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2-Hydroxyethyl substituted NHC precursors: Synthesis, characterization, crystal structure and carbonic anhydrase, ?-glycosidase, butyrylcholinesterase, and acetylcholinesterase inhibitory properties
(Elsevier Science Bv, 2018) Erdemir, Fatos; Celepci, Duygu Barut; Aktas, Aydin; Taslimi, Parham; Gok, Yetkin; Karabiyik, Hasan; Gulcin, Ilhami
This study contains novel a serie synthesis of N-heterocyclic carbene (NHC) precursors that 2-hydroxyethyl substituted. The NHC precursors have been prepared from 1-(2-hydroxyethyl)benzimidazole and alkyl halides. The novel NHC precursors have been characterized by using H-1 NMR, C-13 NMR, FTIR spectroscopy and elemental analysis techniques. Molecular and crystal structures of 2a, 2d, 2e, 2f and 2g were obtained with single-crystal X-ray diffraction studies. These novel NHC precursor's derivatives effectively inhibited the a-glycosidase, cytosolic carbonic anhydrase I and II isoforms (hCA I and II), butyrylcholinesterase (BChE) and acetylcholinesterase (AChE). Inhibition constant (K-i) were found in the range of 0.30-9.22 nM for alpha-glycosidase, 13.90-41.46 nM for hCA I, 12.82-49.95 nM for hCA II, 145.82-882.01 nM for BChE, and 280.92-1370.01 nM for AChE, respectively. (C) 2017 Elsevier B.V. All rights reserved.
Benzimidazolium salts bearing the trifluoromethyl group as organofluorine compounds: Synthesis, characterization, crystal structure, in silico study, and inhibitory profiles against acetylcholinesterase and ?-glycosidase
(Wiley, 2022) Tezcan, Burcu; Gok, Yetkin; Sevincek, Resul; Taslimi, Parham; Taskin-Tok, Tugba; Aktas, Aydin; Guzel, Bilgehan
Here, we report the synthesis, characterization, and biological activities of a series of benzimidazolium salts bearing the trifluoromethylbenzyl group. All benzimidazolium salts were characterized by using nuclear magnetic resonance (NMR) (H-1 NMR and C-13 NMR), Fourier transform-infrared spectroscopy, and elemental analysis techniques. The crystal structures of some of these compounds were obtained by the single-crystal X-ray diffraction method. Furthermore, the acetylcholinesterase (AChE) and alpha-glycosidase (alpha-Gly) enzyme inhibition activities of these compounds were investigated. The obtained results revealed that 2e, with K-i value of 1.36 +/- 0.34 mu M against AChE and 3d with K-i value of 91.37 +/- 10.38 mu M against alpha-Gly, were the most potent compounds against both assigned enzymes. It should be noted that most of the synthesized compounds were more potent than standard inhibitor tacrine (TAC) against AChE. In silico studies, we focused on compound 2e, 3d, 3e, and 3f as potent inhibitors of AChE and alpha-Gly, the compound 2e showed good binding energy (-10.23 kcal/mol), among the three selected compounds and positive control (-10.18, -10.08, and -7.37 kcal/mol for 3d, 3f, and TAC, respectively). Likewise, as a result of the same compounds against the alpha-Gly enzyme, the compound 3d had the highest binding affinity (-8.39 kcal/mol) between the four selected compounds and the positive control (-8.27, -8.10, -8.06, and -7.53 kcal/mol for 3f, 3e, 2e, and acarbose, respectively). From the absorption, distribution, metabolism, excretion, and toxicity analyses, it can be concluded that the compounds under consideration exhibited more drug-likeness properties in the prediction studies compared to positive controls.
