Publications

	2,3-Dichloronaphthoquinone derivatives: Synthesis, antimicrobial activity, molecular modelling and ADMET studies Hakan Kolancılar, Hafize Özcan, Ayşen Şuekinci Yılmaz, Alparslan Semih Salan, Abdulilah Ece Bioorganic Chemistry, DOI: 10.1016/j.bioorg.2024.107300, (2024). (IF= 5.1)
	See Abtsract In the present study, an intermediate namely 2-(3-bromopropylamino)-3-chloronaphthalene-1,4-dione was initially synthesized via the nucleophilic addition–elimination reaction between 2,3-dichloro-1,4-naphthoquinone and 3-bromo-1-aminopropane. Then a coupling reaction between the intermediate and piperazine derivatives yielded a number of 1,4-naphthoquinone derivatives. Spectroscopic analysis successfully characterized the products that were obtained in good yields. In vitro antibacterial properties of the compounds were examined against different bacterial strains. In vitro antibacterial properties of the compounds were examined against the bacterial strains S. Aureus, E. Faecalis, E. Coli and P. Aeruginosa. While compound 9 was found to be effective against all bacterial strains used, compound 12 was active against three strans and compounds 10 and 11 were effective against the two. None of the compounds are effective against C. albicans strain. In silico molecular docking studies revealed that all compounds had docking scores comparable to the antibacterial drugs ciprofloxacin and gentamicin and might be considered as DNA gyrase B inhibitors. Molecular dynamics simulations were also conducted for a better understanding of the stability and the selected docked complexes. Additionally, the drug similarity of the synthesized compounds and ADMET characteristics were examined in conjunction with the antibiotic ciprofloxacin, and drug potentials were then evaluated. Compatible predictions were found with the drug similarity and ADMET parameters.

	Novel spiroindoline derivatives targeting aldose reductase against diabetic complications: Bioactivity, cytotoxicity, and molecular modeling studies Özcan Güleç, Cüneyt Türkeş, Mustafa Arslan, Yeliz Demir, Busra Dincer, Abdulilah Ece, Ömer İrfan Küfrevioğlu, Şükrü Beydemir Bioorganic Chemistry, DOI: 10.1016/j.bioorg.2024.107221, (2024). (IF= 5.1)
	See Abtsract Despite significant developments in therapeutic strategies, Diabetes Mellitus remains an increasing concern, leading to various complications, e.g., cataracts, neuropathy, retinopathy, nephropathy, and several cardiovascular diseases. The polyol pathway, which involves Aldose reductase (AR) as a critical enzyme, has been focused on by many researchers as a target for intervention. On the other hand, spiroindoline-based compounds possess remarkable biological properties. This guided us to synthesize novel spiroindoline oxadiazolyl-based acetate derivatives and investigate their biological activities. The synthesized molecules' structures were confirmed herein, using IR, NMR (1H and 13C), and Mass spectroscopy. All compounds were potent inhibitors with KI constants spanning from 0.186 ± 0.020 nM to 0.662 ± 0.042 nM versus AR and appeared as better inhibitors than the clinically used drug, Epalrestat (EPR, KI: 0.841 ± 0.051 nM). Besides its remarkable inhibitory profile compared to EPR, compound 6k (KI: 0.186 ± 0.020 nM) was also determined to have an unusual pharmacokinetic profile. The results showed that 6k had less cytotoxic effect on normal mouse fibroblast (L929) cells (IC50 of 569.58 ± 0.80 nM) and reduced the viability of human breast adenocarcinoma (MCF-7) cells (IC50 of 110.87 ± 0.42 nM) more than the reference drug Doxorubicin (IC50s of 98.26 ± 0.45 nM and 158.49 ± 2.73 nM, respectively), thus exhibiting more potent anticancer activity. Moreover, molecular dynamic simulations for 200 ns were conducted to predict the docked complex's stability and reveal significant amino acid residues that 6k interacts with throughout the simulation.

	The effects of morin and methotrexate on pentose phosphate pathway enzymes and GR/GST/TrxR enzyme activities: An in vivo and in silico study Cuneyt Caglayan, Yusuf Temel, Cüneyt Türkeş, Adnan Ayna, Abdulilah Ece, Şükrü Beydemir Archiv der Pharmazie, DOI: 10.1002/ardp.202300497, (2023). (IF= 5.1)
	See Abtsract In this study, the mechanisms by which the enzymes glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), glutathione reductase (GR), glutathione-S-transferase (GST), and thioredoxin reductase (TrxR) are inhibited by methotrexate (MTX) were investigated, as well as whether the antioxidant morin can mitigate or prevent these adverse effects in vivo and in silico. For 10 days, rats received oral doses of morin (50 and 100 mg/kg body weight). On the fifth day, a single intraperitoneal injection of MTX (20 mg/kg body weight) was administered to generate toxicity. Decreased activities of G6PD, 6PGD, GR, GST, and TrxR were associated with MTX-related toxicity while morin treatment increased the activity of the enzymes. The docking analysis indicated that H-bonds, pi–pi stacking, and pi–cation interactions were the dominant interactions in these enzyme-binding pockets. Furthermore, the docked poses of morin and MTX against GST were subjected to molecular dynamic simulations for 200 ns, to assess the stability of both complexes and also to predict key amino acid residues in the binding pockets throughout the simulation. The results of this study suggest that morin may be a viable means of alleviating the enzyme activities of important regulatory enzymes against MTX-induced toxicity.

	Structural Characterization of TRAF6 N-Terminal for Therapeutic Uses and Computational Studies on New Derivatives Omur Guven, Belgin Sever, Faika Başoğlu-Ünal, Abdulilah Ece, Hiroshi Tateishi, Ryoko Koga, Mohamed O. Radwan, Nefise Demir, Mustafa Can, Mutlu Dilsiz Aytemir, Jun-ichiro Inoue, Masami Otsuka, Mikako Fujita, Halilibrahim Ciftci and Hasan DeMirci Pharmaceuticals, DOI: doi.org/10.3390/ph16111608, (2023). (IF= 4.6)
	See Abtsract Tumor necrosis factor receptor-associated factors (TRAFs) are a protein family with a wide variety of roles and binding partners. Among them, TRAF6, a ubiquitin ligase, possesses unique receptor binding specificity and shows diverse functions in immune system regulation, cellular signaling, central nervous system, and tumor formation. TRAF6 consists of an N-terminal Really Interesting New Gene (RING) domain, multiple zinc fingers, and a C-terminal TRAF domain. TRAF6 is an important therapeutic target for various disorders and structural studies of this protein are crucial for the development of next-generation therapeutics. Here, we presented a TRAF6 N-terminal structure determined at the Turkish light source “Turkish DeLight” to be 3.2 Å resolution at cryogenic temperature (PDB ID: 8HZ2). This structure offers insight into the domain organization and zinc-binding, which are critical for protein function. Since the RING domain and the zinc fingers are key targets for TRAF6 therapeutics, structural insights are crucial for future research. Separately, we rationally designed numerous new compounds and performed molecular docking studies using this template (PDB ID:8HZ2). According to the results, 10 new compounds formed key interactions with essential residues and zinc ion in the N-terminal region of TRAF6. Molecular dynamic (MD) simulations were performed for 300 ns to evaluate the stability of three docked complexes (compounds 256, 322, and 489). Compounds 256 and 489 was found to possess favorable bindings with TRAF6. These new compounds also showed moderate to good pharmacokinetic profiles, making them potential future drug candidates as TRAF6 inhibitors.

