Browsing by Author "Demir, Yeliz"

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Aminoalkylated Phenolic Chalcones: Investigation of Biological Effects on Acetylcholinesterase and Carbonic Anhydrase I and Ii as Potential Lead Enzyme Inhibitors
(Bentham Science Publ Ltd, 2020) Yamali, Cem; Gul, Halise Inci; Cakir, Tahir; Demir, Yeliz; Gulcin, Ilhami
Background: Phenolic Mannich bases have been reported as acetylcholinesterase (AChE) inhibitors for the medication of Alzheimer's disease. Carbonic Anhydrases (CAs) are molecular targets for anticonvulsant, diuretic and antiglaucoma drugs in the clinic. Phenolic compounds have also been mentioned as CA inhibitors. The importance of Mannich bases in drug design inspired our research group to design novel phenolic Mannic bases as potent enzyme inhibitors. Objective: In this study, novel Mannich bases, 1-(3,5-bis-aminomethyl-4-hydroxyphenyl)-3-(4-substitutedphenyl)-2-propen-1-ones (1-9), were designed to discover new and potent AChE inhibitors for the treatment of Alzheimer's disease and also to report their carbonic anhydrase inhibitory potency against the most studied hCA I and hCA II isoenzymes with the hope to find out promising enzyme inhibitors. Methods: Mannich bases were synthesized by the Mannich reaction. The structures of the compounds were elucidated by H-1 NMR, C-13 NMR, and HRMS. Enzyme inhibitory potency of the compounds was evaluated spectrophotometrically towards AChE, hCA I and hCA II enzymes. Results and Discussion: The compounds showed inhibition potency in nanomolar concentrations against AChE with Ki values ranging from 20.44 +/- 3.17 nM to 43.25 +/- 6.28 nM. They also showed CAs inhibition potency with Ki values in the range of 11.76 +/- 1.29-31.09 +/- 2.7 nM (hCA I) and 6.08 +/- 1.18-23.12 +/- 4.26 nM (hCA II). Compounds 1 (hCA I), 5 (hCA II), and 4 (AChE) showed significant inhibitory potency against the enzymes targeted. Conclusion: Enzyme assays showed that Mannich derivatives might be considered as lead enzyme inhibitors to design more selective and potent compounds targeting enzyme-based diseases.
Determination of in Vitro Antioxidant, Anticholinergic, and Antiepileptic Activities of Some Medicinal and Aromatic Plant Extracts
(Kahramanmaras Sutcu Imam Univ Rektorlugu, 2024) Yurt, Bayram; Sağlamtaş, Rüya; Demir, Yeliz; İzol, Ebubekir; Diril, Halit; Caglayan, Cuneyt
Crocus cancellatus, Scilla siberica subsp. armena, Juniperus oxycedrus subsp. oxycedrus ve Anthriscus nemorosa gibi tıbbi ve aromatik bitkiler birçok farklı biyolojik aktiviteye sahiptir. Antioksidanlar birçok hastalığın önlenmesinde önemli rol oynarken, metabolik enzimlerin inhibisyonu da birçok hastalığın önlenmesinde etkilidir. Bu çalışmada, dört farklı tıbbi ve aromatik bitki türünün su, etanol ve diklorometan ekstraktlarının antioksidan aktiviteleri 1,1-difenil-2-pikrilhidrazil (DPPH•) ve 2,20-azino-bis-3-etilbenzthiazoline-6-sülfonik asit (ABTS•+) radikal giderme ve Cu2+, Fe3+ ve Fe3+-TPTZ indirgeme deneyleri ile belirlenmiştir. Enzim inhibisyon çalışmaları metabolik enzimler olan asetilkolinesteraz, bütirilkolinesteraz, karbonik anhidraz I ve II izoenzimleri ile gerçekleştirilmiştir. A. nemorosa'nın etanol ekstresi DPPH ve ABTS deneylerinde en yüksek aktiviteyi göstermiştir (IC50: 17.36 µg mL-1, IC50: 7.02 µg mL-1). Fe3+ indirgeme deneyinde, A. nemorosa'nın diklorometan ekstresi en yüksek aktiviteyi göstermiştir (1.96±0.060 µg mL-1). Cu2+ indirgeme deneyinde, J. oxycedrus'un diklorometan ekstresi en yüksek aktiviteyi göstermiştir (1.773±0.066 µg mL-1). Fe3+-TPTZ indirgeme deneyinde, S. siberica'nın etanol ekstraktı en yüksek aktiviteyi göstermiştir (1.256±0.011 µg mL-1). Enzim inhibisyon sonuçlarında, tüm bitkilerin çalışılan enzimleri inhibe ettiği belirlenmiştir. Bu çalışma sonucunda tıbbi ve aromatik bitkilerden olan bu dört bitkinin yüksek biyolojik aktiviteye sahip olduğu belirlenmiştir.
