Selenocompounds have been widely synthesized for their potential in pharmacology. Ebselen, a selenazole oxide, is a

glutathione peroxidase mimic which is known to possess high antioxidant activity. Four derivatives of 3-(2-amino-1,3-

selenazol-4-yl)-2H-chromen-2-ones were synthesized by reacting 3-(2-bromoacetyl)-chromen-2-one derivatives with

selenourea through Hantzsch reaction using NaF as a catalyst in methanol-water (1:1) at room temperature. These

reactions were completed in 30 min and purified using column chromatography eluted with n-hexane-ethyl acetate (7:3)

to give 50-83% yields. All the compounds were successfully characterized using IR, 1H and 13C NMR as well as mass

spectrometry. The synthesized compounds were tested with DPPH assay to determine the free radical scavenging activity

and were compared to gallic and ascorbic acids as standard. Nonetheless, all compounds exhibited weak free radical

scavenging activity with IC50 value ranging from 672.13 to 984.03 μM signifying that the derivatives may possess weak

antioxidant activities

Nurul Izzaty Hassan,

Nurul Zawani Alias,

Sharizal Hasan,

Wan Yaacob Wan Ahmad,

Zaini Yusoff,

UKM Journal Article Repository

Sains Malaysiana 47(2)(2018): 347-352http://dx.doi.org/10.17576/jsm-2018-4702-17Synthesis, Characterization and Antioxidant Activity of 3-(2-Amino-1,3-Selenazol-4-yl)-2H-Chromen-2-Ones Derivatives(Sintesis, Pencirian dan Aktiviti Antioksidan Terbitan 3-(2-Amino-1,3-selenazol-4-il)-2H-Kromen-2-On)Nurul ZawaNi alias , Nurul iZZaty HassaN, ZaiNi yusoff, sHariZal HasaN & waN yaacob waN aHmad*abstractSelenocompounds have been widely synthesized for their potential in pharmacology. Ebselen, a selenazole oxide, is a glutathione peroxidase mimic which is known to possess high antioxidant activity. Four derivatives of 3-(2-amino-1,3-selenazol-4-yl)-2H-chromen-2-ones were synthesized by reacting 3-(2-bromoacetyl)-chromen-2-one derivatives with selenourea through Hantzsch reaction using NaF as a catalyst in methanol-water (1:1) at room temperature. These reactions were completed in 30 min and purified using column chromatography eluted with n-hexane-ethyl acetate (7:3) to give 50-83% yields. All the compounds were successfully characterized using IR, 1H and 13C NMR as well as mass spectrometry. The synthesized compounds were tested with DPPH assay to determine the free radical scavenging activity and were compared to gallic and ascorbic acids as standard. Nonetheless, all compounds exhibited weak free radical scavenging activity with IC50 value ranging from 672.13 to 984.03 µM signifying that the derivatives may possess weak antioxidant activities.Keywords: Coumarin; selenazole; synthesisabstrakSebatian seleno telah disintesis secara meluas kerana potensinya dalam bidang farmakologi. Ebselen iaitu sebatian selenazol oksida merupakan mimik glutation peroksida yang diketahui mempunyai aktiviti antipengoksida yang tinggi. Empat sebatian 3-(2-amino-1,3-selenazol-4-il)-2H-kromen-2-on disintesis dengan menindakbalaskan terbitan 3-(2-bromoasetil)-kromen-2-on dengan selenourea melalui tindak balas Hantzsch dan menggunakan NaF sebagai mangkin dalam metanol-air (1:1) pada suhu bilik. Tindak balas ini selesai dalam 30 min dan ditulenkan dengan kromatografi turus yang dielusikan dengan n-heksana-etil asetat (7:3) bagi memberikan 50-83% hasil. Kesemua sebatian dicirikan menggunakan spektroskopi IM, RMN 1H dan 13C serta spektrometri