Design, synthesis, characterization, crystal structure, in silico studies, and inhibitory properties of the PEPPSI type Pd(II)NHC complexes bearing chloro/fluorobenzyl group
(Academic Press Inc Elsevier Science, 2023) Gok, Yetkin; Taslimi, Parham; Sen, Betul; Bal, Selma; Aktas, Aydin; Aygun, Muhittin; Sadeghi, Morteza
This work contains synthesis, characterization, crystal structure, and biological activity of a new series of the PEPPSI type Pd(II)NHC complexes [(NHC)Pd(II)(3-Cl-py)]. NMR, FTIR, and elemental analysis techniques were used to characterize all (NHC)Pd(II)(3-Cl-py) complexes. Also, molecular and crystal structures of complex 1c were established by single-crystal X-ray diffraction. Regarding the X-ray studies, the palladium(II) atom has a slightly distorted square-planar coordination environment. Additionally, the enzyme inhibitory effect of new (NHC)Pd(II)(3-Cl-py) complexes (1a-1g) was studied. They exhibited highly potent inhibition effect on acetyl -cholinesterase (AChE), butyrylcholinesterase (BChE) and carbonic anhydrases (hCAs) (Ki values are in the range of 0.08 +/- 0.01 to 0.65 +/- 0.06 mu M, 10.43 +/- 0.98 to 22.48 +/- 2.01 mu M, 6.58 +/- 0.30 to 10.88 +/- 1.01 mu M and 6.34 +/- 0.37 to 9.02 +/- 0.72 mu M for AChE, BChE, hCA I, and hCA II, respectively). Based on the molecular docking, among the seven synthesized complexes, 1c, 1b, 1e, and 1a significantly inhibited AChE, BChE, hCA I, and hCA II enzymes, respectively. The findings highpoint that (NHC)Pd(II)(3-Cl-py) complexes can be considered as possible inhibitors via metabolic enzyme inhibition.
Imidazolinium chloride salts bearing wingtip groups: Synthesis, molecular docking and metabolic enzymes inhibition
(Elsevier Science Bv, 2019) Yigit, Beyhan; Kaya, Ruya; Taslimi, Parham; Isik, Yilmaz; Karaman, Muhammet; Yigit, Murat; Ozdemir, Ismail
A series of symmetrical imidazolinium chloride salts bearing secondary N-alkyl substituents were synthesized in good yield by the reaction of N,N'-dialkylethane-1,2-diamines and HC(OEt)(3) in the presence of NH4Cl. These salts were characterized by spectroscopic methods. All compounds were tested as enzyme inhibitory agents. These novel symmetrical imidazolinium chloride salts derivatives (3a-h) effectively inhibited the cytosolic hCA I and hCA II, BChE, alpha-glycosidase and AChE with K-i values in the range of 18.41-121.73 nM for hCA I, 12.50-63.12 nM for hCA II, 3.72-34.58 nM for AChE, 5.50-32.36 nM for BChE, and 94.72-364.51 nM for alpha-glycosidase, respectively. CA isoenzymes play a crucial roles including acid-base balance homeostasis by excreting and secreting protons (H+) due to the CO2 hydration, HCO3- reabsorption mechanisms, and renal NH4+ output. Also, the molecular modeling is an implementation for estimation of the binding proximity of symmetrical imidazolinium chloride salts bearing secondary wingtip groups and their inhibition mechanisms and kinetics in atomic levels at the catalytic domains. (C) 2018 Elsevier B.V. All rights reserved.
In vitro cytotoxic and in vivo antitumoral activities of some aminomethyl derivatives of 2,4-dihydro-3H-1,2,4-triazole-3-thiones-Evaluation of their acetylcholinesterase and carbonic anhydrase enzymes inhibition profiles
(Wiley, 2019) Timur, Irfan; Kocyigit, Umit M.; Dastan, Taner; Sandal, Suleyman; Ceribasi, Ali Osman; Taslimi, Parham; Gulcin, Ilhami
The 1,2,4-triazole and its derivatives were reported to exhibit various pharmacological activities such as antimicrobial, analgesic, anti-inflammatory, antitumoural, cytotoxic, and antioxidant properties. In this study, a series of triazole compounds (M1-M10) were evaluated for some biological activities. In vitro qualifications of these compounds on acetylcholinesterase (AChE) and human carbonic anhydrase enzyme activities were performed. Also, their antitumoral activities in human colon cancer (HT29) cell line cultures were examined. In addition, colon cancer experimentation was induced in rats by an in vivo method, and the in vivo anticancer effects of triazole derivatives were investigated. Also, the effects of these derivatives in levels of antioxidant vitamin A, vitamin E, and MDA were studied in rat liver and blood samples. Most of the compounds were found to exhibit significant antioxidant and antitumoral activities. All the compounds had cytotoxic activities on HT29 cell lines with their IC50 values lower than 10 mu M concentrations. The low IC50 values of the compounds are M1 (3.88 mu M), M2 (2.18 mu M), M3 (4.2 mu M), M4 (2.58 mu M), M5 (2.88 mu M), M6 (2.37 mu M), M7 (3.49 mu M), M8 (4.01 mu M), M9 (8.90 mu M), and M10 (3.12 mu M).
