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Aminopyrazole-substituted metallophthalocyanines: Preparation, aggregation behavior, and investigation of metabolic enzymes inhibition properties
(WILEY-V C H VERLAG GMBH, 2019) Guzel, Emre; Kocyigit, Umit M.; Arslan, Baris S.; Atas, Mehmet; Taslimi, Parham; Gokalp, Faik; Nebioglu, Mehmet; Sisman, Ilkay; Gulcin, Ilhami
The synthesis, characterization, aggregation behavior, theoretical studies, and investigation of antimicrobial, antidiabetic, and anticholinergic properties of 4-(2-(5-amino-4-(4-bromophenyl)-3-methyl-1H-pyrazol-1-yl)ethoxy)phthalonitrile (2) and its soluble aminopyrazole-substituted peripheral metallo (Mn, Co, and Ni)-phthalocyanine complexes (3-5) are reported for the first time. The synthesized compounds and phthalocyanine complexes were characterized spectroscopically. The new phthalonitrile derivative (2) and its peripheral metallophthalocyanine complexes (3-5) were found to be effective inhibitors of alpha-glycosidase, acetylcholinesterase (AChE), human carbonic anhydrase I and II isoforms (hCA I and II), and butyrylcholinesterase (BChE) with K-i values in the range of 1.55 +/- 0.47 to 10.85 +/- 3.43 nM for alpha-glycosidase, 8.44 +/- 0.32 to 21.31 +/- 7.91 nM for hCA I, 11.73 +/- 2.82 to 31.03 +/- 4.81 nM for hCA II, 101.62 +/- 26.58 to 326.54 +/- 89.67 nM for AChE, and 68.68 +/- 11.15 to 109.53 +/- 19.55 nM for BChE. This is the first study of peripherally substituted phthalocyanines containing an aminopyrazole group as potential carbonic anhydrase enzyme inhibitor. Also, the antimicrobial activities of the synthesized compounds were evaluated against six microorganisms (four bacteria and two Candida species) using the broth microdilution method. The gram-positive bacteria were detected to be more sensitive than gram-negative bacteria and yeasts in the synthesized compounds.
Characterization and inhibition effects of some metal ions on carbonic anhydrase enzyme from Kangal Akkaraman sheep
(WILEY, 2018) Kocyigit, Umit M.; Taslimi, Parham; Gulcin, Ilhami
In this work, the carbonic anhydrase (CA) enzyme was purified from Kangal Akkaraman sheep in Sivas, Turkey with specific activity value of 6681.57 EU/mg and yield of 14.90% with using affinity column chromatography. For designating the subunit molecular mass and enzyme purity. sodium dodecyl sulfate polyacrylamide gel electrophoresis method was used and single band for this procedure was obtained. The molecular mass of CA enzyme was found as 28.89 kDa. In this study, the optimum temperature and optimum pH were obtained from 30 and 7.5. V-max and K(m )values for p-nitrophenylacetate substrate of the CA were determined from Lineweaver-Burk graphs. Additionally, the inhibitory results of diverse heavy metal ions (He+, Fe2+, pb(2+), co(2+), A(g+), and Cu2+) on sheep were studied. Indeed, CA enzyme activities of Kangal sheep were investigated with using esterase procedure under in vitro conditions. The heavy metal concentrations inhibiting 50% of enzyme activity (IC50) and K-i values were obtained.
Discovery of Potent Carbonic Anhydrase and Acetylcholinesterase Inhibitors: 2-Aminoindan beta-Lactam Derivatives
(MDPI, 2016) Genc, Hayriye; Kalin, Ramazan; Koksal, Zeynep; Sadeghian, Nastaran; Kocyigit, Umit M.; Zengin, Mustafa; Gulcin, Ilhami; Ozdemir, Hasan
beta-Lactams are pharmacologically important compounds because of their various biological uses, including antibiotic and so on. beta-Lactams were synthesized from benzylidene-inden derivatives and acetoxyacetyl chloride. The inhibitory effect of these compounds was examined for human carbonic anhydrase I and II (hCA I, and II) and acetylcholinesterase (AChE). The results reveal that beta-lactams are inhibitors of hCA I, II and AChE. The Ki values of beta-lactams (2a-k) were 0.44-6.29 nM against hCA I, 0.93-8.34 nM against hCA II, and 0.25-1.13 nM against AChE. Our findings indicate that beta-lactams (2a-k) inhibit both carbonic anhydrases (CA) isoenzymes and AChE at low nanomolar concentrations.