	Synthesis, anti-inflammatory activity, inverse molecular docking, and acid dissociation constants of new naphthoquinone-thiazole hybrids Cagla Efeoglu, Sena Taskin, Ozge Selcuk, Begum Celik, Ece Tumkaya, Abdulilah Ece, Hayati Sari, Zeynel Seferoglu, Furkan Ayaz, Yahya Nural Bioorganic & Medicinal Chemistry, DOI: 10.1016/j.bmc.2023.117510, (2023). (IF= 3.5)
	See Abtsract Chronic Inflammation is associated with various types of diseases that involves pro-inflammatory cytokines like IL-6 and TNF-α. High costs and serious side effects of available anti-inflammatory/immunomodulatory drugs led us to design new compounds with promising anti-inflammatory activities. Many drugs and biologically important compounds involve naphthoquinone and thiazole moieties in their core structures. Thereby, here we report the synthesis, characterization and anti-inflammatory activities of new naphthoquinone thiazole hybrids by reaction of naphthoquinone acyl thioureas with various α-bromoketone derivatives. The position of NO2 group in one of the phenyl rings of naphthoquinone thiazole hybrids was changed while different substituents were introduced at the para position of the second phenyl ring. All compounds were tested for potential immunomodulatory effect. No inflammatory cytokines were observed in the absence of LPS stimulant. On the other hand, they had promising anti-inflammatory immunomodulatory activities by being able to decrease the production of the pro-inflammatory cytokines (TNF-α and IL-6) in the LPS-stimulated cells. In an effort to find the possible mechanism of action, several enzymes involved in signalling pathways that play critical roles in inflammatory responses were screened in silico. Subsequent to inverse molecular docking approach, PI3K was predicted be the potential target. The docked complexes of the most potent compounds 5g and 5i were subjected to molecular dynamics simulation to assess the binding stability of the igands with the putative target. Acid dissociation constants (pKa) of the products were also determined potentiometrically.

	Novel coumarin-chalcone derivatives: Synthesis, characterization, antioxidant, cyclic voltammetry, molecular modelling and biological evaluation studies as acetylcholinesterase, α-glycosidase, and carbonic anhydrase inhibitors Hülya Çelik Onar, Eda Mehtap Özden, Hava Dudu Taslak, İlhami Gülçin, Abdulilah Ece, Erol Erçağ Chemico-Biological Interactions, DOI: 10.1016/j.cbi.2023.110655, (2023). (IF= 5.1)
	See Abtsract In this study, a total of 12 coumarin-chalcone derivatives, 6 of which are original were synthesized. The structures of the newly synthesized compounds were elucidated by 1H NMR, 13C NMR, IR, and elemental analysis methods (7g-7l). The antioxidant potencies measured by using CUPRAC method (Trolox equivalent total antioxidant capacity) were as follows: 7j > 7i > 7c > 7d > 7k > 7l > 7f > 7h > 7e > 7g > 7a > 7b. Furthermore, the compounds were evaluated against human carbonic anhydrases I, II, acetylcholinesterase and α-glycosidase enzymes. Compounds 7c, 7e, 7g, 7i, 7j and 7l showed promising human carbonic anhydrase I inhibition compared to the standard Acetazolamide (Ki: 16.64±4.72–49.82±5.82 nM vs Ki: 57.64±5.41 nM). In addition, all compounds exhibited strong inhibition against acetylcholinesterase and α-glycosidase. Ki values were between 2.39±0.97–9.35±3.95 nM (Tacrine Ki: 13.78±4.36 nM) for acetylcholinesterase, and 14.49±8.51–75.67 ± 26.38 nM (Acarbose Ki: 12600±78.00 nM) for α-glycosidase. Binding of 7g was predicted using molecular docking and stability of the complex was confirmed with molecular dynamics simulations which shed a light on the observed activity against acetylcholinesterase. Finally, cyclic voltammetry was also used for the electrochemical characterization of the synthesized compounds.

	Identification of selective inhibitors for phosphodiesterase 5A using e-pharmacophore modelling and large-scale virtual screening-based structure guided drug discovery approaches Arooma Maryam, Abdul Rauf Siddiqi,Sundeep Chaitanya Vedithi, Abdulilah Ece & Rana Rehan Khalid Journal of Biomolecular Structure and Dynamics, DOI: 10.1080/07391102.2023.2242491, (2023). (IF= 4.4)
	See Abtsract The inhibition of Phosphodiesterase 5A (PDEA5) has the potential to modulate pulmonary arterial hypertension and cardiovascular diseases. Exploring the cross-reactivity of clinically available PDE5A therapeutics with PDE6A is intriguing in order to develop highly selective PDE5A compounds in cardiovascular arena. In the current study, we leveraged e-pharmacophore based screening and molecular dynamics (MD) simulation to discover more selective PDE5A inhibitors as compared to the PDE6A catalytic domain. e-Pharmacophore based mapping of the CoCoCo database (7 million compounds: ∼ 150,000,000 conformers), followed by Glide docking, MM-GBSA, and protein–inhibitor interaction analysis, revealed 1536427, 4832637 and 6788240 as stable, tight binders of PDE5A instead of PDE6A. These compounds adhere to Lipinski Rule of Five (RO5) and ADME/Tox criteria. MD simulations analysis showed that 1536427 stays stable and tightly binds to catalytic (Q-region) core of PDE5A catalytic domain as compared to sildenafil. Pronounced inward motions of the hydrophobic (H-region) and Lid region indicate the closure of PDE5A-1536427 complex, whereas this region in PDE6A-1536427 is more open. Significant differences in the interactions, stability, and dynamics of 1536427 were observed in the catalytic domain of PDE6A, demonstrating less specificity for PDE6A in comparison to PDE5A. After lead optimization and therapeutic interventions, this proposed lead may emerge as a promising PDE5A selective inhibitor.

