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Design, Synthesis, Biological Evaluation And Molecular Docking Of Novel Molecules To Parp-1 Enzyme, Fati̇h Tok, Bedi̇a Kaymakçioğlu, Recep İlhan, Si̇nem Yilmaz, Petek Ballar Kirmizibayrak, Tuğba Taşkin Tok Jan 2019

Design, Synthesis, Biological Evaluation And Molecular Docking Of Novel Molecules To Parp-1 Enzyme, Fati̇h Tok, Bedi̇a Kaymakçioğlu, Recep İlhan, Si̇nem Yilmaz, Petek Ballar Kirmizibayrak, Tuğba Taşkin Tok

Turkish Journal of Chemistry

Poly (ADP-ribose) polymerase (PARP) enzyme catalyzes the transfer of ADP-ribose into target proteins. Therefore, PARP is responsible for DNA repair, cell proliferation, and cell death. In this study, potential PARP enzyme inhibitors were designed and synthesized. The synthesized compounds were elucidated by Fourier-transform infrared spectroscopy, $^{1}$H NMR, $^{13}$C NMR, heteronuclear single-quantum correlation, and mass spectrometry, and their purity was checked via thin-layer chromatography, high-performance liquid chromatography, and elemental analysis. A total of 63 newly synthesized compounds were screened in terms of PARP inhibition by cellular PARylation assay in the HeLa cell line. It was found that 19 compounds significantly inhibited …


In Silico And In Vitro Evaluation Of The Biological Activity Of Some Organic Sulfur-Containing Compounds, Victoria Osipova, Maria Polovinkina, Anastasia Osipova, Yulia Gracheva, Andrey Okhlobystin Jan 2019

In Silico And In Vitro Evaluation Of The Biological Activity Of Some Organic Sulfur-Containing Compounds, Victoria Osipova, Maria Polovinkina, Anastasia Osipova, Yulia Gracheva, Andrey Okhlobystin

Turkish Journal of Chemistry

It was predicted, using the Prediction of Activity Spectra for Substances online software, that organic sulfur-containing compounds 2,6-di-tert-butyl-4-mercaptophenol (1), 2,6-di-tert-butyl-4-(3-mercaptopropyl)phenol (2), bis-3-[3,5-di-tert-butyl-4-hydroxyphenyl)propyl] sulfide (3), bis(3,5-di-tert- butyl-4-hydroxyphenyl) disulfide (4), diphenyl disulfide (5), dibenzyl disulfide (6), dibutyl disulfide (7), di-tert-butyl disulfide (8), diallyl disulfide (9), and methyl propyl trisulfide (10) could possess antioxidant activity and act as active scavengers of oxygen metabolites. The antiradical activity of these species was analyzed and it was shown that they were able to react with electrochemically generated the superoxide anion radical. The rate constants for reactions of 1-10 with the superoxide anion radical were calculated. The …


Biological Study On Novel Coumarinyl 1,3,4-Oxadiazoles, Maja Molnar, Ana Amic, Valentina Pavic, Tihomir Kovac, Marija Kovac, Elizabeta Has-Schön Jan 2018

Biological Study On Novel Coumarinyl 1,3,4-Oxadiazoles, Maja Molnar, Ana Amic, Valentina Pavic, Tihomir Kovac, Marija Kovac, Elizabeta Has-Schön

Turkish Journal of Chemistry

Coumarinyl 1,3,4-oxadiazoles were synthesized from Schiff bases and acetic anhydride. All compounds were characterized by melting points and their structures confirmed by mass and $^{1}$H and $^{13}$C NMR spectrometry. These novel coumarinyl derivatives were subjected to antibacterial, antifungal, anta atoxigenic, and antioxidant activity. Their activity varied depending on their structure, where 2-(3-acetyl-5-(((4-methyl-2-oxo-2H-chromen-7-yl)oxy)methyl)- 2,3-dihydro-1,3,4-oxadiazol-2-yl)-1,4-phenylene diacetate showed significant antioxidant and antibacterial activity on B. subtilis. 4-(3-Acetyl-5-(((4-methyl-2-oxo-2H-chromen-7-yl)oxy)methyl)-2,3-dihydro-1,3,4-oxadiazol-2-yl)-1,2-phenylene diacetate was found to possess excellent antifungal and antia atoxigenic activity.


