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- ArticleYalnız künye2026In Vitro Cholinesterase Inhibition and Computational Investigation of some 1,2,3-triazole Derivatives as Dual AChE/BuChE Inhibitors
Tan, Ayse; Dilek, Esra
In vitro anticholinesterase activities of a series of 1,2,3-triazole derivatives, 9(a-e) and 10(f-l), were evaluated against electric eel acetylcholinesterase (eeAChE) and equine serum butyrylcholinesterase (eqBuChE), using donepezil as a reference inhibitor. Enzyme inhibitory activities were characterized by IC50, inhibition constants (Ki), and inhibition mechanisms. All target compounds exhibited potent inhibitory activity against both enzymes. 9e demonstrated the highest activity against eeAChE (Ki = 7.69 ± 1.24 nM), outperforming donepezil (Ki = 25.28 ± 5.79 nM). 9b showed the strongest inhibition against eqBuChE (Ki = 3.36 ± 0.67 nM), whereas donepezil displayed comparatively weak activity (Ki = 43.48 ± 10.36 nM). To further elucidate ligand–enzyme interactions, molecular docking, molecular dynamics simulation (MDS), MM/GBSA, and structure–activity relationship studies were performed. Docking results indicated that all target compounds exhibited higher binding affinities for both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE than for BuChE. MDS and MM/GBSA analyses confirmed the stability of the selected complexes, without significant fluctuations over 50 ns, and showed that while 9e was selective for hAChE-CAS, 9b bound similarly to both hBuChE sites. Taken together, all target compounds, particularly 9e and 9b, may serve as novel dual AChE/BuChE inhibitor candidates.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2026Synthesis and characterization of novel 5-fluoroindolylmethylene hydrazone derivatives as schiff base compounds: In vitro and in silico evaluation as potential cholinesterase (AChE and BChE) inhibitors
Koprulu, Cigdem; Faydali, Nagihan; Muhammed, Muhammed Tilahun; Dilek, Esra; Kucukoglu, Kaan; Sirinzade, Hanif
This study analyzes the inhibitory effects of newly synthesized compounds of the K1–12 series on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes comparatively using IC50 and Kᵢ parameters. Initially, a series of novel 5-fluoroindolylmethylene hydrazone derivatives (K1–12) were designed and synthesized. The structures of the synthesized compounds were elucidated using 1H and 13C NMR spectroscopy as well as mass spectrometric analyses. Subsequently, their inhibitory effects on AChE and BChE were evaluated in vitro . Molecular docking studies performed for all compounds with AChE and BChE enzymes, and pi interactions and conventional hydrogen bonds were involved in protein-ligand interactions. The molecular dynamics (MD) simulation study of the compound with the highest binding potential to the AChE and BChE structures, K10, disclosed that the complexes obtained from docking would be stable. Moreover, the compound is predicted to have a greater tendency to remain within the binding site of the BChE structure. The density functional theory (DFT) study resulted in similar levels of chemical stability and reactivity for the relatively active compounds. The findings revealed that, especially, the K5 and K10 compounds exhibited higher inhibitory activity than donepezil against BChE and AChE, respectively. The results indicate that these compounds could be potential agents for the treatment of neurodegenerative diseases in the future.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2026Design and synthesis of piperazine-based 3,5-disubstituted-1,2,4-oxadiazole derivatives as dual AChE and BChE inhibitors: In vitro and in silico studies
Faydali, Nagihan; Erol, Meryem; Arpaci, Özlem Temiz; Küçükoğlu, Kaan; Dilek, Esra; Muhammed, Muhammed Tilahun