meta-Cyanobenzyl substituted benzimidazolium salts: Synthesis, characterization, crystal structure and carbonic anhydrase, -glycosidase, butyrylcholinesterase, and acetylcholinesterase inhibitory properties
(Wiley-V C H Verlag Gmbh, 2018) Turker, Ferhat; Celepci, Duygu Barut; Aktas, Aydin; Taslimi, Parham; Gok, Yetkin; Aygun, Muhittin; Gulcin, Ilhami
meta-Cyanobenzyl-substituted N-heterocyclic carbene (NHC) precursors were synthesized by the reaction of a series of N-(alkyl)benzimidazolium with 3-bromomethyl-benzonitrile. These benzimidazolium salts were characterized by using H-1 NMR, C-13 NMR, FTIR spectroscopy, and elemental analysis techniques. The molecular and crystal structures of 2f and 2g complexes were obtained by using the single-crystal X-ray diffraction method. The derivatives of these novel NHC precursors were effective inhibitors of -glycosidase (AG), the cytosolic carbonic anhydrase I and II isoforms (hCA I and II), butyrylcholinesterase (BChE), and acetylcholinesterase (AChE) with K-i values in the range of 1.01-2.12nM for AG, 189.56-402.44nM for hCA I, 112.50-277.37nM for hCA II, 95.45-352.58nM for AChE, and 132.91-571.18nM for BChE. In the last years, inhibition of the CA enzyme has been considered as a promising factor for pharmacologic intervention in a diversity of disturbances such as obesity, glaucoma, cancer, and epilepsy.
New palladium complexes with N-heterocyclic carbene and morpholine ligands: Synthesis, characterization, crystal structure, molecular docking, and biological activities
(Wiley, 2024) Behcet, Ayten; Taslimi, Parham; Sen, Betul; Taskin-Tok, Tugba; Aktas, Aydin; Gok, Yetkin; Aygun, Muhittin
This work includes the synthesis of a new series of palladium-based complexes containing both morpholine and N-heterocyclic carbene (NHC) ligands. The new complexes were characterized using NMR (1H and 13C), FTIR spectroscopic, and elemental analysis techniques. The crystal structure of complex 1b was obtained by utilizing the single-crystal X-ray diffraction method. X-ray studies show that the coordination environment of palladium atom is completed by the carbene carbon atom of the NHC ligand, the nitrogen atom of the morpholine ring, and a pair of bromide ligand, resulting in the formation of slightly distorted square planar geometry. All complexes were determined for some metabolic enzyme activities. Results indicated that all the synthetic complexes exhibited powerful inhibitory actions against all aims as compared to the control molecules. Ki values of new morpholine-liganded complexes bearing 4-hydroxyphenylethyl group 1a-e for hCA I, hCA II, AChE, BChE, and alpha-glycosidase enzymes were obtained in the ranges 0.93-2.14, 1.01-2.03, 4.58-10.27, 7.02-13.75, and 73.86-102.65 mu M, respectively. Designing of reported complexes is impacted by molecular docking study, and interaction with the current enzymes also proclaimed that compounds 1e (-12.25 kcal/mol for AChE and -11.63 kcal/mol for BChE), 1c (-10.77 kcal/mol and -9.26 kcal/mol for alpha-Gly and hCA II, respectively), and 1a (-8.31 kcal/mol for hCA I) are showing binding affinity and interaction from the synthesized five novel complexes.
New PEPPSI-Pd-NHC complexes bearing 4-hydroxyphenylethyl group: Synthesis, characterization, molecular docking, and bioactivity properties
(Wiley-V C H Verlag Gmbh, 2022) Behcet, Ayten; Taslimi, Parham; Gok, Yetkin; Aktas, Aydin; Taskin-Tok, Tugba; Gulcin, Ilhami
Five 4-hydroxyphenylethyl substituted pyridine enhanced, precatalyst, preparation, stabilization, and initiation-Pd-N-heterocyclic carbene (PEPPSI-Pd-NHC) complexes are synthesized in a straightforward way. All PEPPSI-Pd-NHC complexes were prepared by mixing 4-hydroxyphenylethyl substituted NHC precursors, palladium chloride, potassium carbonate, and potassium bromide in pyridine. All complexes were screened for human carbonic anhydrase I (hCA I) and hCA II, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and alpha-glucosidase (alpha-Glu) inhibitory activities. The ChE inhibitory activities of the new PEPPSI-Pd-NHC complexes bearing the 4-hydroxyphenylethyl group (12-e) against alpha-Glu, AChE, and BChE were determined by the Tao and Ellman methods. The results indicated that all the synthetic complexes exhibited potent inhibitory activities against all targets as compared to the standard inhibitors, revealed by IC50 values. The K-i values of the new PEPPSI-Pd-NHC complexes 1a-e for hCA I, hCA II, AChE, BChE, and alpha-Glu were obtained in the ranges of 18.98-32.65, 22.95-38.13, 3.67-11.65, 4.09-9.36, 186.92-287.45 mu M, respectively. Among the synthesized complexes, the most potent complexes were 1c toward hCA I and II with K-i values 18.98 and 22.95 mu M, and 1d toward AChE and BChE with K-i = 3.67 and 4.09 mu M, respectively.