Synthesis And Evaluation Of Novel 1,3,4-Thiadiazole--Fluoroquinolone Hybrids As Antibacterial, Antituberculosis, And Anticancer Agents, Asli Demi̇rci̇, Kaan Gökçe Karayel, Esra Tatar, Si̇nem Öktem Okullu, Ni̇han Ünübol, Paki̇ze Nesli̇han Taşli, Zühtü Tanil Kocagöz, Fi̇kretti̇n Şahi̇n, İlkay Küçükgüzel Jan 2018

Synthesis And Evaluation Of Novel 1,3,4-Thiadiazole--Fluoroquinolone Hybrids As Antibacterial, Antituberculosis, And Anticancer Agents, Asli Demi̇rci̇, Kaan Gökçe Karayel, Esra Tatar, Si̇nem Öktem Okullu, Ni̇han Ünübol, Paki̇ze Nesli̇han Taşli, Zühtü Tanil Kocagöz, Fi̇kretti̇n Şahi̇n, İlkay Küçükgüzel

Turkish Journal of Chemistry

A series of 5-substituted-1,3,4-thiadiazole-based fluoroquinolone derivatives were designed as potential antibacterial and anticancer agents using a molecular hybridization approach. The target compounds 16-25 were synthesized by reacting the corresponding $N$-(5-substituted-1,3,4-thiadiazol-2-yl)-2-chloroacetamides with ciprofloxacin or norfloxacin. The purity and identity of the synthesized compounds were determined by the use of chromatographic and spectral techniques (NMR, IR, MS, etc.) besides elemental analysis. Antibacterial, antituberculosis, and anticancer activity of the target compounds were evaluated against selected strains and cancer cell lines. Compound 20 was appreciated as the most active agent representing antibacterial activity against Escherichia coli and Staphylococcus aureus with MIC values of 4 …


Characterization Of An Al$^{3+}$-Selective Fluorescent Probe Based On A Benzoyl Hydrazine Derivative And Its Application In Cell Imaging, Yuxiang Ji, Chunwei Yu, Shaobai Wen, Jun Zhang Jan 2016

Characterization Of An Al$^{3+}$-Selective Fluorescent Probe Based On A Benzoyl Hydrazine Derivative And Its Application In Cell Imaging, Yuxiang Ji, Chunwei Yu, Shaobai Wen, Jun Zhang

Turkish Journal of Chemistry

A fluorescent probe based on benzoyl hydrazine was synthesized and characterized as an Al$^{3+}$-selective fluorescent probe. This probe showed good selectivity towards Al$^{3+\, }$compared to other common ions. Under optimized experimental conditions, the probe exhibited a linear dynamic response for Al$^{3+}$ from 5.0 $\times $ 10$^{-7}$ to 4.5 $\times $ 10$^{-6}$ M with a detection limit of 1.3 $\times $ 10$^{-7}$ M in ethanol-water solution (9:1, v:v, pH 6.8, 20 mM HEPES). Furthermore, it was used for imaging of Al$^{3+}$ in living cells with satisfying results.


Revisiting The Biodesulfurization Capability Of Hyperthermophilic Archaeon Sulfolobus Solfataricus P2 Revealed Dbt Consumption By The Organism In An Oil/Water Two-Phase Liquid System At High Temperatures, Gökhan Gün, Yuda Yürüm, Gi̇zem Di̇nler Doğanay Jan 2015

Revisiting The Biodesulfurization Capability Of Hyperthermophilic Archaeon Sulfolobus Solfataricus P2 Revealed Dbt Consumption By The Organism In An Oil/Water Two-Phase Liquid System At High Temperatures, Gökhan Gün, Yuda Yürüm, Gi̇zem Di̇nler Doğanay

Turkish Journal of Chemistry

The ability of the hyperthermophilic archaeon Sulfolobus solfataricus P2 to grow on organic and inorganic sulfur sources was investigated. A sulfur-free mineral medium was employed with different sources of carbon. The results showed that inorganic sulfur sources display growth curve patterns significantly different from the curves obtained with organic sulfur sources. Solfataricus has the ability to utilize DBT and its derivatives, but it lacks BT utilization. Solfataricus} utilizes DBT at a rate of 1.23 \mu mol 2-HBP h^{-1} g DCW^{-1} even at 78 °C, at which DBT is known to be unstable. After enabling DBT stabilization using a two-phase culture …


Cover And Contents Jan 2015

Cover And Contents

Turkish Journal of Chemistry

No abstract provided.


