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Öğe Convenient synthesis of disubstituted tacrine derivatives via electrophilic and copper induced reactions(Pergamon-Elsevier Science Ltd, 2016) Ekiz, Makbule; Tutar, Ahmet; Okten, SalihThe bromination of 2-aminobenzonitrile (2) with molecular bromine (2 equiv) furnished 2-amino-3,5-dibromobenzonitrile (7) in 98% yield. One-pot syntheses are described for dibromotacrine derivatives (6,14-18) utilizing Friedlander reactions. A convenient route is described for disubstituted derivatives of tacrines from dibromotacrine 6 and 15 by various substitution reactions. Several disubstituted tacrines were synthesized by treatment of dibromo 6 and 15 derivatives with n-BuLi followed by trapping with an electrophile [Si(Me)(3)Cl, S-2(Me)(2)]. Both were converted to the corresponding cyano derivatives (21-23) via copper-assisted nucleophilic substitution reactions in moderate yields (30%, 50%, and 60%, respectively). Copper-induced nucleophilic substitution of dibromide 15 with NaOMe afforded mono methoxide 31 in 25% yield. (C) 2016 Elsevier Ltd. All rights reserved.Öğe Decision making for promising quinoline-based anticancer agents through combined methodology(WILEY, 2020) Ozcan, Evrencan; Okten, Salih; Eren, TamerDuring the development of effective drugs for the treatment of cancer, one of the most important tasks is to identify effective drug candidates having maximum antiproliferation and minimum side effects. This paper considers the problem of selecting the most promising anticancer agents, showing inhibition at low IC50 concentration and low releasing lactate dehydrogenase percentage (cytotoxicity). Recently, we prepared quinoline analogs bearing different functional groups and determined their anticancer potential against the HeLa, C6, and HT29 cancer cell lines using different anticancer assays. Experimentally, seven quinoline derivatives consisting of different substituents were determined as promising anticancer agents. We propose a multicriteria recommendation method to identify the most promising anticancer agents against all tested cell lines with an accurate prediction algorithm according to the available input data. A multicriteria decision-making methodology (MCDM) was used for the solution of the relevant problem in this study. Both the experimental results and MCDM method indicated that 5,7-dibromo-8-hydroxyquinoline (2) and 6,8-dibromo-1,2,3,4-tetrahydroquinoline (6) are the most promising anticancer agents against the HeLa, HT29, and C6 cell lines.Öğe Detection of mechanism and anticancer activity of the new quinoline compounds MC20 and MC21(Elsevier Science Bv, 2014) Koprulu, Tugba Kul; Tekin, Saban; Okten, Salih; Cinar, Merve; Duman, Seda; Cakmak, Osman…Öğe Determination of anticancer activities of some quinoline derivatives against C6 tumor cells(Elsevier Science Bv, 2012) Sahin, Onem Yuce; Okten, Salih; Tekin, Saban; Cakmak, Osman…Öğe Facile, Expeditious and Cost-effective Preparation of N-Phthaloyl (S)-Amino Acids and Their in silico Activities against Staphylococcus Aureus(Taylor & Francis Inc, 2022) Saddiqa, Aisha; Shahzadi, Iram; Usman, Muhammad; Cakmak, Osman; Okten, Salih[Abstract No tAvailable]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 In vitro antiproliferative/cytotoxic activity of 2,3 '-biindole against various cancer cell lines(Tubitak Scientific & Technical Research Council Turkey, 2015) Okten, Salih; Erenler, Ramazan; Koprulu, Tugba Kul; Tekin, Saban2,3'-Biindole (2) was synthesized via bromination of indole (1) with molecular bromine and underwent simultaneous dimerization. Antiproliferative and cytotoxic activity of 2 was investigated in vitro on C6 (rat brain tumor), HeLa (human cervix carcinoma), and HT29 (human colon carcinoma) cells lines by using BrdU cell proliferation ELISA and lactate dehydrogenase (LDH) assays. In contrast to 5-fluorouracil (5-FU), 2,3'-biindole (2) significantly inhibited proliferation of HeLa and HT29 cell lines. According to LDH assay, the cytotoxicity of compound 2 was low on HT29 cell lines and high on HeLa and C6 cell lines. Moreover, 2 did not cause any DNA laddering on the DNA of tested cells; therefore, it is suggested that the mechanism of action of this compound may not involve apoptosis. In addition, 2 inhibited relaxation of supercoiled plasmid DNA by topoisomerase activity. Results of the present study indicates that biindole (2) may have promising anticancer and antitopoisomerase potential with an unknown mechanism of action.