	Novel beta-lactam substituted benzenesulfonamides: in vitro enzyme inhibition, cytotoxic activity and in silico interactions Özcan Güleç ,Cüneyt Türkeş ,Mustafa Arslan ,Yeliz Demir ,Busra Dincer,Abdulilah Ece & Şükrü Beydemir Journal of Biomolecular Structure and Dynamics, DOI: 10.1080/07391102.2023.2240889, (2023). (IF= 4.4)
	See Abtsract In this study, a library of twelve beta-lactam-substituted benzenesulfonamides (5a–l) was synthesized using the tail-approach method. The compounds were characterized using IR, 1H NMR, 13C NMR and elemental analysis techniques. These newly synthesized compounds were tested for their ability to inhibit the activity of two carbonic anhydrases (hCA) isoforms, I and II, and acetylcholinesterase (AChE) in vitro. The results showed that the synthesized compounds were potent inhibitors of hCA I, with KIs in the low nanomolar range (66.60–278.40 nM) than the reference drug acetazolamide (AAZ), which had a KI of 439.17 nM. The hCA II was potently inhibited by compounds 5a, 5d–g and 5l, with KIs of 69.56, 39.64, 79.63, 74.76, 78.93 and 74.94 nM, respectively (AAZ, KI of 98.28 nM). Notably, compound 5a selectively inhibited hCA II with a selectivity of > 4-fold over hCA I. In terms of inhibition of AChE, the synthesized compounds had KIs ranging from 30.95 to 154.50 nM, compared to the reference drug tacrine, which had a KI of 159.61 nM. Compounds 5f, 5h and 5l were also evaluated for their ability to inhibit the MCF-7 cancer cell line proliferation and were found to have promising anticancer activity, more potent than 5-fluorouracil and cisplatin. Molecular docking studies suggested that the sulfonamide moiety of these compounds fits snugly into the active sites of hCAs and interacts with the Zn2+ ion. Furthermore, molecular dynamics simulations were performed for 200 ns to assess the stability and dynamics of each enzyme-ligand complex. The acceptability of the compounds based on Lipinski’s and Jorgensen’s rules was also estimated from the ADME/T results. These results indicate that the synthesized molecules have the potential to be developed into effective and safe inhibitors of hCAs and AChE and could be lead agents.

	Design, Synthesis, and Evaluation of a New Series of Hydrazones as Small-Molecule Akt Inhibitors for NSCLC Therapy Burak Erdönmez, Mehlika Dilek Altıntop, Gülşen Akalın Çiftçi, Ahmet Özdemir, and Abdulilah Ece ACS Omega, 8, 22, 20056–20065 DOI: https://doi.org/10.1021/acsomega.3c02331, (2023). (IF= 4.1)
	See Abtsract In an endeavor to identify small molecules for the management of non-small-cell lung carcinoma, 10 new hydrazone derivatives (3a–j) were synthesized. MTT test was conducted to examine their cytotoxic activities against human lung adenocarcinoma (A549) and mouse embryonic fibroblast (L929) cells. Compounds 3a, 3e, 3g, and 3i were determined as selective antitumor agents on A549 cell line. Further studies were conducted to figure out their mode of action. Compounds 3a and 3g markedly induced apoptosis in A549 cells. However, both compounds did not show any significant inhibitory effect on Akt. On the other hand, in vitro experiments suggest that compounds 3e and 3i are potential anti-NSCLC agents acting through Akt inhibition. Furthermore, molecular docking studies revealed a unique binding mode for compound 3i (the strongest Akt inhibitor in this series), which interacts with both hinge region and acidic pocket of Akt2. However, it is understood that compounds 3a and 3g exert their cytotoxic and apoptotic effects on A549 cells via different pathway(s).

	Computer-aided drug design Abdulilah Ece BMC Chemistry, 17(1), 26, DOI: https://doi.org/10.1186/s13065-023-00939-w, (2023). (IF= 4.6)
	See Abtsract Computer-Aided Drug Design tools are now an indispensable part of drug discovery that have made key contributions to the development of drugs. In this editorial, I briefly provide an overview of CADD emphasizing its potential and invite authors from academia and the pharmaceutical and biotechnology sector to present their research in this collection.

	Structural characterization and biological evaluation of uracil-appended benzylic amines as acetylcholinesterase and carbonic anhydrase I and II inhibitors Zafer Bulut, Nurgül Abul, Ayşe Halıç Poslu, İlhami Gülçin, Abdulilah Ece, Erol Erçağ, Ömer Koz, Gamze Koz Journal of Molecular Structure, DOI: https://doi.org/10.1016/j.molstruc.2023.135047, (2023). (IF= 3.8)
	See Abtsract A series of novel uracil-appended benzylic amines were synthesized through reductive amination with moderate to good yields (30–84% yields). In situ prepared 5-(arylidene)-6-aminouracils with the condensation reaction between 5,6-diamino-1,3-dimethyluracil and substituted salicylaldehydes were reduced by excess sodium borohydride. All of the compounds were characterized using FT-IR, 1H NMR, 13C NMR spectroscopy and elemental analysis. The inhibition abilities of novel uracil-appended benzylic amines (1–9) were evaluated against acetylcholinesterase (AChE) and human carbonic anhydrase I and II (hCA I and II) isoenzymes that are linked to some global disorders such as Alzheimer's disease (AD), epilepsy, diabetes and glaucoma. The compounds exhibited inhibition profiles with Ki values ranging from 2.28±0.41 nM to 5.25±0.75 nM for AChE, 36.10±5.22–110.31±54.81 nM for hCA I and 16.33±4.91–72.03±28.86 for hCA II. Tacrine was used as a reference inhibitor for AChE and exhibited a Ki value of 2.59±0.92 nM against the AChE enzyme. On the other hand, Acetazolamide was used as a standard inhibitor towards hCA I and hCA II isoforms with Ki values of 31.38±8.56 nM and 18.72±1.67 nM, respectively. The results of enzyme inhibition associated with some global metabolic diseases indicate that novel uracil-appended benzylic amines may have the potential to develop new drugs to treat some common diseases such as Alzheimer's disease (AD), epilepsy and glaucoma. Molecular docking simulations were conducted to explain the binding interactions of compounds with AChE, hCA I and hCA II. Pharmacokinetic profiles were predicted to be within the acceptable ranges.

	A new series of thiazole-hydrazone hybrids for Akt-targeted therapy of non-small cell lung cancer Turana Orujova, Abdulilah Ece, Gülşen Akalın Çiftçi, Ahmet Özdemir, Mehlika D. Altıntop Drug Development Research, DOI: https://doi.org/10.1002/ddr.22022, (2022). (IF= 5.004)
	See Abtsract In an attempt to identify potent antitumor agents for the fight against non-small cell lung cancer, new thiazolyl hydrazones (2a–n) were synthesized and examined for their in vitro cytotoxic effects on A549 human lung adenocarcinoma and L929 mouse embryonic fibroblast cells by means of the MTT assay. Furthermore, the effects of the most potent anticancer agents on apoptosis and Akt inhibition were investigated. 2-[2-((Isoquinolin-5-yl)methylene)hydrazinyl]−4-(4-methylsulfonylphenyl)thiazole (2k) (IC50 = 1.43 ± 0.12 µM) and 2-[2-((isoquinolin-5-yl)methylene)hydrazinyl]−4-(1,3-benzodioxol-5-yl)thiazole (2l) (IC50 = 1.75 ± 0.07 µM) displayed more pronounced anticancer activity than cisplatin (IC50 = 3.90 ± 0.10 µM) on A549 cell lines; 2-[2-((isoquinolin-5-yl)methylene)hydrazinyl]−4-(4-methoxyphenyl)thiazole (2j) (IC50 = 3.93 ± 0.06 µM) showed anticancer activity close to cisplatin. These compounds were found to induce apoptosis in A549 cells. Compound 2j (IC50 = 3.55 ± 0.64 µM) showed stronger Akt inhibitory activity than GSK690693 (IC50 = 4.93 ± 0.06 µM), while compounds 2k and 2l did not cause Akt inhibition at IC50 concentrations (1.43 and 1.75 µM, respectively). To comprehensively elucidate the binding pose of compound 2j and to provide a detailed understanding on the ligand' binding mechanism, induced-fit docking calculations were also conducted. Both in vitro and in silico studies suggest that compound 2j shows its cytotoxic and apoptotic effects on A549 cell lines via Akt inhibition. However, it is understood that compounds 2k and 2l exert their strong anticancer effects on A549 cells through different pathways.