In this study, ten original 3,5-disubstituted-1,2,4-oxadiazole derivatives were successfully synthesized and characterized by mass spectrometry and ¹H and ¹³C NMR spectroscopy. The potential of these compounds to inhibit butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) was assessed, and the results were reported as IC50 and Kᵢ values. The compounds' Ki values ranged from 21.82 ± 7.87 to 83.67 ± 22.16 nM against BChE and from 9.52 ± 2.10 to 34.99 ± 11.33 nM against AChE. Consequently, it was found that all compounds, except 4f, demonstrated more effective inhibitory action against BChE than donepezil, and that 4g, 4e, and 4i demonstrated more effective inhibitory activity against AChE than donepezil. All compounds were subjected to molecular docking against AChE and BChE, and hydrogen bonding and π-interactions between the compounds and the enzymes were observed. Stabilities of enzyme-compound complexes generated from the docking were investigated by molecular dynamics (MD) simulation. The generated complexes were determined to be stable during the simulation period. To further deepen our understanding, computational DFT analysis revealed key insights into the structures, electronic properties, and reactivity of these materials. To broaden our research, absorption, distribution, metabolism, excretion, and toxicity (ADMET) calculations of the compounds were also carried out.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2026Synthesis of new halo-substituted quinolinecarboxaldehyde-hydrazone derivatives, structural illuminations, investigation of effects on acetylcholinesterase activity and molecular modeling studies
Sirinzade, Hanif; Faydali, Nagihan; Muhammed, Muhammed Tilahun; Dilek, Esra
Acetylcholinesterase (AChE) is a key serum esterase with antiatherosclerotic effects by preventing lipid peroxide oxidation. AChE inhibitors also serve as therapeutic targets for Alzheimer's disease. Newly developed halo-substituted quinolinecarboxaldehyde-hydrazone derivatives (1a–1 s) show significant pharmacological potential due to their broad biological activities. This study evaluated the inhibitory effects of halo-substituted quinolinecarboxaldehyde-hydrazone derivatives on AChE. Acetylcholine esterase IC₅₀ values ranged from 0.143 to 2.015 µM, and Kᵢ values from 0.078 ± 0.030 to 1.074 ± 0.105 µM. Tacrine served as the positive control. Molecular docking studies revealed that compounds 1b and 1k displayed pi-pi interactions (pi-alkyl, pi-pi stacking) and conventional hydrogen bonding. The molecular dynamics simulation study disclosed that compounds 1b and 1k formed stable complexes with the enzyme structure. Moreover, the density functional theory study demonstrated that the active compounds had similar electrical property and reactivity. Together with this, compound 1e was anticipated to exhibit the highest chemical stability among the compounds investigated. All of the compounds were shown to have a high absorption from the gastrointestinal tract and to meet Lipinski's criterion in SwissADME. As a result, it was determined that new halo-substituted quinoline carboxaldehyde-hydrazone derivatives showed strong inhibition effect on this enzyme. In comparison to the reference chemical Tacrine, 1k had the most potent inhibitory activity against AChE. In this context, we anticipate that the findings of this study will aid in identifying the adverse effects of both existing and novel quinolinecarboxaldehyde-hydrazone-based pharmaceutical drugs under development. Additionally, it should be effective in the production of novel AChE inhibitors.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2026In vitro and in silico investigation of the cytotoxic potential of Tanacetum armenum (DC.) Sch.Bip. Extracts against human breast cancer MCF-7 cells
Güven, Zühal Bayrakçeken; Barlak, Neslişah; Türkmenoğlu, Burçin; Karadayı, Mehmet; Yilmaz, Mustafa Abdullah; Dilek, Esra; Inceer, Huseyin; Cakir, Oguz
Introduction: The genus Tanacetum has a long history of use and is well known for its traditional applications in food, medicine, cosmetics, and agriculture. The biological effects of Tanacetum armenum were investigated, and its phytochemical profiles were analysed. Methods: Phytochemical analysis was conducted using liquid chromatography-mass spectrometry/mass spectrometry, and antioxidant, target enzyme inhibition, and antigenotoxic effects were evaluated. The antiproliferative effects and mechanisms of the extracts were investigated in vitro, and the possible mechanisms of the main compounds were analysed in silico. Results: Phytochemical profile analysis revealed significantly higher levels of chlorogenic acid (64.894 mg/g extract), quinic acid (45.377 mg/g extract), and 1,5-dicaffeoylquinic acid (18.150 mg/g extract). The methanol extract (IC50:116.56 ± 2.84 µg/mL) exhibited strong tyrosinase