Öğe In vitro antiproliferative/cytotoxic activity of novel quinoline compound SO-18 against various cancer cell lines(Elsevier Science Bv, 2014) Okten, Salih; Sahin, Onem Yuce; Tekin, Saban; Cakmak, Osman…Öğe In-silico Pharmacokinetic and Affinity Studies of Piperazine/Morpholine Substituted Quinolines in Complex with GAK as Promising Anti-HCV Agent(World Scientific Publ Co Pte Ltd, 2021) Andac, Cenk A.; Cakmak, Osman; Okten, Salih; Caglar-Andac, Sena; Isildak, IbrahimPiperazine/morpholine derivatives of quinoline substituted at positions C-3, C-6 and C-8 has been previously prepared by SNAr reactions of 3,6,8-tribromoquinoline (1) under microwave or conventional heating reaction conditions. In this study, we evaluated binding interactions between the piperazine/morpholine substituted quinolines and its highly-likely receptor, Cyclin G associated kinase (GAK) involved in hepatitis C virus (HCV) entry into host cells, via docking, molecular dynamics (MD), thermodynamic and pharmacokinetics computations in order to select a possible lead compound, which may be used for lead-optimization in our future studies to develop novel drug candidates against HCV infections. 372 nsec MD simulations followed by MM-PBSA thermodynamic computations revealed that compound 23 (K-d= 0.08nM) possesses the greatest potential to inhibit GAK. Pharmacokinetics computations suggest that compound 23 is a drug-like molecule as it conforms to the Lipinski filter. We determined that compound 23 could be a lead-like molecule for peripheric and cerebral HCV infections.Öğe In-Vitro Anticancer and Antibacterial Activities of Brominated Indeno[1,2-b]qinoline Amines Supported with Molecular Docking and MCDM**(Wiley-V C H Verlag Gmbh, 2021) Aydin, Ali; Okten, Salih; Erkan, Sultan; Bulut, Merve; Ozcan, Evrencan; Tutar, Ahmet; Eren, TamerThe present study describes mono substituted indeno[1,2-b]quinolines (3 a-c and 5) have much more antiproliferative potentials than positive controls against A549, HeLa, MCF7 and Hep3B cell lines (IC50 values 1.1-29.6 mu g/mL) and show similar cytotoxicity (14.3 % to 19.8 %) to cells such as controls. Moreover, the mono substituted indeno[1,2-b]quinoline amines (3 a-c and 5) exhibit significant antimicrobial activity with MIC values between 15.62 mu g/mL and 250 mu g/mL. The compounds can also bind to DNA in the groove binding mode with a binding constant range of 1.1x10(3)-1.1x10(5) M-1. The anticancer and antibacterial properties of compounds were confirmed with the molecular docking simulation for their pharmacokinetic. As a result, the preliminary experimental data and a multi-criteria decision-making methodology (MCDM) indicated that the mono substituted indeno[1,2-b]quinoline amine derivatives, especially 3 a and 5, exhibit effective pharmacological properties. parameters and their interaction with related cells at the molecular level.Öğe 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 Reinvestigation of bromination of 8-substituted quinolines and synthesis of novel phthalonitriles(Acg Publications, 2016) Okten, Salih; Cakmak, Osman; Saddiqa, Aisha; Keskin, Bahadir; Ozdemir, Seda; Inal, MerveBromination of a series of 8-substituted quinolines was reinvestigated and specified for optimum yields and isolation conditions. Mono bromination of 8-hydroxyquinoline (2a) and 8-aminoquinoline (2c) gave mixture of mono and dibromo derivatives 5,7-dibromo-8-hydroxyquinoline (3a), 5,7-dibromo-8aminoquinoline (3c), 7-bromo-8-hydroxyquinoline (3d), 5-bromo-8-aminoquinoline (3e) while 8methoxyquinoline (2b) furnished 5-bromo-8-methoxyquinoline (3f) as sole product. Novel phthalonitriles, 4(quinolin-8-yloxy) phthalonitrile (6) and 4-chloro-5-(quinolin-8-yloxy) phthalonitrile (8) of 8-hydroxyquinoline (2a) were synthesized and converted into their respective bromo derivatives 4-(5-bromoquinolin-8yloxy) phthalonitrile (7) and 4-((5-bromoquinolin-8-yl) oxy)-5-chlorophthalonitrile (9).