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Synthesis and Biological Activity Evaluation of Schiff Bases of 5-Acyl-1,2,4-Triazine.

Byline: Mariusz Mojzych and Marek Sebela

Summary

A simple and general method has been developed for the synthesis of various Schiff bases (oximes, hydrazones, semicarbazones and thiosemicarbazones) derived from 5-acyl-1,2,4- triazines. Some of the new synthesized Schiff bases were tested for biological activity but only oximes 2a-c shown poor antiviral activity. The oxime derivatives of 5-acyl-3-methylsulfanyl-1,2,4- triazine were tested with pea-seedling diamine oxidase as the enzyme is known to be inhibited by oxime compounds. However, only weak non-competitive inhibitory effects were observed (Ki of 10-2 M).

Keywords: Oximes of 5-acyl-1,2,4-triazines, Hydrazones of 5-acyl-1,2,4-triazines, Thiosemicarbazones and Semicarbazones of 5-acyl-1,2,4-triazines, Antiviral activity, Schiff base.

Introduction

1,2,4-Triazine derivatives constitute an important class of heterocyclic compounds. Both naturally occurring and synthesized derivatives of this ring system occupy an important position in medicinal chemistry and agro-chemistry due to a wide range of biological activities [1]. Furthermore,1,2,4-triazine derivatives have been shown to be intermediates for the synthesis of other nitrogen- containing heterocycles, via electron demand Diels- Alder reactions with rich dienophiles [2], or nucleophilic substitution [3]. It is worthy of mentioning that the synthesis of poly-substituted or fused 1,2,4-triazines has been an active research area for many years in our laboratory [4-6]. Recently we reported that the reaction of 1,2,4-triazines with alkyl nitronate anions has considerable synthetic utility and allows a highly efficient entry into oximes of alkyl (1,2,4-triazyn-5-yl)ketones [7].

The latter may serve as common intermediates for construction of 5-acyl- 1,2,4-triazines [8], chiral 1,2,4-triazine alcohols [9], -acylpyridines [10], pyrazolo[4,3-e][1,2,4]triazines [11], and 3-acyl-5,6,7,8-tetrahydroisoquinolines, the valuable precursor for the synthesis of sempervirine, and its analogues [12], possessing interesting pharmacological activity. 5-Acyl-1,2,4-triazines are useful building blocks for the preparation of Schiff bases e.g. semicarbazides, thiosemicarbazides and hydrazones are intermediates for the construction of pyrazolo[4,3-e][1,2,4]triazines [13].

Numerous heterocyclic Schiff bases exhibit a broad spectrum biological activity [14] including bactericidal, fungicidal, antipyretic, antitumour, antitubercular, anticancer and sterease inhibitory activities. Furthermore, some of the Schiff bases have shown antiviral, antimicrobial and anti-inflammatory activities. In analytical chemistry, Schiff bases find applications as chelating agents and analytical reagents for transition metal analysis. As a result of these useful properties, a large number of Schiff bases with 1,2,4-triazine core have been developed. Considering these applications it was planed to evaluate Schiff bases derived from 5-acyl-1,2,4- triazines with the hope to find new biologically active compounds.

In the present work, we report synthesis and antiviral evaluation of new Schiff bases containing 1,2,4-triazine moiety. As inhibitory properties towards pea seedling amine oxidase of various oxime compounds have been reported in the literature [15], two selected oxime derivatives of 5-acyl-3- methylsulfanyl-1,2,4-triazine were analyzed toward this end.

Experimental

Melting points were determined in open capillaries and are uncorrected. 1H-NM spectra were recorded on a Varian Gemini 200MHz spectrometer using tetramethylsilane as the internal standard. IR spectra were measured with a Magna IR-760 spectrometer in KBr pellets. Mass spectra were acquired using an AMD 604 spectrometer (electron impact, 70eV). Elemental analyses were obtained on a Perkin-Elmer 2400-CHN analyzer and the results for the indicated elements were within 0.3 % of the calculated values. Compounds 2a-e, 4a-e, 5, 6-36 and 37-41 was synthesized according to literature procedures [8, 9, 11, 13, 16-19].

General method for the synthesis of oxime dimers (3ab).

To a solution of oxime of 5-acyl-3- methylsulfamyl-1,2,4-triazine (1.84g, 10 mmol) in anhydrous DMF (20 mL), potassium hydroxide (0.6 g, 11 mmol) and appropriate dihalogeno compound (5 mmol) were added. The reaction mixture was stirred at rt for 2 h. Then the reaction mixture was poured into ice/water and the formed precipitate was collected by filtration, washed with cold water and recrystallized from aqueous ethanol to yield the corresponding dimer.