enzyme inhibition than ethylacetate (IC50:184.04 ± 3.02 µg/mL) and aqueous extracts (IC50:340.84 ± 3.46 µg/mL). The aqueous extract (IC50:328.23 ± 4.22 µg/mL) showed the highest inhibition of acetylcholinesterase, while the methanol extract (IC50:504.87 ± 4.78 µg/mL) demonstrated the highest inhibition of butyrylcholinesterase. The ethylacetate extract exhibited the strongest antimicrobial effect against Staphylococcus aureus, with a MIC value of 62.5 µg/mL. The extracts did not show any genotoxic effects. The ethyl acetate extract exhibited significant cytotoxic effects (IC50:25.00–108.16 µg/mL) against cancer cell lines (p < 0.001). To investigate the mechanism by which the extracts inhibit MCF-7 cell viability, the expression levels of the cyclin E1 and caspase-8 were evaluated using western blot analysis. In addition, a colony formation assay was performed, and migration potential was analysed using a scratch wound healing assay. Using in silico approaches, the molecular docking and binding parameter values of cyclin E1 and caspase-8 were calculated. Chlorogenic acid was found to have the best binding value and mode of in silico interaction with the target crystal structures. The docking scores calculated from these binding parameter values were -7.824 kcal/mol for the cyclin E1 (8H6P) target, -7.126 kcal/mol for the caspase-8 (3KJQ) target, and -8.182 kcal/mol for the human oestrogen receptor (3ERT) target. Conclusion: T. armenum, which has demonstrated a strong cytotoxic effect through in vitro and in silico mechanism studies, can be considered a promising potential natural resource for cancer treatment.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye20262-Substituted-5-(4-substitutedsulfonylamido)benzoxazoles as potent cholinesterase inhibitors: Synthesis, in vitro, molecular docking, molecular dynamics simulation, and DFT studies
Faydali, Nagihan; Erol, Meryem; Temiz Arpaci, Özlem; Dilek, Esra; Muhammed, Muhammed Tilahun
Alzheimer's disease (AD), the most worrisome neurological condition in the world, is one of the primary causes of dementia and is characterized by cognitive and memory loss. This disease is multifactorial, and there is currently no cure, although treatments based on the cholinergic hypothesis have been successful in relieving symptoms. This study examined the inhibitory effects of 11 compounds with a sulfonamide group at position 5 of the benzoxazole ring system on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Two of these 11 compounds are original, and FT-IR, ¹H NMR, ¹³C NMR, and mass spectrometry were used to characterize their structures. The compounds showed significantly greater biological activity as inhibitors of both AChE and BChE than the reference drug, donepezil. In particular, 2a showed the highest activity against AChE with a Ki value of 7.45 ± 2.79 nM, and 1b showed the highest activity against BChE with a Ki value of 3.37 ± 0.68 nM. Furthermore, a molecular docking study was performed to investigate the interaction modes of the active compounds with the active sites of the crystal structures of AChE and BChE. Hydrogen bond and π interactions were observed in the protein–ligand interactions. The stabilities of the complexes obtained from docking were assessed using a molecular dynamics (MD) simulation. The MD simulation revealed that the complexes remained stable throughout. Density functional theory (DFT) analysis was also conducted to determine the compounds' most stable conformers and investigate their chemical stability and reactivity.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2025Investigation of 2-substituted-5-methylsulfonylbenzoxazole derivatives as potential cholinesterase inhibitors: Synthesis, in vitro, and computational studies
Cihan, Cansu; Faydali, Nagihan; Erol, Meryem; Arpaci, Özlem Temiz; Muhammed, Muhammed Tilahun; Dilek, Esra