Synthesis, Characterization, Biological Studies, And Molecular Modeling Of Mixed Ligand Bivalent Metal Complexes Of Schiff Bases Based On $N$-Aminopyrimidine-2-One/2-Thione, Hati̇ce Gamze Soğukömeroğullari, Tuğba Taşkin Tok, Feyza Yilmaz, İsmet Berber, Mehmet Sönmez Jan 2015

Synthesis, Characterization, Biological Studies, And Molecular Modeling Of Mixed Ligand Bivalent Metal Complexes Of Schiff Bases Based On $N$-Aminopyrimidine-2-One/2-Thione, Hati̇ce Gamze Soğukömeroğullari, Tuğba Taşkin Tok, Feyza Yilmaz, İsmet Berber, Mehmet Sönmez

Turkish Journal of Chemistry

New mixed Schiff bases, Cu(II), Co(II), Ni(II), and Mn(II) complexes, were synthesized derived from 5-chloro-2-hydroxyacethophenone and 1-amino-5-benzoyl-4-phenyl-1H-pyrimidine-2-one/thione. These complexes were characterized by elemental analysis, magnetic measurements, molar conductivity, IR, electronic, NMR, and mass spectral studies. All the complexes showed nonelectrolytic behavior. Moreover, the newly synthesized mixed ligand complexes were evaluated for their in vitro antimicrobial efficiency against bacteria and yeast. The compound named Co(L$_{1}$L) had good antifungal activity against Candida species, but no profound antibacterial effect against bacterial strains. In addition, the ground state geometries of the complexes were optimized using a semi-empirical method at PM6 level, which is a …


A New Series Of Cu(Ii) And Ni(Ii) Complexes Of No Bidentate 4-No$_{2}$-Benzoylhydrazones: Synthesis, Characterization, And Biological Studies, Hati̇ce Başpinar Küçük, Emel Mataraci Kara, Berna Özbek Çeli̇k Jan 2015

A New Series Of Cu(Ii) And Ni(Ii) Complexes Of No Bidentate 4-No$_{2}$-Benzoylhydrazones: Synthesis, Characterization, And Biological Studies, Hati̇ce Başpinar Küçük, Emel Mataraci Kara, Berna Özbek Çeli̇k

Turkish Journal of Chemistry

A series of new nickel(II) and copper(II) hydrazone complexes \textbf{1--14}, containing a bidentate NO-donor hydrazone ligand, derived from 4-nitrobenzoylhydrazide and several aliphatic and aromatic aldehydes were synthesized, and their chemical structures were confirmed by means of FT-IR, UV-Vis, $^{1}$H and $^{13}$C NMR, mass spectral data, conductance measurements, and elemental analyses. The spectral data of the newly synthesized complexes show the formation of a 1:2 [metal:ligand] ratio. The ligands and their complexes were also investigated for their possible in vitro antimicrobial activities against \textit{S. aureus}, \textit{S. epidermidis}, \textit{E. coli}, \textit{K. pneumonia}, \textit{P. aeruginosa}, \textit{P. mirabilis}, \textit{E. faecalis}, and \textit{C. albicans}. Among …


Cover And Contents Jan 2015

Cover And Contents

Turkish Journal of Chemistry

No abstract provided.


Antioxidant, Anticholinesterase, And Antimicrobial Activities And Fatty Acid Constituents Of Achillea Cappadocica Hausskn. Et Bornm., Abdulselam Ertaş, Mehmet Boğa, Nesri̇n Haşi̇mi̇, Yeter Yeşi̇l, Ahmet Ceyhan Gören, Gülaçti Topçu, Ufuk Kolak Jan 2014

Antioxidant, Anticholinesterase, And Antimicrobial Activities And Fatty Acid Constituents Of Achillea Cappadocica Hausskn. Et Bornm., Abdulselam Ertaş, Mehmet Boğa, Nesri̇n Haşi̇mi̇, Yeter Yeşi̇l, Ahmet Ceyhan Gören, Gülaçti Topçu, Ufuk Kolak

Turkish Journal of Chemistry

This study was the first fatty acid analysis and biological activity report on an endemic Achillea species, Achillea cappadocica Hausskn. et Bornm. The major compounds in the fatty acid were identified as oleic (34.7 %), palmitic (23.1 %), and linoleic acids (20.6 %). The methanol and water extracts indicated higher ABTS cation radical scavenging activity than that of \alpha-tocopherol and BHT at 100 \mu g/mL. The acetone extract showed 70.62 % inhibitory activity against butyrylcholinesterase at 200 \mu g/mL. The acetone and methanol extracts exhibited moderate antimicrobial activity.