The Effects of Some Cephalosporins on Acetylcholinesterase and Glutathione S-Transferase: an in Vivo and in Vitro Study
(Taylor & Francis Ltd, 2019) Turkan, Fikret; Huyut, Zubeyir; Demir, Yeliz; Ertas, Fatma; Beydemir, Sukru
Background: Glutathione S-transferase (GST) and acetylcholinesterase (AChE) are important enzymes in the metabolism. GSTs are primarily available in phase II metabolism. AChE is vital for neurodegenerative disorders. Subjects and methods: The in vitro and in vivo effects of cefoperazone sodium (CFP), cefuroxime (CXM), and cefazolin (CZO) were investigated on GST and AChE activity in the present study. GST was purified using Glutathione-Agarose affinity chromatography. Results: K-i constants of CFP, CXM, and CZO were 0.1392 +/- 0.02, 1.5179 +/- 0.33, and 1.006 +/- 0.11 mM for GST and 0.3010 +/- 0.07, 0.3561 +/- 0.09, and 0.3844 +/- 0.04 mM, for AChE, respectively. The most effective inhibitor was CFP for both enzymes in in vitro. CZO (50 mg/kg), CXM (25 mg/kg), and CFP (100 mg/kg) inhibit in vivo GST and AChE activities. CXM had the most effective in vivo inhibition on AChE and GST. Conclusions: CZO, CXM, and CFP are effective AChE and GST inhibitors in both in vitro and in vivo.
Imidazo[1,2-A]pyridine Mannich Bases: Synthesis, Anticholinesterase Evaluation, and in Silico Studies
(Springer int Publ Ag, 2025) Kuzu, Burak; Demir, Yeliz
In this study, a series of imidazo[1,2-a]pyridine-mannich bases were designed and synthesized for the inhibition of cholinesterases, one of the important pathways in the treatment of Alzheimer's dementia. The imidazopyridine scaffold, which is found in the structure of many active compounds in pharmaceutical use, is derived from Mannich-bases containing morpholine and various aromatic groups. In vitro AChE and BChE enzyme activities and enzyme kinetics studies of new potential drug candidates (9a-j) that can target the critical binding regions of cholinesterases were conducted. In vitro evaluation with donepezil, tacrine (control compounds), and 9a-j, it was found that naphthalene-substituted compound 9j exhibited the most potential anti-cholinesterase activity (IC50s: 57.75 nM for AChE; 99.0 nM for BChE). Molecular docking studies performed with hAChE and hBChE enzyme crystal structures revealed that compound 9j has a higher binding affinity by targeting the CAS and PAS binding sites. Additionally, drug-likeness and pre-ADMET evaluation of the compounds showed that compound 9j had the most favorable drug properties. These results might be a new milestone in terms of the promising importance of the imidazopyridine scaffold in future drug design for the treatment of AD.
Some Novel Oxirane-Thiirane Derivatives: Synthesis, Molecular Docking and Enzymatic Inhibition for Therapeutic Potential
(Humana Press inc, 2025) Farzaliyev, Vagif; Erturk, Adem; Huseynova, Afat; Demir, Yeliz; Kiziltas, Hatice; Sujayev, Afsun; Gulcin, Ilhami
In this study, a series of new oxirane and thiirane (2a-g), were assessed for their influence on various metabolic enzymes, including acetylcholinesterase (AChE) and human carbonic anhydrase isoenzymes (hCA I and hCA II). So, in the first stage, 1-chloro-3-phenothiazylpropanol-2 (2), methyl, methoxy-substituted oxirane, thiirane (2a and 2b), methyl, 1,2-aminopropanethiols (2c-2f), trifluorinated aminethiol derivative (2g), have been synthesized. The structures of synthesized compound were confirmed by IR, NMR analysis. Enzyme inhibition studies demonstrated that all these compounds exhibited potent inhibitory effects on all the target enzymes, surpassing the standard inhibitors, as evidenced by their IC50 and Ki values. The Ki values for the compounds concerning AChE, hCA I, and hCA II enzymes were in the ranges of 1.21 +/- 0.072-12.64 +/- 0.12, 5.93 +/- 0.028- 81.87 +/- 12.52 and 61.43 +/- 10.01-344.22 +/- 33.87 nM, respectively. Additionally, molecular docking studies were conducted to investigate further the binding interactions of the most potent inhibitors with enzyme active sites, revealing strong hydrogen bonding, pi-stacking, and halogen interactions. These findings indicate that the synthesized compounds exhibit high affinity and specificity for the target enzymes, suggesting their potential for further development as therapeutic agents. Future studies will focus on optimizing the structural features of these compounds to enhance their selectivity and bioavailability, conducting in vivo evaluations to assess their pharmacokinetic and pharmacodynamic properties, and exploring their potential applications in the treatment of neurodegenerative and metabolic disorders.