The effects of wireless electromagnetic fields on the activities of carbonic anhydrase and acetylcholinesterase enzymes in various tissues of rats
(WILEY, 2018) Kocyigit, Umit Muhammet; Taslimi, Parham; Gurses, Fatih; Soylu, Sinan; Dastan, Sevgi Durna; Gulcin, Ilhami
The purpose of our study is to assist in understanding the effects of wireless electromagnetic waves on carbonic anhydrase (CA) and acetylcholinesterase (AChE) enzymes activities in the different tissues of the rats. For this purpose, two different groups each of which contains eight rats (n=8) were formed as being control group and wireless electromagnetic wave-administered group. The rats were necropsied after 60min from the injection of chemicals into the rats intraperitoneally. The different tissues of the rats were extracted. CA and AChE enzymes activities were measured for each tissue. All the experimental results were provided in mean +/- S.D. Statistical significance was identified to be P<0.05. It was observed that there were significant changes of enzyme activities in wireless-administered group in salivary gland, stomach, colon, liver, and striated muscle tissues.
Evaluation of acetylcholinesterase and carbonic anhydrase inhibition profiles of 1,2,3,4,6-pentasubstituted-4-hydroxy-cyclohexanes
(WILEY, 2017) Kocyigit, Umit M.; Taslimi, Parham; Gezegen, Hayreddin; Gulcin, Ilhami; Ceylan, Mustafa
Carbonic anhydrase (CA; EC 4.2.1.1) is used for remedial purposes for several years, as there is significant focus on expanding more new activators (CAAs) and high affinity inhibitors. Alzheimers disease and other similar ailments such as dementia and vascular dementia with Lewy bodies reduce cholinergic activity in the important areas involved in cognition and memory. Prevalent drugs for the symptomatic therapy of dementia are significant in increasing the associated cholinergic deficiency by inhibiting acetylcholinesterase (AChE). These six-membered carbocycles showed nice inhibitory action against AChE and human carbonic anhydrase (hCA) II and I isoforms. The hCA I, II, and AChE were efficiently inhibited by these molecules, with K-i values in the range of 6.70-35.85nM for hCA I, 18.77-60.84nM for hCA II, and 0.74-4.60 for AChE, respectively.
Evaluation of Anticholinergic, Antidiabetic and Antioxidant Activity of Astragalus dumanii, an Endemic Plant
(Kahramanmaras Sutcu Imam Univ Rektorlugu, 2022) Kocyigit, Umit Muhammet; Eruygur, Nuraniye; Atas, Mehmet; Tekin, Mehmet; Taslimi, Parham; Gokalp, Faik; Gulcin, Ilhami
The research was conducted to separately evaluate and detect the possible in vitro antioxidant, antimicrobial activity of ethanol extracts prepared from aerial parts and roots of Astragalus dumanii and anti-cholinesterase and alpha-glucosidase inhibitory activity from only aerial parts of its The antioxidant capacity was tested by scavenging of DPPH and ABTS free radicals. Compared with the standard antioxidant compound gallic acid; Root and aerial part extract showed lower DPPH radical scavenging activity, however aerial part extract demonstrated higher ABTS radical scavenging activity. The phenolic contents were detected as 5.31 +/- 0.03 and 13.23 +/- 0.05 mg gallic acid equivalent g-1 extract, flavonoid contents were found as 8.26 +/- 0.004 and 7.93 +/- 0.005 mg Qercetin equivalent g-1 extract. In addition, the effects of the extracts obtained from aerial parts of the plant on acetylcholinesterase, butyrylcholinesterase and a-glycosidase enzymes were investigated in vitro and IC50 values were obtained as 1.47, 0.83 and 0.48 mu g mL-1, respectively. When these values were compared with standard substances, it was seen that Astragalus dumanii could be a good enzyme inhibitory agent. Antimicrobial activity of the plant extracts were determined using the microdilution method and the extracts was not observed to have any antimicrobial activities..
