Antioxidant activities and acidic properties of some novel 4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one derivatives

Özlem Gürsoy-Kol; Elif Ayazoğlu

doi:10.1016/j.arabjc.2013.11.015

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Original article

10 (

2_suppl

); S2881-S2889

doi:

10.1016/j.arabjc.2013.11.015

Antioxidant activities and acidic properties of some novel 4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one derivatives

Özlem Gürsoy-Kol^⁎, Elif Ayazoğlu

Department of Chemistry, Kafkas University, 36100 Kars, Turkey

⁎Corresponding author. Address: Department of Chemistry, Faculty of Science and Letters, Kafkas University, 36100 Kars, Turkey. Tel.: +90 4742251150; fax: +90 4742251179. ozlemgursoy@gmail.com (Özlem Gürsoy-Kol)

Received: 2013-3-5, Accepted: 2013-11-16, Published: 2013-05-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

In this study, seven new 3-alkyl(aryl)-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-ones (4) were synthesized by the reactions of 3-alkyl(aryl)-4-amino-4,5-dihydro-1H-1,2,4-triazol-5-ones (2) with 3,4-di-(4-nitrobenzoxy)-benzaldehyde (3) which had also been synthesized by the reactions of 3,4-dihydroxybenzaldehyde with 4-nitrobenzoyl chloride by using triethylamine. The acetylation reactions of compounds 4 were investigated and six new 5 type compounds were obtained. The new thirteen compounds were characterized by elemental analyses and IR, ¹H NMR, ¹³C NMR, UV and mass spectral data. In addition, the synthesized compounds were analysed for their in vitro potential antioxidant activities in three different methods. Compound 4g showed the best activity for antioxidant results. Moreover, the compounds 4 were titrated potentiometrically with tetrabutylammonium hydroxide (TBAH) in four non-aqueous solvents. Thus, the half-neutralization potential values and the corresponding pK_a values were determined in all cases.

Keywords

1,2,4-Triazol-5-one

Schiff base

Synthesis

Antioxidant activity

Acidity

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1 Introduction

In the last two decades there has been an increasing interest in the role of reactive oxygen species (ROS) and of reactive nitrogen species (RNS) in food, drugs, and even living system. Therefore, scientists in various disciplines have become more interested in naturally-occurring antioxidants as well as in related synthetic derivatives that could provide active components which prevent or reduce the impact of oxidative stress (Hussain et al., 2003).

Exogenous chemicals and endogenous metabolic processes in the human body or in the food system might produce highly reactive free radicals, especially oxygen-derived radicals. At high concentrations, they can be important mediators of damage among cell structures, including lipids and membranes, proteins, and nucleic acids (McClements and Decker, 2000). In this regard, it is important to search for and synthesize new classes of compounds that have antioxidant properties.

1,2,4-Triazole and 4,5-dihydro-1H-1,2,4-triazol-5-one derivatives are reported to possess a broad spectrum of biological activities such as antibacterial (Yuksek et al., 1997; Pitucha et al., 2010), antifungal (Kahveci et al., 2008), antioxidant (Arslantas et al., 2012; Gursoy-Kol et al., 2012), anti-inflammatory (Uzgoren-Baran et al., 2012), anticonvulsant (Zhang et al., 2012), antiparasitic (Saadeh et al., 2010), analgesic (Chidananda et al., 2012), antiviral (Henen et al., 2012), antitumor (Demirbas et al., 2002), anti-HIV (Li et al., 2013), antihypertensive and diuretic (Ali et al., 2011) properties. In addition, several articles reporting the synthesis of some N-arylidenamino-4,5-dihydro-1H-1,2,4-triazol-5-one derivatives have been published so far (Yuksek et al., 1997; Arslantas et al., 2012; Gursoy-Kol et al., 2012 ).

On the other hand, it is known that 1,2,4-triazole and 4,5-dihydro-1H-1,2,4-triazol-5-one rings have weak acidic properties, so that some 1,2,4-triazole and 4,5-dihydro-1H-1,2,4-triazol-5-one derivatives were titrated potentiometrically with TBAH in non-aqueous solvents, and the pK_a values of the compounds were determined (Arslantas et al., 2012; Gursoy-Kol et al., 2012).