	Indane Based Molecular Motors: UV-Switching Increases Number of Isomers Valeriy P. Shendrikov, Anna S. Alekseeva, Erik F. Kot, Konstantin S. Mineev, Daria S. Tretiakova, Abdulilah Ece and Ivan A. Boldyrev Molecules, DOI: https://doi.org/10.3390/molecules27196716, (2022). (IF= 4.927)
	See Abtsract We describe azophenylindane based molecular motors (aphin-switches) which have two different rotamers of trans-configuration and four different rotamers of cis-configuration. The behaviors of these motors were investigated both experimentally and computationally. The conversion of aphin-switch does not yield single isomer but a mixture of these. Although the trans to cis conversion leads to the increase of the system entropy some of the cis-rotamers can directly convert to each other while others should convert via trans-configuration. The motion of aphin-switches resembles the work of a mixing machine with indane group serving as a base and phenol group serving as a beater. The aphin-switches presented herein may provide a basis for promising applications in advanced biological systems or particularly in cases where on demand disordering of molecular packing has value, such as lipid bilayers.

	Quinazolinone-based benzenesulfonamides with low toxicity and high affinity as monoamine oxidase-A inhibitors: Synthesis, biological evaluation and induced-fit docking studies Cem Yamali, Halise Inci Gul, Mehtap Tugrak Sakarya, Begum Nurpelin Saglik, Abdulilah Ece, Goksun Demirel, Merve Nenni, Serkan Levent, Ahmet Cihat Oner Bioorganic Chemistry, DOI: https://doi.org/10.1016/j.bioorg.2022.105822, (2022). (IF= 5.307)
	See Abtsract The research in selective monoamine oxidases (MAO-A and MAO-B) inhibitors has been increased due to their therapeutic value for neurodegenerative diseases. In this study, 4-((2-(aryl)-4-oxoquinazolin-3(4H)-yl)amino)benzenesulfonamides were synthesized and their MAOs inhibition potentials were investigated applying in vitro fluorometric technique. The most potent compounds 7 and 8 against MAO-A had IC50 values of 0.058 ± 0.002 and 0.094 ± 0.003 µM, respectively, while the reference moclobemide had an IC50 value of 6.061 µM. Compounds 7 (>1724 times) and 8 (>1063 times) more selective and reversible inhibitors of MAO-A rather than MAO-B. Toxicity studies of 7 (IC50 = 210.23 µM) and 8 (IC50 = 259.27 µM) showed that compounds can be considered as non-toxic towards SH-SY5Y cell line at their effective concentrations against MAO-A. In silico docking simulations successfully explained the observed activities and also highlighted structural water molecules to play a key role in the ligand-enzyme interactions. Calculated molecular descriptors are also obeying Lipinski’s rule of five and brain/blood partition coefficients, a critical parameter in neurodegenerative diseases. These reversible inhibitors can have considerable advantages compared to irreversible inhibitors which may possess serious pharmacological side effects.

	Novel urea-thiourea hybrids bearing 1,4-naphthoquinone moiety: Anti-inflammatory activity on mammalian macrophages by regulating intracellular PI3K pathway, and molecular docking study Cagla Efeoglu, Derya Yetkin, Yahya Nural, Abdulilah Ece, Zeynel Seferoğlu & Furkan Ayaz Journal of Molecular Structure, DOI: https://doi.org/10.1016/j.molstruc.2022.133284, (2022). (IF= 3.841)
	See Abtsract In this study, four novel urea-thiourea hybrids bearing 1,4-naphthoquinone moiety were synthesized by the reaction of 2,3-diaminonaphthalene-1,4-dione and various isothiocyanate derivatives in 75–88% yield, and their molecular structures were characterized by using 1H/13C NMR, FT-IR and HRMS techniques. Urea-thiourea hybrids have been known for their anti-inflammatory activities. Therefore, in our study, we aimed to decipher their biological activities on mammalian macrophages. Macrophages were stimulated by LPS and pro-inflammatory TNF, IL6, GMCSF and IL12p40 cytokine production levels were measured in the presence of these derivatives by ELISA. Our results suggest that these derivatives on stimulated mammalian macrophages had anti-inflammatory activities. In order to examine their intracellular mechanism of action, intracellular phosphorylated (activated) PI3K protein levels were measured in the presence of our novel derivatives by flow cytometry. Our results suggest that these novel derivatives had anti-inflammatory activities on mammalian macrophages by blocking the PI3K activation and decreasing the production of pro-inflammatory cytokines. Molecular docking calculations were also employed to elucidate the theoretical binding modes of our studied compounds with PI3Kγ. These derivatives have the potential to be utilized as anti-inflammatory drug agents against versatile inflammatory and autoimmune disorders.

	Epichlorohydrin and tripolyphosphate-crosslinked chitosan–kaolin composite for Auramine O dye removal from aqueous solutions: Experimental study and DFT calculations Zeynep Mine Şenol, Serap Çetinkaya, Ali Fazıl Yenidünya, Faika Başoğlu-Ünal, Abdulilah Ece International Journal of Biological Macromolecules, DOI: https://doi.org/10.1016/j.ijbiomac.2022.01.008, (2022). (IF= 8.025)
	See Abtsract Chitosan (Ch, a natural polymer) and kaolin (K, a natural mineral) composite (Ch-K) was produced with the help of two crosslinkers, epichlorohydrin and tripolyphosphate, and then moulded into uniform beads in tripolyphosphate solution. The synthesis was proved by the analyses involving FT-IR and SEM-EDX. The beads were then used as the natural adsorbent for removal of the auramine O (AO), a frequently-used industrial dye, in aqueous solutions. Adsorbent performance of the Ch-K composite for AO dye molecules was optimized: 500 mg L−1 at pH 7.5 at 25 °C. The Langmuir model found 0.118 mol kg−1 for the maximum adsorption capacity of the Ch-K and the D-R isotherm model showed that the nature of the adsorption process was physical. Kinetics of the adsorption could be explained by using both IPD (intraparticle diffusion) and PSO (pseudo second order) models. Thermodynamic parameters demonstrated that the behaviour of the adsorption was an endothermic and spontaneous. The activity of the composite adsorbent was recovered (88%) after the five sequential adsorption/desorption cycles. Supported by experimental findings, the results obtained from in silico modeling at M06-2X/6–31+G (d,p) level helped hypothesise a mechanism for the formation of the Ch-K composite, and shed some light onto the adsorption behaviour of AO dye by assuming several favourable intermolecular interactions.