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; Koparir, Metin; Karatepe, Mustafa; Ciftci, Mehmet
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).
Inhibitory effects of oxytocin and oxytocin receptor antagonist atosiban on the activities of carbonic anhydrase and acetylcholinesterase enzymes in the liver and kidney tissues of rats
(WILEY, 2017) Kocyigit, Umit M.; Taskiran, Ahmet Sevki; Taslimi, Parham; Yokus, Ahmet; Temel, Yusuf; Gulcin, Ilhami
The aim of this study was to investigate the effects of oxytocin (OT), atosiban, which is an OT receptor antagonist, and OT-atosiban chemicals injected to rats on the activities of carbonic anhydrase (CA) and acetylcholinesterase (AChE) enzymes in liver and kidney tissues of rats. For this purpose, four different groups, each consisting of six rats (n=6), were formed (control group, OT administered group, atosiban administered group, and both OT and atosiban administered group). The rats were necropsied 60min after intraperitoneal injection of chemicals into the rats. Liver tissues of rats were extracted. CA and AChE enzyme activities were measured for each tissue by using hydratase, esterase, and acetylcholiniodide methods. Activity values for each enzyme obtained were statistically calculated.
Inhibitory effects of Pb2+, Fe2+, Cd2+ and Co2+ on carbonic anhydrase enzyme from muscle of the Kangal fish ( Garra rufa)
(Polish Society Magnesium Research, 2024) Kocyigit, Umit M.; Gulcin, Ilhami
The Kangal fish (Garra rufa), known as the doctor fish, lives in the Kangal Spring in Sivas, Turkiye. In this study, carbonic anhydrase (CA) was purified and characterized for the first time from the muscle tissues of the Kangal fish (Garra rufa). To this end, CA was purified using a Sepharose-4B-L-Tyrosine-sulfanilamide affinity column (STAC) with specific activity of 34.36 EU.mg(-1), yield of 17.98 % and 201.0 purification fold. To control the CA enzyme purity, SDS-PAGE was performed and a single band was found. The Michaelis constant (K-m) and maximum velocity (V-max) were determined for CA. Also, p-nitrophenylacetate (PNA) was used as CA substrate. Furthermore, inhibition constants (Ki) and half maximal enzyme inhibitory concentration (IC50) for each metal ion were determined using by Lineweaver-Burk graphs. Additionally, optimum ionic strength was found to be 1.0 M (Tris-SO4), optimum pH was calcu-lated as 9.0 (Tris-SO4) and stable 8.5 pH was found (phosphate buffer) for the CA from the muscle tissues of the fish. Furthermore, activation enthalpy (Delta H), activation energy (Ea), optimum temperature and Q(10) values were obtained from the Arrhenius plot of CA from Garra rufa muscle tissue as 6.70 kcal/mol, 7.32 Kcal mol(-1), 35.0 oC, 1.37, respectively. Kcat and V0values of CA from Garra rufa muscle CA were calculated as 19.21 s(-1) and 1.8x10(4) mM s(-1), respectively. Finally, Ki values of some heavy metal ions (Co2+, Pb2+, Cd2+, and Fe2+) in the Kangal fish muscle CA were calculated in the range of 0.25-26.09 mM using the esterase activity assay.