jisim. Sebatian yang telah disintesis diuji dengan asai DFPH bagi menentukan aktiviti penggarutan radikal bebas dan dibandingkan dengan asid galik dan askorbik sebagai piawai. Walau bagaimanapun, kesemua sebatian menunjukkan aktiviti penggarutan radikal bebas yang lemah dengan julat nilai IC50 diantara 672.13 ke 984.03 µM menandakan terbitan sebatian ini mungkin mempunyai aktiviti antioksida yang lemah.Kata kunci: Koumarin; selenazol; sintesisiNtroductioNThe 1,3-Selenazoles were mainly synthesized by the application of the Hantzsch procedure. Various 1,3-selenazole derivatives have been prepared but so far there are only three studies reported on the synthesis of coumaryl 1,3-selenazoles. Madhav et al. (2008) have developed an efficient method to synthesize 1,3-selenazoles in good yields with high purity. The α-Bromoketones and selenourea with CuPy2Cl2 which act as a catalyst were ground in a mortar and pestle at room temperature without any solvent. The reactions were completed in 30 min with percentage yields of 87-96%. The experimental procedure was extremely simple with mild reaction conditions, environmentally friendly catalyst, no product waste or toxic solvent and a reusable catalyst. Following this study, Banothu et al. (2014) employed NaF as a catalyst in methanol-water (1:1) which decreases the reaction time from 30 min to between 1-3 min only. Recently, Ramesh et al. (2015) took a further step by applying ultrasonic irradiation and successfully shortened the reaction time from 1-3 min to only 10-60 s. All the described procedures gave excellent percentage yields of about 87-99%. 3-(2-amino-1,3-selenazol-4-yl)-2H-chromen-2-ones constitutes two important classes of compounds which are coumarins and 1,3-selenazoles. Both of them were known for their wide applications in pharmaceutical industry. Coumarins in both natural or synthesized exhibit wide range of bioactivities including anti-HIV, antimalarial, insecticides, antioxidant, anti-inflammatory, antitumor, hepatoprotective, anti-allergic, antiviral, antifungal, antimicrobial, antiasthmatic, antinociceptive, 348antidiabetic and antidepressant activity (Anand et al. 2012; Kumar et al. 2011). Similarly, 1,3-selenazoles have been widely synthesized for their potential in pharmacology and material sciences. Selenazofurins which contain 1,3-selenazole rings are known as potent antiviral agents and 2-phenyl-1,2-benzisoselenazol-3(2H)-one or Ebselen is a known glutathione peroxidase mimics which possesses antioxidant activity (Madhu et al. 2014; Mao et al. 2013; Pizzo & Mahler 2014; Zhao et al. 2013). This study attempt to combine coumarin and 1,3-selenazole to form a new compound with wide application in bioactivities. We hypothesized that the combination of these two moieties may exhibit high potential as antiviral, antifungal, antimicrobial and antioxidants. This report will provide new insight on the potential of these compounds as free radical scavengers considering that there are no previous reports deliberating on the biological activities of these derivatives. This study aims to synthesize 3-(2-amino-1,3-selenazol-4-yl)-2H-chromen-2-ones and to determine the free radical scavenging activities of these derivatives.materials aNd metHods3-(2-bromo-acetyl)-chromen-2-one, selenourea, NaF, anhydrous Na2SO4 and solvents (methanol, n-hexane, ethyl acetate) were purchased from Sigma-Aldrich and Friendemann Schmidt and used directly without further purification. Melting points were determined by using Electrothermal Melting Point Model 9100. Infrared spectra were obtained using FTIR Perkin Elmer-with spotlight 400 Imaging System in the spectral range of 4000-650 cm–1. 