Novel 2-aminopyridine liganded Pd(II) N-heterocyclic carbene complexes: Synthesis, characterization, crystal structure and bioactivity properties
(Academic Press Inc Elsevier Science, 2019) Erdemir, Pato; Celepci, Duygu Barut; Aktas, Aydin; Gok, Yetkin; Kaya, Ruya; Taslimi, Parham; Demir, Yeliz
In this work, the synthesis, crystal structure, characterization, and enzyme inhibition effects of the novel a series of 2-aminopyridine liganded Pd(II) N-heterocyclic carbene (NHC) complexes were examined. These complexes of the Pd-based were synthesized from PEPPSI complexes and 2-aminopyridine. The novel complexes were characterized by using C-13 NMR, H-1 NMR, elemental analysis, and FTIR spectroscopy techniques. Also, crystal structures of the two compounds were recorded by using single-crystal X-ray diffraction assay. Also, these complexes were tested toward some metabolic enzymes like a-glycosidase, aldose reductase, butyrylcholinesterase, acetylcholinesterase enzymes, and carbonic anhydrase I, and II isoforms. The novel 2-aminopyridine liganded (NHC) PdI2(2-aminopyridine) complexes (1a-i) showed Ki values of in range of 5.78 +/- 0.33-22.51 +/- 8.59 nM against hCA I, 13.77 +/- 2.21-30.81 +/- 4.87 nM against hCA II, 0.44 +/- 0.08-1.87 +/- 0.11 nM against AChE and 3.25 +/- 0.34-12.89 +/- 4.77 nM against BChE. Additionally, we studied the inhibition effect of these derivatives on aldose reductase and alpha-glycosidase enzymes. For these compounds, compound 1d showed maximum inhibition effect against AR with a Ki value of 360.37 +/- 55.82 nM. Finally, all compounds were tested for the inhibition of alpha-glycosidase enzyme, which recorded efficient inhibition profiles with Ki values in the range of 4.44 +/- 0.65-12.67 +/- 2.50 nM against aglycosidase.
Novel 2-methylimidazolium salts: Synthesis, characterization, molecular docking, and carbonic anhydrase and acetylcholinesterase inhibitory properties
(Academic Press Inc Elsevier Science, 2020) Bal, Selma; Kaya, Ruya; Gok, Yetkin; Taslimi, Parham; Aktas, Aydin; Karaman, Muhammet; Gulcin, Ilhami
In this work, structures of different imidazolium compounds were designed and synthesized. These compounds were synthesized from 2-methylimidazole and alkyl/aryl halides. Their structures were characterized by using H-1 NMR, C-13 NMR, FTIR spectroscopic techniques. All the synthesized compounds were tested for their inhibition activities on different enzymes. Inhibition experiments gave good and moderate results, proving their activities of these compounds as anticholinergics potential. These obtained novel 2-methylimidazolium salts (1a-e and 2a-e) molecules were effective inhibitors of the carbonic anhydrase I and II isozymes (hCA I and II) and acetylcholinesterase (AChE) enzymes with Ki values in the range of 26.45 +/- 6.49-77.60 +/- 9.53 nM for hCA I, 27.87 +/- 5.00-86.61 +/- 5.71 nM for hCA II, and 1.15 +/- 0.19-8.89 +/- 0.49 nM for AChE, respectively. AChE enzyme inhibitors are the most common drugs applied in the therapy of diseases such as senile dementia, Alzheimer's disease, ataxia, Parkinson's disease, and among others.