Inhibitory effects of some drugs on carbonic anhydrase enzyme purified from Kangal Akkaraman sheep in Sivas, Turkey
(WILEY, 2018) Kocyigit, Umit M.; Dastan, Sevgi Durna; Taslimi, Parham; Dastan, Taner; Gulcin, Ilhami
In this study, carbonic anhydrase (CA) enzyme was purified and characterized from blood samples of Kangal Akkaraman sheep and inhibitory properties on certain antibiotics were examined. CA purification was composed of preparation of the hemolysate and conducting the Sepharose-4B-tyrosine-sulfanilamide affinity gel chromatography in having specific activity of 11626EUmg(-1), yield of 14.40%, and 242.76-fold purification. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis was performed to assess the enzyme purity and a single band was observed. Some antibiotics were exhibited in vitro inhibition on the CA activity. IC50 values of these inhibitors were calculated by plotting activity percentage. IC50 values of certain drugs (dexamethasone; caffeine; metamizole sodium; tetramisol; ceftiofur HCl; ivermectin; tavilin 50; penokain G; neosym; and sulfamezathine) were found as 0.38, 8.24, 285.53, 114.77, 5.33, 2.76, 27.58, 213.50, 208.28, and 36.60M, respectively. K-i values of different drugs on Kangal Akkaraman sheep blood CA activity were found in the range of 0.21 +/- 0.038-266.64 +/- 37.11 mu M.
Investigation of acetylcholinesterase and mammalian DNA topoisomerases, carbonic anhydrase inhibition profiles, and cytotoxic activity of novel bis(-aminoalkyl)phosphinic acid derivatives against human breast cancer
(WILEY, 2017) Dastan, Taner; Kocyigit, Umit M.; Dastan, Sevgi Durna; Kilickaya, Pakize Canturk; Taslimi, Parham; Cevik, Ozge; Koparir, Metin; Orek, Cahit; Gulcin, Ilhami; Cetin, Ahmet
The aim of this study was to evaluate biologically active novel molecules having potentials to be drugs by their antitumor properties and by activities of apoptotic caspase and topoisomerase. Following syntheses of novel eight bis(-aminoalkyl)phosphinic acid derivatives (4a-h) as a result of array of reactions, compounds were evaluated by cytotoxic effects in vitro on human breast cancer (MCF-7) and normal endothelial (HUVEC) cell lines. All phosphinic acid derivatives were effective for cytotoxicity on both MCF-7 and HUVEC lines, while 4c, 4e, and 4f compounds were found significantly more effective. For the evaluation of antitumor properties of compounds in a highly sensitive method, their effects on inhibiting topoisomerases I and II were investigated. Also, some of the bis(-aminoalkyl)phosphinic acid derivatives (4a, 4e-h) showed nice inhibitory action against acetylcholinesterase and human carbonic anhydrase isoforms I and II.
Isofraxidin: Antioxidant, Anti-carbonic Anhydrase, Anti-cholinesterase, Anti-diabetic, and in Silico Properties
(Wiley-V C H Verlag Gmbh, 2023) Durmaz, Lokman; Gulcin, Ilhami; Taslimi, Parham; Tuzun, Burak
The development of innovative pharmacological formulations for the treatment and prevention of various major diseases, including cancer, diabetes, and glaucoma, has been facilitated by some natural compounds. This study tested the inhibitory effects of isofraxidin on acetylcholinesterase, & alpha;-glycosidase, and butyrylcholinesterase enzymes, as well as human carbonic anhydrase I and II (hCA I and II) isoenzymes. Esterase activity was used to gauge Isofraxidin's ability to inhibit CA (in vitro). For the isoenzymes hCA I and hCA II, the half maximal inhibitory concentration (IC50) values of isofraxidin were determined to be 67.61 and 52.42 nM, respectively. At the same manner, inhibition constant (Ki) values were determined as 12.58 & PLUSMN;0.50 and 4.41 & PLUSMN;0.35 nM, respectively. Then, IC50 value of compound for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were calculated as 18.50 and 10.75 nM, respectively. On the other hand, IC50 and Ki values of & alpha;-glycosidase were determined as 55.16 and 56.81 & PLUSMN;2.30 nM, respectively. Additionally, the antioxidant properties of isofraxidin were investigated using techniques like 2,2 & PRIME;-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 1,1-Diphenyl-2-picrylhydrazyl (DPPH), N,N-dimethyl-& rho;-phenylenediamine (DMPD), cupric ions (Cu2+) reducing antioxidant capacity (CUPRAC), and iron reduction