In this study, a new series of 2-substituted-5-methylsulfonylbenzoxazole derivatives (C1-C16) were successfully synthesized. The structures of the compounds were confirmed by FT-IR, 1H NMR, 13C NMR, and mass spectroscopy, and the results for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzyme inhibitory activity were reported as IC₅₀ and Ki values. The compounds' Ki values against AChE ranged from 7.55 ± 2.88 to 87.39 ± 11.67 nM, and their Ki values against BChE ranged from 3.23 ± 0.64 to 107.86 ± 13.38 nM. Accordingly, all compounds except C1, C2, C11, and C12 were found to be more effective than donepezil against AChE, and all compounds except C1, C5, and C12 were found to be more effective than donepezil against BChE. Molecular docking studies were performed for all compounds against the AChE and BChE enzymes. Conventional hydrogen bonds and π interactions (π-π stacked, π-π T-shaped, π-alkyl, π-sigma, π-cation) were observed in the interactions of the compounds with the target enzymes. Molecular dynamics (MD) simulation of complexes formed by compounds with the highest inhibition activity on the two enzymes affirmed formation of stable complexes. Additionally, the molecular electrostatic potential (MEP) map of all compounds and the extent to which the HOMO-LUMO energy gaps affect the reactivity, stability, and inhibitor profiles of these compounds were investigated using density functional theory (DFT) studies, a computational analysis method. The study proves that 2-substituted-5-methylsulfonylbenzoxazole derivatives exhibit potent and selective cholinesterase inhibition.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025SYNTHESIS AND CHARACTERIZATION OF NOVEL 5-FLOUROINDOLYLMETHYLEN HYDRAZON DERIVATIVES AS SCHIFF BASE COMPONDS: IN VITRO AND IN SILICO EVALUATION AS POTENTIAL CARBONIC ANHYDRASES (CAI-CAII) INHIBITORS; [YENİ 5-FLOROİNDOLİLMETİLEN HİDRAZON TÜREVLERİNİN SCHİFF BAZ BİLEŞİKLERİ OLARAK SENTEZİ VE KARAKTERİZASYONU: POTANSİYEL KARBONİK ANHİDRAZ (CAI-CAII) İNHİBITÖRLERİ OLARAK İN VİTRO VE İN SİLİCO DEĞERLENDİRMESİ]
Kedik, Cheeghdam; Faydali, Nagihan; Dilek, Esra; Şirinzade, Hanif
Objective: In this study, novel 5-fluoroindolylmethylene hydrazone derivatives were synthesized and assessed for their potential inhibitory effects on human carbonic anhydrase I and II (hCA I and II) enzymes through both in vitro and in silico approaches. Material and Method: Accordingly, starting from 5-fluoroindole, 5-fluoroindole-3-carboxaldehyde was synthesized. The target final compounds were then obtained by condensing substituted phenylhydrazine with 5-fluoroindole-3-carboxaldehyde, resulting in three Schiff base derivatives (2a, 2b, and 2c). Result and Discussion: The synthesized compounds demonstrated effective inhibition of cytosolic carbonic anhydrase isoforms hCA I and II, with Ki values ranging from 32.28±7.09 to 74.86±10.90 nM for hCA I and 8.79±1.92 to 60.40±14.64 nM for hCA II. Among them, compound 2a exhibited the most potent inhibitory effect on both isoenzymes. In vitro results were verified with the results obtained by docking studies and interactions with enzymes were demonstrated. These novel 5-fluoroindolylmethylene hydrazone derivatives show promise as potent inhibitors of cytosolic CA isoenzymes.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2025Phytochemical Profile, Antioxidant, Anticholinesterase, and Antiproliferative Activities of Endemic Onosma discedens: In Vitro and In Silico Approaches
Akman, Tugrul Cagri; Simsek, Samed; Erken, İrem Nisa; Yildiztekin, Kübra Gizem; Tasci, Hayrunnisa; Türkoğlu, Halil İbrahim; Dilek, Esra
This study presents the first comprehensive analysis of the phytochemical profile and biological activities of root and stalk extracts from endemic Onosma discedens Hausskn. ex Bornm. (OD). The extracts of OD were analyzed by liquid chromatography–electrospray ionization–tandem mass spectrometry (LC–ESI–MS/MS), and 16 phenolics, including vanillic acid (2077.1332 µg/g extract in root) and hesperidin (1185.3621 µg/g extract in stalk), were detected. In antioxidant activity tests, DPPH• radical scavenging activity of root extract (IC50: 60.69 µg/mL) was found to be higher than stalk extract (IC50: 95.66 µg/mL), but both extracts showed lower activity than standard antioxidants. In antiproliferative activity assays, the OD extract exhibited low cytotoxicity against MCF7 cell lines, with an IC50 value exceeding 500 µg/mL. The stem extract was more effective on the butyrylcholinesterase (BChE) enzyme (IC50: 546.09 ± 0.533 µg/mL) than on the acetylcholinesterase (AChE) enzyme (IC50: 721.156 ± 0.410 µg/mL). When the plant is evaluated as a whole, it has a dual inhibitory effect on both cholinesterase enzymes. Molecular docking analyses confirmed the interactions of vanillic acid and hesperidin with target enzymes. As a result, it was revealed that OD, which has a rich structure in phenolic compounds and significant bioactivity due to its cholinesterase inhibitory effect, can be utilized to treat neurodegenerative illnesses like Alzheimer's.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2025Benzoxazole Derivatives as Dual p38α Mitogen-Activated Protein Kinase and Acetylcholinesterase Inhibitors: Design, Synthesis, and Evaluation for Alzheimer's Disease and Cancer Therapy
