Publications

	Design, Synthesis, SAR and Molecular Modeling Studies of Novel Imidazo[2,1-b][1,3,4]Thiadiazole Derivatives as Highly Potent Antimicrobial Agents Hakan Tahtaci, Hatice Karacık, Abdulilah Ece, Mustafa Er and Mine Gül Şeker Molecular Informatics, 1-15, DOI: 10.1002/minf.201700083, (2017).
	See Abtsract In this study, a novel series of phenyl substituted imidazo[2,1-b][1,3,4]thiadiazole derivatives were synthesized, characterized and explored for antibacterial activity against Gram-negative Escherichia coli, Gram-positive Staphylococcus aureus and Bacillus subtilis and antifungal activity against Candida albicans. Most of the synthesized compounds exhibited remarkable antimicrobial activities, some of which being ten times more potent than positive controls. The most promising compound showed excellent activity with MIC value of 0.03 mg/ml against both S. aureus and B. subtilis (MIC values of positive compound Chloramphenicol are 0.4 mg/ml and 0.85 mg/ml, respectively). Furthermore, structure-activity relationship was also investigated with the help of computational tools. Some physicochemical and ADME properties of the compounds were calculated too. The combination of electronic structure calculations performed at PM6 level and molecular docking simulations using Glide extra-precision mode showed that the hydrophobic nature of keto aryl ring with no electron withdrawing substituents at para position enhances activity while electron-donating substituents at the second aryl ring is detrimental to activity.

	Synthesis, characterization, preliminary SAR and molecular docking study of some novel substituted imidazo [2, 1-b][1, 3, 4] thiadiazole derivatives as antifungal agents Mustafa Er, Buğracan Ergüven, Hakan Tahtaci, Abdurrahman Onaran, Tuncay Karakurt, Abdulilah Ece Medicinal Chemistry Research 26 (3), 615-630, DOI: 10.1007/s00044-017-1782-4, (2017).
	See Abtsract The aim of this study was to synthesize imidazo[2,1-b][1,3,4]thiadiazole derivatives, characterize them with various spectroscopic methods and investigate their antifungal activities. 2-Αmino-1,3,4-thiadiazole derivatives 2a, b were synthesized by reacting nitrile compounds 1a, b with thiosemicarbazide (yields 75 and 88%). We then synthesized imidazo[2,1-b][1,3,4]thiadiazole derivatives 4–21, the target compounds, from the reactions of 2-amino-1,3,4-thiadiazole derivatives 2a, b with phenacyl bromide derivatives 3 (yields 52–69%). The structures of all synthesized compounds were characterized by infrared, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, elemental analysis and mass spectroscopy and X-ray diffraction analysis was also used for the compounds 7, 8, 10, and 17. Subsequently, in vitro antifungal activity tests were applied to all synthesized compounds. Inhibition zones, percentages of inhibition and LD50 doses were determined. Most of the synthesized compounds exhibited good antifungal activity against plant pathogens. Molecular docking and electronic properties calculations were carried out in order to see the potential binding conformations of the ligands and the effect of the substituents on the activities. Docking score successfully reflects the activity of the most active compound 10, which was found to have the lowest octanol/water partition coefficient and high HOMO energy value. The combination of experimental and computational work show that all the synthesized compounds have promising activities and might serve as novel drug candidates.

	Synthesis, structural characterization, and antiproliferative/cytotoxic effects of a novel modified poly (maleic anhydride-co-vinyl acetate)/doxorubicin conjugate Gulderen Karakus, Abdulilah Ece, Ayse Sahin Yaglioglu, Haci Bayram Zengin, Mesut Karahan Polymer Bulletin 74 (6), 2159-2184, DOI: 10.1007/s00289-016-1821-1, (2016).
	See Abtsract Drug carrier, poly(maleic anhydride-co-vinyl acetate) (MAVA or poly[MA-co-VA]) copolymer, was traditionally synthesized by free radical chain polymerization reaction, in methyl ethyl ketone (MEK) organic media at 80 °C, using benzoyl peroxide (BPO) as the radicalic initiator. The purified copolymer was then modified with a chemotherapeutic agent, doxorubicin hydrochloride (DOX) at 75 °C for 72 h, using N-(3-dimethyl-aminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) as the carboxylic acid-activating agent. Structural characterization of the MAVA and the modified MAVA/DOX conjugate was carried out by Fourier transform infrared (FTIR) and nuclear magnetic resonance (1H-NMR and 13C-NMR). Their molecular weights were determined by size-exclusion chromatography (SEC). The spectroscopic and SEC results confirmed that conjugated/modification reaction was successfully carried out. UV spectrophotometric measurements indicated that MAVA/DOX preserved its molecular stability in physiological body fluid, PBS (physiological pH 7.40 at 37 °C). Antiproliferative activities of MAVA/DOX were determined by BrdU cell proliferation ELISA assay using C6 (Rat Brain tumor cells) and HeLa (human uterus carcinoma) cell lines in vitro by comparing with free DOX agent (reference compound). Although MAVA showed low antiproliferative activity, both MAVA/DOX and DOX exhibited greater activity against HeLa and C6. Lactate dehydrogenase (LDH) leakage assay was performed for MAVA/DOX and DOX, which detected a non-toxic effect against C6 even at the highest dose (100 μg/mL). IC50 and IC75 values were also determined using ED50 plus v1.0. Molecular modeling at M06-L/6-31 + G(d,p)//AM1 level showed that the electron density in MAVA/DOX is more localized resulting a higher polarization and thereby a higher dipole moment which shed light on the solubility of MAVA/DOX conjugate.