procedures. Following the graphing of the antioxidant results, IC50 values were determined. As a result, the natural phenolic molecule showed strong profiles of inhibition profile. We therefore think that these findings may pave the way for novel therapeutic development for the management of some major illnesses. Several plant-based natural substances and extracts have gained attention in recent years as potential inhibitors of & alpha;-glycosidase enzyme. The activities of Isofraxidin molecule with various enzyme proteins were compared. Finally, ADME/T analysis was performed to predict the movements of Isofraxidin molecules in human metabolism. This study tested the antioxidant potential and inhibitory effects of isofraxidin on acetylcholinesterase, & alpha;-glycosidase, and butyrylcholinesterase enzymes, as well as human carbonic anhydrase I and II (hCA I and II) isoenzymes.image
Novel carvacrol based new oxypropanolamine derivatives: Design, synthesis, characterization, biological evaluation, and molecular docking studies
(Elsevier, 2020) Bytyqi-Damoni, Arlinda; Kestane, Ali; Taslimi, Parham; Tuzun, Burak; Zengin, Mustafa; Bilgicli, Hayriye Genc; Gulcin, Ilhami
Carvacrol, as a natural product used for many years in the treatment of various diseases, therefore it was chosen as the starting compound for this study. Novel carvacrol based new oxypropanolamine derivatives were synthesized and characterized by spectroscopic methods. All new compounds were tested as metabolic enzyme inhibitory agents. Their clinical usage of carvacrol has been established as diuretics, antiepileptics, and anti-glaucoma factors, in the management of gastric, duodenal ulcers, mountain sickness, osteoporosis, idiopathic intracranial hypertension, or neurological disorders. The in vitro anti-hyperglycemic screening results showed that the compound 3d exhibits the maximum inhibitory effect against alpha-glycosidase enzyme (IC50: 904.10 nM). In addition, the compounds 3d (IC50: 29.74 nM and 23.64 nM) and 3e (IC50: 31.28 nM and 26.11 nM) were found to have a significant response to inhibit carbonic anhydrase I, and II isoenzymes (hCA I and II), respectively. The novel carvacrol based oxypropanolamine compounds were effective inhibitors of the hCA I and II isozymes, and acetylcholinesterase with Ki values in the range of 27.18-44.84 nM for hCA I, 25.62-38.71 nM for hCA II, and 99.83-146.25 nM for AChE, respectively. (C) 2019 Elsevier B.V. All rights reserved.y
Novel phenolic Mannich base derivatives: synthesis, bioactivity, molecular docking, and ADME-Tox Studies
(Springer, 2022) Tokali, Feyzi Sinan; Taslimi, Parham; Demirciolu, Ibrahim Hakki; Sendil, Kivilcim; Tuzun, Burak; Gulcin, Ilhami
In this study, it was aimed to synthesize novel molecules containing potential biological active phenolic Mannich base moiety and evaluate the inhibition properties against alpha-glycosidase (alpha-Gly) and acetylcholinesterase (AChE). For this purpose, phenolic aldehydes (1-3) were synthesized from 4-hydroxy-3-methoxy benzaldehyde (vanillin) according to the Mannich Reaction. Five different carboxylic acid hydrazides (4a-e) were synthesized from esters obtained from carboxylic acids. Fifteen Schiff base derivatives (5a-e, 6a-e, and 7a-e) were synthesized from the condensation reaction of compounds 1-3 with 4a-e. In this work, a series of novel Schiff bases from Phenolic Mannich bases (5a-e, 6a-e, and 7a-e) were tested toward alpha-Gly and AChE enzymes. Compounds 5a-e, 6a-e, and 7a-e showed Kis in ranging of 341.36 +/- 31.84-904.76 +/- 93.56 nM on AChE and 176.27 +/- 22.87-621.77 +/- 69.98 nM on alpha-glycosidase. Finally, novel compounds were found using molecular docking method to calculate the biological activity of these bases against many enzymes. The enzymes used in these calculations are acetylcholinesterase and alpha-glycosidase, respectively. Molecule 6b is more effective and active than other molecules with a docking score parameter value of - 8.77 against AChE enzyme and 6d is more effective and active than other molecules with a docking score parameter value of - 4.94 against alpha-Gly enzyme. After calculating the biological activities of novel compounds, ADME/T analysis parameters were examined to calculate the future drug use properties.
