Synthesis, and Anti-Cancer Activity of Some Novel 3-(Piperazin-1-Yl)Pyrazin-2-Amine Derivatives

Nagaraja Naik et al. / Journal of Pharmacy Research 2016,10(6),419-425 Research Article Available online through ISSN: 0974-6943 http://jprsolutions.info Synthesis, and anti-cancer activity of some novel 3-(piperazin-1-yl)pyrazin-2-amine derivatives Sadagopan Sekar1, Nagaraja Naik *1, Ajjanna M Sridhara 2, Shivanna Yogish3 1 Department of Chemistry, University of Mysore, Manasagangotri, Mysore-570 006, Karnataka, India 2 Department of Industrial Chemistry, Kuvempu University, Shankaragatta -577 451, Karnataka, India 3 Skanda Life Sciences Pvt Ltd, Sunkadakatte, Bengaluru-560091, Karnataka,India Received on:16-04-2016; Revised on: 23-05-2016; Accepted on: 19-06-2016 ABSTRACT Aim: Synthesis of some new 2-aminopyrazine derivatives for the preliminary studies on cytotoxicity against breast cancer cells. Methods: The starting materials for the synthesis of new 2-aminopyrazine derivatives (PP1-18) are aryl-piperazines and 3,5-dibromo-2- aminopyrazine , which were prepared by the known literature procedure and condensed to get the new derivatives. The structure of newly synthesized compounds were characterized by spectral data and studied for their cytoxicity activity against breast cancer lines. Results: Some compounds showed moderate cytotoxicity on breast cancer cells and some have non toxic. Conclusions: In this article we reported the synthesis of a new (PP1-18) 2-aminopyrazine derivatives. The cytotoxicity studies showed that compounds were moderately toxic and some are non-toxic Hence the fact that the compounds prepared in this study are chemically new and not related to current medication and further work is clearly warranted. KEYWORDS: Breast cancer cells, 2-aminopyrazine, aryl-piperazines, cytotoxicity, 2-amino-3,5-dibromopyrazine. Graphical Abstract A series of new 2-aminopyrazine derivatives were synthesized starting from anilines and evaluated for their cytotoxicity activities. N NH2 NH NH 2 Cl N NH Br N Br 2 N N N HCl NH HCl N R R Br R 4 Cl 5 6 INTRODUCTION Nitrogen containing heterocyclic molecules constitutes the largest atoms at opposite positions in the ring. There are many important portion of chemical entities, which are part of many natural products, biologically active molecules which contain piperazine moiety such fine chemicals, and biologically active pharmaceuticals. In the field of are Ranolazine1 and Trimetazidine2 (antianginals drugs), Amoxapine3, six membered heterocyclic structures piperazine & pyrazine Befuraline4, Buspirone5, Flesinoxan6, Ipsapirone7, Nefazodone8 pharmacophores have significant therapeutic values in medicinal (Antidepressant drugs), Niaprazine9 , (Antihistamine drug), Imatinib10 chemistry. (used to treat certain cancers), Antrafenine11 (analgesic and anti- inflammatory drug) meta-Chlorophenylpiperazine12 (psychoactive Piperazine is a broad class of heterocyclic symmetrical aliphatic drug), Olanzapine13 (atypical antipsychotic drug). molecule consists of a six-membered ring containing two nitrogen *Corresponding author. Pyrazine is another broad class of heterocyclic symmetrical aromatic Dr. Nagaraja Naik, molecule with two nitrogen atoms at opposite position in the ring. Professor, Pyrazine