1H and 13C were recorded by using Jeol JNM-ECP 400MHz NMR spectrometer. The gas chromatograph mass spectrometer (GC/MS) analysis were performed on an Agilent 7890A gas chromatograph (GC) directly coupled to the mass spectrometer system (MS) of an Agilent 5975C inert MSD with triple-axis detector. Electrospray ionization mass spectrometry (ESIMS) was recorded on Dionex, Bruker, MicroToF Q apparatus.SYNTHESIS OF 3-(2-AMINO-1,3-SELENAZOL-4-YL)-2H-CHROMEN-2-ONESThe general procedure for synthesizing 3-(2-amino-1,3-selenazol-4-yl)-2H-chromen-2-one (Scheme 1) was as follows: A mixture of 3-(2-Bromoacetyl)-chromen-2-one (1 mmol) and selenourea (1 mmol) were dissolved in 2 mL methanol and 2 mL water and added 0.02 g NaF. The mixture was stirred at room temperature for 30 min. After the completion of the reaction, water (5 mL) was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure and the resulting product was further purified by column chromatography (n-hexane-ethyl acetate 7:3) (Ramesh et al. 2015; Madhav et al. 2008).FREE RADICAL-SCAVENGING ACTIVITY (RSA): DPPH ASSAYThe RSA of the derivatives was measured according to the method reported previously with some modification (Mahdavi et al. 2016). Briefly, 1.5 mL aliquot of each samples at 16.125, 31.25, 62.50, 125 and 250 µg/mL was added to 1 mL of 0.1 mM DPPH in methanol. The mixture was agitated vigorously for 1 min, and allowed to stand in the dark for 90 min at room temperature. The absorbance value was recorded at 517 nm. Gallic and ascorbic acids were used as reference control. All measurements were carried out in triplicate. The RSA of samples, was expressed as percentage inhibition of DPPH using the following equation:  I(%) = [ Ac – A0––––––Ac ] × 100,where Ac is the absorbance value of the control (DPPH solution without samples); and A0 is the absorbance value of the compound (DPPH solution with samples).results aNd discussioN3-(2-Amino-1,3-selenazol-4-yl)-2H-chromen-2-ones, b(1-4) were characterized by IR, 1H and 13C NMR and mass spectral data. In addition, radical scavenging activity for these compounds were also determine using DPPH assay presented as IC50 value. Overall, the reactions gave reasonable to good yields (50.1-83.2%) as summarized in Table 1. The melting points measured were similar with previous studies.INFRARED SPECTRAIn the infrared spectrum of 3-(2-amino-1,3-selenazol-4-yl)-2H-chromen-2-one, b1 it was possible to observe the O OOBr H2N NH2SeO OSeNNH2+NaF, MeOH-H2O (1:1)r.t, 30 min5'4'3'2'1'8 976 5 432110R2R1R2R1ab1, R1: H; R2: Hb2, R1: H; R2: CH3b3, R1: Br; R2: Brb4, R1: Cl; R2: ClscHeme 1. Formation of 3-(2-amino-1,3-selenazol-4-yl)-2H-chromen-2-ones349absorptions at 3377 and 3305 cm–1 relating to N-H stretch for primary amine, absorption at 1687 cm–1 for coumarin carbonyl stretch and absorption at 1254 cm–1 relating to C-N stretch for amine group (Figure 1).The characteristic functional groups for all derivatives were listed in Table 2. Two clear absorptions for primary amine were observed in the range of 3305-3397 cm–1 and 3377-3484 cm–1. A strong absorption for C=O group were observed between 1687-1735 cm–1. Compound b2, b3 and b4 showed higher absorption for C=O