(1Z,1'Z)-1-(3-(methylthio)-1,2,4-triazin-5- yl)ethanone O-2-(1-(3-(methylthio)-1,2,4-triazin-5- yl)ethylidene-aminooxy)ethyl oxime (3a): Yield: 95%; m.p.: 167-169oC; 1H-NMR (CDCl3) d: 2.25 (s,6H), 2.67 (s, 6H), 4.63 (s, 4H), 9.41 (s, 2H); 13C-NMR (CDCl3) d: 9.90, 14.03, 141.68, 152.11, 153.85,173.55; Anal. Calcd. for C14H18N8O2S2: C, 42.63; H, 4.60; N, 28.41. Found: C, 42.43; H, 4.63; N, 28.27.

(1Z,1'Z)-1-(3-(methylthio)-1,2,4-triazin-5- yl)ethanone O-5-(1-(3-(methylthio)-1,2,4-triazin-5- yl)ethylidene-aminooxy)pentyl oxime (3b): Yield: 90%; m.p.: 110-112oC; 1H-NMR (DMSO-d6) d: 1.51-1.56 (m, 2H), 1.78-1.85 (m, 4H), 2.19 (s, 6H), 2.66 (s, 6H), 4.34-4.38 (t, J = 6.4 Hz, 4H), 9.38 (s,2H); 13C-NMR (DMSO-d6) d: 9.50, 13.84, 22.23, 28.82, 75.63, 141.53, 152.16, 152.49, 173.13; Anal. Calcd. for C17H24N8O2S2: C, 46.77; H, 5.54; N, 25.67. Found: C, 46.57; H, 5.57; N, 25.48.

Results and Discussion

Chemistry

The route used for the synthesis of Schiff bases assessed in this study is outlined in Scheme 1. The key intermediates for the presented synthesis are oximes 2a-e prepared, in good yield, by nucleophilic substitution reaction of hydrogen with nitronate anions under basic condition according to published procedure [7]. The oximes 2a-e occurred to be useful intermediates for the synthesis of ketones 4a-e [8] and dimers 3ab. In order to obtain the desired bis- oxime ethers 3ab, the oxime 2a was allowed to react with appropriate dihalogeno alkyl compounds, in a molar ratio of 2:1, in DMF in the presence of potassium carbonate at room temperature. The reaction of ketone 4a (R1 = SCH3, R2 = CH3) with hydrazine hydrochloride in ethanol produced a derivative (5) [16, 20].

Condensation of 5-acetyl- 1,2,4-triazines 4a-e with phenylhydrazine derivatives in ethyl alcohol containing catalytic amount of hydrochloric acid formed appropriate arylhydrazone of 5-acyl-1,2,4-triazine 6-36 in excellent yield [13, 17, 18, 21]. In an attempt to prepare the thio- and semi- carbazide derivatives 37-41 the carbonyl compounds 4a and 4d were treated with thio- and semi- carbazide in ethanol under acidic conditions [18].

The structures of the evaluated compounds were established by spectroscopic methods 1H-NMR, 13C-NMR, MS and elemental analysis [8, 9, 11, 13, 16-19] and some of them were subjected to x-ray analysis and the results were published elsewhere [20, 21].

Biological Activity

Pea diamine oxidase was isolated from 7- day-old etiolated seedlings following a published procedure [22]. The final enzyme preparation showed a specific activity of 42 Umg-1 determined by the guaiacol spectrophotometric method with putrescine as a substrate [23]. Kinetic parameters of inhibitors were characterized by measuring Lineweaver-Burk plots, stock solutions of the measured compounds were made in methanol.

The synthesized Schiff bases were evaluated for activity against several RNA- and DNA-viruses, using the following cell-based-assays: (a) Vero cells infected with parainfluenza-3 virus, reovirus-1, Sindbis virus, Coxsackie B4 virus, or Punta Toro virus; (b) human embryonic lung (HEL) fibroblasts infected with herpes simplex virus-1 (KOS), herpes simplex virus-2 (G), acyclovir-resistant herpes simplex virus-1 (KOS ACVr TK-), vaccinia virus or vesicular stomatitis virus; (c) human epithelial (HeLa) cells infected with vesicular stomatitis virus, coxsackie B4 virus or respiratory syncytial virus and (d) Madin Darby canine kidney (MDCK) cells infected with influenza virus, subtype A/H1N1, A/H3N2 or B. Antiviral activity of tested compounds in HEL, Vero and HeLa cell cultures are presented in Table-2. Against MDCK cell culture none of the tested compounds were active.