	New bis-and tetrakis-1, 2, 3-triazole derivatives: Synthesis, DNA cleavage, molecular docking, antimicrobial, antioxidant activity and acid dissociation constants Yahya Nural, Sadin Ozdemir, Mustafa Serkan Yalcin, Bunyamin Demir, Hasan Atabey, Zeynel Seferoglu, Abdulilah Ece Bioorganic & Medicinal Chemistry Letters, DOI: https://doi.org/10.1016/j.bmcl.2021.128453, (2022). (IF= 2.94)
	See Abtsract In this study, a series of bis– and tetrakis–1,2,3–triazole derivatives were synthesized using copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry in 73–95% yield. The bis– and tetrakis–1,2,3–triazoles exhibited significant DNA cleavage activity while the tetrakis–1,2,3–triazole analog 6g completely degraded the plasmid DNA. Molecular docking simulations suggest that compound 6g acts as minor groove binder of DNA by binding through several noncovalent interactions with base pairs. All bis- and tetrakis–1,2,3-triazole derivatives were screened for antibacterial activity against E. coli, B. cereus, S. aureus, P. aeruginosa, E. hirae, L. pneumophila subsp. pneumophila strains and antifungal activity against microfungus C. albicans and C. tropicalis strains. Compound 4d exhibited the best antibacterial activity among bis–1,2,3–triazoles against E. coli and E. hirae, while 6c exhibited the best antibacterial activity among tetrakis–1,2,3–triazoles against E. hirae. Furthermore, the best antifungal activity against C. albicans and C. tropicalis was reported for the compound 5, while 6d displayed the best antifungal activity against C. tropicalis and C. albicans. Reasonable iron chelating activities and DPPH radical scavenging abilities were found for some of the compounds. Finally, the acid dissociation constants (pKa) of the bis–1,2,3–triazoles were also determined with the help of HYPERQUAD program using the data obtained from potentiometric titrations. The reported data here concludes that the bis- and tetrakis-1,2,3- triazoles are important cores that should be considered for further development of especially new anticancer agents acting through the DNA cleavage activity.

	Synthesis, Biological Evaluation, Molecular Docking, and Acid Dissociation Constant of New Bis-1,2,3-triazole Compounds Yahya Nural, Sadin Ozdemir, Mustafa Serkan Yalcin, Bunyamin Demir, Hasan Atabey, Abdulilah Ece, Zeynel Seferoglu Chemistry Select, DOI: https://doi.org/10.1002/slct.202101148, (2021). (IF= 2.307)
	See Abtsract In this study, new bis-1,2,3-triazole derivatives, N,N′-(1,3-phenylene)bis(2-(4-R-1H-1,2,3-triazol-1-yl)acetamide), were synthesized by copper-catalyzed azide-alkyne cycloaddition click chemistry in 84–96 % yield. A wide range bioactivity screening was performed to determine DNA cleavage, antioxidant, antibacterial and antifungal activities. All of the synthesized bis-1,2,3-triazoles showed excellent DNA cleavage activity and 4e, bearing 2-bromoethyl moiety as a substituent, was almost degraded all of the plasmid DNA. Molecular docking simulations suggest that the synthesized compounds act as minor groove binders of DNA. The antioxidant activities of the bis-1,2,3-triazoles were determined based on the radical scavenging effect of the stable 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical and iron chelating activity. The compounds exhibited effective iron chelating activity at 200 mg/L while showing a moderate ability to scavenge DPPH radical. The compounds exhibited antibacterial activity against B. cereus, L. pneumophila subsp. pneumophila, S. aureus, P. aeruginosa, E. coli and E. hirae bacterial strains, and antifungal activity against C. albicans and C. tropicalis microfungus strains with a MIC value in the range of 4–128 μg/mL. 4d, bearing cyclohexylmethyl moiety as substituent, exhibited a broad-spectrum antimicrobial activity (both antibacterial and antifungal). Four different acid dissociation constant (pKa) values of each product were determined potentiometrically in 20 % (v/v) dimethyl sulfoxide-water at 25±0.1 °C, at an ionic background of 0.1mol/L of NaCl using the HYPERQUAD program.

	Design, synthesis, characterization, in vitro and in silico evaluation of novel imidazo[2,1-b][1,3,4]thiadiazoles as highly potent acetylcholinesterase and non-classical carbonic anhydrase inhibitors Sercan Askin, Hakan Tahtaci, Cüneyt Türkeş, Yeliz Demir, Abdulilah Ece, Gülşen Akalın Çiftçi, Şükrü Beydemir Bioorganic Chemistry, DOI: 10.1016/j.bioorg.2021.105009, (2021). (IF= 5.307)
	See Abtsract Imidazole and thiadiazole derivatives display an extensive application in pharmaceutical chemistry, and they have been investigated as bioactive molecules for medicinal chemistry purposes. Classical carbonic anhydrase (CA) inhibitors are based on sulfonamide groups, but inhibiting all CA isoforms nonspecifically, thereby causing undesired side effects, is the main drawback of these types of inhibitors. Here we reported an investigation of novel 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives (9a-k, 10a, and 11a) and 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives (12a-20a) that do not possess the zinc-binding sulfonamide group for the inhibition of human carbonic anhydrase (hCA, EC 4.2.1.1) I and II isoforms and also of acetylcholinesterase (AChE, EC 3.1.1.7). Imidazo[2,1-b][1,3,4]thiadiazoles demonstrated low nanomolar inhibitory activity against hCA I, hCA II, and AChE (KIs are in the range of 23.44–105.50 nM, 10.32–104.70 nM, and 20.52–54.06 nM, respectively). Besides, compound 9b inhibit hCA I up to 18-fold compared to acetazolamide, while compound 10a has a 5-fold selectivity towards hCA II. The synthesized compounds were also evaluated for their cytotoxic effects on the L929 mouse fibroblast cell line. Molecular docking simulations were performed to elucidate these inhibitors’ potential binding modes against hCA I and II isoforms and AChE. The novel compounds reported here can represent interesting lead compounds, and the results presented here might provide further structural guidance to discover and design more potent hCA and AChE inhibitors.

	Novel imidazo[2,1‐b]thiazole‐based anticancer agents as potential focal adhesion kinase inhibitors: synthesis, in silico, and in vitro evaluation Faika Başoğlu, Nuray Ulusoy-Güzeldemirci, Gülşen Akalın-Çiftçi, Serap Çetinkaya, Abdulilah Ece Chemical Biology & Drug Design, DOI: 10.1111/cbdd.13896, (2021).(IF= 2.873)
	See Abtsract The purpose of this study was to synthesize imidazo[2,1-b]thiazole derivatives, characterize them with spectroscopical techniques and investigate for cytotoxic and apoptotic effects on glioma C6 cancer cell line. The in vitro anticancer activities were also investigated against focal adhesion kinase. Most of the compounds, particularly the derivatives carrying 3-oxo-1-tiya-4-azaspiro[4.5]decane moiety, exhibited higher or comparable activities in comparison with the reference drug, cisplatin. Compounds with methyl, propyl, phenyl moieties at the eighth and second position of the spirothiazolidinone ring showed high FAK inhibitory activities. In addition, molecular docking studies shed light on the binding modes of the synthesized compounds. The critical interactions with amino acid residues located in the active site were revealed. The results obtained from both biological assay data and computational results might provide insight into developing new inhibitors against focal adhesion kinase.

