Synthesis, biological evaluation and docking analysis of substituted piperidines and (2-methoxyphenyl)piperazines

J. Serb. Chem. Soc. 81 (4) 347–356 (2016) JSCS–4851 UDC 577.354+547.233–304.2+547.822.3+ 547.828:57.02:543 Original scientific paper Synthesis, biological evaluation and docking analysis of substituted piperidines and (2-methoxyphenyl)piperazines JELENA Z. PENJIŠEVIĆ1#, VLADIMIR V. ŠUKALOVIĆ1#, DEANA B. ANDRIĆ2*#, GORAN M. ROGLIĆ2#, IRENA T. NOVAKOVIĆ1#, VUKIĆ ŠOŠKIĆ3# and SLAĐANA V. KOSTIĆ-RAJAČIĆ1# 1ICTM – Center of Chemistry, University of Belgrade, Njegoševa 12, Belgrade, Serbia, of Chemistry, University of Belgrade, Studentski trg 12–16, Belgrade, Serbia and 3ORGENTEC Diagnostica GmbH, Carl-Zeiss-Straße 49–51, Mainz, Germany 2Faculty (Received 21 October, revised 25 November, accepted 26 November 2015) Abstract: A series of sixteen novel substituted piperidines and (2-methoxyphenyl)piperazines were synthesized, starting from the key intermediates 1-(2-methoxyphenyl)-4-(piperidin-4-yl)piperazine and 1-(2-methoxyphenyl)-4-[(piperidin-4-yl)methyl]piperazine. Biological evaluation of the synthesized compounds was illustrated by seven compounds, of which 1-(2-methoxyphenyl)-4-{[1-(2-nitrobenzyl)piperidin-4-yl]methyl}piperazine had the highest affinity for the dopamine D2 receptor. For all seven selected compounds, docking analysis was performed in order to establish their structure-to-activity relationship. Keywords: dopamine D2 receptor; docking analysis; allosteric; orthosteric binding site. INTRODUCTION G-protein-coupled receptors (GPCRs) are transmembrane receptors that mediate most of their intracellular actions through pathways involving an activation of the G-protein.1 D2 Dopamine receptors (D2DAR) are members of this large protein family. Dysfunction of the dopaminergic system in CNS can lead to a number of diseases, such as Parkinson’s disease, schizophrenia, some neurohumoral disturbances, etc.2,3 Therefore it is not surprising that the design and synthesis of new potential dopaminergic drugs is one of the main objectives of organic and medicinal chemistry. Arylpiperazines are a common structural motif included in various compounds that interact in a specific manner with various GPCRs.4 Within the scope * Corresponding author. E-mail: # Serbian Chemical Society member. doi: 10.2298/JSC151021097P 347 Available on line at www.shd.org.rs/JSCS/ _________________________________________________________________________________________________________________________ (CC) 2016 SCS. All rights reserved. 348 PENJIŠEVIĆ et al. of the program aimed at the discovery of new dopaminergic (DA-ergic) ligands and in order to explore further previously published data, a series of sixteen novel arylpiperazines were synthesized.5 For all the synthesized ligands, their in vitro binding affinities at rat D2DAR were estimated and compared with the results obtained through docking analysis, using an available D2DAR molecular model. EXPERIMENTAL General Melting points were measured on a Boetius PHMK apparatus (VEB Analytic, Dresden, Germany) and are uncorrected. The 1H- and 13C-NMR (200 and 50 MHz) spectra of the compounds in deuterochloroform, unless otherwise stated, were recorded on a Gemini 2000 instrument (Varian, Oxford). The chemical shifts (δ) are reported in ppm downfield from the internal standard tetramethylsilane. The LC-MS results were acquired on a 6210 time-of-flight LC–MS system (Agilent Technologies, Germany); MassHunter workstation software was used for data analysis. The IR spectra were taken on a Thermo Scientific spectrometer. A MicroSYNTH Milestone and a Biotage Initiator 2.5 EXP were used for the microwave irradiations. Analytical TLC was performed on Polygram SIL G/UV254 plastic-backed thinlayer silica gel plates (Macherey-Nagel, Germany). The chromatographic purifications were realized on Merck-60 silica gel columns (diameter 70 mm, h = 45 mm; the same for all compounds), 230–400 mesh ASTM, medium pressure (dry column flash chromatography). The reagents and solvents (Alfa–Aesar or Sigma–Aldrich) were used without purification. The solutions were routinely dried over anhydrous Na2SO4 prior to evaporation. Chemistry Ethyl 4-[4-(2-methoxyphenyl)piperazin-1-yl]piperidine-1-carboxylate (3). To a stirred solution of N-carbethoxy-4-piperidone (1, 1.7 g, 0.01 mol) in methanol (25 mL; the pH value of the solution was adjusted to 7 by addition of CH3CO2H), 1-(2-methoxyphenyl)piperazine (2, 3.24 g, 0.02 mol) was added, followed by the addition of NaBH3CN (0.4 g, 0.0072 mol) in portions (Scheme 1). Stirring was continued at room temperature for 24 h. The pH value of the resulting solution was adjusted to 2 by the addition of 10 % HCl solution and the excess of the methanol was removed under vacuum. The pH value of the residue was adjusted to 9 by the addition of 10 % NaOH solution and extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo. The product was purified by dryflash chromatography using a gradient of CH3OH (0–10 %) in dichloromethane as the solvent. Yield: 88 %. General procedure for the hydrolysis of the carbamates 3 and 9. Carbamate 3 or 9 (0.02 mol) was suspended in cc HCl (60 mL), transferred into a sealed tube and placed into a microwave oven. Irradiation at 130 °C was completed after 90 min at an initial power of 300 W (Schemes 2 and 3). The reaction mixture was poured into water, the pH value adjusted to 9 by addition of 10 % NaOH solution and extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo. The product was purified by dryflash chromatography using a gradient of methanol (0–10 %) in dichloromethane as the solvent. 1-(Ethoxycarbonyl)piperidine-4-carboxylic acid (6). To a solution of piperidine-4-carboxylic acid (5, 20 g, 0.155 mol) in water (200 mL), Na2CO3 (20 g) was added, mixture stirred at room temperature for 30 min and a solution of ethyl chloroformate (25.5 g, 0.28 mol) in toluene (240 mL) was added dropwise (Scheme 2). Stirring was continued at room tempe- Available on line at www.shd.org.rs/JSCS/ _________________________________________________________________________________________________________________________ (CC) 2016 SCS. All rights reserved. SUBSTITUTED PIPERIDINES AND (2-METHOXYPHENYL)PIPERAZINES 349 rature for 20 h. After separation of the layers, the aqueous layer was acidified with conc. HCl to pH ≈2, and extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo. Yield: 78 %. Scheme 1. Synthesis of 1-(2-methoxyphenyl)-4-(piperidin-4-yl)piperazine (4); reagents: a) NaBH3CN, MeOH, pH 7, r.t; b) conc. HCl, MW, 180 °C, 300 W. Scheme 2. Synthesis of 1-(2-methoxyphenyl)-4-[(piperidin-4-yl)methyl]piperazine (10); reagents: a) Na2CO3, ethyl chloroformate, toluene, r.t; b) thionyl chloride, CH2Cl2, 0 °C; c) triethylamine, chloroform, 5 °C; d) NaBH4, boron trifluoride diethyl etherate, diglyme, –5 °C; e) conc. HCl, MW, 180 °C, 300 W. 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