	E-Pharmacophore Mapping Combined with Virtual Screening and Molecular Docking to Identify Potent and Selective Inhibitors of P90 Ribosomal S6 Kinase (RSK) Abdulilah ECE Turkish Journal of Pharmaceutical Sciences . 2016, Vol. 13 Issue 2, p241-247, (2016).
	See Abtsract The p90 ribosomal S6 kinases (RSK) are a family of serine/threonine protein kinases and are shown to be involved in cancer cell proliferation. The lack of highly selective inhibitors and also the lack of structural information regarding the mechanism of those inhibitors restricts the progress in this field. It has also been reported that without a proper crystal structure of RSK, the protein-inhibitor interactions in silico studies had been erroneously concluded. The first e-pharmacophore model for RSK2 has been generated in this study using recently resolved high resolution crystal structure of RSK2 in complex with LJH685 that is amongst the most potent and selective RSK inhibitors to date. 12 compounds have been suggested as promising potent and selective RSK inhibitors after the combination of virtual screening of a large database (ca. 7 million compounds with more than 144 million conformations), followed by a series of molecular docking work flow and visual inspection of all hits for critical binding modes. Amongst those hits, 5777208 and 5919607 have been found to have remarkable docking score and binding interactions. Copyright of Turkish Journal of Pharmaceutical Sciences is the property of Turkish Pharmacists' Association, Academy of Pharmacy and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.

	A computational insight into acetylcholinesterase inhibitory activity of a new lichen depsidone Abdulilah Ece, Boris Pejin Journal of enzyme inhibition and medicinal chemistry, Vol. 24, No. 8, 1276-1286, DOI: 10.3109/14756366.2014.949256, (2015).
	See Abtsract Acetylcholinesterase (AChE) inhibitors are yet the best drugs currently available for the management of Alzheimer’s disease. The recent phytochemical investigation has led to the isolation of a new depsidone 1 with moderate AChE activity (1 μg). This work was focused on its electronic properties analysed using commercially available programs. Both the active depsidone molecule 1 and galanthamine showed to have higher HOMO energies than the inactive depsidones 2–4, isolated from the same lichen species. However, the amino depsidone derivative 7, whose structure was proposed using computational approaches, is expected to be more active AChE inhibitor than the depsidone 1, due to the improved HOMO energy value. In addition, the molecular docking study indicated that the compound 7 has ability to make the well-known interactions of potent AChE inhibitors with the enzyme active site. The data presented herein support the design of novel AChE inhibitors based on the depsidone scaffold.

	Redox pathways of aliskiren based on experimental and computational approach and its voltammetric determination Deniz Pamuk, İbrahim Hüdai Taşdemir, Abdulilah Ece, Esin Canel, Esma Kılıç Journal of the Brazilian Chemical Society, 24 (8), 1276-1286, DOI: 10.5935/0103-5053.20130162, (2013).
	See Abtsract Electrochemical behavior of aliskiren (ALS) was studied via experimental electrochemical methods and theoretical calculations performed at B3LYP/6-31+G (d)//AM1. Cyclic voltammetry studies were carried out based on the adsorption-controlled reversible reduction at ca. -1.5 V on hanging mercury drop electrode (HMDE) and irreversible electrochemical oxidation of ALS at ca. 1.0 V on glassy carbon electrode (GCE), vs. Ag/AgCl, KCl (3.0 mol L-1), in Britton-Robinson buffer at pH 10 and 8, respectively. According to computational and experimental findings, ALS is expected to be oxidized irreversibly at benzylic position and reduced reversibly at amide carbonyl groups. Voltammetric methods with and without adsorptive stripping mode were developed and validated for quantification of ALS in different samples. Limits of detection and of quantification for ALS were 6.3 × 10-8 and 2.1 × 10-7 mol L-1 for differential pulse voltammetry on HMDE and 1.2 × 10-8 and 3.9 × 10-8 mol L-1 for square-wave cathodic adsorptive stripping voltammetry. The methods were successfully applied to assay the drug in tablets and human serum with good recoveries, between 91.7 and 102.3%, having relative standard deviation less than 10%.