Zoatier, Bayan; Yildiztekin, Gizem; Alagoz, Mehmet Abdullah; Hepokur, Ceylan; Dilek, Esra; Algul, Oztekin
Alzheimer's disease (AD), the most prevalent form of dementia, leads to progressive cognitive decline due to pathological hallmarks including amyloid plaques, neurofibrillary tangles, synaptic loss, neuroinflammation, and neuronal cell death, highlighting the urgent need for multitarget therapeutic strategies. The p38α mitogen-activated protein kinase (p38α MAPK) pathway is a key regulator of neuroinflammation and has been implicated in AD pathogenesis. Additionally, dysregulation of p38α MAPK is associated with tumorigenesis, making it a promising target for both neurodegenerative and proliferative diseases. In this article, a series of benzoxazole derivatives is designed and synthesized to evaluate their dual inhibitory potential against p38α MAPK and acetylcholinesterase (AChE), aiming for a multifaceted therapeutic approach to AD. A total of 31 compounds are synthesized and assessed for their antiproliferative activity, p38α MAPK inhibition, and AChE inhibitory effects. In vitro assays demonstrate that several compounds exhibit potent dual inhibition of p38α MAPK and AChE, while molecular docking studies provide insights into their binding interactions within the active sites. These findings suggest that benzoxazole-based scaffolds offer a promising framework for the development of dual-acting inhibitors targeting both neuroinflammation and tumorigenesis. Further in vivo and mechanistic studies are warranted to explore their therapeutic potential.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024Schiff Baz Bileşikleri olarak yeni benzotiyofen-3-karboksaldehid hidrazon türevleri: Potansiyel kolinesteraz (AChE-BuChE) ve karbonik anhidraz (CAI-CAII) inhibitörleri olarak in vitro ve in silico değerlendirmesi
Gürsoy, Şule; Sirinzade, Hanif; Dilek, Esra; Çaka, Zeynep; Faydalı, Nagihan
Bu çalışmada, birçok sitozolik enzimin inhibisyonunu değerlendirdi ve Alzheimer, Parkinson ve Glokom gibi çeşitli ilişkili hastalıkları aydınlatılması ve potansiyel olarak tedavi edilmesi amaçlanmıştır. Amacımız, tek bir molekülde birden fazla etkiyi birleştirerek ilaç yan etkilerini en aza indirmektir. Bunun için, iki yeni benzotiyofen Schiff bazının kolinesterazlar (AChE ve BuChE) ile insan karbonik anhidraz izoformları (CAI ve CAII) üzerindeki in vitro etkileri araştırılmıştır. Bu iki bileşiğin enzimler üzerindeki inhibisyon mekanizmasını aydınlatmak için moleküler modelleme çalışmaları da yürütülmüştür. Daha sonra, her iki bileşiği (1a ve 1b) söz konusu enzimler üzerinde in vitro olarak test edildi. Ayrıca, in vitro sonuçlarımızı in silico çalışmalardan elde edilen verilerle desteklendi. Bulgular, benzotiyofen türevlerinin bu enzimleri önemli ölçüde inhibe ettiğini göstermektedir. Bileşik 1b, AZA kontrol bileşiğine kıyasla CAI ve CAII üzerinde daha güçlü bir inhibisyon etkisi sergiledi. Ayrıca, her iki bileşiğin de kolinesterazlar (AChE ve BuChE) üzerinde kontrol bileşiği takrin'e kıyasla daha güçlü inhibisyon etkileri gösterdiği belirlenmiştir.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2024Hydrazide-Bridged Pyridazines for Cholinesterase Inhibitors: Synthesis, Characterizations, In Silico, and In Vitro Evaluation
Gursoy, Sule; Taskor Onel, Gulce; Turkmenoglu, Burcin; Bozbey Merde, Irem; Dilek, Esra; Hepokur, Ceylan; Algul, Oztekin