compared to b1 cause by the presence of CH3, Cl and Br group which tend to draw in the electrons between carbon and oxygen atoms through its electron-withdrawing effect, so that the C=O becomes stronger.NUCLEAR MAGNETIC RESONANCE SPECTROSCOPYFigure 2 shows the 1H NMR spectrum for compound b1 (C12H8N2O2Se) as representative for 3-(2-amino-1,3-TABLE 1. The yield (%) and melting point (°C) of 3-(2-Amino-1,3-selenazol-4-yl)-2H-chromen-2-one derivativesCompounds Yield (%) Melting point (°C)Observed Literature review (Ref.)b1 50.1 218-220 218-220 (Ramesh et al. 2015)b2 81.7 212-214 166 (Madhav et al. 2008)b3 83.2 252-253 326-328 (Ramesh et al. 2015)b4 56.9 242-244 98 (Madhav et al. 2008)FIGURE 1. The infrared spectrum of compound 3-(2-Amino-1,3-selenazol-4-yl)-2H-chromen-2-oneTABLE 2. The stretching frequencies for 3-(2-Amino-1,3-selenazol-4-yl)-2H-chromen-2-one derivativesCompounds IR Spectrum (cm–1)υ (N-H) primary υ (C=O) υ (C-N)b1 3377, 3305 1687 1254b2 3440, 3397 1718 1252b3 3484, 3379 1735 1297b4 3381, 3342 1720 1250selenazol-4-yl)-2H-chromen-2-one derivatives. While the chemical shifts for 1H NMR and 13C NMR for b1 (C12H8N2O2Se), b2 (C13H10N2O2Se), b3 (C12H6Br2N2O2Se) and b4 (C12H6Br2N2O2Se) were listed in Tables 3 and 4, respectively. 1H NMR spectrum for b1 showed clear signals for all protons except for NH protons which overlapped with H-8 signal. The spectrum also showed that H-4 is the most downfield proton at 8.54 ppm.Compound b2 showed a CH3 signal at 2.38 ppm for a methyl group at C-8. All signals for aromatic protons were observed between 7.35 and 8.54 ppm. Signals for H-5 and H-7 were observed at 7.46-8.06 ppm and 7.35-8.06 ppm, respectively, with clear multiplicity except for b3 which only exhibit a singlet. Compound b3 and b4 exhibit higher chemical shifts for H-5 and H-7 because the presence of two halogen group and C-6 and C-8. Other than that, H-6 signals were observed at 7.58 ppm for b1 and 7.24 ppm for b2 while signal for H-8 for compound b1 was observed at 7.42 ppm. A broad NH2 proton signal for all derivatives were observed between 7.43-7.52 ppm while H-4 and H-5′ signals showed two clear singlet signals at 8.42-8.54 ppm and 8.06-8.14 ppm, respectively.From the 13C NMR spectra, the signals for all compounds were observed between 110.2 and 169.6 ppm except for CH3 signal for compound b2 which was observed at 15.4 ppm. Signals for C-5′ of selenazole rings were observed at the most upfield region between 110.2 and 116.1 ppm while signals for C-4′ of selenazole rings appeared between 143.7 and 145.8 ppm. Signals at 158.0-159.4 ppm belong to C=O for coumarin ring and the most 100908070605040% T4000 3745 17053490 3235 2980 2980 2470 2215 1960 1450 1195 940 685cm–1υ(N-H)primary υ(C-H)stretchingυ(C=O)υ(C=C)aromaticυ(C-N)350downfield signals around 169.0-169.6 ppm belong to C-2′ of selenazole rings (Koketsu & Ishihara 2008; Kurt et al. 2015).FIGURE 2. 1H NMR spectrum for compound b1 in DMSO-d6 solventTABLE 3. The 1H NMR signals for 3-(2-amino-1,3-selenazol-4-yl)-2H-chromen-2-one derivativesCompounds δ, ppm (coupling patterns, J-coupling)H5, H7 H6, H8 H4 H5′ NH2 CH3b1C12H8N2O2Se7.80 (d, J=7.2) 7.35 (t, J=7.4)7.58 (td, J=7.2, 1.2)7.42 (t, J=8.4)8.54 (s) 8.10 (s) 7.43 (br) -b2C13H10N2O2Se7.46 (d, J=6.4) 7.58 (d, J=7.2)7.24 (t, J=7.2, 7.6)-8.49 (s) 8.06 (s) 7.52 (br) 2.38 (s)b3C12H6Br2N2O2Se8.06 (s) - 8.42 (s) 8.12 (s) 7.51 (br) -b4C12H6Cl2N2O2Se7.86 (d, J=1.6), 7.92 (d, J=1.6)- 