Structure-Based Inhibition of Acetylcholinesterase and Butyrylcholinesterase With 2-Aryl Benzoxazole Derivatives: Synthesis, Enzymatic Assay, and in Silico Studies
(Springer, 2025) Kuzu, Burak; Alagoz, M. Abdullah; Demir, Yeliz; Gulcin, Ilhami; Burmaoglu, Serdar; Algul, Oztekin
An important research topic is the discovery of multifunctional compounds targeting different disease-causing components. This research aimed to design and synthesize a series of 2-aryl-6-carboxamide benzoxazole derivatives that inhibit cholinesterases on both the peripheral anionic and catalytic anionic sides. Compounds (7-48) were prepared from 4-amino-3-hydroxybenzoic acid in three steps. The Ellman test, molecular docking with Maestro, and molecular dynamics simulation studies with Desmond were done (Schrodinger, 12.8.117). Compound 36, the most potent compound among the 42 new compounds synthesized, had an inhibitory concentration of IC50 12.62 nM for AChE and IC50 25.45 nM for BChE (whereas donepezil was 69.3 nM and 63.0 nM, respectively). Additionally, compound 36 had docking values of - 7.29 kcal/mol for AChE and - 6.71 kcal/mol for BChE (whereas donepezil was - 6.49 kcal/mol and - 5.057 kcal/mol, respectively). Furthermore, molecular dynamics simulations revealed that compound 36 is stable in the active gorges of both AChE (average RMSD: 1.98 & Aring;) and BChE (average RMSD: 2.2 & Aring;) (donepezil had average RMSD: 1.65 & Aring; and 2.7 & Aring;, respectively). The results show that compound 36 is a potent, selective, mixed-type dual inhibitor of both acetylcholinesterase and butyrylcholinesterase. It does this by binding to both the catalytically active and peripheral anionic sites of cholinesterases at the same time. These findings show that target compounds may be useful for establishing the structural basis for new anti-Alzheimer agents. [GRAPHICS] .
Synthesis and Inhibitor Effect Novel Alkoxymethyl Derivatives of Dihetero Cycloalkanes on Carbonic Anhydrase and Acetylcholinesterase
(Wiley-v C H verlag Gmbh, 2024) Farzaliyev, Vagif; Erturk, Adem; Abbasova, Malahat; Nabiyev, Oruj; Demir, Yeliz; Kiziltas, Hatice; Gulcin, Ilhami
1,3-Diheterocycloalkanes derivatives are important starting materials in fine organic synthesis. These compounds can be widely used in various fields such as industry, medicine, biotechnology and chemical technology. The paper is focused on synthesis and study of alkoxymethyl derivatives of diheterocycloalkanes (M1-M15) and inhibition effect on carbonic anhydrase and acetylcholinesterase. The structures of compounds were confirmed by 1H and 13C NMR spectroscopy. Also, in this study alkoxymethyl derivatives of diheterocycloalkanes were assessed for their influence on various metabolic enzymes, including acetylcholinesterase (AChE) and human carbonic anhydrase isoenzymes (hCA I and hCA II). The results demonstrated that all these compounds exhibited potent inhibitory effects on all the target enzymes, surpassing the standard inhibitors, as evidenced by their IC50 and Ki values. The Ki values for the compounds concerning AChE, hCA I, and hCA II enzymes were in the ranges of 1.02 +/- 0.17-8.38 +/- 1.02, 15.30 +/- 3.15-58.14 +/- 5.17 and 24.05 +/- 3.70-312.94 +/- 27.24 nM, respectively. image
Synthesis of Novel Pyrazino[1,2-A]indol Derivatives as Potent Cholinesterase Inhibitors and Their in Vitro and in Silico Evaluations
(Elsevier Science Inc, 2025) Kuzu, Burak; Demir, Yeliz
The development of effective cholinesterase inhibitors remains a critical strategy in the search for novel therapeutics for Alzheimer's disease (AD). In this work, a series of novel 3-substituted pyrazino[1,2-a]indol-1(2H)-one derivatives were rationally designed, synthesized, and fully characterized through comprehensive spectral analyses. The cholinesterase inhibitory activities of the compounds were systematically evaluated, demonstrating potent inhibition against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) at nanomolar concentrations. Notably, compound 16g emerged as the most promising candidate, exhibiting 14.28-fold and 9.7-fold greater potency against AChE compared to tacrine and donepezil, respectively, and 3.39-fold and 2.3fold higher activity against BChE. Molecular docking studies elucidated key binding interactions within the active sites of the enzymes, supporting the observed biological activities and providing mechanistic insights. Furthermore, in silico drug-likeness and pre-ADMET profiling confirmed the favorable predicted pharmacokinetic properties of compound 16g, underscoring its potential as a lead compound. These findings collectively highlight the pyrazino[1,2-a]indol-1(2H)-one core as a promising structural framework for developing next-generation cholinesterase inhibitors aimed at combating AD.