	Comprehensive study on potent and selective carbonic anhydrase inhibitors: Synthesis, bioactivities and molecular modelling studies of 4-(3-(2-arylidenehydrazine-1-carbonyl)-5-(thiophen-2-yl)-1H-pyrazole-1-yl) benzenesulfonamides Cem Yamali, Hiroshi Sakagami, Yoshihiro Uesawa, Kota Kurosaki, Keitaro Satoh, Yoshiko Masuda, Satoshi Yokose, Abdulilah Ece, Silvia Bua, Andrea Angeli, Claudiu T Supuran, Halise Inci Gul European Journal of Medicinal Chemistry, DOI: 10.1016/j.ejmech.2021.113351, (2021).(IF= 7.088)
	See Abtsract In this research, rational design, synthesis, carbonic anhydrases (CAs) inhibitory effects, and cytotoxicities of the 4-(3-(2-arylidenehydrazine-1-carbonyl)-5-(thiophen-2-yl)-1H-pyrazole-1-yl)benzenesulfonamides 1–20 were reported. Compound 18 (Ki = 7.0 nM) was approximately 127 times more selective cancer-associated hCA IX inhibitor over hCA I, while compound 17 (Ki = 10.6 nM) was 47 times more selective inhibitor of hCA XI over hCA II compared to the acetazolamide. Compounds 11 (CC50 = 5.2 μM) and 20 (CC50 = 1.6 μM) showed comparative tumor-specificity (TS= > 38.5; >128.2) with doxorubicin (TS > 43.0) towards HSC-2 cancer cell line. Western blot analysis demonstrated that 11 induced slightly apoptosis whereas 20 did not induce detectable apoptosis. A preliminary analysis showed that some correlation of tumor-specificity of 1–20 with the chemical descriptors that reflect hydrophobic volume, dipole moment, lowest hydrophilic energy, and topological structure. Molecular docking simulations were applied to the synthesized ligands to elucidate the predicted binding mode and selectivity profiles towards hCA I, hCA II, and hCA IX.

	Exploring the structural basis of conformational heterogeneity and autoinhibition of human cGMP-specific protein kinase Iα through computational modelling and molecular dynamics simulations Maryam, Arooma, Rana Rehan Khalid, Sundeep Chaitanya Vedithi, Abdulilah Ece, Suleyman Selim Çınaroğlu, Abdul Rauf Siddiqi, and Tom L. Blundell Computational and Structural Biotechnology Journal, DOI: 10.1016/j.csbj.2020.06.016, (2020).(IF= 6.155)
	See Abtsract Protein kinase Iα (PKGIα) is a pivotal cyclic guanosine monophosphate (cGMP) signalling protein. Major steps related to the structural plasticity of PKGIα have been inferred but the structural aspects of the auto-inhibition and multidomain tertiary organization of human PKGIα in active and inactive form are not clear. Here we combine computational comparative modelling, protein–protein docking and molecular dynamics (MD) simulations to investigate structural details of the repressed state of the catalytic domain of PKGIα. Exploration of the potential inhibitory conformation of the auto-inhibitory domain (AI) within the catalytic cleft reveals that the pseudo-substrate motif binds with residues of the glycine rich loop and substrate-binding lobe. Dynamic changes as a result of coupling of the catalytic and AI domains are also investigated. The three-dimensional homodimeric models of PKGIα in the active and inactive state indicate that PKGIα in its inactive-state attains a compact globular structure where cyclic nucleotide binding (CNB-A/B) domains are buried, whereas the catalytic domains are inaccessible with their substrate-binding pockets facing the N-terminal of CNB-A. Contrary to this, the active-state model of PKGIα shows an extended conformation where CNB-A/B domains are slightly rearranged and the catalytic domains of homodimer flanking the C-terminal with their substrate binding lobes free to entrap downstream proteins. These findings are consistent with previously reported static images of the multidomain organization of PKGIα. Structural insights pertaining to the conformational heterogeneity and auto-inhibition of PKGIα provided in this study may help to understand the dynamics-driven effective regulation of PKGIα.

	Bioactive indanes: insight into the bioactivity of indane dimers related to the lead anti-inflammatory molecule PH46A Kit Chan, Neil Frankish, Tao Zhang, Abdulilah Ece, Aoife Cannon, Jacintha O'Sullivan, Helen Sheridan Journal of Pharmacy and Pharmacology, DOI: 10.1111/jphp.13269, (2020). (IF= 3.765)
	See Abtsract Objectives PH46A (1) demonstrates significant anti-inflammatory activity in phenotypic models but its mechanism and site of action have been elusive. Current study focused on the bioactivity of PH46 (2) and related novel indane dimers (6-10) to investigate the impact of changes in substitution and stereochemistry at the C-1 and C-2 positions of the PH46 (2) scaffold. Methods Cytotoxicity profiles of compounds were established using THP-1 macrophages and SW480 cells. Effects of the compounds were then evaluated at 10 μM using 5-lipoxygenase (LOX) and 15-LOX enzymes, and 5-LOX binding was evaluated in silico against NDGA, nitric oxide (NO) released from LPS-induced SW480 cells and cytokines in THP-1 macrophages (IL-6, IL-1b, TNF-a and IFN-c) and in SW480 cells (IL-8). Key findings PH46 (2) and 7 cause reduction in NO, inhibition of 5-LOX with high binding energy and no cytotoxicity effects in THP-1 macrophages and SW480 cell lines (up to 50 μM). The cytokine profiling of the series demonstrated inhibition of IL-6 and TNF-a in THP-1 macrophages together with IL-8 in SW480 cells. Conclusions The observed profile of cytokine modulation (IL-6/ TNF-a, IL-8) and inhibition of release of NO and 5-LOX may contribute to the in vivo effects demonstrated by indane dimers and PH46A (1) in murine models of colitis.

	E-pharmacophore based virtual screening for identification of dual specific PDE5A and PDE3A inhibitors as potential leads against cardiovascular diseases Arooma Maryam, Rana Rehan Khalid, Abdul Rauf Siddiqi & Abdulilah Ece Journal of Biomolecular Structure and Dynamics, DOI: 10.1080/07391102.2020.1748718, (2020).(IF= 5.235)
	See Abtsract The need of circumventing life-threatening cardiovascular disorders (CVDs) and pulmonary hypertension (PHT) worldwide prompts researchers to develop effective therapeutic agents. Crucial role of cyclic nucleotide phosphodiesterase-5 (PDE5A) and cyclic nucleotide phosphodiesterase-3 (PDE3A) in cardiovascular signaling makes them potential drug targets for the treatment of CVDs and PHT. In this study, one-drug-multiple-target strategy has been employed to screen inhibitors exhibiting dual specificity through Phase-generated and statistically validated e-pharmacophore models of PDE5A and PDE3A. An extensive CoCoCo database of 7 million compounds with ∼150,000,000 conformations was virtually screened by sequential e-pharmacophore mapping followed by Lipinski Rule of Five (RO5) evaluation and hierarchical docking simulations. Finally, docked hits were subjected to rigorous MMGBSA analysis to estimate the relative spatial affinity of the drug-like compounds. The hits (354 and 366 ligands against PDE5A and PDE3A, respectively) were further optimized through 2D clustering followed by a comprehensive 2D and 3D interaction analysis. Five structurally diverse hits mapped equally well with the e-pharmacophore models and showed promising inhibitory interactions with conserved four catalytic features of PDE5A and PDE3A, thus exhibiting dual specificity. Proposed lead compounds exhibited the lowest MMGBSA binding energies and were found to be in agreement with Lipinski Rule of Five (RO5) and ADME/Tox criteria as compared to sildenafil. The proposed dual inhibitors could thus provide promising outcomes for the discovery of dual as well as multipotent drug like compounds after lead optimization and primary therapeutic interventions.