8.45 (s) 8.14 (s) 7.47 (br) -s: singlet; d: doublet; t: triplet; td: triple doublet; br: broadTABLE 4. The 13C NMR signals for 3-(2-amino-1,3-selenazol-4-yl)-2H-chromen-2-one derivativesCarbon δ, ppmb1 b2 b3 b4CH3 - 15.4 - -C5′ 114.3 114.1 110.2 116.1C8 116.2 119.5 116.0 120.8C10 119.9 120.8 116.9 122.4C3 121.4 124.8 122.8 122.8C6 125.1 125.2 126.3 128.8C5 129.0 126.8 130.6 127.0C7 131.8 133.0 136.0 130.6C4 139.1 139.6 137.4 137.3C4′ 144.6 143.7 145.8 143.8C9 152.6 150.9 148.4 146.9C=O 159.3 159.4 158.2 158.0C2′ 169.0 169.4 169.6 169.3MASS SPECTROMETRYThe mass spectral data for compounds b(1-4) were listed in Table 5 and the fragmentation for compound 3-(2-amino-1,3-selenazol-4-yl)-2H-chromen-2-one, b1 (C12H8N2O2Se) were shown in Figure 3. The molecular ion peak for compound b1 is observed at m/z = 292.0 and an intense fragmentation peak is observed at m/z = 211 after the cleavage of SeH molecule (MW = 81 g/mol).While m/z for b2, b3 and b4 were recorded at 306.99, 448.80 and 360.90, respectively, which represent TABLE 5. The mass spectral data for compounds b(1-4)Compounds Mol. Formula(Mol. weight) EIMS (m/z)/ESIMSb1 C12H8N2O2Se(290.96)EIMS: (m/z) = 292.0b2 C13H10N2O2Se(305.99)ESIMS: [M+H]+ = 306.99b3 C12H6Br2N2O2Se(447.80)ESIMS: [M+H]+ = 448.80b4 C12H6Cl2N2O2Se(359.90)ESIMS: [M+H]+ = 360.90351[C13H10N2O2Se+H]+, [C12H6Br2N2O2Se+H]+ and [C12H6Cl2N2O2Se+H]+.FREE RADICAL-SCAVENGING ACTIVITYTable 6 shows the IC50 (µM) values for each compound and standards. Unfortunately, the tested compounds did not exhibit a remarkable free radical scavenging activity with IC50 values recorded between 672.13-984.03 µM which are greater than standards (9.09 and 28.43 µM for gallic and ascorbic acids).(CRIM), Universiti Kebangsaan Malaysia are very much appreciated.REFERENCESAnand, P., Singh, B. & Singh, N. 2012. A review on coumarins as acetylcholinesterase inhibitors for alzheimer’s disease. Bioorganic and Medicinal Chemistry 20(3): 1175-1180. doi:10.1016/j.bmc.2011.12.042.Banothu, J., Vaarla, K., Bavantula, R. & Crooks, P.A. 2014. Sodium fluoride as an efficient catalyst for the synthesis of 2,4-disubstituted-1,3-thiazoles and selenazoles at ambient temperature. Chinese Chemical Letters 25(1): 172-175. doi:10.1016/j.cclet.2013.10.001.Koketsu, M. & Ishihara, H. 2008. 1,3-Selenazoles. Reference Module in Chemistry, Molecular Sciences and Chemical Engineering Comprehensive Heterocyclic Chemistry III 4 (1): 791-821.Kumar, A., Gupta, M.K. & Kumar, M. 2011. An efficient non-ionic surfactant catalyzed multicomponent synthesis of novel benzylamino coumarin derivative via mannich type reaction in aqueous media. Tetrahedron Letters 52: 4521-4525.Kurt, B.Z., Gazioglu, I., Sonmez, F. & Kucukislamoglu, M. 2015. Synthesis, antioxidant and anticholinesterase activities of novel coumarylthiazole derivatives. Bioorganic Chemistry 59: 80-90. doi:http://dx.doi.org/10.1016/j.bioorg.2015.02.002.Madhav, J.V., Kuarm, B.S. & Rajitha, B. 2008. Solid-state synthesis of 1,3-selenazoles employing cupy 2 cl 2 as a lewis acid catalyst. Synthetic Communications 38: 3514-3522. doi:10.1080/00397910802162975.Madhu, C., Panguluri, N.R., Narendra, N., Panduranga, V. & Sureshbabu, V.V. 2014. One-pot synthesis of orthogonally protected dipeptide selenazoles employing n (a) -amino selenocarboxamides and a -bromomethyl ketones. Tetrahedron Letters 55(50): 6831-6835. doi:http://dx.doi.org/10.1016/j.tetlet.2014.10.085.Mahdavi, B., Yaacob, W.A., Din, L.B., Heng, L.Y. & Ibrahim, N. 