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Öğe 3,6,8-Tribromoquinoline(WILEY-BLACKWELL, 2010) Celik, Ismail; Akkurt, Mehmet; Okten, Salih; Cakmak, Osman; Garcia-Granda, SantiagoThe title molecule, C(9)H(4)Br(3)N, is almost planar, the maximum deviation being 0.110 (1) angstrom. The crystal structure is stabilized by weak aromatic pi-pi interactions [centroid-centroid distance = 3.802 (4) angstrom] between the pyridine and benzene rings of the quinoline ring systems of adjacent molecules.Öğe 6,8-Dibromoquinoline(WILEY-BLACKWELL, 2010) Celik, Ismail; Akkurt, Mehmet; Cakmak, Osman; Okten, Salih; Garcia-Granda, SantiagoThe title molecule, C9H5Br2N, is almost planar, with an r.m.s. deviation of 0.027 angstrom. The dihedral angle between the aromatic rings is 1.5 (3)degrees. In the crystal, pi-pi stacking interactions are present between the pyridine and benzene rings of adjacent molecules [centroid-centroid distances = 3.634 (4) angstrom], and short Br center dot center dot center dot Br contacts [3.4443 (13) angstrom] occur.Öğe Functionalized methoxy quinoline derivatives: Experimental and in silico evaluation as new antiepileptic, anti-Alzheimer, antibacterial and antifungal drug candidates(Elsevier, 2024) Ciftci, Bilge; Okten, Salih; Kocyigite, Umit Muhammet; Atalay, Vildan Enisoglu; Atas, Mehmet; Cakmak, OsmanThe objective of this study was to assess the inhibitory effects of newly synthesized quinoline derivatives on human carbonic anhydrase I and II (hCA I and II), as well as acetylcholinesterase (AChE) enzymes, alongside their impact on various microorganisms. The synthesized compounds were assessed using IC50, Ki and MIC values via Ellman and Esterease Method and Microdilution assay. Most compounds exhibited strong inhibitory effects on human carbonic anhydrase I and II (hCA I and II) and acetylcholinesterase (AChE), notably compounds 9, 12, and 17 for hCA I, and 9, 12, 16 and 17 for hCA II, alongside robust AChE inhibition by compounds 8 and 13. Antimicrobial tests highlighted compounds 13 and 15 as promising inhibitors against pathogens, particularly effective across various strains. Molecular docking supported these findings, indicating potent binding abilities, notably by compounds 16 and 17 across specific protein structures (2COP, 5E2M, and 6KM3). The discussion emphasized the impact of substituents, particularly methoxy groups at specific positions, on enzyme inhibition, revealing how structural modifications affected enzyme inhibitory properties. The comprehensive analysis bridged experimental and computational findings, uncovering essential structure-activity relationships in quinoline derivatives and identifying potential candidates for further studies in enzyme inhibition and antimicrobial research.Öğe Novel diarylated tacrine derivatives: Synthesis, characterization, anticancer, antiepileptic, antibacterial, and antifungal activities(Wiley, 2024) Misir, Busra A.; Derin, Yavuz; Okten, Salih; Aydin, Ali; Kocyigit, Umit M.; Sahin, Hatice; Tutar, AhmetIn this study, our goal was to synthesize novel aryl tacrine derivatives and assess their potential as anticancer, antibacterial agents, and enzyme inhibitors. We adopted a two-step approach, initiating with the synthesis of dibromotacrine derivatives 3 and 4 through the Friedlander reaction. These intermediates underwent further transformation into diarylated tacrine derivatives 3a-e and 4a-e using a Suzuki-Miyaura cross-coupling reaction. Thorough characterization of these novel diarylated tacrines was achieved using various spectroscopic techniques. Our findings highlighted the potent anticancer effects of these innovative compounds across a range of cancer cell lines, including lung, gynecologic, bone, colon, and breast cancers, while demonstrating low cytotoxicity against normal cells. Notably, these compounds surpassed the control drug, 5-Fluorouracil, in terms of antiproliferative activity in numerous cancer