Novel propanolamine derivatives attached to 2-metoxifenol moiety: Synthesis, characterization, biological properties, and molecular docking studies
(Academic Press Inc Elsevier Science, 2020) Bilgicli, Hayriye Genc; Ergon, Derya; Taslimi, Parham; Tuzun, Burak; Kuru, Inci Akyazi; Zengin, Mustafa; Gulcin, Ilhami
The synthesis of seven new beta-amino alcohols was designed and performed by starting from eugenol, a natural phenolic compound known to be biologically active. The synthesized compounds were obtained in yields ranging from 54 to 81%. Molecule structures were determined with FT-IR, H-1 NMR and C-13 NMR spectroscopies. In addition, the inhibitory effects of these substances on acetylcholinesterase (AChE), alpha-glycosidase (alpha-Gly), human carbonic anhydrase I (hCA I), and human carbonic anhydrase II (hCA II) enzymes have been investigated. It has been seen that all compounds have a better ability to inhibit compared to existing tried inhibitors. Among these, the best inhibitor against AChE enzyme is 2b (Ki 62.08 +/- 11.67 mu M and IC50 90.33), and against alpha-Gly, 2c showed the highest effect (Ki 0.33 +/- 0.08 mu M and IC50 0.28). The best inhibitor against hCA I, and hCA II enzymes is compound 2f. For hCA I and hCA II, Ki value was measured as 9.68 +/- 1.32 and 11.46 +/- 2.64 mu M and IC50 values as 7.37 and 8.26 mu M respectively. The interactions of the studied new propanolamine derivatives with the enzymes were done by molecular docking calculations and their biological activities were compared to the experimental tests. Studied enzymes in molecular docking calculations are acetylcholinesterase (AChE) is PDB ID: 4M0E, alpha-glycosidase (alpha-Gly) is PDB ID: 1R47, human carbonic anhydrase isoenzyme I (hCA I) PDB ID: 3LXE is human carbonic anhydrase isoenzyme II (hCA II) is PDB ID: 5 AML.
Novel Quinazolinone Derivatives: Potential Synthetic Analogs for the Treatment of Glaucoma, Alzheimer's Disease and Diabetes Mellitus
(Wiley-V C H Verlag Gmbh, 2023) Tokali, Feyzi Sinan; Taslimi, Parham; Tuzun, Burak; Karakus, Ahmet; Sadeghian, Nastaran; Gulcin, Ilhami
Quinazolinones, which represent an important part of nitrogen-containing six-membered heterocyclic compounds, are frequently used in drug design due to their wide biological activity properties. Therefore, the novel quinazolinones were synthesized from the reaction of acylated derivatives of 4-hydroxy benzaldehyde with 3-amino-2-alkylquinazolin-4(3H)-ones with good yields (85-94 %) and their structures were characterized using Fourier-transform Infrared (FT-IR), Nuclear Magnetic Resonance ((1) H-NMR, (13) C-NMR), and High-Resolution Mass Spectroscopy (HR-MS). As the application of the synthesized compounds, their inhibition properties of the synthesized compounds on alpha-Glucosidase (alpha-Glu), Acetylcholinesterase (AChE), Butyrylcholinesterase (BChE), and Carbonic anhydrase I-II (hCA I-II) metabolic enzymes were investigated. All compounds showed inhibition at nanomolar level with the K-i values in the range of 12.73 +/- 1.26-93.42 +/- 9.44 nM for AChE, 8.48 +/- 0.92-25.84 +/- 2.59 nM for BChE, 66.17 +/- 5.16-818.06 +/- 44.41 for alpha-Glu, 2.56 +/- 0.26-88.23 +/- 9.72 nM for hCA I, and 1.68 +/- 0.14-85.43 +/- 7.41 nM for hCA II. Molecular docking study was performed to understand the interactions of the most potent compounds with corresponding enzymes. Also, absorption, distribution, metabolism, excretion, and toxicity (ADME/T) properties of the compounds were investigated.