In the present study, due to a wide range of applications to find their possible antioxidant activity, the newly synthesized 4,5-dihydro-1H-1,2,4-triazol-5-one derivatives were investigated by using different antioxidant methodologies such as: reducing power, 1,1-diphenyl-2-picryl-hydrazyl (DPPH) free radical scavenging and metal chelating activities. Besides, in order to determine the pK_a values of the compounds, they were titrated potentiometrically with TBAH in four non-aqueous solvents, including isopropyl alcohol, tert-butyl alcohol, acetone and N,N-dimethylformamide (DMF).

2 Materials and methods

2.1

2.1 Chemical reagents and apparatus

Chemical reagents used in this study were purchased from Merck AG, Aldrich and Fluka. Melting points were determined in open glass capillaries using a WRS-2A Microprocessor melting point apparatus and are uncorrected. The IR spectra were recorded on an Alpha-P Bruker FT-IR spectrometer. ¹H and ¹³C NMR spectra were recorded in deuterated dimethyl sulfoxide with TMS as internal standard using a Bruker spectrometer at 200 and 50 MHz, respectively. UV absorption spectra were measured in 10 mm quartz cells between 200 and 400 nm using a PG Instruments Ltd T80 UV/vis spectrometer. Extinction coefficients (ε) are expressed in L mol⁻¹ cm⁻¹. Elemental analyses were carried out on a LECO, CHNS-932 for C, H, and N. Mass spectra were recorded on a Thermo Scientific DSQ II Single Quadrupole GC/MS in the electron impact (EI) ionization mode (70 eV).

2.2

2.2 General procedure for the synthesis of compounds 4

3,4-Dihydroxybenzaldehyde (0.01 mol) dissolved in ethyl acetate (100 mL) was treated with 4-nitrobenzoyl chloride (0.02 mol), and to this solution was slowly added triethylamine (0.02 mol) with stirring at 0–5 °C. Stirring was continued for 2 h, and then the mixture was refluxed for 3 h and filtered. The filtrate was evaporated in vacuo, and the crude product was washed with water and recrystallized from DMSO-H₂O (1:3) to afford compound 3, yield 5.82 g (98%). mp 164 °C; IR (KBr) (ν, cm⁻¹): 2842 and 2739 (CHO); 1739, 1670 (C⚌O); 1516 and 1347 (NO₂); 1239 (COO); 828 (1,4-disubstituted benzenoid ring). ¹H NMR (DMSO-d₆): δ 7.20 (d, 1H, ArH), 7.77–7.81 (m, 1H, Ar-H), 8.16–8.19 (m, 2H, Ar-H), 8.21–8.26 (m, 1H, Ar-H), 8.32–8.64 (m, 6H, Ar-H), 9.79 (s, 1H, CHO). ¹³C NMR (DMSO-d₆): δ 117.77, 124.13 (2C), 124.53 (2C), 124.72, 129.11, 130.42, 131.12 (2C), 131.81 (2C), 134.59, 136.94, 139.03, 150.42, 151.04, 155.52 (Ar-C), 163.10, 166.28 (COO), 190.99 (CHO). UV λ_max (ε): 256 (16,437), 240 (16,523), 218 (16,145) nm. The corresponding compound 2 (0.01 mol) was dissolved in acetic acid (15 mL) and treated with 3,4-di-(4-nitrobenzoxy)-benzaldehyde 3 (0.01 mol). The mixture was refluxed for 1.5 h and then evaporated at 50–55 °C in vacuo. Several recrystallizations of the residue from appropriate solvent gave pure compounds 4a–g as colourless crystals.

2.2.1

2.2.1 3-Methyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (4a)