A Novel Ag-N-Heterocyclic Carbene Complex Bearing the Hydroxyethyl Ligand: Synthesis, Characterization, Crystal and Spectral Structures and Bioactivity Properties
(Mdpi, 2020) Aktas, Aydin; Celepci, Duygu; Gok, Yetkin; Taslimi, Parham; Akincioglu, Hulya; Gulcin, Ilhami
In this study, a novel silver N-heterocyclic carbene (Ag-NHC) complex bearing hydroxyethyl substituent has been synthesized from the hydroxyethyl-substituted benzimidazolium salt and silver oxide by using in-situ deprotonation method. A structure of the Ag-NHC complex was characterized by using UV-Vis, FTIR, H-1-NMR and C-13-NMR spectroscopies and elemental analysis techniques. Also, the crystal structure of the novel complex was determined by single-crystal X-ray diffraction method. In this paper, compound 1 showed excellent inhibitory effects against some metabolic enzymes. This complex had Ki of 1.14 0.26 mu M against human carbonic anhydrase I (hCA I), 1.88 +/- 0.20 mu M against human carbonic anhydrase II (hCA I), and 10.75 +/- 2.47 mu M against alpha-glycosidase, respectively. On the other hand, the Ki value was found as 25.32 +/- 3.76 mu M against acetylcholinesterase (AChE) and 41.31 +/- 7.42 mu M against butyrylcholinesterase (BChE), respectively. These results showed that the complex had drug potency against some diseases related to using metabolic enzymes.
Novel amine-functionalized benzimidazolium salts: Synthesis, characterization, bioactivity, and molecular docking studies
(Elsevier, 2020) Yigit, Murat; Yigit, Beyhan; Taslimi, Parham; Ozdemir, Ismail; Karaman, Muhammet; Gulcin, Ilhami
A series of amine-tethered benzimidazolium salts were synthesized by the reactions between 1-(1-methyl-2-dimethylaminoethyl)benzimidazole and various alkyl halides. The characterization of the newly synthesized salts was done by spectroscopic methods. Also, 2e, 2f, and 2h have been docked into the catalytic active site hCA I, hCA II, AChE, BChE, and alpha-glycosidase enzymes. We have identified high binding affinity and explained inhibition mechanism of the compounds against the enzymes. These novel amine-functionalized benzimidazolium salts derivatives were good inhibitor compounds of the aglycosidase, hCA I and II isoforms, and both cholinesterase enzymes with K-i values in the range of 0.63 +/- 0.05-3.63 +/- 0.83 nM for a-glycosidase, 8.42 +/- 1.03-27.04 +/- 3.74 nM for hCA I, 7.94 +/- 0.74 - 21.82 +/- 5.81 nM for hCA II, 136.38 +/- 19.55-247.34 +/- 34.06 nM for BChE, and 124.24 +/- 13.94 - 283.55 +/- 54.06 nM for AChE, respectively. Among the inhibitors, 2e, 2e, 2f, 2f, and 2h were obtained to be the excellent inhibitors with Ki values of 8.42 +/- 1.03, 7.94 +/- 0.74,124.24 +/- 13.94,136.38 +/- 19.55, and 0.63 +/- 0.05 nM for hCA I, hCA II, AChE, BChE, alpha-glycosidase enzymes, respectively. The ability to model some metabolic enzymes receptors and theirs inhibitors in silico are important because they can save valuable resources and help to rationalize the mode of binding, and to design better inhibitors. (C) 2020 Elsevier B.V. All rights reserved.
Novel Benzylic Substituted Imidazolinium, Tetrahydropyrimidinium and Tetrahydrodiazepinium Salts: Potent Carbonic Anhydrase and Acetylcholinesterase Inhibitors
(Wiley-V C H Verlag Gmbh, 2018) Yigit, Beyhan; Yigit, Murat; Celepci, Duygu Barut; Gok, Yetkin; Aktas, Aydin; Aygun, Muhittin; Taslimi, Parham
The new imidazolinium, tetrahydropyrimidinium and tetrahydrodiazepinium salts were synthesized in good yield by the reaction of the corresponding N,N'-dialkylalkanediamine with triethyl orthoformate in the presence of ammonium chloride. All of the compounds were obtained, and spectroscopically characterized. The crystal structure for the 1,3-bis(4-benzyloxy-3-methoxybenzyl)-3,4,5,6-tetrahydropyrimidinium chloride (5g) was determined by single-crystal X-ray diffraction. The biological properties of all novel compounds were tested and the influence of ring size and benzylic N-substituents on the biological activities were examined. Also, they were found as effective inhibitors against cytosolic carbonic anhydrase I and II isoforms (hCA I and II), and acetylcholinesterase (AChE) enzyme. Among these compounds, 1,3-bis(4-(1-piperidinyl)benzyl)-3,4,5,6-tetrahydropyrimidinium chloride (5f) demonstrated the the best inhibition effects against hCA I, 1,3-bis(4-benzyloxy-3-methoxybenzyl)-3,4,5,6-tetrahydropyrimidinium chloride (5g) demonstrated the the best inhibition effects against cytosolic hCA II isoenzyme. On the other hand, 1,3-Bis(4-methylthiobenzyl)-3,4,5,6-tetrahydropyrimidinium chloride, (5e) demonstrated the the best inhibition effects against AChE enzyme.