cell lines. Moreover, our investigation included an analysis of the inhibitory properties of these novel compounds against various microorganisms and cytosolic carbonic anhydrase enzymes. The results suggest their potential for further exploration as cancer-specific, enzyme inhibitory, and antibacterial therapeutic agents. Notably, four compounds, namely, 5,7-bis(4-(methylthio)phenyl)tacrine (3d), 5,7-bis(4-(trifluoromethoxy)phenyl)tacrine (3e), 2,4-bis(4-(trifluoromethoxy)phenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-amine (4e), and 6,8-dibromotacrine (3), emerged as the most promising candidates for preclinical studies. The novel aryl substituted tacrine were efficiently synthesized and their anticancer potentials were highlighted in this study. Their inducing apoptosis, cell migration, and mitochondrial membrane potentials were screened. imageÖğe Novel piperazine and morpholine substituted quinolines: Selective synthesis through activation of 3,6,8-tribromoquinoline, characterization and their some metabolic enzymes inhibition potentials(Elsevier, 2020) Cakmak, Osman; Okten, Salih; Alimli, Dilek; Ersanli, Cem Cuneyt; Taslimi, Parham; Kocyigit, Umit MuhammetRegioselective routes are described for convenient preparation of novel piperazine/morpholine substituted quinoline derivatives at C-3, C-6 and C-8 starting with 3,6,8-tribromoquinoline (6) by nucleophilic substitution via conventional heating or microwave assisted reaction conditions. 3,6,8-Tribromoquinoline (6) was treated with piperazine and morpholine under microvawe irradiation, which selectively furnished 3-mopholinyl and 3-piperazinyl quinoline derivatives 7 and 8 in yields of 58% and 60%, respectively. On the other hand, the activation of benzene cycle of quinoline by nitration of 3,6,8-tribromoquinoline, giving 5-nitro-3,6,8-tribromoquinoline (18) in quantitative yield, was enabled. Then, the bromines at C-6 and C-8 were selectively exchanged by morpholine and piperazine via SNAr reactions. Thus, 6,8-dimopholinylquinoline (22) and 5-nitro-6,8-dipiperazinylquinoline (24), biologically valuable derivatives, were prepared in high yields (82% and 72%, respectively). The synthesized compounds were fully characterizated by H-1 NMR, C-13 NMR, 2D NMR, XRD, HRMS and IR spectra. The novel molecules had effective inhibition profiles against some metabolic enzymes. Also, they have the potential of drug candidates to treat of some diseases including glaucoma, epilepsy, Alzheimer's disease (AD), leukemia, and type-2 diabetes mellitus (T2DM). (C) 2020 Elsevier B.V. All rights reserved.Öğe Quinoline-based promising anticancer and antibacterial agents, and some metabolic enzyme inhibitors(Wiley-V C H Verlag Gmbh, 2020) Okten, Salih; Aydin, Ali; Kocyigit, Umit M.; Cakmak, Osman; Erkan, Sultan; Andac, Cenk A.; Taslimi, ParhamA series of substituted quinolines was screened for their antiproliferative, cytotoxic, antibacterial activities, DNA/protein binding affinity, and anticholinergic properties by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation, lactate dehydrogenase cytotoxicity, and microdilution assays, the Wolfe-Shimmer equality method, the Ellman method, and the esterase assay, respectively. The results of the cytotoxic and anticancer activities of the compounds displayed that 6-bromotetrahydroquinoline (2), 6,8-dibromotetrahydroquinoline (3), 8-bromo-6-cyanoquinoline (10), 5-bromo-6,8-dimethoxyquinoline (12), the novelN-nitrated 6,8-dimethoxyquinoline (13), and 5,7-dibromo-8-hydroxyquinoline (17) showed a significant antiproliferative potency against the A549, HeLa, HT29, Hep3B, and MCF7 cancer cell lines (IC50 = 2-50 mu g/ml) and low cytotoxicity (similar to 7-35%) as the controls, 5-fluorouracil and cisplatin. The compound-DNA linkages are hyperchromic or hypochromic, causing variations in their spectra. This situation shows that they can be bound to DNA with the groove-binding mode, withK(b)value in