	A cooperative computational and experimental investigation on electrochemical behavior of metoprolol and its voltammetric determination Seraceddin Levent Zorluoğlu, İbrahim Hüdai Taşdemir, Abdulilah Ece, Esma Kiliç Canadian Journal of Chemistry, 2013, 91(10): 951-959, 1276-1286, DOI: 10.1139/cjc-2012-0531, (2013).
	See Abtsract The electrochemical behavior of metoprolol (MTP) was studied via experimental and computational approaches. Theoretical calculations were performed at the B3LYP/6-31+G(d)//AM1 level whereas experimental studies were carried out on a hanging mercury drop electrode (HMDE) and glassy carbon electrode (GCE). According to the computational results, both HOMO and LUMO of MTP were located at the phenyl ring. Hence, oxidation and reduction are expected to take place at the phenyl ring. Experimental studies on HMDE were based on reversible reduction at approximately –1.4 V and studies on GCE were based on irreversible oxidation at approximately 0.9 V versus Ag/AgCl (3 mol L−1 KCl) in Britton−Robinson buffer. Voltammetric methods with and without adsorptive stripping modes were developed. Proposed methods were successfully applied to tablet solutions and spiked human serum samples. Results are satisfactory with recovery values between 94.5% and 102.5% and a relative standard deviation lower than 6%.

	The discovery of potential cyclin A/CDK2 inhibitors: a combination of 3D QSAR pharmacophore modeling, virtual screening, and molecular docking studies Abdulilah Ece, Fatma Sevin Medicinal Chemistry Research, 22 (12), 5832-5843, DOI: 10.1007/s00044-013-0571-y, (2013).
	See Abtsract Cyclin-dependent kinases are a family of enzymes that regulates the cell cycle process. They have been found to be novel targets for potential anti-cancer drugs. In the present study, a 3D pharmacophore model has been developed for cyclin A/CDK2 from its known inhibitors. The most reliable quantitative HypoGen model (Hypo1) consists of two hydrogen bond acceptors, one hydrogen bond donor and one hydrophobic feature. Hypo1, with a correlation coefficient of 0.98, a root mean square deviation of 0.84, a configuration cost of 16.25 and a cost difference of 102.93, showed a remarkable predictive power and has >90 % probability of representing a true correlation in the activity data. The model was validated using Fisher’s test at 95 % confidence level and test set prediction (r = 0.96). Hypo1 was then employed for virtual screening of Life Chemicals and NCI2003 databases of which multiple conformations were generated for each compound (596,030 compounds, 45,603,414 conformers). Hits were filtered according to the Lipinski, Ghose, and Veber’s rules. Following docking simulations, consensus scoring was used to determine the ligand poses that interact best with the protein binding site and to reduce number of false positives. 11 hits were ultimately selected as potent candidate leads. This work may help in the identification or design of novel anti-cancer drugs based on hits determined. The pharmacophore model obtained and validated in this study can be used as a three-dimensional query in searches for CDK2 inhibitors in additional compound databases.

	Experimental and theoretical study on the electrochemical behavior of zofenopril and its voltammetric determination Ibrahim Hudai Tasdemir, Abdulilah Ece, Esma Kilic Current Pharmaceutical Analysis, 8 (4), 339-348, DOI: 10.2174/157341212803341627, (2012).
	See Abtsract Electrochemical behavior of zofenopril (ZOF) was studied via experimental electrochemical methods and theoretical calculations performed at B3LYP/6-31+G(d)//AM1 level. Optimum conditions for quantitative determination were investigated by several electrochemical methods such as cyclic voltammetry, square-wave voltammetry and bulk electrolysis. Electrochemical parameters like charge transfer, diffusion and surface coverage coefficients of adsorbed molecules and also number of electrons transferred in electrode mechanisms were calculated. All studies were based on the irreversible and adsorption-controlled electrochemical oxidation signal of ZOF at about 1.1 V versus Ag/AgCl at pH 5.0 in Britton-Robinson buffer (BR). This adsorptive character of ZOF was used to develop fully validated, new, rapid, selective and simple voltammetric methods for the direct determination of the molecule in pharmaceutical dosage forms and biological samples without time-consuming steps prior to drug analysis. Peak current of electrochemical oxidation of ZOF was found to change linearly with the concentration in the range from 2.0x10-6 molL-1 (0.86 mgL-1) to 1.0x10-4 molL-1 (42.9 mgL-1) in direct voltammetric methods and found to change linearly with the concentration in the range from 2.0x10-8 molL-1 (8.59 μgL-1) to 1.0x10-6 molL-1 (0.43 mgL-1) in adsorptive stripping voltammetric methods. Limit of detection (LOD) and limit of quantification (LOQ) were found to be 1.17x10-8 molL-1 (5.03 μgL-1) and 3.89x10-8 molL-1 (16.8 μgL-1) respectively in anodic adsorptive stripping voltammetry. The methods were successfully applied to assay the drug in tablets, human serum and human urine with good recoveries (between 95.0 % and 104.6 %) and relative standard deviation less than 10 %.