Synthesis, Anticandidal Activity, And Cytotoxicity Of Some Thiazole Derivatives With Dithiocarbamate Side Chains, Leyla Yurttaş, Yusuf Özkay, Fati̇h Demi̇rci̇, Gamze Göger, Şafak Ulusoylar Yildirim, Usama Abu Mohsen, Ömer Öztürk, Zafer Asim Kaplancikli Jan 2014

Synthesis, Anticandidal Activity, And Cytotoxicity Of Some Thiazole Derivatives With Dithiocarbamate Side Chains, Leyla Yurttaş, Yusuf Özkay, Fati̇h Demi̇rci̇, Gamze Göger, Şafak Ulusoylar Yildirim, Usama Abu Mohsen, Ömer Öztürk, Zafer Asim Kaplancikli

Turkish Journal of Chemistry

Some thiazole derivatives bearing dithiocarbamic acid esters were synthesized in order to investigate their anticandidal activity and cytotoxicity. The structures of the obtained final compounds (6a--j) were confirmed by spectral data (IR, ^1H NMR, ^{13}C NMR, and MS) and elemental analysis. The anticandidal activity of the compounds was determined (6a--j) using the microbroth dilution method and their cytotoxicity was evaluated according to the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay against normal cells. Contrary to expectations, weak antifungal activity was observed with IC_{50} values ranging between 30 and 403 \mu g/mL.


Molecular Docking And Qsar Study On Imidazole Derivatives As 14 /Alpha -Demethylase Inhibitors, Asghar Davood, Maryam Iman Jan 2013

Molecular Docking And Qsar Study On Imidazole Derivatives As 14 /Alpha -Demethylase Inhibitors, Asghar Davood, Maryam Iman

Turkish Journal of Chemistry

14\alpha-Demethylase (CYP51) inhibitors have been widely used in the treatment of fungal infections. In this study, a series of imidazole derivatives with CYP51 inhibitory activity were subjected to a molecular docking study followed by quantitative structure-activity relationship (QSAR) analyses in search of the ideal physicochemical characteristics of potential CYP51 inhibitors. Desired imidazoles were built using the HyperChem program, and conformational studies were performed through a semiempirical method followed by the PM3 method. Docking study was performed using the AutoDock program on all of the compounds. Different QSAR descriptors were calculated using DRAGON, AutoDock, and HyperChem. Multilinear regression was used as …


Design, Synthesis, And Biological Evaluation Of Indole-Based 1,4-Disubstituted Piperazines As Cytotoxic Agents, Meri̇ç Köksal Akkoç, Mi̇ne Yarim Yüksel, İrem Durmaz, Rengül Çeti̇n Atalay Jan 2012

Design, Synthesis, And Biological Evaluation Of Indole-Based 1,4-Disubstituted Piperazines As Cytotoxic Agents, Meri̇ç Köksal Akkoç, Mi̇ne Yarim Yüksel, İrem Durmaz, Rengül Çeti̇n Atalay

Turkish Journal of Chemistry

A series of 3-[(4-substitutedpiperazin-1-yl)methyl]-1H-indole derivatives were synthesized, and their structures were confirmed by spectral analysis. All the compounds were tested for their cytotoxic activity in vitro against 3 human tumor cell lines: human liver (HUH7), breast (MCF7), and colon (HCT116). Among the designed derivatives, most of the compounds showed significant cytotoxicity against liver and colon cancer cell lines with lower IC_{50} concentrations than the standard drug 5-fluorouracil. Compound 3s, with 3,4-dichlorophenyl substituent on the piperazine ring, was the most active in suppressing the growth of all screened cancer cells.