	Design, synthesis and molecular modelling studies of some pyrazole derivatives as carbonic anhydrase inhibitors Yazgı Dizdaroglu, Canan Albay, Tayfun Arslan, Abdulilah Ece, Emir A. Turkoglu, Asiye Efe, Murat Senturk, Claudiu T. Supuran & Deniz Ekinci Journal of Enzyme Inhibition and Medicinal Chemistry, DOI: 10.1080/14756366.2019.1695791, (2019). (IF= 5.756)
	See Abtsract In this study, newly synthesised compounds 6, 8, 10 and other compounds (1–5, 7 and 9) and their inhibitory properties against the human isoforms hCA I and hCA II were reported for the first time. Compounds 1–10 showed effective inhibition profiles with KI values in the range of 5.13–16.9 nM for hCA I and of 11.77–67.39nM against hCA II, respectively. Molecular docking studies were also performed with Glide XP to get insight into the inhibitory activity and to evaluate the binding modes of the synthesised compounds to hCA I and II. More rigorous binding energy calculations using MM-GBSA protocol which agreed well with observed activities were then performed to improve the docking scores. Results of in silico calculations showed that all compounds obey drug likeness properties. The new compounds reported here might be promising lead compounds for the development of new potent inhibitors as alternatives to classical hCA inhibitors.

	Synthesis, biological evaluation and in silico modelling studies of 1,3,5- trisubstituted pyrazoles carrying benzenesulfonamide as potential anticancer agents and selective cancer-associated hCA IX isoenzyme inhibitors Cem Yamali, Halise Inci Gul, Abdulilah Ece, Silvia Bua, Andrea Angeli, Hiroshi Sakagami, Ertan Sahin, Claudiu T.Supuran Bioorganic Chemistry, DOI: 10.1016/j.bioorg.2019.103222, (2019). (IF= 5.307)
	See Abtsract Inhibition of carbonic anhydrases (CAs, EC 4.2.1.1) has clinical importance for the treatment of several diseases. They participate in crucial regulatory mechanisms for balancing intracellular and extracellular pH of the cells. Among CA isoforms, selective inhibition of hCA IX has been linked to decreasing of cell growth for both primary tumors and metastases. The discovery of novel CA inhibitors as anticancer drug candidates is a current topic in medicinal chemistry. 1,3,5-Trisubstituted pyrazoles carrying benzenesulfonamide were evaluated against physiologically abundant cytosolic hCA I and hCA II and trans-membrane, tumor-associated hCA IX isoforms by a stopped-flow CO2 hydrase method. Their in vitro cytotoxicities were screened against human oral squamous cell carcinoma (OSCC) cell lines (HSC-2) and human mesenchymal normal oral cells (HGF) via 3-(4,5- Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) test. Compounds 6, 8, 9, 11, and 12 showed low nanomolar hCA II inhibitory potency with Ki < 10 nM, whereas compounds 9 and 12 displayed Ki < 10 nM against hCA IX isoenzyme when compared with reference Acetazolamide (AZA). Compound 9, 4-(3-(hydrazinecarbonyl)- 5-(4-nitrophenyl)-1H-pyrazol-1-yl)benzenesulfonamide, can be considered as the most selective hCA IX inhibitor over off-target cytosolic isoenzymes hCA I and hCA II with the lowest Ki value of 2.3 nM and selectivity ratios of 3217 (hCA I/hCA IX) and 3.9 (hCA II/hCA IX). Isoform selectivity profiles were also discussed using in silico modelling. Cytotoxicity results pointed out that compounds 5 (CC50=37.7 μM) and 11 (CC50=58.1 μM) can be considered as lead cytotoxic compounds since they were more cytotoxic than 5- Fluorouracil (5-FU) and Methotrexate (MTX).

	Towards more effective acetylcholinesterase inhibitors: a comprehensive modelling study based on human acetylcholinesterase protein–drug complex Abdulilah Ece Journal of Biomolecular Structure and Dynamics, DOI: 10.1080/07391102.2019.1583606, (2019). (IF= 5.235)
	See Abtsract Alzheimer's disease is a progressive neurodegenerative disorder and as the exact cause of the disease remains unknown, it still has no cure to date. Due to the fact that, until recently, there has been no crystal structure of human AChE in complex with drugs, researchers have had to use mainly Torpedo californica homologues which were later reported to have significantly different binding sites. In this study, an energy-based pharmacophore model that has the advantages of both ligand- and structure-based approaches was generated using hAChE crystal structures in complex with drugs. This model was validated utilizing several commonly used statistical measures such as the enrichment factor, BEDROC, RIE and AUAC. A huge database consisting of around 7 million compounds with approximately 150,000,000 conformations from 8 vendors was used in virtually screening workflow, in which Lipinski’s filter and basic and precise docking algorithms were utilized. A rigorous MM-GBSA binding affinity calculation was also applied to accurately predict relative free energy that produced 361 hits. The selected top ranked 15 compounds were shown to have extra intermolecular interactions with hAChE which is an indication of a more stable complex and high binding affinity. The e-pharmacophore model and overall results obtained might be used for further experimental studies in designing the next generation of hAChE inhibitors.

	An integrated approach towards the development of novel antifungal agents containing thiadiazole: synthesis and a combined similarity search, homology modelling, molecular dynamics and molecular docking study Mustafa Er, Abdulati Miftah Abounakhla, Hakan Tahtaci, Ali Hasin Bawah, Süleyman Selim Çınaroğlu, Abdurrahman Onaran and Abdulilah Ece Chemistry Central Journal, 12(1), 121, DOI: 10.1186/s13065-018-0485-3, (2018). (IF= 4.215)
	See Abtsract Background: This study aims to synthesise and characterise novel compounds containing 2-amino-1,3,4-thiadiazole and their acyl derivatives and to investigate antifungal activities. Similarity search, molecular dynamics and molecular docking were also studied to find out a potential target and enlighten the inhibition mechanism. Results: As a first step, 2-amino-1,3,4-thiadiazole derivatives (compounds 3 and 4) were synthesised with high yields (81 and 84%). The target compounds (6a–n and 7a–n) were then synthesised with moderate to high yields (56–87%) by reacting 3 and 4 with various acyl chloride derivatives (5a–n). The synthesized compounds were characterized using the IR, 1H-NMR, 13C-NMR, Mass, X-ray (compound 7n) and elemental analysis techniques. Later, the in vitro antifungal activities of the synthesised compounds were determined. The inhibition zones exhibited by the compounds against the tested fungi, their minimum fungicidal activities, minimum inhibitory concentration and the lethal dose values (LD50) were determined. The compounds exhibited moderate to high levels of activity against all tested pathogens. Finally, in silico modelling was used to enlighten inhibition mechanism using ligand and structure-based methods. As an initial step, similarity search was carried out and the resulting proteins that belong to Homo sapiens were used as reference in sequence similarity search to find the corresponding amino acid sequences in target organisms. Homology modelling was used to construct the protein structure. The stabilised protein structure obtained from molecular dynamics simulation was used in molecular docking. Conclusion: The overall results presented here might be a good starting point for the identification of novel and more active compounds as antifungal agents.