Yield 5.09 g (95%). Mp 303 °C. IR (KBr): 3171 (NH); 1743, 1712 (C⚌O); 1604 (C⚌N); 1518 and 1355 (NO₂); 1250 (COO); 851 (1,4-disubstituted benzenoid ring) cm⁻¹. ¹H NMR (DMSO-d₆): δ 2.31 (s, 3H, CH₃), 7.77 (d, 1H, Ar-H), 7.96 (d, 1H, Ar-H), 8.14 (m, 1H, Ar-H), 8.22–8.26 (m, 4H, Ar-H), 8.32–8.34 (m, 4H, Ar-H), 9.84 (s, 1H, N⚌CH), 11.89 (s, 1H, NH). ¹³C NMR (DMSO-d₆): δ 11.58 (CH₃), 122.64, 124.60, 124.62 (2C), 125.31, 127.79, 129.62, 131.70 (2C), 131.76, 133.65, 135.70, 142.63, 142.77, 144.24, 144.82, 151.30, 151.64 (arom-C), 146.72 (triazole C₃), 151.25 (N⚌CH), 151.96 (triazole C₅), 162.29, 162.64 (COO). UV λ_max (ε): 262 (18,858), 212 (30,476) nm. Anal. Calcd for C₂₄H₁₆N₆O₉ (532.43): C 54.14, H 3.03, N 15.78. Found: C 53.71, H 3.09, N 14.58. MS (GC) m/z = 555 [M+23].

2.2.2

2.2.2 3-Ethyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (4b)

Yield 5.16 g (95%). Mp 265 °C. IR (KBr): 3176 (NH); 1744, 1710 (C⚌O); 1602 (C⚌N); 1520 and 1355 (NO₂); 1253 (COO); 851 (1,4-disubstituted benzenoid ring) cm⁻¹. ¹H NMR (DMSO-d₆): δ 1.22 (t, 3H, CH₂CH₃), 2.72 (q, 2H, CH₂CH₃), 7.77 (d, 1H, Ar-H), 7.95 (d, 1H, Ar-H), 8.12 (m, 1H, Ar-H), 8.22–8.26 (m, 4H, Ar-H), 8.31–8.34 (m, 4H, Ar-H), 9.83 (s, 1H, N⚌CH), 11.92 (s, 1H, NH). ¹³C NMR (DMSO-d₆): δ 10.48 (CH₂CH₃), 18.91 (CH₂CH₃), 122.66, 124.23 (3C), 124.60 (2C), 125.00, 127.71, 131.18, 131.70 (2C), 131.86 (2C), 133.63, 142.64, 144.23, 151.23, 151.79 (arom-C), 148.56 (triazole C₃), 151.23 (N⚌CH), 152.01 (triazole C₅), 162.48, 162.63 (COO). UV λ_max (ε): 260 (21,800), 214 (27,200) nm. MS (GC) m/z = 546 [M]; C₂₅H₁₈N₆O₉.

2.2.3

2.2.3 3-Benzyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (4c)

Yield 5.87 g (97%). Mp 240 °C. IR (KBr): 3165 (NH); 1749, 1715 (C⚌O); 1586 (C⚌N); 1522 and 1348 (NO₂); 1246 (COO); 825 (1,4-disubstituted benzenoid ring); 777 and 709 (monosubstituted benzenoid ring) cm⁻¹. ¹H NMR (DMSO-d₆): δ 4.09 (s, 2H, CH₂Ph), 7.18–7.36 (m, 5H, Ar-H), 7.75 (d, 1H, Ar-H), 7.91 (d, 1H, Ar-H), 8.05 (m, 1H, Ar-H), 8.18–8.27 (m, 3H, Ar-H), 8.31–8.34 (m, 3H, Ar-H), 8.36–8.44 (m, 2H, Ar-H), 9.80 (s, 1H, N⚌CH), 12.07 (s, 1H, NH). ¹³C NMR (DMSO-d₆): δ 31.53 (CH₂Ph), 117.80, 122.69, 124.51, 124.59, 124.94, 125.58, 127.19, 127.65, 128.84, 128.90 (2C), 129.31, 129.35 (2C), 131.41 (2C), 131.83, 133.54, 133.67, 136.23, 142.56, 144.18, 151.56, 152.56 (arom-C), 146.76 (triazole C₃), 151.23 (N⚌CH), 153.34 (triazole C₅), 162.48, 163.15 (COO). UV λ_max (ε): 262 (18,842), 214 (32,713) nm. Anal. Calcd for C₃₀H₂₀N₆O₉ (608.52): C 59.21, H 3.31, N 13.81. Found: C 57.73, H 3.46, N 13.61. MS (GC) m/z = 608 [M].