As a results of broad spectrum antiviral screening of the derivatives, which had minimal antivirally effective concentration less than one-fifth of minimal cytotoxic concentration, were considered active. Compounds 2b and 2c emerged as the best antiviral agents among the tested Schiff bases against Coxsackie Virus B4 (EC50=2 g/mL for 2b and EC50=9 g/mL for 2c, Table-2) and Punto Toro virus (EC50=59 g/mL for 2b and EC50=12 g/mL for 2c, Table-2) in Vero cell culture, Vesicular Stomatitis virus (EC50=50 g/mL for 2b and EC50=9 g/mL for 2c, Table-2) and Coxsackie Virus B4 (EC50=2 g/mL for 2b and EC50=12 g/mL for 2c, Table 2) in HeLa cell culture. Against viruses in HEL cell culture, no activity was observed with any of the screened derivatives, except of oxime 2b (Table 2) which was much less active than the reference compounds: brivudin, cidofovir and ganciclovir.

Further, oxime 2a emerged as promising antiviral agent against both Coxsackie Virus B4 in Vero cell culture and Coxsackie Virus B4 in HeLa cell culture with an EC50 value of 20 and 45g/mL, respectively. It would be worthwhile to design several analogues of the evaluated oximes (2a-c) to optimize them antiviral potency and this will be the subject of our future research.

Various oximes have been shown to inhibit copper-containing amine oxidases due to their interaction with the enzyme-bound cupric ions [15]. For that reason, we performed also an enzymological experiment as a part of this study. Two oxime compounds, 1-(3-methylsulfanyl-[1,2,4]triazin-5-yl)- ethanone oxime (2a) and 1-(3-methylsulfanyl- [1,2,4]triazin-5-yl)-propan-1-one oxime (2b) displayed only a very weak effect on pea diamine oxidase. They were found to be non-competitive inhibitors characterized by high Ki values of 14 and 16 mM, respectively. Thus, their inhibitory properties can be considered negligible, which becomes apparent namely in comparison with the behaviour of previously studied aliphatic, alicyclic and aromatic oximes [15].

Table-1: The minimum cytotoxic concentration of Schiff bases.

###Minimum cytotoxic concentration (g/mL)a

###Compounds###R1###R2###R3###X

###HEL###Vero###HeLa

###2a###SCH3###CH3###greater than 100###greater than 100###greater than 100

###2b###SCH3###C2H5###100###100###greater than 100

###2c###SCH3###C3H7###20###100###100

###3a###SCH3###CH3###100###100###100

###3b###SCH3###CH3###20###100###100

###5###SCH3###CH3###100###100###20

###6###SCH3###CH3###CH3###100###100###100

###7###OCH3###CH3###Ph###100###100###20

###8###SCH3###CH3###p-CH3-Ph###0.8###100###100

###9###SCH3###CH3###p-OCH3-Ph###20###100###100

###10###SCH3###CH3###m-Cl-Ph###100###100###100

###11###SCH3###CH3###o,p-diCl-Ph###20###100###100

###12###SCH3###CH3###p-NO2-Ph###100###100###100

###13###SCH3###CH3###o,p-diNO2-Ph###100###100###100

###14###SCH3###C2H5###Ph###100###100###100

###15###SCH3###C2H5###o-CH3-Ph###100###20###100

###16###SCH3###C2H5###m-CH3-Ph###20###20###20

###17###SCH3###C2H5###p-CH3-Ph###20###100###100

###18###SCH3###C2H5###p-OCH3-Ph###100###100###100

###19###SCH3###C2H5###p-Cl-Ph###100###100###100

###20###SCH3###C2H5###m-Cl-Ph###20###100###20

###21###SCH3###C2H5###o,p-diCl-Ph###100###100###100

###22###SCH3###C3H7###p-CH3-Ph###100###100###100

###23###SCH3###C3H7###p-OCH3-Ph###100###100###20

###24###SCH3###C3H7###p-Cl-Ph###100###100###100

###25###SCH3###C3H7###m-Cl-Ph###100###20###20

###26###SCH3###C3H7###p-NO2-Ph###100###100###100

###27###Ph###CH3###p-CH3-Ph###100###100###100

###28###Ph###CH3###m-CH3-Ph###100###greater than 100###100

###29###Ph###CH3###p-OCH3-Ph###100###100###100

###30###Ph###CH3###m-Cl-Ph###100###100###100

###31###Ph###CH3###o,p-diNO2-Ph###100###100###100

###32###Ph###CH3###o,p-diCl-Ph###100###100###100

###33###Ph###C2H5###o,p-diCl-Ph###100###100###100

###34###Ph###CH3###5-NO2-2-pyridyl###20###20###20

###35###Ph###CH3###3-NO2-4-pyridyl###greater than 100###greater than 100###greater than 100

