1,2-a]pyridine Derivatives(Amer Chemical Soc, 2024) Kaya, Betul; Cevik, Ulviye Acar; Ciftci, Bilge; Duran, Hatice Esra; Turkes, Cuneyt; Isik, Mesut; Bostanci, Hayrani ErenInhibition ofaldose reductase (AR), alpha-glycosidase (alpha-GLY), and alpha-amylase (alpha-AMY) are some of the essential targets in diabetes mellitus (DM). Here, a series of imidazo[1,2-a]pyridine-based 1,3,4-thiadiazole derivatives (8a-k) were successfully synthesized and characterized using 1H NMR, 13C NMR, and HRMS spectroscopic techniques. The inhibition effects of the synthesized derivatives against AR, alpha-GLY, and alpha-AMY were evaluated using both in vitro and in silico methods. In vitro studies revealed that the derivatives (8a-k) showed significant inhibition activity. The results showed that the novel derivatives (8a-k) demonstrated potential inhibitory activity, with K I values covering the following ranges: 23.47 +/- 2.40 to 139.60 +/- 13.33 nM for AR and 6.09 +/- 0.37 to 119.80 +/- 12.31 mu M for alpha-GLY, with IC50 values 81.14 to 153.51 mu M for alpha-AMY. Furthermore, many of these compounds exhibited high inhibition activity, while some of them showed higher potency than the reference compounds. Molecular docking of the target compounds was carried out in the active sites of AR (PDB ID: 4JIR) and alpha-GLY (PDB ID: 5NN8).