2.2.4

2.2.4 3-p-Methylbenzyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (4d)

Yield 6.06 g (98%). Mp 230 °C. IR (KBr): 3167 (NH); 1747, 1698 (C⚌O); 1595 (C⚌N); 1527 and 1348 (NO₂); 1244 (COO); 841, 805 (1,4-disubstituted benzenoid ring) cm⁻¹. ¹H NMR (DMSO-d₆): δ 2.22 (s, 3H, PhCH₃), 4.03 (s, 2H, CH₂Ph), 7.05–7.23 (m, 4H, Ar-H), 7.75 (d, 1H, Ar-H), 7.91 (d, 1H, Ar-H), 8.05 (m, 1H, Ar-H), 8.23–8.27 (m, 3H, Ar-H), 8.31–8.35 (m, 3H, Ar-H), 8.37–8.46 (m, 2H, Ar-H), 9.78 (s, 1H, N = CH), 12.03 (s, 1H, NH). ¹³C NMR (DMSO-d₆): δ 21.05 (PhCH₃), 31.15 (CH₂Ph), 117.78, 122.65, 124.49, 124.57, 124.92 (2C), 127.64, 129.17, 129.91 (2C), 129.45 (2C), 129.53, 131.67 (2C), 131.82, 133.09, 133.56, 133.66, 136.30, 142.55, 144.16, 151.20, 151.61 (arom-C), 146.89 (triazole C₃), 151.04 (N⚌CH), 152.54 (triazole C₅), 162.47, 163.15 (COO). UV λ_max (ε): 262 (24,184), 218 (27,883) nm. Anal. Calcd for C₃₁H₂₂N₆O₉ (622.55): C 59.81, H 3.56, N 13.50. Found: C 58.98, H 3.69, N 13.65. MS (GC) m/z = 622 [M].

2.2.5

2.2.5 3-p-Chlorobenzyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (4e)

Yield 5.94 g (92%). Mp 241 °C. IR (KBr): 3198 (NH); 1744, 1705 (C⚌O); 1604 (C⚌N); 1522 and 1351 (NO₂); 1253 (COO); 850, 802 (1,4-disubstituted benzenoid ring) cm⁻¹. ¹H NMR (DMSO-d₆): δ 4.07 (s, 2H, CH₂Ph), 7.31–7.39 (m, 4H, Ar-H), 7.74 (d, 1H, Ar-H), 7.90 (d, 1H, Ar-H), 8.05 (m, 1H, Ar-H), 8.20–8.27 (m, 4H, Ar-H), 8.31–8.34 (m, 4H, Ar-H), 9.80 (s, 1H, N⚌CH), 12.08 (s, 1H, NH). ¹³C NMR (DMSO-d₆): δ 30.85 (CH₂Ph), 122.64, 124.61 (3C), 124.96, 127.78, 128.83 (3C), 131.31 (3C), 131.70 (3C), 131.89, 133.50, 133.62, 133.68, 135.20, 142.57, 144.21, 151.23, 151.60 (arom-C), 146.44 (triazole C₃), 151.23 (N⚌CH), 151.60 (triazole C₅), 162.49, 162.59 (COO). UV λ_max (ε): 262 (27,700), 216 (34,857) nm. Anal. Calcd for C₃₀H₁₉ClN₆O₉ (642.97): C 56.04, H 2.98, N 13.07. Found: C 54.69, H 3.12, N 12.48. MS (GC) m/z = 642 [M].

2.2.6

2.2.6 3-m-Chlorobenzyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (4f)

Yield 6.03 g (94%). Mp 242 °C. IR (KBr): 3197 (NH); 1745, 1715 (C⚌O); 1601 (C⚌N); 1521 and 1353 (NO₂); 1254 (COO); 849 (1,4-disubstituted benzenoid ring); 790 and 711 (1,3-disubstituted benzenoid ring) cm⁻¹. ¹H NMR (DMSO-d₆): δ 4.12 (s, 2H, CH₂Ph), 7.25–7.45 (m, 4H, Ar-H), 7.76 (d, 1H, Ar-H), 7.91 (d, 1H, Ar-H), 8.05 (m, 1H, Ar-H), 8.31–8.41 (m, 8H, Ar-H), 9.80 (s, 1H, N⚌CH), 12.08 (s, 1H, NH). ¹³C NMR (DMSO-d₆): δ 31.15 (CH₂Ph), 122.44, 124.53, 124.61 (2C), 124.64, 124.99, 127.15, 127.22, 127.96, 128.02, 129.54, 130.70, 130.76, 131.70, 131.84 (2C), 133.37, 133.52, 133.63, 138.64, 142.60, 144.26, 151.26, 151.63 (arom-C), 146.26 (triazole C₃), 151.08 (N⚌CH), 152.62 (triazole C₅), 162.47, 162.61 (COO). UV λ_max (ε): 262 (20,197), 214 (34,239) nm. Anal. Calcd for C₃₀H₁₉ClN₆O₉ (642.97): C 56.04, H 2.98, N 13.07. Found: C 55.02, H 3.07, N 12.88. MS (GC) m/z = 642 [M].