Novel morpholine liganded Pd-based N-heterocyclic carbene complexes: Synthesis, characterization, crystal structure, antidiabetic and anticholinergic properties
(Pergamon-Elsevier Science Ltd, 2019) Aktas, Aydin; Celepci, Duygu Barut; Kaya, Ruya; Taslimi, Parham; Gok, Yetkin; Aygun, Muhittin; Gulcin, Ilhami
This study involves the synthesis of novel N-heterocyclic carbene (NHC)PdX2(morpholine) complexes (1a-i). These Pd-based complexes are synthesized from pyridine enhanced precatalyst preparation stabilization and initiation (PEPPSI) complexes and morpholine. The new complexes were characterized by spectroscopy (IR, H-1 and C-13 NMR) techniques. Also, the crystal structures of lb and if were obtained by utilizing the single-crystal X-ray diffraction method. The synthesized compounds in this study were investigated for their inhibition action against equin serum butyrylcholinesterase (BChE) and Electrophorus electricus acetylcholinesterase (AChE) as the capability drug aims for Alzheimer's disease (AD). These novel morpholine liganded Pd-based N-heterocyclic complexes were good inhibitors of BChE, alpha-glycosidase, cytosolic carbonic anhydrase I and II isoforms (hCA I and II), and AChE, with K-i values in the range of 10.77 +/- 1.01-45.86 +/- 5.65 mu M for hCA I, 25.42 +/- 5.18-57.82 +/- 3.01 mu M for hCA II, 12.26 +/- 3.32-50.36 +/- 6.19 mu M for a-glycosidase, 9.97 +/- 1.26-60.75 +/- 15.98 M for BChE, and 10.28 1.55-30.12 3.22 M for AChE. The inhibition of the alpha-glycosidase enzyme, an important carbohydrate hydrolyzing catalyst, could be used as one of the efficient methodologies in both treating and preventing diabetes by controlling the suppressing postprandial hyperglycemia and postprandial glucose amounts. (C) 2018 Elsevier Ltd. All rights reserved.
Novel N-propylphthalimide- and 4-vinylbenzyl-substituted benzimidazole salts: Synthesis, characterization, and determination of their metal chelating effects and inhibition profiles against acetylcholinesterase and carbonic anhydrase enzymes
(Wiley, 2018) Sari, Yakup; Aktas, Aydin; Taslimi, Parham; Gok, Yetkin; Gulcin, Ilhami
The novel N-propylphthalimide-substituted and 4-vinylbenzyl-substituted N-heterocyclic carbene (NHC) precursors were synthesized by N-substituted benzimidazolium with aryl halides. The novel N-propylphthalimide-substituted and 4-vinylbenzyl-substituted NHC precursors have been characterized by using H-1 NMR, C-13 NMR, FTIR spectroscopy, and elemental analysis techniques. They were tested for the inhibition of AChE and hCA enzymes and demonstrated efficient inhibition profiles with K-i values in the range of 351.0-1269.9 nM against hCA I, 346.6-1193.1 nM against hCA II, and 19.0-76.3 nM against AChE. On the other hand, acetazolamide, a clinically used molecule, utilized as CA inhibitor, obtained a K-i value of 1246.7 nM against hCA I and 1407.6 nM against hCA II. Additionally, tacrine inhibited AChE and obtained a K-i value of 174.6 nM.