	Synthesis, Structure Elucidation and Biological Activities of Some Novel 4(3H)-Quinazolinones as Anti-Biofilm Agents Sevda Turk, Sevgi Karakus, Abdulilah Ece, Seyhan Ulusoy, Gulgun Bosgelmez-Tınaz Letters in Drug Design & Discovery, DOI: 10.2174/1570180815666180621101123, (2018).
	See Abtsract Background: Pseudomonas aeruginosa is an opportunistic pathogen that causes chronic infections in immunocompromised patients. The inhibition of quorum sensing (QS) system has been recognized as an attractive strategy for the treatment of P. aeruginosa infections. In the present study, a series of novel 2-methyl-3-[4-(substituedaminosulfonyl)phenyl]-4(3H)-quinazolinones (1-8) were synthesized and tested for their biofilm formation and swarming motility inhibitory activities in P. aeruginosa PA01. Findings: These compounds were found to reduce biofilm formation by 20-32% and swarming motility by 51-62% in P. aeruginosa PA01 at a concentration of 12.5µM. Molecular docking studies were also performed to elucidate the possible key interactions of these compounds with the active site of the P. aeruginosa QS receptor LasR. Furthermore, some molecular properties related to drug likeness and ADME were predicted. Results and Conclusion: Results of this study demonstrated that compounds 1-8 can influence QS-regulated biofilm formation and swarming motility in P. aeruginosa PA01 by binding LasR protein and could be developed as anti-biofilm agents to treat chronic biofilm associated infections caused by P. aeruginosa and other clinically significant pathogens.

	Experimental and theoretical studies on tautomeric structures of a newly synthesized 2,2′(hydrazine-1,2-diylidenebis(propan-1-yl-1-ylidene))diphenol Tuncay Karakurt, Alaaddin Cukurovali, Nuriye Tuna Subasi, Abdurrahman Onaran, Abdulilah Ece, Sıtkı Eker, Ibrahim Kani Chemical Physics Letters, DOI: 10.1016/j.cplett.2018.01.016, (2018).
	See Abtsract In the present study, a single crystal of a Schiff base, 2,2′(hydrazine-1,2-diylidenebis(propan-1-yl-1-ylidene))diphenol, was synthesized. The structure of the synthesized crystal was confirmed by 1H and 13C NMR spectroscopic and X-ray diffraction analysis techniques. Experimental and theoretical studies were carried out on two tautomeric structures. It has been observed that the title compound studied can be in two different tautomeric forms, phenol-imine and keto-amine. Theoretical calculations have been performed to support experimental results. Accordingly, the geometric parameters of the compound were optimized by the density functional theory (DFT) method using the Gaussian 09 and Quantum Espresso (QE) packet program was used for periodic boundary conditions (PBC) studies. Furthermore, the compound was also tested for in vitro antifungal activity against Sclerotinia sclerotiorum, Alternaria solani, Fusarium oxysporum f. sp. lycopersici and Monilinia fructigena plant pathogens. Promising inhibition profiles were observed especially towards A. solani. Finally, molecular docking studies and post-docking procedure based on Molecular Mechanics‐Generalized Born Surface Area (MM‐GBSA) were also carried out to get insight into the compound’s binding interactions with the potential. Although theoretical calculations showed that the phenol-imine form was more stable, keto-amine form was predicted to have better binding affinity which was concluded to result from loss of rotational entropy in phenol-imine upon binding. The results obtained here from both experimental and computational methods might serve as a potential lead in the development of novel anti-fungal agents.

	In Vitro Antibacterial and Antifungal Activity and Computational Evaluation of Novel Indole Derivatives Containing 4-Substituted Piperazine Moieties Tunca Gul Altuntas, Nilufer Yilmaz, Abdulilah Ece, Nurten Altanlar, Sureyya Olgen Letters in Drug Design & Discovery, DOI: 10.2174/1570180815666180109161948, (2018).
	See Abtsract Background: Lack of specificity and occurence of resistance to current antibacterial and antifungal agents are major shortcomings for the treatment of microbial diseases. Finding novel antimicrobial agents is therefore highly needed to develop more potent drugs. Within this framework, several indole derivatives were designed and reported in the literature. Methods: In vitro antibacterial and antifungal activities of previously synthesized novel indole compounds containing 4-substituted piperazine moieties were tested against Staphylococcus aureus (ATCC 25923), Methicilline resistant Staphylococcus aureus (MRSA, ATCC 43300), Escherichia coli (ATCC 25922), Bacillus subtilis (ATCC 6633) and Candida albicans (ATTC 10231). Sultamicillin T, ampicillin, ciprofloxacin and fluconazole were used as positive controls. Molecular docking was used to study the interaction of active compounds with their receptor. Results: Fifteen compounds were synthesized and their antibacterial activities were similar to that of the reference drugs used as controls. Compounds 4 and 15 were more active (MIC 25 μg/ml) than ampicillin (MIC 50 μg/ml) against MRSA, while they showed the same activity as sultamicillin T (MIC 25 μg/ml). All compounds showed lower activity than ciprofloxacin (MIC 25 μg/ml) against the tested microorganisms. However, none of the compounds showed remarkable antifungal activity against C. albicans. Compound 6 showed the best interaction with the amino acid residues of the targeted cofactor NAD+.

	Synthesis, molecular modeling, and biological evaluation of 4-[5-aryl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl] benzenesulfonamides toward acetylcholinesterase, carbonic anhydrase I and II enzymes Cem Yamali, Halise Inci Gul, Abdulilah Ece, Parham Taslimi, Ilhami Gulcin Chemical Biology & Drug Design, DOI: 10.1111/cbdd.13149, (2017). (IF= 2.817)
	See Abtsract In this study, 4-[5-aryl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl] benzenesulfonamides were synthesized, and inhibition effects on AChE, hCA I, and hCA II were evaluated. Ki values of the compounds toward hCA I were in the range of 24.2 ± 4.6-49.8 ± 12.8 nm, while they were in the range of 37.3 ± 9.0-65.3 ± 16.7 nm toward hCA II. Ki values of the acetazolamide were 282.1 ± 19.7 nm and 103.60 ± 27.6 nm toward both isoenzymes, respectively. The compounds inhibited AChE with Ki in the range of 22.7 ± 10.3-109.1 ± 27.0 nm, whereas the tacrine had Ki value of 66.5 ± 13.8 nm. Electronic structure calculations at M06-L/6-31 + G(d,p)//AM1 level and molecular docking studies were also performed to enlighten inhibition mechanism and to support experimental findings. Results obtained from calculations of molecular properties showed that the compounds obey drug-likeness properties. The experimental and computational findings obtained in this study might be useful in the design of novel inhibitors against hCA I, hCA II, and AChE.

	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).(IF= 4.050)
	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, DOI: 10.4274/tjps.28290, (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.

	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). (IF= 5.756)
	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.