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PCHHAX Synthesis and Cytotoxic Activity Available online a t www.derpharmachemica.com ISSN 0975-413X Der Pharma Chemica, 2016, 8(9):30-38 CODEN (USA): PCHHAX (http://derpharmachemica.com/archive.html) Synthesis and Cytotoxic Activity Evaluation of Novel Piperazine-quinoline Derivatives on Brest cancer Cell Lines S. Sekar a, Nagaraja Naik *a , A. M. Sridhara b and S. Yogishac aDepartment of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore-570 006; bDepartment of Studies in Industrial Chemistry, Kuvempu University, Jnana Sahyadri, Shankaragatta -577 451, Karnataka, India cSkanda Life Sciences Pvt Ltd, Sunkadakatte, Bengaluru, Karnataka 560091 _____________________________________________________________________________________________ ABSTRACT A series of new piperizine-quinoline derivatives (RB1-10) were designed and synthesized from 4- (bromomethyl)quinolin-2(1H)-one and arylpiperazines. The structure of newly synthesized compounds were characterized by spectral data’s and screened for their cytotoxic activity against barest cancer cell lines. The compound RB1 with trifluoromethoxy substitution on aryl group showed moderate activity. Keywords: 4-(Bromomethyl)quinolin-2(1 H)-one, aryl-piperazine, cytotoxicity, biological assays, anti-cancer. _____________________________________________________________________________________________ INTRODUCTION Nitrogen containing heterocyclic molecules constitutes the largest portion of chemical entities, which are part of many natural products, fine chemicals, and biologically active pharmaceuticals. In the field of six membered heterocyclic structures piperazine & quinolinone pharmacophores have significant therapeutic values in medicinal chemistry. Piperazine is a broad class of heterocyclic symmetrical aliphatic molecule consists of a six-membered ring containing two nitrogen atoms at opposite positions in the ring. There are many important biologically active molecules which contain piperazine moiety such are Ranolazine [1] and Trimetazidine [2] (antianginals drugs), Amoxapine [3], Befuraline [4], Buspirone [5], Flesinoxan [6], Ipsapirone [7], Nefazodone [8] (Antidepressant drugs), Niaprazine [9] (Antihistamine drug), Imatinib [10] (used to treat certain cancers), Antrafenine [11] (analgesic and anti-inflammatory drug) meta-chlorophenylpiperazine [12] (psychoactive drug), Olanzapine [13] (atypical antipsychotic drug) Quinolinone represents another most important class of heterocyclic molecule possessing wide spectrum of biological activities. Also, they have occupied a unique place in the medicinal and biological chemistry due to their diverse pharmacological displays as antitumor [14], antimicrobial [15], antibacterial [16] HIV-1 integrase inhibitors [17], antifungal [18], herbicidal [19]. antineoplastic [20], gastric, antiulcer and antischistosomal agents [21]. They are also useful intermediates in the manufacture of azo dyestuffs that can be used for dyeing both naturally occurring and synthetic fibers [22]. These properties of piperazines and quinolinones with numerous pharmacological and physiological activities encouraged us to develop new scaffold of molecules to synthesize novel compounds. The development of new and efficient methodologies for synthesis of potentially bioactive piperazine-quinolineone derivatives is important. 