the range of 2.0 x 10(3)-2.2 x 10(5) M-1. Studies on human Gram(+) and Gram(-) pathogenic bacteria showed that the substituted quinolines exhibited selective antimicrobial activities with MIC values of 62.50-250 mu g/ml. All tested quinoline derivatives were found to be effective inhibitors of acetylcholinesterase (AChE) and the human carbonic anhydrase I and II isoforms (hCA I and II), withK(i)values of 46.04-956.82 nM for hCA I, 54.95-976.93 nM for hCA II, and 5.51-155.22 nM for AChE. As a result, the preliminary data showed that substituted quinolines displayed effective pharmacological features. Molecular docking studies were performed to investigate the binding modes and interaction energies for compounds2-17with AChE (PDB ID: 4EY6), hCA I (PDB ID: 1BMZ), and hCA II (PDB ID: 2ABE).Öğe SAR Evaluation of Disubstituted Tacrine Analogues as Promising Cholinesterase and Carbonic Anhydrase Inhibitors(ASSOC PHARMACEUTICAL TEACHERS INDIA, 2019) Okten, Salih; Ekiz, Makbule; Tutar, Ahmet; Butun, Burcu; Kocyigit, Umit Muhammet; Topcu, Gulacti; Gulcin, IlhamiBackground: The inhibition of both hydrolysis products of acetylcholine (ACh), Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE), is essential for successful treatment of Alzhemier patients. Objectives: This study was investigated inhibition potentials of recently synthesized disubstituted tacrines derivatives on going our research against AChE, BChE and carbonic anhydrase cyctosolic (hCA I and H) enzymes to explore the Structure activity relationship (SAR). Methods: Inhibitory activities of tested compounds against AChE and BChE were measured by spectrophotometric method, developed by Ellman et al. Furthermore, the disubstituted tacrines were determined as inhibitors of two physiologically relevant CA isoforms, the cytosolic hCA I and H by an esterase assay method. Results: The silyl, thiomethyl and cyano substituted seven membered hydrocycle tacrines (9, 11 and 14) significantly inhibited AChE, compared with starting compound 3 (6,8-dibromo-2,3,4,5-teytrahydro-1H-cyclohepta[1,2-b] quinoline) and reference compounds, galantamine and tacrine, while methoxy substituted seven membered hydrocycle tacrine derivative 10 showed selective inhibition against BChE (IC50 = 563 nM). Interestingly, disubstituted tacrines displayed higher or parallel inhibition to galantamine. Additionally, all these tacrine analogues were recorded to be powerful inhibitor compounds of the cytosolic isoenzyme hCA I with K-i in the range of 43.81-471.67 nM, as well as a moderate selectivity toward hCA II isoenzyme with K-i in the range from 87.14 to 614.68 nM compared with AZA, as standard. Conclusion: The disubstituted seven membered hydrocycle tacrine analogues 9-12 and 14 may have promising anti Alzhemier drug candidate and dibromo six membered hydrocycle 2 and dibromo seven membered hydrocycle 3 derivatives may be novel hCA I and II enzyme inhibitors.Öğe Synthesis, characterization, and SAR of arylated indenoquinoline-based cholinesterase and carbonic anhydrase inhibitors(WILEY-V C H VERLAG GMBH, 2018) Ekiz, Makbule; Tutar, Ahmet; Okten, Salih; Butun, Burcu; Kocyigit, Umit M.; Taslimi, Parham; Topcu, GuelactiWe report the synthesis of bromoindenoquinolines (15a-f) by Friedlander reactions in low yields (13-50%) and the conversion of the corresponding phenyl-substituted indenoquinoline derivatives 16-21 in high yields (80-96%) by Suzuki coupling reactions. To explore the structure-activity relationship (SAR), their inhibition potentials to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase cyctosolic (hCA I and II) enzymes were determined. Monophenyl (16-18) indenoquinolines significantly inhibited the AChE and BChE enzymes in ranges of IC50 37-57nM and 84-93nM, respectively, compared with their starting materials 15a-c and reference compounds (galanthamine and tacrine). On the other hand, these novel arylated indenoquinoline-based derivatives were effective inhibitors of the BChE, hCA I and II, BChE and AChE enzymes with K-i values in the range of 37 +/- 2.04 to 88640 +/- 1990nM for AChE, 120.94 +/- 37.06 to 1150.95 +/- 304.48nM for hCA I, 267.58 +/- 98.05 to 1568.16 +/- 438.67nM for hCA II, and 84 +/- 3.86 to 144120 +/- 2910nM for BChE. As a result, monophenyl indenoquinolines 16-18 may have promising anti-Alzheimer drug potential and 3,8-dibromoindenoquinoline amine (15f) can be novel hCA I and hCA II enzyme inhibitors.