Novel NHC Precursors: Synthesis, Characterization, and Carbonic Anhydrase and Acetylcholinesterase Inhibitory Properties
(Wiley-V C H Verlag Gmbh, 2017) Aktas, Aydin; Taslimi, Parham; Gulcin, Ilhami; Gok, Yetkin
Three series of imidazolidinium ligands (NHC precursors) substituted with 4-vinylbenzyl, 2-methyl-1,4-benzodioxane, and N-propylphthalimide were synthesized. N-Heterocyclic carbene (NHC) precursors were prepared from N-alkylimidazoline and alkyl halides. The novel NHC precursors were characterized by H-1 NMR, C-13 NMR, FTIR spectroscopy, and elemental analysis techniques. The enzymes inhibition activities of the NHC precursors were investigated against the cytosolic human carbonic anhydrase I and II isoenzymes (hCA I and II) and the acetylcholinesterase (AChE) enzyme. The inhibition parameters (IC50 and K-i values) were calculated by spectrophotometric method. The inhibition constants (K-i) were found to be in the range of 166.65-635.38nM for hCA I, 78.79-246.17nM for hCA II, and 23.42-62.04nM for AChE. Also, the inhibitory effects of the novel synthesized NHCs were compared to acetazolamide as a clinical CA isoenzymes inhibitor and tacrine as a clinical cholinergic enzymes inhibitor.
Novel PEPPSI-type N-heterocyclic carbene palladium(II) complexes: Synthesis, characterization, in silico studies and enzyme inhibitory properties against some metabolic enzymes
(Elsevier Science Sa, 2023) Yigit, Beyhan; Taslimi, Parham; Celepci, Duygu Barut; Taskin-Tok, Tugba; Yigit, Murat; Aygun, Muhittin; Ozdemir, Ismail
In this study, a series of PEPPSI-type N-heterocyclic carbene palladium(II) complexes 3a-e were synthesized using amine functionalized benzimidazolium salts 2a-e as N-heterocyclic carbene precursors. These complexes were characterized by FT-IR, 1H NMR and 13C NMR spectroscopy, elemental analysis and mass spectrometry. Also, the molecular and crystal structure of 3b has been determined by the single-crystal X-ray diffraction method. According to the structural analysis, the geometry of the palladium center of the complex adopts a slightly distorted square planar environment. The benzimidazolium salts 2a-e and their palladium(II) complexes 3a-e were screened for human carbonic anhydrase I, II (hCAs I and II), and alpha-glycosidase inhibitory activities. Results indicated that all the synthetic compounds exhibited potent inhibitory activities against all targets as compared to the standard inhibitors, revealed by IC50 values. Ki values of 2a-e and 3a-e for hCA I, hCA II, and alpha-glycosidase enzymes were obtained in the ranges 1.17 +/- 0.11-65.50 +/- 8.20 mu M, 1.02 +/- 0.08-57.60 +/- 6.41 mu M, and 118.86 +/- 11.92-509.21 +/- 26.61 nM, respectively. Besides these, molecular docking calculations of potent compounds 2b, 2d, 2e, 3a, 3b, 3c and 3e towards human carbonic anhydrase I (hCA I), human carbonic anhydrase II (hCA II), and alpha-glycosidase (alpha-Gly) were presented using AutoDock 4. Among the compounds discussed, compounds 3c, 3a, 2e and 2b have the best binding affinity for alpha-Gly (-9.87,-9.77,-9.04 and-8.63 kcal/mol); compounds 3e, 3b, 2d and 2e turn out to have the second-best binding affinity (-8.80,-8.74,-8.39 and-7.57 kcal/mol) against hCA II. Lastly, compounds showing the lowest binding affinity for hCA I enzyme are 3e, 3b, 2d and 2e, respectively. These findings show that especially NHC-palladium(II) complexes 3a-e are more active for all three enzyme structures than their N-heterocyclic carbene precursors 2a-e and may be potential candidates for the discovery and development of effective inhibitors for the related enzymes in the future.