derivatives such as phenazine14 are well known for their Department of Studies in Chemistry antitumor15, antibiotic16 and also as dyestuffs17. Tetramethylpyrazine 18 University of Mysore,Manasagangotri, (also known as ligustrazine) is reported to scavenge superoxide anion Mysore – 570006,Karnataka, India. Journal of Pharmacy Research Vol.10 Issue 6 June 2016 419-425 Nagaraja Naik et al. / Journal of Pharmacy Research 2016,10(6),419-425 and decrease nitric oxide production in human polymorpho nuclear Procedures: leukocytes19 , and is a component of some herbs in traditional Chinese Preparation of 2-amino-3,5-dibromopyrazine31 5a: medicine20. Some of the pyrazine containing active molecules with N-Bromosuccinimide (440 gm) was added to a mixture of 2- various pharmacological activity are Glipzide21 (Anti-diabetic drug), Aminopyrazine (100 gm) in N,N-dimethylsulfoxide (2000 mL) and methoxypyrazine22 (produce odours), isopropylmethoxypyrazine23 water (26 mL) at 10-15 °C. Stirred the reaction mass for 1 hour, after (flavor compound in coffee), MK-21224 (promotes the secretion of completion of reaction, transferred the to 5% aqueous sodium serem prolactum and cortisol in humans), morinamide25 ( used in the carbonate solution (5000 mL), extracted with ethyl acetate (500 mL X treatment of tuberculosis), Oltipraz26 (used in tumer prevention), 3 times), distilled of the solvent completely under vacuum and varenicline27(used to treat smoking addiction), Telaprevir28 (used for crystallized from ethanol to get off-white coloured solid. the treatment of hepatitis-C), Zibotentan29 (an anticancer candidate), WAY-20846630 (antidepressant and anxoiolytic). Weight: 135 gm Yield: 50.76 %; Mp= 115-117 oC; MS: m/z=254.1 (M+2); 1 H NMR (400 MHz, DMSO-d6) : 6.96 (s, 2H, NH2), 8.10 (s, 1H, ArH), -1 These properties of piperazines and pyrazines with numerous IR: (KBr) max : 3448, 3286, 3155, 1620, 1504, 1365, 1099 cm . pharmacological and physiological activities encouraged us to 32 develop new scaffold of molecules to synthesize a large number of Preparation of aryl-piperazines: General procedure : novel compounds. The development of new and efficient A slurry of amine (1 mol) and bis(2-chloroethylamine) hydrochloride methodologies for synthesis of potentially bioactive piperazine- ( 1.3 mol) in sulfolane (3 volumes) were heated to 150 °C for 15 hours, after completion of reaction, cooled to 25-35 °C and diluted with pyrazine derivatives is important. Compounds of the nature shown acetone (6 volumes) and further cooled to 0 °C, maintained for 5h to in figure 1 revealed the framework of piperazine-pyrazine precipitate the desired product. The product was filtered, slurry pharmacophoric component systems. washed with acetone (1 volume), and dried at 60 °C under vacuum for 8 h to yield phenyl-piperazine hydrochlorides. N NN Pyrazine Preparation of Aryl piperazine-pyrazines (PP1-18): N R General procedure Variations Piperazine The mixture of aryl-piperazines (6a-p) (10.0 mmol), 2-Amino-3,5- Figure 1: Scaffold of pyrazine-piperazine molecules dibromopyrazine (10.0 mmol), potassium carbonate (20.0 mmol), and For preliminary research we choose substituted and un-substituted tetra butyl ammonium bromide (0.1g) in N,N-dimethyl formamide aryl moieties attached to piperazine-pyrazine