In this study, we investigate the inhibitory potential of a series of hydrazide derivatives bearing different substituents with the pyridazine structure (5 a–i and 6 a–f) against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using a modified Ellman's method. The inhibitory profiles of the synthesized compounds were assessed by comparing their IC50 and Ki values. Our results demonstrate that all the compounds exhibit significant inhibitory activity against both AChE and BChE when compared to the reference compound, tacrine. Particularly, compound 6 a exhibited the highest activity against Electrophorus electricus AChE (EeAChE) with a Ki value of 3.26 nM, while compound 5 a displayed the most potent inhibition against equine BChE (eqBChE) with a Ki value of 0.94 nM. The compounds did not possess significant cytotoxicity action using the MTT assay on the cancer cell lines. The DPPH assays revealed that all the compounds have moderate antioxidant activities. Furthermore, molecular docking studies provided valuable insights into the interaction mechanisms of these compounds within the active sites of AChE and BChE crystal structures (PDB ID: 4EY7 and 4BDS, respectively). The above results indicated that the pyridazine-based compounds were a promising functional agent for the treatment of Alzheimer's disease.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024Enzyme inhibitory potential of some indole Schiff bases on acetylcholinesterase and human carbonic anhydrase isoforms I and II enzymes: an in vitro and molecular docking study
Akman, Ebru; Sirinzade, Hanif; Ozguven, Serap Yilmaz; Dilek, Esra; Suzen, Sibel
In this study, the in vitro effects of some indole Schiff bases on acetylcholinesterase and human carbonic anhydrase isoforms I and II were investigated. A series of N-methylindole hydrazide/hydrazone derivatives (1a-1t) were tested on these enzymes. The interactions of the synthesized indole derivatives with target enzymes were studied by molecular docking methodology. The results revealed that indole derivative Schiff base compounds inhibited the enzymes significantly. Ki values for hCAI isoenzyme were determined to be in the range of 36.18 ± 3.07–224.29 ± 5.78 nM; for the hCAII isoenzyme in the range of 31.30 ± 2.63–201.64 ± 7.25 nM; for acetylcholinesterase in the range of 6.82 ± 0.72–110.30 ± 9.26 nM. Compared to the control compound Acetazolamide (AZA), 1k and 1p were found to have the best inhibitory effect for hCAI; 1p was found to be the best inhibitory effect for hCAII. Compared to the control compound Tacrine (TAC), 1s showed the best inhibitory effect for AChE. In vitro results were verified with the results obtained by docking studies and interactions with enzymes were demonstrated. Communicated by Ramaswamy H. Sarma.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2024Assessing indole derivative molecules as dual acetylcholinesterase and butyrylcholinesterase inhibitors through In Vitro inhibition and molecular modelling studies
Alım, Zuhal; Şirinzade, Hanif; Kılınç, Namık; Dilek, Esra; Süzen, Sibel
Alzheimer's Disease (AD) is the most common type of dementia that develops with age, threatens the quality of life, is increases in number around the world, and has no effective treatment. The most important therapeutic targets in drug development studies for the treatment of AD are acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The inadequacy of existing AChE and BChE inhibitors in the treatment of AD has led to the need to identify new AChE/BChE inhibitors with fewer side effects. In this study, considering the pharmacological importance indole derivatives, inhibition effects of some indole derivative molecules (a-e) on AChE and BChE activity were investigated. IC50 values of a-e against AChE were found to be 0.480 µM, 1.682 µM, 0.916 µM, 1.093 µM, 0.340 µM, respectively. On the other hand, IC50 values of compounds a-e on BChE activity were determined as 2.18 µM, 4.49 µM, 2.28 µM, 6.36 µM, 1.940 µM, respectively. As a result, it was seen that indole derivatives (a-e) showed strong inhibition effect on both enzymes. Additionally, these inhibition results were supported by molecular modelling studies. As a conclusion, results of this study will contribute to studies on the synthesis of new indole-derived AChE and BChE inhibitors for the treatment of AD.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024Exploring new 5-Nitroimidazole Derivatives as Potent Acetylcholinesterase and Butyrylcholinesterase Enzyme Inhibitors
Gursoy, Sule; Satici, Doruk; Kuzu, Burak; Turkmenoglu, Burcin; Dilek, Esra; Algul, Oztekin