30 Nagaraja Naik et al Der Pharma Chemica, 2016, 8 (9):30-38 ___________________ __________________________________________________________ Compounds of the nature shown in figure 1 revealed the framework of piperazine-quinolinone pharmacophoric component systems. O N Quinolinone N NH R piperizines Figure-1: Piperazine-quinoline scaffold Currently cancer is one of the most deadly diseases and requires chemotherapy for the treatment [23]. Chemotherapeutic compounds are drugs that are used to destroy cancer cells. The study of destroying the cancer cell is called cytotoxicity. The cytotoxicity study is important to know about the toxic nature of compounds on cell lines. In this research we choose breast cancer lines for our studies against piperizine-quinoline scaffold molecules. For preliminary research we choose substituted and un-substituted aryl moieties attached to piperazine-quinolinone pharmacophores. The synthesised new molecules are characterized by spectral data’s like mass, IR, NMR and physical constants. The synthesised new molecules were subjected to pharmacological studies. MATERIALS AND METHODS All chemicals used for the synthesis were of reagent grade and were procured from Sigma Aldrich Chemical Co, Bangalore; SDFCL, Mumbai; and the intermediates were prepared as per the known literature procedure. NMR spectra were recorded on 400 MHz Varian-AS NMR spectrometer using TMS as an internal standard. IR spectra were recorded by using PerkinElmer Spectrum 100 Series FT-IR spectrometer. Mass spectra were recorded on Agilent 1200 Series LC/MSD VL system. Melting points were determined by using Buchi melting point B-545 instrument and are uncorrected. All the reactions were monitored by thin layer chromatography (TLC) using pre- coated silica 60 F 254 , 0.25 mm aluminum plates (Merck). The crude compounds were crystallized with appropriate solvents. Preparation of aryl-piperazines: General procedure [24]: The slurry of amine (0.1 mol) and bis(2-chloroethylamine) hydrochloride ( 0.13 mol) in sulfolane (3 volumes) were heated to 150 °C for 15 hours, after completion of reaction, cooled to 30 °C and diluted with acetone (6 volumes) and further cooled to 0 °C, maintained for 5h to precipitate the desired product. The product was filtered, slurry washed with acetone (1 volume), and dried at 60 °C under vacuum for 8 h to yield aryl-piperazine hydrochlorides. Table-1: Aryl-piperizine hydrochlorides Sl. No Amine Product Yield MP °C 1 4-(Trifluoromethoxy)aniline 1-[4-(Trifluoromethoxy)phenyl]piperazine Hydrochloride 55 % 192-195 2 4-Methyl aniline 1-(4-Methylphenyl)piperazine Hydrochloride 79 % 214-216 3 4-chloroaniline 1-(4-chlorophenyl)piperazine Hydrochloride 82 % 276-278 4 2,4-difluoroaniline 1-(2,4-Difluorophenyl)piperazine Hydrochloride 78 % 207-212 5 3-Chloroaniline 1-(3-chlorophenyl)piperazine Hydrochloride 59 % 235-237 6 2-Isopropyl-6-methyl aniline [2-Methyl-6-isopropylphenyl]piperazine hydrochloride 49 % 223-225 7 2-Fluoro-3-chloro aniline 1-(3-Chloro-2-fluorophenyl)piperazine Hydrochloride 55 % 237-239 8 2,3-Dichloroaniline 1-(2,3-Dichlorophenyl)piperazine Hydrochloride 82 % 