Constituents Of Plantago Major Subsp. Intermedia With Antioxidant And Anticholinesterase Capacities, Ufuk Kolak, Mehmet Boğa, Emi̇ne Akalin Uruşak, Ayhan Ulubelen Jan 2011

Constituents Of Plantago Major Subsp. Intermedia With Antioxidant And Anticholinesterase Capacities, Ufuk Kolak, Mehmet Boğa, Emi̇ne Akalin Uruşak, Ayhan Ulubelen

Turkish Journal of Chemistry

The methanol extract of Plantago major subsp. intermedia (Gilib.) Lange afforded 4 known compounds, namely isomartynoside (1), 10-hydroxymajoroside (2), \beta -sitosterol (3), and ursolic acid (4). Their structures were established by spectroscopic methods. After determination of the total phenolic and flavonoid contents of the methanol extract, the antioxidant potentials of the crude extract and isolated compounds 1-4 were determined by \beta -carotene bleaching, DPPH free radical and ABTS cation radical scavenging, and cupric reducing antioxidant capacity methods. The methanol extract, rich in phenolic contents, indicated the same DPPH free radical scavenging activity (72\% inhibition) as a standard compound, butylated hydroxytoluene, …


Some Bioactive Organotin(Iv) Derivatives With 3,4-Dichlorophenylacetic Acid: Synthesis, Spectroscopic Properties, And X-Ray Structure Of [Sn_4(C_4h_9)_8(Oocch_2c_6h_3cl_2)_4o_2], Muhammad Adeel Saeed, Muhammad Khawar Rauf, . Imtiaz-Ud-Din, Amin Badshah, Muhammad Zaeem Akhtar, Bushra Mirza Jan 2010

Some Bioactive Organotin(Iv) Derivatives With 3,4-Dichlorophenylacetic Acid: Synthesis, Spectroscopic Properties, And X-Ray Structure Of [Sn_4(C_4h_9)_8(Oocch_2c_6h_3cl_2)_4o_2], Muhammad Adeel Saeed, Muhammad Khawar Rauf, . Imtiaz-Ud-Din, Amin Badshah, Muhammad Zaeem Akhtar, Bushra Mirza

Turkish Journal of Chemistry

Some bioactive organotin(IV) derivatives of 3,4-dichlorophenylacetic acid (HL) were synthesized by reacting the ligand acid with various di- or tri-organotin compounds (in suitable mole ratios) in the presence of triethylamine. The structural investigation was carried out via multinuclear (^1H, ^{13}C, and ^{119}Sn) NMR, IR spectroscopy, and X-ray crystallography. The crystal structure of 4 comprises a central Sn_2O_2 core with O atoms bonded to 2 dibutylbis(3,4-dichlorophenylacetato)tin(IV) units. All the Sn atoms of 4 are essentially 5-coordinated in distorted trigonal-bipyramidal geometry. Some of the compounds exhibited significant antibacterial and antifungal activity.


Spectroscopic Characterisation And Biological Applications Of Organotin(Iv) Derivatives Of 3-(N-Naphthylaminocarbonyl)-2-Propenoic Acid, Sajjad Ahmad, Moazzam H. Bhatti, Saqib Ali, Fiaz Ahmed Jan 2006

Spectroscopic Characterisation And Biological Applications Of Organotin(Iv) Derivatives Of 3-(N-Naphthylaminocarbonyl)-2-Propenoic Acid, Sajjad Ahmad, Moazzam H. Bhatti, Saqib Ali, Fiaz Ahmed

Turkish Journal of Chemistry

In an effort to develop new organotin materials for investigation and biocidal evaluation, a series of compounds with the general formula R_{4 - n}SnL_n (where R = CH_3, n-C_4H_9, C_6H_5, C_6H_5CH_2 and L = 3-(N-naphthylaminocarbonyl)-2-propenoic acid) were synthesised, and characterised by elemental analysis, IR, multinuclear (^1H, ^{13}C and ^{119}Sn) NMR, ^{119m}Sn Mössbauer spectroscopy and mass spectrometry. The biological activity of these compounds against various bacteria and fungi was investigated. All of the compounds were active against the fungi tested with a few exceptions. These compounds also showed significant antibacterial activity. LD_{50} data show that the investigated compounds have significant toxicity.