Öğe Synthesis, characterization, crystal structures, theoretical calculations and biological evaluations of novel substituted tacrine derivatives as cholinesterase and carbonic anhydrase enzymes inhibitors(ELSEVIER SCIENCE BV, 2019) Okten, Salih; Ekiz, Makbule; Kocyigit, Umit Muhammet; Tutar, Ahmet; Celik, Ismail; Akkurt, Mehmet; Gokalp, Faik; Taslimi, Parham; Gulcin, IlhamiThe six and seven hydrocycle membered disilylanilino acridine (tacrine) analogues (9-11) were synthesized by one-pot procedures. The structures of novel silyl tacrine derivatives were characterized by NMR spectroscopy, elemental analysis and XRD investigations. The silyl substituted novel tacrine derivatives (9-11) were investigated as cholinesterase inhibitors and defined the relative role of AChE (Acetylcholinesterase) versus BChE (Butyrylcholinesterase) inhibition. Novel substituted tacrine derivatives are known as important inhibitors of Carbonic anhydrase (CA) isoenzymes I, and II (hCA I and II), therefore, the synthesized compounds (9-11) were investigated for inhibitory effects on the both CA isoenzymes. Additionally, we evaluated four different enzymes, which were inhibited in the very low nanomolar (nM) range by these compounds. According to the present studies, for AChE, BChE, hCA I and II, the ranges of results are recorded as 30.26 +/- 6.71-117.54 +/- 42.22 nM, 22.45 +/- 5.81-77.41 +/- 4.02 nM, 57.28 +/- 22.16-213.41 +/- 82.75 nM and 46.95 +/- 11.32-274.94 +/- 62.15 nM, respectively. (C) 2018 Elsevier B.V. All rights reserved.Öğe The Anticancer Potentials of Substituted Indeno[1,2-b]quinoline Amines against HT29 and SW620: Experimental and In silico Approach(Bentham Science Publ Ltd, 2024) Okten, Salih; Aydin, Ali; Erkan, Sultan; Tutar, AhmetBackground: This study aimed the determination of the antiproliferative and cytotoxic activities of recently prepared indeno [1,2-b]quinoline amines against colon carcinoma, HT29 and SW620 cell lines by using cell proliferation and cytotoxicity assays.Methods: In vitro inhibition of cell proliferation of indenoquinoline derivatives was determined with an MTT cell proliferation assay. On the other hand, their cell cytotoxicities and apoptotic potential were investigated by LDH cytotoxicity and DNA laddering assays. Moreover, molecular docking studies were performed between the compounds and PDB ID: 1OLG and 4LVT target proteins using virtual scanning techniques.Results: Most of the compounds (1, 3, and 7-9) exhibit much more potent antiproliferative activity than positive controls against HT29 and SW620 cell lines (IC50 values 1.1 - 4.1 mu g/mL) and show slightly toxic properties (percent cytotoxicity 9.8% to 33.5%) to cells compared to positive control. On the other hand, it was determined that effective compounds 1, 2, 3 and 9 stimulated apoptosis on HT29 and SW620. Moreover, the anticancer effect of the recent indeno[1,2-b]quinoline amine derivatives was investigated with the help of molecular docking simulations for their pharmacokinetics. The molecular docking results displayed that mono bromo (1-3) and phenyl (7-9) substituted indeno [1,2-b]quinoline amines interact with mutated p53 and protein Blc-2 residues with hydrogen bonding and polar interactions, respectively.Conclusion: As a result, the preliminary experimental data and in silico studies indicated that the monosubstituted indenoquinoline amine derivatives, especially 1, 3, and 7-9, exhibit effective pharmacological properties.