###36###Ph###CH3###3-NO2-2-pyridyl###greater than 100###greater than 100###greater than 100

###37###SCH3###CH3###S###20###100###20

###38###SCH3###CH3###O###100###100###100

###39###Ph###CH3###O###100###greater than 100###100

###40###SCH3###CH3###S###100###100###100

###41###SCH3###CH3###O###greater than 100###greater than 100###greater than 100

###DS-5000###-###greater than 100###greater than 100

###(S)-DHPA###-###greater than 250###greater than 250

###Ribavirin###greater than 250###greater than 250###greater than 250

###Brivudin###greater than 250###-###-

###Cidofovir###greater than 250###-###-

###Ganciclovir###greater than 100###-###-

Table-2: Antiviral activity of Schiff bases in HEL, Vero and HeLa cell cultures.

###EC50a (g/mL)

HEL###Vero###HeLa

Compounds

Herpes Simplex###Herpes Simplex###Vaccinia virus###Vesicular###Herpes Simplex###Para-###Reovirus- 1 Sindbis virus###Coxsackie Virus B4 Punta Toro virus Vesicular###Coxsackie###Respiratory###Syncytial virus

Virus-1(KOS)###virus-2 (G)###Stomatitis virus###virus-1 KOS###Influenza-3 virus###Stomatitis virus###Virus B4###

###2a###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###20###100###greater than 100###45###greater than 100

###2b###59###59###greater than 100###greater than 100###100###greater than 100###greater than 100###greater than 100###2###59###50###2###greater than 100

###2c###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4###greater than 20###greater than 20###greater than 20###9###12###9###12###greater than 20

###3a###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###3b###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###5###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###6###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###7###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###8###greater than 0.8###greater than 0.8###greater than 0.8###greater than 0.8###greater than 0.8###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###9###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###11###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 2###greater than 20###greater than 20###greater than 20

###12###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###13###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###14###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###15###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4###greater than 20###greater than 20###greater than 20

###16###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4

###17###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###18###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###19###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###21###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 20###greater than 20###greater than 20

###22###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###23###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###24###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###25###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4###greater than 20###greater than 20###greater than 20

###26###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###27###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 20###greater than 20###greater than 20###greater than 20###greater than 2 0###greater than 20###greater than 20###greater than 20

###28###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100

###29###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###30###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###31###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###32###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###33###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20

###34###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4###greater than 4

###35###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100

###36###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 20###greater than 20###greater than 20

###37###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 0.16###greater than 0.16###greater than 0.16

###38###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 0.8###greater than 0.8###greater than 0.8

###39###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 20###greater than 20###greater than 20

###40###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 20###greater than 0.8###greater than 0.8###greater than 0. 8

###41###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 100###greater than 0.16###greater than 0.16###greater than 0.16

###DS-5000###-###-###-###-###-###greater than 100###greater than 100###59###greater than 100###9###12###100###0.5

###(S)-DHPA###-###-###-###-###-###greater than 250###greater than 250###greater than 250###greater than 250###greater than 250###250###greater than 250###greater than 250

###Ribavirin###greater than 250###greater than 250###greater than 250###126###greater than 250###112###greater than 250###greater than 250###greater than 250###112###22###146###29

###Brivudin###0.04###126###4###greater than 250###250###-###-###-###-###-###-###-###-

###Cidofovir###1###4###3###greater than 250###4###-###-###-###-###-###-###-###-

Ganciclovir###0.06###0.03###greater than 100###greater than 100###2###-###-###-###-###-###-###-###-

Conclusion

A series of new Schiff bases (oximes, hydrazones, semicarbazones and thiosemicarbazones) derived from 5-acyl-1,2,4-triazines were synthesized in order to evaluate their biological activities. Among the synthesized compounds only oximes: 2a, 2b, and 2c showed significant antiviral activities. The results of antiviral activity of the tested compounds are shown in table 2. None of the other Schiff bases exhibited specific antiviral activity, which means that they do not inhibit replication (formation of viral cytopathogenicity) of any the viruses tested at a concentration that was =5-fold lower than the minimum cytotoxic concentration. In our opinion only oximes 2a-c are suitable as a subject to further structural modifications for biological study.

Acknowledgments

This research was supported by Grant No. NN405 092340 from the National Science Centre, Poland. The authors are thankful to Prof. Jan Balzarini from Riga Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium for antiviral study.

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Author:Mojzych, Mariusz; Sebela, Marek
Publication:Journal of the Chemical Society of Pakistan
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Date:Apr 30, 2015
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