2.2.7

2.2.7 3-Phenyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (4g)

Yield 5.82 g (98%). Mp 261 °C. IR (KBr): 3172 (NH); 1734, 1716 (C⚌O); 1606 (C⚌N); 1520 and 1350 (NO₂); 1255 (COO); 849 (1,4-disubstituted benzenoid ring); 762 and 709 (monosubstituted benzenoid ring) cm⁻¹. ¹H NMR (DMSO-d₆): δ 7.50–7.57 (m, 4H, Ar-H), 7.78 (d, 1H, Ar-H), 7.88–7.96 (m, 2H, Ar-H), 8.08 (m, 1H, Ar-H), 8.30–8.33 (m, 4H, Ar-H), 8.36–8.39 (m, 4H, Ar-H), 9.76 (s, 1H, N⚌CH), 12.45 (s, 1H, NH). ¹³C NMR (DMSO-d₆): δ 123.28, 124.14, 124.46, 124.55, 124.58, 125.11, 126.99, 127.48, 128.28, 128.45, 129.00 (2C), 129.05, 130.64, 131.67, 131.69, 131.84, 133.27, 133.60, 133.69, 142.61, 144.40, 151.20, 151.88 (arom-C), 145.47 (triazole C₃), 151.03 (N⚌CH), 155.13 (triazole C₅), 162.46, 162.57 (COO). UV λ_max (ε): 262 (13,588), 212 (25,280) nm. Anal. Calcd for C₂₉H₁₈N₆O₉ (594.50): C 58.59, H 3.05, N 14.14. Found: C 57.44, H 3.13, N 13.84. MS (GC) m/z = 594 [M].

2.3

2.3 General procedure for the synthesis of compounds 5

The corresponding compound 4 (0.01 mol) was refluxed with acetic anhydride (20 mL) for 0.5 h. After the addition of absolute ethanol (100 mL), the mixture was refluxed for 1 h. Evaporation of the resulting solution at 40–45 °C in vacuo and several recrystallizations of the residue from EtOH gave pure compounds 5 as colourless needles.

2.3.1

2.3.1 1-Acetyl-3-methyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (5a)

Yield 5.32 g (93%). Mp 206 °C. IR (KBr): 1766, 1740, 1720 (C⚌O); 1605 (C⚌N); 1523 and 1349 (NO₂); 1240 (COO); 817 (1,4-disubstituted benzenoid ring) cm⁻¹. ¹H NMR (DMSO-d₆): δ 2.34 (s, 3H, CH₃), 2.51 (s, 3H, COCH₃), 7.79–8.34 (m, 11H, Ar-H), 9.73 (s, 1H, N⚌CH). UV λ_max (ε): 258 (10,862), 210 (37,270) nm. Anal. Calcd for C₂₆H₁₈N₆O₁₀ (574.46): C 54.36, H 3.16, N 14.63. Found: C 53.76, H 3.23, N 14.27. MS (GC) m/z = 597 [M+23].

2.3.2

2.3.2 1-Acetyl-3-ethyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (5b)