Synthesis, Spectroscopic (Ft-Ir, ^1h, ^{13}C, Mass Spectrometry), And Biological Investigation Of Five-Coordinated Germanium-Substituted Tricyclohexyl Antimony Dipropionates: Crystal Structure Of Tricyclohexylantimony Dibromide, Muhammad Kaleem Khosa, Muhammad Mazhar, Saqib Ali, Kieran C. Molloy, Sarim Dastgir, Farkhanda Shaheen Jan 2006

Synthesis, Spectroscopic (Ft-Ir, ^1h, ^{13}C, Mass Spectrometry), And Biological Investigation Of Five-Coordinated Germanium-Substituted Tricyclohexyl Antimony Dipropionates: Crystal Structure Of Tricyclohexylantimony Dibromide, Muhammad Kaleem Khosa, Muhammad Mazhar, Saqib Ali, Kieran C. Molloy, Sarim Dastgir, Farkhanda Shaheen

Turkish Journal of Chemistry

A series of five-coordinated germanium-substituted tricyclohexylantimony dipropionates have been synthesized and characterized by different instrumental techniques, such as elemental analyses, FT-IR, multinuclear NMR (^1H, ^{13}C) and mass spectrometry. These compounds have also been screened against different microbes and they showed good activity against different bacteria that was comparable to the reference drugs. The crystal structure of the precursor (C_6H_{11})_3SbBr_2 is reported here, which showed that the antimony atom in an asymmetric unit exists in trigonal bipyramidal geometry, having space group C2/c with the monoclinic crystal system.


^{1}H, ^{13}C, ^{119}Sn Nmr, Mass, Mössbauer And Biological Studies Of Tri-,Di- And Chlorodiorganotin(Iv) Carboxylates, Hajra Masood, Saqib Ali, Mohummad Mazhar, Saira Shahzadi, Khadija Shahid Jan 2004

^{1}H, ^{13}C, ^{119}Sn Nmr, Mass, Mössbauer And Biological Studies Of Tri-,Di- And Chlorodiorganotin(Iv) Carboxylates, Hajra Masood, Saqib Ali, Mohummad Mazhar, Saira Shahzadi, Khadija Shahid

Turkish Journal of Chemistry

The reaction of 2-[(2,3-dimethylphenyl)amino]benzoic acid (HL) with tri- and diorganotin(IV) chlorides yielded complexes of the type R_{3}SnL and R_{2}SnL_{2} (R = n-C_{4}H_{9}, C_{6}H_{5}, C_{6}H_{5}CH_{2}, n-C_{8}H_{17}). The compounds R_{2}SnClL were obtained by a redistribution reaction between R_{2}SnL_{2} and R_{2}SnCl_{2}. All the compounds were characterized by CHN analysis, infrared, multinuclear NMR, mass and Mössbauer spectroscopy. The possible mode of carboxylate group bonding in solid as well as in solution is proposed on the basis of infrared, Mössbauer and NMR (^{1}H, ^{13}C, ^{119}Sn) spectroscopy.


Cover And Contents Jan 2004

Cover And Contents

Turkish Journal of Chemistry

No abstract provided.


Kinetic Studies Of The Thermal Decomposition Of Di- And Tri-Organotin Derivatives Of 1-Nitroso-2-Naphthol, Saqib Ali, Moazzam H. Bhatti, Sohail Mahmood, Muhammad Mazhar, M. Saleem Khalid, Nazar Hussain Jan 1998

Kinetic Studies Of The Thermal Decomposition Of Di- And Tri-Organotin Derivatives Of 1-Nitroso-2-Naphthol, Saqib Ali, Moazzam H. Bhatti, Sohail Mahmood, Muhammad Mazhar, M. Saleem Khalid, Nazar Hussain

Turkish Journal of Chemistry

The di- and tri-organotin complexes of general formula R$_2$SnL$_2$ and R$_3$SnL where R = C$_4$H$_9$, C$_6$H$_5$, C$_6$H$_5$CH$_2$, C$_6$H$_{11}$ and L=1-nitroso-2-naphthol, were subjected to thermal decomposition by means of thermogravimetry (TG). The decomposition occurred in steps and the kinetics of every set of reactions were determined using the method described by Coats and Redfern. These results were analysed to establish the decomposition kinetics and hence to calculate activation energies. The activation energies were also determined by applying the method described by Horowitz, which yielded comparable results.