Discovering new compounds capable of inhibiting physiologically and metabolically significant drug targets or enzymes is of paramount importance in biological chemistry. With this aim, new 5-nitroimidazole derivatives (1–4) were designed and synthesized, and their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were discovered using acetyl (butyryl) thiocholine and Ellman's reagents for spectrophotometric assay. The inhibitory profiles of the synthesized compounds were assessed by comparing their IC50 and Ki values. Results demonstrate significant inhibitory activity of all synthesized compounds against both AChE and BuChE compared to the reference compound, donepezil. Notably, compound 4 exhibited dual inhibition of these enzymes, showing the highest activity against Electrophorus electricus AChE (EeAChE) with a Ki value of 0.024±0.009 nM and against equine BuChE (eqBuChE) with a Ki value of 0.087±0.017 nM. Furthermore, molecular modeling was conducted to study the interaction modes of the most potent compound (4) and donepezil in the active site of their related enzymes’ crystal structures (PDB ID: 4EY7 and 4BDS, respectively). Additionally, drug-likeness, ADME, and toxicity profiles of the compounds and metronidazole were predicted. The above results indicated that the dual inhibition of these enzymes is considered as a promising strategy for the treatment of neurological disorder especially Alzheimer's disease.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2022The paraoxonase 1 activity and lipid levels in umbilical cord blood and maternal venous blood, and their relations according to birth weight
Kadıoğlu, Berrin Göktuğ; Nalçakan, Aysel; Dilek, Esra
Objectives: Aim of this study is to find out the clinical relevance of estimating paraoxonase activity of PON1 enzyme, triglyceride (TG), total cholesterol, HDL, and LDL levels in maternal serum and umbilical cord blood according to birth weight. Methods: Venous blood samples were taken from mothers just before birth. Babies were divided into four groups: normal-weight babies, premature babies, low birth weight babies, and postmature babies. The weight of the newborns was measured and cord blood was taken. The samples were looked at HDL, LDL, total cholesterol, triglyceride levels and PON1 activities. We have investigated the paraoxonase activity of the PON1 enzyme. Enzyme activity assay was obtained spectrophotometrically measurement of p‐nitrophenol at 412 nm. Results: Maternal PON1 paraoxonase activity levels in Pre-Term show a significant decrease in cases as compared to other groups. Baby PON1 paraoxonase activity levels are also found to be significantly decreased in cases concerning the Term and Post-Term groups. There was a significant difference in all values the such as baby's weight, TG, Total cholesterol, HDL, LDL and PON1.belonging to babies (p < 0.05).Conclusions: Decreased paraoxonase activity in maternal serum may be considered as an additional risk factor for the development of low birth weight. It appears that PON1 activity plays an important role in infant development and affects birth weight. We think that the paraoxonase activity of the PON1 enzyme in mothers may be a marker in predicting the babies who are at risk in terms of birth weight.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2022Synthesis of (p-tolyl)-3(2H)pyridazinone Derivatives as Novel Acetylcholinesterase Inhibitors
Merde, İrem Bozbey; Önel, Gülce Taşkor; Türkmenoğlu, Burçin; Gürsoy, Şule; Dilek, Esra; Özçelik, Azime Berna; Uysal, Mehtap
In this study, a series of N-substituted-(p-tolyl)pyridazin-3(2H)-one derivatives were synthesized and evaluated for their AChE inhibitory activity. The chemical structures of novel compounds 5(a–m) were confirmed by 1H-NMR, 13C-NMR, IR and HRMS analysis. In order to eliminate the symptomatic effects of Alzheimer's disease, the proposed compounds were evaluated by acetylcholinesterase inhibition activity study in accordance with the cholinergic hypothesis. The results revealed that the N-substituted-(p-tolyl)pyridazin-3(2H)-one derivatives inhibited the enzymes significantly. Ki values for acetylcholinesterase in the range of 0.56±0.15–4.12±1.42 μM. Compound 5 h demonstrated the greatest in AChE activity compared with tacrine (0.56±0.15 μM). Molecular docking studies were performed for all compounds that compared tacrine in AChE activity in-vitro. As a result of molecular docking studies (ΔGBind, docking score, XP Gscore, Glide energy, Glide emodel), 5 f, 5 g and 5 h compounds showed good inhibitory properties in the AChE active site as in silico.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2022Evaluation of Naphthalenylmethylen Hydrazine Derivatives as Potent Inhibitors on, Antiatherogenic Enzymes, Paraoxonase I and Acetylcholinesterase Activities