Yield 5.32 g (91%). Mp 158 °C. IR (KBr): 1770, 1743, 1722 (C⚌O); 1607 (C⚌N); 1525 and 1352 (NO₂); 1256 (COO); 847 (1,4-disubstituted benzenoid ring) cm⁻¹. ¹H NMR (DMSO-d₆): δ 1.21–1.28 (m, 3H, CH₂CH₃), 2.21 (s, 3H, COCH₃), 2.75–2.82 (m, 2H, CH₂CH₃), 7.55 (d, 1H, Ar-H), 7.90–7.93 (m, 1H, Ar-H), 8.08 (m, 1H, Ar-H), 8.23–8.26 (m, 2H, Ar-H), 8.31–8.37 (m, 4H, Ar-H), 8.45–8.47 (m, 2H, Ar-H), 9.67 (s, 1H, N⚌CH). ¹³C NMR (DMSO-d₆): δ 9.91 (CH₂CH₃), 19.00 (CH₂CH₃), 23.95 (COCH₃), 122.92, 124.59, 124.72 (2C), 125.06, 127.89, 131.70, 131.82 (2C), 132.48, 133.06, 133.67, 133.91, 142.79, 144.62, 144.89, 151.24, 151.30 (arom-C), 148.53 (triazole C₃), 150.66 (N⚌CH), 154.13 (triazole C₅), 162.59, 166.46 (COO), 168.43 (COCH₃). UV λ_max (ε): 254 (33,688), 216 (34,975) nm. Anal. Calcd for C₂₇H₂₀N₆O₁₀ (588.49): C 55.11, H 3.43, N 14.28. Found: C 54.41, H 3.68, N 13.54. MS (GC) m/z = 588 [M].

2.3.3

2.3.3 1-Acetyl-3-benzyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (5c)

Yield 5.95 g (92%). Mp 123 °C. IR (KBr): 1767, 1743 (C⚌O); 1606 (C⚌N); 1524 and 1351 (NO₂); 1256 (COO); 850 (1,4-disubstituted benzenoid ring); 765 and 709 (monosubstituted benzenoid ring) cm⁻¹. ¹H NMR (DMSO-d₆): δ 2.25 (s, 3H, COCH₃), 4.16 (s, 2H, CH₂Ph), 7.20–7.42 (m, 7H, Ar-H), 7.53 (d, 1H, Ar-H), 7.81–7.85 (m, 1H, Ar-H), 8.05 (m, 1H, Ar-H), 8.23–8.27 (m, 1H, Ar-H), 8.32–8.38 (m, 3H, Ar-H), 8.44–8.48 (m, 2H, Ar-H), 9.63 (s, 1H, N⚌CH). ¹³C NMR (DMSO-d₆): δ 24.00 (COCH₃), 31.47 (CH₂Ph), 122.92, 124.59, 124.76 (2C), 124.90, 125.00, 127.43, 127.90, 128.96 (2C), 129.54 (2C), 131.69, 131.80 (2C), 132.46, 133.88, 135.13, 142.76, 142.77, 144.88, 148.44, 151.24, 151.31 (arom-C), 148.78 (triazole C₃), 151.31 (N⚌CH), 153.61 (triazole C₅), 162.56, 166.43 (COO), 168.45 (COCH₃). UV λ_max (ε): 250 (32,259), 226 (32,159) nm. Anal. Calcd for C₃₂H₂₂N₆O₁₀ (650.56): C 59.08, H 3.41, N 12.92. Found: C 59.24, H 4.13, N 12.37. MS (GC) m/z = 650 [M].

2.3.4

2.3.4 1-Acetyl-3-p-methylbenzyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (5d)

Yield 6.54 g (99%). Mp 247 °C. IR (KBr): 1767, 1743, 1723 (C⚌O); 1605 (C⚌N); 1524 and 1349 (NO₂); 1254 (COO); 848 (1,4-disubstituted benzenoid ring) cm⁻¹. ¹H NMR (DMSO-d₆): δ 2.21 (s, 3H, CH₃), 2.26 (s, 3H, COCH₃), 4.10 (s, 2H, CH₂Ph), 7.07–7.28 (m, 5H, Ar-H), 7.52 (d, 1H, Ar-H), 7.76–7.78 (m, 1H, Ar-H), 8.00 (m, 1H, Ar-H), 8.23–8.27 (m, 2H, Ar-H), 8.31–8.38 (m, 3H, Ar-H), 8.44–8.48 (m, 2H, Ar-H), 9.62 (s, 1H, N⚌CH). ¹³C NMR (DMSO-d₆): δ 21.06 (PhCH₃), 23.98 (COCH₃), 31.11 (CH₂Ph), 122.95, 124.58, 124.61, 124.75, 124.99, 129.19, 129.40, 129.43, 129.44, 129.51, 131.69, 131.80, 131.96, 132.47, 133.03, 133.87, 133.91, 136.22, 136.53, 142.68, 144.83, 146.87, 151.22, 151.61 (arom-C), 148.42 (triazole C₃), 148.91 (N⚌CH), 153.56 (triazole C₅), 162.55, 166.42 (COO), 168.44 (COCH₃). UV λ_max (ε): 258 (47,996), 222 (49,726) nm. Anal. Calcd for C₃₃H₂₄N₆O₁₀ (664.59): C 59.64, H 3.64, N 12.65. Found: C 58.79, H 4.13, N 12.54. MS (GC) m/z = 687 [M+23].