pharmacophores. The (10 mL) were heated to 100-105 °C for 4 hr. The progress of the synthesised new molecules are characterized by spectral data’s like reaction was monitored by TLC, after completion of reaction, cooled mass, IR, NMR and physical constants. The synthesised new to 25-30 °C, quenched with ice water (100 mL), stirred for 30 min. The molecules were subjected for pharmacological studies. precipitated product was filtered, washed with water and dried to get crude compound. The crude compounds were crystallized from MATERIALS AND METHODS isopropanol to get pure compounds. CHEMISTRY 5-Bromo-3-(4-phenylpiperazin-1-yl)pyrazin-2-amine PP1: All chemicals used for the synthesis were of reagent grade and were Off-White solid; Yield: 62.2 %; Mp: 130-132 °C; MS: m/z=336, 337 procured from Sigma Aldrich Chemical Co, Bangalore; SDFCL, (M+1, M+2); IR (KBr) cm-1: 3472, 3279, 3124, 1627, 1450 ; 1H NMR Mumbai; and the intermediates were prepared as per the known (400 MHz, DMSO-d6) : 3.22-3.30 (m, 8H,Piperazine-H), 4.52 (s, 2H, literature procedure. 1H and 13C NMR spectra were recorded on 400 NH2), 6.81-6.85 (t,1H, Ar-H), 6.94-9.67 (d, 2H, Ar-H), 7.24-7.30 (m, 2H, MHz Varian-AS NMR spectrometer using TMS as an internal Ar-H), 7.77 (s,1H, Pyrazine-H). standard. IR spectra were recorded by using PerkinElmer Spectrum 100 Series FT-IR spectrometer. Mass spectra were recorded on Agilent 5-bromo-3-[4-(2-fluorophenyl)piperazin-1-yl]pyrazin-2-amine 1200 Series LC/MSD VL system. Melting points were determined by PP2: using Buchi melting point B-545 instrument and are uncorrected. All White solid; Yield: 43.2 %; Mp=158-160 °C; MS: m/z=354.0 (M+2); IR the reactions were monitored by thin layer chromatography (TLC) (KBr) cm-1: 3441, 3266, 2831, 1613, 1450. 1H NMR (400 MHz, DMSO- using pre-coated silica 60 F , 0.25 mm aluminum plates (Merck). The 254 d6) : 3.21-3.23 (t, 4H, Piperazine-H), 3.36-3.39 (t, 4H, Piperazine-H), crude compounds were crystallized with appropriate solvents. 4.54(s, 2H, NH2), 6.92-7.0 (m, 4H, Ar-H), 7.76 (s, 1H, Pyrazine-H). Journal of Pharmacy Research Vol.10 Issue 6 June 2016 419-425 Nagaraja Naik et al. / Journal of Pharmacy Research 2016,10(6),419-425 3-[4-(3-amino-6-bromopyrazin-2-yl)piperazin-1-yl]phenol PP3: 1 3440, 3284, 1609, 1455. H NMR (400 MHz, CDCl3): 3.23-3.36 (m, 8H, White solid; Yield: 43.2 %; Mp=191-193 °C; MS: m/z=352.2 (M+2); IR Piperazine-H), 4.57 (s, 2H, NH2), 6.86-6.98 (m, 2H, Ar-H), 7.00-7.24 (m, (KBr) cm-1: 3456, 3286, 3140, 1604, 1450, 1H NMR (400 MHz, DMSO- 2H, Ar-H), 7.77 (s, 1H, Pyrazine-H). d63) : 3.17-3.24 (m, 8H, Piperazine-H ), 6.21-6.23 (m, 1H, Ar-H), 6.22 (s, 2H, NH2), 6.35 (s, 1H, Ar-H), 6.40-6.43 (dd, 1H, Ar-H), 6.98-7.02 (t, 5-bromo-3-[4-(2,6-dimethylphenyl)piperazin-1-yl]pyrazin-2-amine 1H, Ar-H), 7.70 (s, 1H, Pyrazine-H), 9.17 (s, 1H, -OH). PP10: White solid; Yield: 62.6 %; Mp=144-148 °C; MS: m/z=364.0 (M+2); IR 5-bromo-3-[4-(4-chlorophenyl)piperazin-1-yl]pyrazin-2-amine -1 1 (KBr) cm : 3472, 3302, 2955, 1612, 1450. H NMR (400 MHz, CDCl3) : PP4: 2.34 (s, 6H, Two-CH3) 3.25-3.27 (m, 8H, Piperazine-H), 4.61 (s, 2H, White solid; Yield: 70.4 %; Mp=132-138 °C; MS: m/z=370 (M+2); IR NH2), 6.93-7.01 (m, 3H, Ar-H), 7.76 (s, 1H, Pyrazine-H).

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