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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 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; 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.