Shirinzadeh, Hanif; Dilek, Esra; Alım, Zuhal
Acetylcholinesterase (AChE) and paraoxonase 1 (PON1) are two important serum ester hydrolases that have antiatherosclerotic effect by inhibiting the oxidation of lipid peroxides. In addition, AChE inhibitors are target molecules for the treatment of Alzheimer's. Naphthalene derivatives are important molecules in the field of pharmacology due to their wide range of biological activities. In this study, the inhibition effects of naphthalenylmethylen hydrazine derivatives on these two metabolic enzymes were investigated. IC50 values of these molecules were determined in the range of 0.158 μM to 6.862 μM against PON1, 0.0214 μM to 0.675 μM against AChE. As a result, naphthalenylmethylen hydrazine derivatives had strong inhibition effect on both enzymes. In this context, we hope that the results obtained in this study contribute to the determination of the side effects of current and new naphthalene-based pharmacological compounds to be developed. And also be effective in the synthesis studies of new AChE inhibitors.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2022(p-Chlorophenyl)-3(2H)pyridazinone Derivatives: Synthesis, in Silico, and AChE/BChE Inhibitory Activity
BozbeyMerde, İrem; Önel, Gülce Taşkor; Türkmenoğlu, Burçin; Gürsoy, Şule; Dilek, Esra
A series of novel (p-chlorophenyl)-3(2H)pyridazinone compounds were synthesized starting from p-chloroacetophenone as AChE/BChE inhibitors. The chemical structures of all the compounds were identified by spectral analysis. Cholinesterase inhibition activity studies and in silico studies of compounds designed to eliminate the symptomatic effects of Alzheimer's disease and slow down neurodegeneration were evaluated. According to the results obtained, it was revealed that N-substituted-(p- chlorophenyl)pyridazin-3(2H)-one derivatives inhibited enzymes significantly. Ki values were found for acetylcholinesterase in the range of 10.2±4.0–20.9±7.6 nM and for butyrylcholinesterase in the range of 0.70±0.34–1.67±1.12 nM. Compound 5e showed the best effect on AChE activity compared to Tacrine. Also, compound 5b showed the best effect in BChE inhibition. The interactions of the synthesized compounds with the best experimental activities against AChE, BChE, respectively, were investigated by in silico approaches. In molecular docking, 5b compound with AChE crystal structure (PDB ID:1ACJ), binding site and binding parameters of 5e compound with BChE crystal structure were investigated in detail. The results indicated that compound 5b and 5e could be a promising lead compound for further development as a therapeutic agent for Alzheimer's disease.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2022Inhibitory effects of novel 3(2H)pyridazinone-triazole derivatives against acetylcholinesterase enzyme
Bozbey, İrem; Önel, Gülce Taşkor; Türkmenoğlu, Burçin; Gürsoy, Şule; Dilek, Esra; Ergün, Muhammed; Özçelik, Azime Berna; Uysal, Mehtap
Alzheimer's disease is a neurological disease characterized by the destruction of brain cells. In this disease, which causes a decrease in thought, memory and behavioral functions, the symptoms appear gradually with age. In this study, inhibition of acetylcholinesterase enzyme which is an important target in accordance with the cholinergic hypothesis, was studied. New 3(2H)pyridazinone-triazole derivatives were synthesized, confirmed by1H-NMR,13C-NMR, HRMS analysis and their IC50 and Ki values were studied. The inhibition constants (Ki) of the compounds against the AChE enzyme ranged from 2.35 ± 0.18 to 5.15 ± 0.46 µM. The compound with the best inhibitory properties was compound 6d with a Ki value of 2.35 ± 0.18 µM. In addition, to support the experimental data, molecular docking studies were carried out with 6b, 6d, 6e and 6f compounds with AChE crystal structure (PDB ID:4M0E).
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