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 A SAR Study: Evaluation of Bromo Derivatives of 8-Substituted Quinolines as Novel Anticancer Agents(Bentham Science Publ Ltd, 2017) Okten, Salih; Cakmak, Osman; Tekin, Saban; Koprulu, Tugba KulBackground: Brominated 8-hydroxy, 8-methoxy, 8-amino quinolines 5, 6, 8, 9 and novel cyano 8-hydroxyquinolines 11, 12 were evaluated in vitro for their anticancer effects on various cell lines. 5,7-Dibromo-5, 7-bromo-6, 7-cyano-11 and 5,7-dicyano-12 8-hydroxyquinolines were shown to have strong antiproliferative activity against various tumor cell lines, including C6 (rat brain tumor), HeLa (human cervix carcinoma), and HT29 (human colon carcinoma) with IC50 values ranged from 6.7 to 25.6 mu g/mL. Methods: A structure activity relationship (SAR) was conducted that quinoline core containing hydroxly group at C-8 positon led to more anti cancer potentials. Results: The results of Lactate Dehydrogenase (LDH) cytotoxic, DNA laddering and inhibition assays indicated that 5, 6, 11 and 12 have high cytotoxic effects and appototic potentials. Conclusion: Furthermore, 5 and 12 have inhibitory effects on relaxation of supercoiled plazmid DNA by supressed the Topoisomerase I enzyme. As a result, 5, 6, 11 and 12 may have promising anticancer drug potential and 5 and 12 may be novel topoisomerase inhibitors.Öğe Simple and convenient preparation of novel 6,8-disubstituted quinoline derivatives and their promising anticancer activities(Scientific Technical Research Council Turkey-Tubitak, 2013) Okten, Salih; Cakmak, Osman; Erenler, Ramazan; Yuce, Onem; Tekin, SabanA short and easy route is described for 6,8-disubstituted derivatives of quinoline and 1,2,3,4-tetrahydroquinoline from 6,8-dibromoquinolines 2 and 7 by various substitution reactions. While copper-promoted substitution of 6,8-dibromide 2 produced monomethoxides 3 and 4, a prolonged reaction time mainly afforded dimethoxide 6 instead of 5, whose aromatization with DDQ and substitution reaction of dibromide 7 with NaOMe in the presence of CuI also gave rise to dimethoxide 6. Several 6,8-disubstituted quinolines were obtained by treatment of 6,8-dibromoquinoline (7) with n-BuLi followed by trapping with an electrophile [Si(Me)(3)Cl, S-2(Me)(2), and DMF]. Furthermore, 7 was also converted to mono and dicyano derivatives. The anticancer activities of compounds 2, 7, 6, 12, 13, 15, and 16 against HeLa, HT29, and C6 tumor cell lines were tested, and 6,8-dibromo-1,2,3,4-tetrahydroquinoline (2) and 6,8-dimethoxyquinoline (6) showed significant anticancer activities against the tumor cell lines.Öğe Synthesis Of Brominated Quinolines(Yildiz Technical Univ, 2015) Okten, Salih; Eyigun, Dilek; Cakmak, Osmanthis study, bromination reactions of 1,2,3,4-tetrahydroquinoline by molecular bromine and aromatization reactions of brominated tetrahydroquinolines were reinvestigated. Optimal reaction conditions were established for 6-Bromo-1,2,3,4-tetrahydroquinoline (6-BrTHQ) and 6,8-dibromo-1,2,3,4-tetrahydroquinoline (6,8-diBrTHQ). Improved yields and more shortened reaction times were described for the conversion of 6-BrTHQ and 6,8-diBrTHQ into 6-bromoquinoline and 6,8-dibromoquinoline.Öğe Synthesis of novel cyano quinoline derivatives(Pergamon-Elsevier Science Ltd, 2015) Okten, Salih; Cakmak, Osman6,8-Dibromo-1,2,3,4-tetrahydroquinoline (2) and 3,6,8-tribromoquinoline (3) were converted into the corresponding cyano derivatives via copper assisted nucleophilic substitution reactions. While bromination of 6-bromo-8-cyanotetrahydroquinoline (11) gave 3,6-dibromo-8-cyanoquinoline (8), the reaction of dicyano-1,2,3,4-tetrahydroquinoline (12) resulted in the formation of an unexpected dimer (15). (C) 2015 Elsevier Ltd. All rights reserved.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; 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.