2.3.5

2.3.5 1-Acetyl-3-p-chlorobenzyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (5e)

Yield 6.26 g (92%). Mp 168 °C. IR (KBr): 1768, 1740 (C⚌O); 1606 (C⚌N); 1519 and 1351 (NO₂); 1259 (COO); 847, 801 (1,4-disubstituted benzenoid ring) cm⁻¹. ¹H NMR (DMSO-d₆): δ 2.23 (s, 3H, COCH₃), 4.10 (s, 2H, CH₂), 7.34–7.44 (m, 6H, Ar-H), 7.53 (d, 1H, Ar-H), 7.87–7.89 (m, 1H, Ar-H), 8.09 (m, 1H, Ar-H), 8.23–8.27 (m, 1H, Ar-H), 8.31–8.40 (m, 3H, Ar-H), 8.45–8.48 (m, 2H, Ar-H), 9.64 (s, 1H, N⚌CH). ¹³C NMR (DMSO-d₆): δ 23.99 (COCH₃), 30.82 (CH₂Ph), 122.64, 124.60, 124.75 (2C), 124.91, 125.01, 127.55, 128.00, 128.88 (2C), 131.28 (2C), 131.48, 131.70 (2C), 131.81, 132.17, 132.44, 132.78, 133.88, 142.73, 144.86, 151.31, 151.60 (arom-C), 146.43 (triazole C₃), 148.48 (N⚌CH), 153.52 (triazole C₅), 162.57, 166.41 (COO), 168.44 (COCH₃). UV λ_max (ε): 302 (26,771), 286 (29,447), 242 (32,881) nm. Anal. Calcd for C₃₂H₂₁ClN₆O₁₀ (685.01): C 56.11, H 3.09, N 12.27. Found: C 54.75, H 3.48, N 11.89. MS (GC) m/z = 708 [M+23].

2.3.6

2.3.6 1-Acetyl-3-phenyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (5g)

Yield 6.26 g (99%). Mp 279 °C. IR (KBr): 1772, 1733, 1707 (C⚌O); 1607 (C⚌N); 1523 and 1346 (NO₂); 1245 (COO); 851 (1,4-disubstituted benzenoid ring); 771 and 691 (monosubstituted benzenoid ring) cm⁻¹. ¹H NMR (DMSO-d₆): δ 2.28 (s, 3H, COCH₃), 7.58–7.68 (m, 5H, Ar-H), 7.85–8.00 (m, 5H, Ar-H), 8.22–8.25 (m, 1H, Ar-H), 8.31–8.46 (m, 5H, Ar-H), 9.71 (s, 1H, N⚌CH). ¹³C NMR (DMSO-d₆): δ 24.07 (COCH₃), 123.20, 124.36, 124.49 (2C), 124.72, 125.22, 127.07, 127.33, 128.28 (2C), 128.42, 129.06 (2C), 129.15, 129.21, 130.87, 131.80 (2C), 132.71, 133.84, 142.73, 144.67, 151.28, 151.73 (arom-C), 146.49 (triazole C₃), 148.60 (N⚌CH), 155.38 (triazole C₅), 162.56, 166.75 (COO), 168.46 (COCH₃). UV λ_max (ε): 262 (26,431), 214 (32,125) nm. MS (GC) m/z = 675 [M+39]; C₃₁H₂₀N₆O₁₀.

2.4

2.4 Antioxidant activity: chemicals

Butylated hydroxytoluene (BHT) was obtained from E. Merck. Ferrous chloride, α-tocopherol, DPPH^•, 3-(2-pyridyl)-5,6-bis(phenylsulfonic acid)-1,2,4-triazine (ferrozine), butylated hydroxyanisole (BHA), ethylenediaminetetraacetic acid (EDTA) and trichloroacetic acid (TCA) were obtained from Sigma.