2016. Chemical composition, antioxidant, and antibacterial activities of essential oils from Etlingera brevilabrum valeton. Records of Natural Products 10(1): 22-31.Mao, F., Chen, J., Zhou, Q., Luo, Z., Huang, L. & Li, X. 2013. Novel tacrine – ebselen hybrids with improved cholinesterase inhibitory, hydrogen peroxide and peroxynitrite scavenging activity. Bioorganic & Medicinal Chemistry Letters 23: 6737-6742. doi:10.1016/j.bmcl.2013.10.034.Pizzo, C. & Mahler, S.G. 2014. Synthesis of selenazoles by in situ cycloisomerization of propargyl selenoamides using oxygen-selenium exchange reaction. The Journal of Organic Chemistry 79(4): 1856-1860. doi:10.1021/jo402661b.FIGURE 3. The mass-spectrum showing the molecular ion of 3-(2-amino-1,3-selenazol-4-yl)-2H-chromen-2-one (b1) and its fragmentationsTABLE 6. IC50 (µM) values for compounds b1-b4 and standardsCompounds IC50 (µM)b1 843.59 ± 71.41b2 639.81 ± 9.67b3 672.13 ± 81.68b4 984.03 ± 156.47Gallic acid 9.09 ± 0.15Ascorbic acid 28.43 ± 1.52coNclusioNIn conclusion, four derivatives of 3-(2-amino-1,3-selenazol-4-yl)-2H-chromen-2-one were successfully synthesized via Hantzsch reaction and their radical scavenging activities were evaluated. Even though the synthesized compounds exhibited weak free radical scavenging activity signifying a weak antioxidant, these derivatives may possess high potential as antiviral, antifungal, antimicrobial or other bioactivities. This report provides new insight on the free radical scavenging activity of 3-(2-amino-1,3-selenazol-4-yl)-2H-chromen-2-ones considering that there are no previous reports deliberating on the biological activities of these compounds. ACKNOWLEDGEMENTSThe authors would like to thank the Ministry of Higher Education, Malaysia and Universiti Teknologi MARA for research grant FRGS/1/2015/SG01/UITM/03/1 and Universiti Kebangsaan Malaysia for research grant GUP-2016-059. Research facilities provided by the School of Chemical Sciences and Food Technology (PPSKTM) and Centre of Research and Instrumentation Management 352Ramesh, G., Janardhan, B. & Rajitha, B. 2015. green approach: An efficient synthesis of 2,4-disubstituted-1,3-thiazoles and selenazoles in aqueous medium under ultrasonic irradiation. Research on Chemical Intermediates 41(11): 8099-8109.Zhao, H-C., Shi, Y-P., Liu, Y-M., Li, C-W., Xuan, L-N., Wang, P., Zhang, K. & Chen, B-Q. 2013. Synthesis and antitumor-evaluation of 1,3-selenazole-containing 1,3,4-thiadiazole derivatives. Bioorganic & Medicinal Chemistry Letters 23: 6577-6579.Nurul Zawani Alias, Zaini Yusoff & Sharizal HasanFaculty of Applied SciencesUniversiti Teknologi MARA (UiTM) Perlis02600 Arau, Perlis Indera KayanganMalaysiaNurul Zawani Alias, Nurul Izzaty Hassan &  Wan Yaacob Wan Ahmad*School of Chemical Sciences and Food TechnologyFaculty of Science and TechnologyUniversiti Kebangsaan Malaysia43600 Bangi, Selangor Darul EhsanMalaysia*Corresponding author; email: wanyaa@ukm.edu.myReceived: 22 March 2017Accepted: 17 August 2017

Synthesis, characterization and antioxidant activity of 3-(2-Amino-1,3-Selenazol-4-yl)-2H-Chromen-2-Ones derivatives

http://journalarticle.ukm.my/12014/1/UKM%20SAINSMalaysiana%2047%2802%29Feb%202018%2017.pdf

Synthesis, characterization and antioxidant activity of 3-(2-Amino-1,3-Selenazol-4-yl)-2H-Chromen-2-Ones derivatives

Abstract

Similar works

Full text

Available Versions

UKM Journal Article Repository