Peripheral (E)-2-[(4-hydroxybenzylidene)-3,4-dihydronaphthalen-1(2H)-one)]-coordinated phthalocyanines with improved enzyme inhibition properties and photophysicochemical behaviors
(Wiley-V C H Verlag Gmbh, 2024) Gulec, Ozcan; Bilgicli, Ahmet T.; Tuzun, Burak; Taslimi, Parham; Gunsel, Armagan; Gulcin, Ilhami; Arslan, Mustafa
In this study, (E)-4-{4-[(1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl]phenoxy}phthalonitrile (4) and its phthalocyanine derivatives (5-8) were synthesized for the first time. Aggregation behaviors of the novel soluble phthalocyanines in organic solvents were investigated. In addition, the efficiency of O-1(2) production of (5) and ZnPc (6) was investigated. The singlet oxygen quantum yields (Phi(Delta)) for 2HPc (5) and ZnPc (6) were found to be 0.58 and 0.83, respectively. Additionally, novel phthalocyanines (5-8) were investigated for their ability to inhibit enzymes. They exhibited a highly potent inhibition effect on human carbonic anhydrase I and II (hCA I and II) and alpha-glycosidase (alpha-Gly) enzymes. K-i values are in the range of 2.60 +/- 9.87 to 11.53 +/- 6.92 mu M, 3.35 +/- 0.53 to 15.47 +/- 1.20 mu M, and 28.60 +/- 4.82 to 40.58 +/- 7.37 nM, respectively. The calculations of the studied molecule at the B3LYP, HF, and M062X levels in the 6-31G basis sets were made using the Gaussian package program. Afterward, the interactions occurring in the docking calculation against a protein that is the crystal structure of hCA I (PDB ID: 2CAB), the crystal structure of hCA II (PDB ID: 5AML), and the crystal structure of alpha-Gly (PDB ID: 1R47), were examined. Following that, Protein-Ligand Interaction Profiler (PLIP) analysis was used to look at the interactions that occurred during the docking calculation in further detail.
Phthalocyanine complexes with (4-isopropylbenzyl)oxy substituents: preparation and evaluation of anti-carbonic anhydrase, anticholinesterase enzymes and molecular docking studies
(Taylor & Francis Inc, 2022) Guzel, Emre; Kocyigit, Umit M.; Taslimi, Parham; Gulcin, Ilhami; Erkan, Sultan; Nebioglu, Mehmet; Arslan, Baris S.
In this study, the preparation, aggregation behavior and investigation of carbonic anhydrase and cholinesterase enzyme inhibition features of non-peripherally (4-isopropylbenzyl)oxy-substituted phthalocyanines (4-6) are reported for the first time. The chemical structures of these new phthalocyanines were elucidated by UV-Vis (ultraviolet-visible), FT-IR (Fourier transform infrared spectrometry), NMR (nuclear magnetic resonance) and MALDI-TOF (matrix-assisted laser desorption/ionization time-of-flight) mass spectrometry. The substitution of 4-isopropylbenzyl)oxy groups benefits a remarkable solubility and redshift of the phthalocyanines Q-band. Also, these complexes were tested against some enzymes such as butyrylcholinesterase enzyme, human carbonic anhydrase I and II isoforms and acetylcholinesterase enzyme. The phthalocyanine complexes showed Ki values of in the range of 478.13 +/- 57.25-887.25 +/- 101.20 mu M against hCA I, 525.16 +/- 45.87-921.14 +/- 81.25 mu M against hCA II, 68.33 +/- 9.13-201.15 +/- 35.86 mu M against AChE and 86.25 +/- 13.65-237.54 +/- 24.7 mu M against BChE. Molecular docking studies were performed to investigate the binding modes and interaction energies of the (2-6) complexes with the hCA I (PDB ID:1BMZ), hCA II (PDB ID:2ABE), AChE (PDB ID:4EY6) and BChE (PDB ID:2PM8).