245-247 9 4-Methoxy aniline 1-(4-Methoxyphenyl)piperazine. Hydrochloride 80 % 248-250 10 2-Fluoro aniline 1-(2-Fluorophenyl)piperazine Hydrochloride 83 % 187-189 Preparation of aryl-piperazine-quinolinones Rb(1-10): General procedure: The mixture of 4-(bromomethyl)quinolin-2(1H)-one (4) (10.0 mmole), substituted piperazines (3a-j) (11.0 mmol), potassium carbonate (30.0 mmole) and tetrabutyl ammonium bromide (0.1g) in N,N-dimethyl formamide (20 mL) were heated to 100-105 °C for 8 h. The reaction progress was monitored by TLC, after completion of reaction, cooled to 25-30 °C, quenched with ice water (100 mL), stirred the mass for 30 min. The precipitated product was filtered, washed with water and dried to get crude compound. The crude compound was crystallized from isopropanol to get pure compounds. RB(1-10). 31 Nagaraja Naik et al Der Pharma Chemica, 2016, 8 (9):30-38 ___________________ __________________________________________________________ 4-({4-[4-(Trifluoromethoxy)phenyl]piperazin-1-yl}methyl)quinolin-2(1H)-one (RB1). Off-white solid; Yield: 62.2 %; Mp: 225-227 oC; MS: m/z=404.1 (M+1); IR (KBr) cm -1: 2962, 1666, 1396, 1064; 1H-NMR (400 MHz, DMSO-d6) δ: 2.48-2.55 (dd, 4H, -CH2-N-CH2-), 3.14-3.30 (dd, 4H, -CH2-N-CH2-), 3.71 (s, 2H,C H2), 6.52 (s, 1H, Ar-H), 6.96-6.98 (m,2H, Ar-H), 7.14-7.16 (m,3H, Ar-H), 7.29-7.31 (m, 1H, Ar-H), 7.44-7.46 (m, 1H, Ar-H) 7.90- 13 7.92 (m, 1H, Ar-H), 11.66 (s,1H, NH ). C NMR (400 MHz, CDCl 3) δ: 40.63 (2C), 48.60 (2C), 59.06, 151,91, 116.64 (2C), 119.09 (2C), 119.44, 121.61, 121.90, 122.24, 125.54, 130.63, 139.52, 140.93, 147.58, 150.48, 162.02. 4-{[4-(4-Methylphenyl)piperazin-1-yl]methyl}quinolin-2(1H)-one (RB2). White solid; Yield: 43.2 %; Mp=255- o -1 1 257 C; MS: m/z=334.1 (M+1); IR (KBr) cm : 3001, 2955, 28216, 1975, 1658; H NMR (400 MHz, CDCl 3) δ: 2.17 (S, 3H, C H3), 2.48-2.59 (d, 4H, -CH2-N-CH2-), 3.05-3.30 (d, 4H, -CH2-N-CH2-), 3.70 (s, 2H,-CH2-), 6.51 (s, 1H, Ar-H), 6.79-6.81 (m, 2H, Ar-H), 6.98-7.0 (m,2H, Ar-H), 7.13-7.15 (m,1H, Ar-H), 7.17-7.28 (m, 1H, Ar-H), 7.30- 13 7.44 (m, 1H, Ar-H), 7.90-7.92 (d, 1H, Ar-H), 11.65 (s,1H, NH ). C NMR (400 MHz, CDCl 3) δ: 20.48, 49.24 (2C), 53.31 (2C), 59.17, 115.98, 116.16 (2C), 119.09 (2C), 121.58, 121.91, 125.56, 128.08, 129.79, 130.63, 139.49, 147.68, 149.38, 162.02. 4-{[4-(4-chlorophenyl)piperazin-1-yl]methyl}quinolin-2(1H)-one (RB3). Brown solid; Yield: 43.2 %; Mp=248- o -1 1 252 C; MS: m/z=354.1 (M+1); IR (KBr) cm : 3063, 2931, 1718, 1658, 1504; H NMR (400 MHz, CDCl 3) δ: 2.63- 2.69 (d, 4H, -CH2-N-CH2-), 2.98-3.00 (d, 4H, -CH2-N-CH2-), 3.71 (s, 2H,C H2), 6.51 (s, 1H, Ar-H), 6.95-7.17 (m, 5H, Ar-H), 7.28-7.30 (m, 1H, Ar-H), 7.44-7.50 (m, 1H, Ar-H), 7.90-7.92 (d, 1H, Ar-H), 11.65 (s,1H, NH ). 4-{[4-(2,4-difluorophenyl)piperazin-1-yl]methyl}quinolin-2(1H)-one (RB4). Off-white solid; Yield: 70.4 %; Mp=252-257 oC; MS: m/z=356.1 (M+1); IR (KBr) cm -1: 3064, 2930, 1720, 1657, 1591; 1H NMR (400 MHz, CDCl 3) δ: 2.48-2.61 (d, 4H, -CH2-N-CH2-), 2.80-2.87 (d, 4H, -CH2-N-CH2-), 3.72 (s, 2H,C H2), 6.51 (s, 1H, Ar-H), 6.95-6.98 (m, 1H, Ar-H), 7.01-7.04 (m,2H, Ar-H), 7.05-7.12 (m,2H, Ar-H), 7.13-7.18 (m, 1H, Ar-H), 7.28-7.30 (m, 1H, Ar-H), 7.90-7.92 (m, 1H, Ar-H), 11.65 (s,1H, NH ).
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