Novel silver(I)N-heterocyclic carbene complexes bearing 2-(4-hydroxyphenyl)ethyl group: Synthesis, characterization, and enzyme inhibition properties
(Wiley, 2021) Behcet, Ayten; Aktas, Aydin; Gok, Yetkin; Kaya, Ruya; Taslimi, Parham; Gulcin, Ilhami
Herein, novel silver-based N-heterocyclic carbene (NHC) complexes bearing 2-(4-hydroxyphenyl)ethyl group were synthesized. Novel Ag(I)NHC complexes were synthesized from the 2-(4-hydroxyphenyl)ethyl-substituted benzimidazolium salts and silver oxide via in situ deprotonation method. The successful formation of all Ag(I)NHC complexes was proved by using H-1 NMR, C-13 NMR, FTIR spectroscopy, and elemental analysis techniques. In addition, their inhibitory effects have been investigated of these substances on acetylcholinesterase (AChE), alpha-glycosidase (alpha-Gly), human carbonic anhydrase I (hCA I), and human carbonic anhydrase II (hCA II) enzymes. It has been seen that all compounds have a better ability to inhibit compared with existing tried inhibitors. Among these, the best inhibitor against AChE enzyme is 1g (K-i : 9.54 +/- 0.98 mu M and IC50 : 17.40), and against alpha-Gly, 1c showed the highest effect (K-i 3.09 +/- 0.36 mu M and IC50 7.91). The best inhibitor against hCA I and hCA II enzymes are 1c and 1g compounds. For hCA I and hCA II, IC50 values were calculated as 17.85 and 9.06 mu M and K-i values were measured as 5.45 +/- 2.02 and 8.99 +/- 2.02 mu M, respectively.
PEPPSI type Pd(II)NHC complexes bearing chloro-/fluorobenzyl group: Synthesis, characterization, crystal structures, ?-glycosidase and acetylcholinesterase inhibitory properties
(Pergamon-Elsevier Science Ltd, 2021) Bal, Selma; Demirci, Ozlem; Sen, Betul; Taslimi, Parham; Aktas, Aydin; Gok, Yetkin; Aygun, Muhittin
This work reported the synthesis of a new PEPPSI (Pyridine Enhanced Precatalyst Preparation, Stabilization and Initiation) type Pd(II)N-heterocyclic carbene (NHC) complexes bearing halo-benzyl (4-florobenzyl and 2-chloro-4-florobenzyl) group. These new complexes were synthesized from the florobenzyl / chlorofluorobenzyl substituted benzimidazolium salts, PdCl2 and pyridine. Characterizations of all the synthesized complexes were done using elemental analysis, H-1 NMR, C-13 NMR and FT-IR spectroscopy techniques. The molecular and crystal structures of the new PEPPSI type Pd(II)NHC complexes were determined by single-crystal X-ray diffraction method. X-ray studies show that molecular structures of three complexes comprise a palladium(II) atom with a slightly distorted square-planar coordination environment. These synthesized salts were found to be effective inhibitors for the alpha-glycosidase, and acetylcholinesterase (AChE) enzyme with K-i values in the range of 27.36 +/- 5.06-124.88 +/- 18.05 mu M for alpha-glycosidase, and 0.78 +/- 0.11-4.34 +/- 1.02 mu M for AChE, respectively. The significant group of drugs currently utilized for the therapy of Alzheimer's disease (AD) is acetylcholinesterase/cholinesterase inhibitor compounds. The first cholinesterase inhibitor licensed for symptomatic therapy of AD was tacrine. Inhibition acts of alpha-glycosidase enzyme by inhibitors tend to slow the breakdown and release of sugar molecules into the bloodstream and can be utilized as therapeutic factors in the therapy of obesity and diabetes. (C) 2021 Elsevier Ltd. All rights reserved.
Schiff bases and their amines: Synthesis and discovery of carbonic anhydrase and acetylcholinesterase enzymes inhibitors
(Wiley-V C H Verlag Gmbh, 2018) Yigit, Beyhan; Yigit, Murat; Taslimi, Parham; Gok, Yetkin; Gulcin, Ilhami
Three series of symmetrical Schiff bases were synthesized from 1,2-diaminoethane, 1,3-diaminopropane and 1,4-diaminobutane and substituted benzaldehydes, and reduced by sodium borohydride to the corresponding benzylic diamines 4-6. All of the compounds obtained were characterized using elemental analysis, FT-IR, H-1 NMR, and C-13 NMR spectroscopy. The enzyme inhibitory properties of these compounds were tested and the influence of the alkane chain length and the substituents on the phenyl group on the enzyme inhibition activity were examined. The novel Schiff bases and their amine derivatives (1a-d, 2a-d, 3b-d, 4a-c, 5a-c, 6a, 6c, 6d) were effective inhibitors of the cytosolic carbonic anhydrase I and II isoforms (hCA I and II), and acetylcholinesterase (AChE) with K-i values in the range of 159.43 +/- 30.03 to 563.73 +/- 115.30nM for hCA I, 104.88 +/- 18.44 to 524.32 +/- 95.03nM for hCA II, and 3.95 +/- 0.74 to 30.83 +/- 6.81nM for AChE.

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