Purification of glutathione S-transferase enzyme from quail liver tissue and inhibition effects of (3aR,4S,7R,7aS)-2-(4-((E)-3-(aryl)acryloyl)phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione derivatives on the enzyme activity
(WILEY, 2018) Temel, Yusuf; Kocyigit, Umit M.; Taysi, M. Serif; Gokalp, Faik; Gurdere, Meliha Burcu; Budak, Yakup; Ceylan, Mustafa; Gulcin, Ilhami; Ciftci, Mehmet
The use of quail meat and eggs has made this animal important in recent years, with its low cost and high yields. Glutathione S-transferases (GST, E.C.2.5.1.18) are an important enzyme family, which play a critical role in detoxification system. In our study, GST was purified from quail liver tissue with 47.88-fold purification and 12.33% recovery by glutathione agarose affinity chromatography. The purity of enzyme was checked by SDS-PAGE method and showed a single band. In addition, inhibition effects of (3aR,4S,7R,7aS)-2-(4-((E)-3-(aryl)acryloyl)phenyl)-3a,4,7,7a-tetrahydro-1H-4,7methanoisoindole-1,3(2H)-dion derivatives (1a-g) were investigated on the enzyme activity. The inhibition parameters (IC50 and K-i values) were calculated for these compounds. IC50 values of these derivatives (1a-e) were found as 23.00, 15.75, 115.50, 10.00, and 28.75M, respectively. K-i values of these derivatives (1a-e) were calculated in the range of 3.04 +/- 0.50 to 131.50 +/- 32.50M. However, for f and g compounds, the inhibition effects on the enzyme were not found.
SAR Evaluation of Disubstituted Tacrine Analogues as Promising Cholinesterase and Carbonic Anhydrase Inhibitors
(ASSOC PHARMACEUTICAL TEACHERS INDIA, 2019) Okten, Salih; Ekiz, Makbule; Tutar, Ahmet; Butun, Burcu; Kocyigit, Umit Muhammet; Topcu, Gulacti; Gulcin, Ilhami
Background: The inhibition of both hydrolysis products of acetylcholine (ACh), Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE), is essential for successful treatment of Alzhemier patients. Objectives: This study was investigated inhibition potentials of recently synthesized disubstituted tacrines derivatives on going our research against AChE, BChE and carbonic anhydrase cyctosolic (hCA I and H) enzymes to explore the Structure activity relationship (SAR). Methods: Inhibitory activities of tested compounds against AChE and BChE were measured by spectrophotometric method, developed by Ellman et al. Furthermore, the disubstituted tacrines were determined as inhibitors of two physiologically relevant CA isoforms, the cytosolic hCA I and H by an esterase assay method. Results: The silyl, thiomethyl and cyano substituted seven membered hydrocycle tacrines (9, 11 and 14) significantly inhibited AChE, compared with starting compound 3 (6,8-dibromo-2,3,4,5-teytrahydro-1H-cyclohepta[1,2-b] quinoline) and reference compounds, galantamine and tacrine, while methoxy substituted seven membered hydrocycle tacrine derivative 10 showed selective inhibition against BChE (IC50 = 563 nM). Interestingly, disubstituted tacrines displayed higher or parallel inhibition to galantamine. Additionally, all these tacrine analogues were recorded to be powerful inhibitor compounds of the cytosolic isoenzyme hCA I with K-i in the range of 43.81-471.67 nM, as well as a moderate selectivity toward hCA II isoenzyme with K-i in the range from 87.14 to 614.68 nM compared with AZA, as standard. Conclusion: The disubstituted seven membered hydrocycle tacrine analogues 9-12 and 14 may have promising anti Alzhemier drug candidate and dibromo six membered hydrocycle 2 and dibromo seven membered hydrocycle 3 derivatives may be novel hCA I and II enzyme inhibitors.

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