	Exploring QSAR on 4-cyclohexylmethoxypyrimidines as antitumor agents for their inhibitory activity of cdk2 Abdulilah Ece, Fatma Sevin Letters in Drug Design & Discovery 7 (9), 625-631, DOI: 10.2174/157018010792929612, (2010).
	See Abtsract Cyclin-dependent kinases have essential role in the regulation of the cell division cycle. The structure-activity relationship of 4-cyclohexylmethoxypyrimidines, inhibitors of CDK2 as antitumor agents was explored. Since some of the studied 4-cyclohexylmethoxypyrimidines were reported to be among the most potent and selective CDK2 inhibitors reported to date, it was of interest to study QSAR. Useful QSAR equations were generated using dielectric energy (DE), N_Count, indicator parameter, Shadow_XYfrac and Jurs_RASA to consider quantitatively the effect of the structural variation of 4-cyclohexylmethoxypyrimidines on the inhibition of CDK2. The statistical measures such as r, r2, q2, and F values obtained for the training set were in acceptable range and hence this relationship was used and the equations were validated using a test set. The models obtained showed not only statistical significance but also predictive ability and highlights the active compounds' spatial pose in the CDK2 inhibition and that minor values for DE combined with an NO substituent lead to an increasing of CDK2 inhibitory activity. The models obtained might be able to be used predictively to guide design of additional potential CDK2 inhibitors.

	Reaction of Atomic Carbon with Isomeric Cresols Ilkay Sokmen, Abdulilah Ece, Bulent Duz, Fatma Sevin Letters in Organic Chemistry, 6 (8), 650-653, DOI: 10.2174/157017809790442907, (2009).
	See Abtsract Reaction of atomic carbon with isomeric cresols generates methyltropones and xylenols. Methyltropone to xylenol ratio was found to be highest for m-cresol and lowest for p-cresol. Stability of singlet carbenes produced after insertion of atomic carbon into C-H bonds of cresols plays an important role in the observed ratios.

	Application of carbon arc‐generated Mo‐and W‐based catalyst systems to the ROMP of norbornene Bülent Düz, Can Koray Elbistan, Abdulilah Ece, Fatma Sevin Applied Organometallic Chemistry, 23 (9), 359-364, DOI: 10.1002/aoc.1518, (2009).
	See Abtsract This study focuses on the application of the carbon arc-generated molybdenum- and tungsten-based catalyst systems, MoCl5-C and WCl6-C, to effect ring-opening metathesis polymerization (ROMP) of bicyclo[2.2.1]hept-2-ene (norbornene). The results are compared with those previously obtained by the electrochemically generated MoCl5-ē-Al-CH2Cl2 and WCl6-ē-Al-CH2Cl2 systems. The polymer products are characterized using 1H and 13C NMR, gel permeation chromatography, differential scanning calorimetry and thermo gravimetric analysis. According to NMR spectra analyses, the molybdenum-based catalyst system produced polynorbornene with ca 48% cis structure whereas tungsten system produced ca 56% cis structure polynorbornene and in both cases the polynorbornene had a blocky distribution.

	The first example of tungsten-based carbene generation from WCl 6 and atomic carbon and its use in olefin metathesis Bülent Düz, Dilek Yüksel, Abdulilah Ece, Fatma Sevin Tetrahedron letters, 47 (29), 5167-5170, DOI: 10.1016/j.tetlet.2006.05.054, (2006).
	See Abtsract We describe a new route for the synthesis of tungsten-based carbenes generated by the reaction of WCl6 with atomic carbon in a carbon arc reactor. The active species formed under these conditions, [W] = CCl2, was found to catalyze olefin metathesis reactions of 1-octene, 2-octene and 1-heptene. We also evaluated the mechanism of formation of [W] = CCl2 within the WCl6/C system at the DFT level.