2.4.1

2.4.1 Reducing power

The reducing power of the synthesized compounds was determined according to the method of Oyaizu (1986) as explained in Arslantas et al., 2012; Gursoy-Kol et al., 2012.

2.4.2

2.4.2 Free radical scavenging activity

Free radical scavenging activity of compounds was measured by DPPH^•, using the method of Blois (1958) as explained in Arslantas et al., 2012; Gursoy-Kol et al., 2012.

2.4.3

2.4.3 Metal chelating activity

The chelation of ferrous ions by the synthesized compounds and standards was estimated by the method of Dinis et al. (1994) as explained in Arslantas et al., 2012; Gursoy-Kol et al., 2012.

2.5

2.5 Potentiometric titrations

A Jenco model ion analyser and an Ingold pH electrode were used for potentiometric titrations. For each compound that was titrated, the 0.001 M solution was separately prepared in each non-aqueous solvent. The 0.05 M solution of TBAH in isopropyl alcohol, which is widely used in the titration of acids, was used as titrant. The mV values that were obtained in pH-meter were recorded. Finally, the half-neutralization potential (HNP) values were determined by drawing the mL (TBAH)-mV graphic.

3 Results and discussion

In this study the 3-alkyl(aryl)-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-ones 4a–g were prepared. The starting compounds 2a–g were prepared as described in the literature (Ikizler and Un, 1979; Ikizler and Yuksek, 1993). Compounds 4 were obtained from the reactions of compounds 2 with 3,4-di-(4-nitrobenzoxy)-benzaldehyde 3 which were synthesized by the reactions of 3,4-dihydroxybenzaldehyde with 4-nitrobenzoyl chloride by using triethylamine. Then the reactions of compounds 4a–e and 4g with acetic anhydride were investigated, and compounds 5a–e and 5g were prepared (Scheme 1).

Synthesis route of compounds 2–5: (i) Et3N, AcOEt, 0–5 °C; (ii) N2H4, H2O, reflux, 6 h; (iii) AcOH, reflux, 1 h; (iv) Ac2O, reflux, 1 h; (a) R = CH3, (b) R = CH2CH3, (c) R = CH2C6H5, (d) R = CH2C6H4·CH3 (p-), (e) R = CH2C6H4·Cl (p-), (f) R = CH2C6H4·Cl (m-) and (g) R = C6H5.

The structures of seven new 3-alkyl(aryl)-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-ones 4a–g and six new 1-acetyl-3-alkyl(aryl)-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-ones 5a–e and 5g were characterized by using elemental analyses and IR, ¹H NMR, ¹³C NMR, UV and mass spectral data.

3.1

3.1 Antioxidant activity

The antioxidant activities of 13 new compounds 4a–g, 5a–e and 5g were determined. Several methods have been used to determine antioxidant activities and the methods used in the study are given below:

3.1.1

3.1.1 Total reductive capability using the potassium ferricyanide reduction method

The reductive capabilities of compounds were assessed by the extent of conversion of the Fe³⁺/ferricyanide complex to the Fe²⁺/ferrous form. The reducing powers of the compounds were observed at different concentrations, and results were compared with BHA, BHT and α-tocopherol. It has been observed that the reducing capacity of a compound may serve as a significant indicator of its potential antioxidant activity (Meir et al., 1995). The antioxidant activity of putative antioxidant has been attributed to various mechanisms, among which are prevention chain initiation, binding of transition metal ion catalyst, decomposition of peroxides, prevention of continued hydrogen abstraction, reductive capacity and radical scavenging (Yildirim et al., 2001).

In this study, all the amounts of the compounds showed lower absorbance than standard antioxidants. Hence, no activities were observed to reduce metal ion complexes to their lower oxidation state or to take part in any electron transfer reaction. In other words, synthesized compounds did not show the reductive activities, but compounds 4c and 4g showed higher activities than blank and their reductive ability was concentration-dependent as seen in Fig. 1. Reducing power of the compounds and the standards were found as the following order: BHA > BHT > α-tocopherol > 4c > 4g.

Total reductive potential of different concentrations of compounds 4c, 4g, BHT, BHA and α-tocopherol.

3.1.2

3.1.2 DPPH^• radical scavenging activity

The model of scavenging the stable DPPH radical model is a widely used method to evaluate antioxidant activities in a relatively short time compared with other methods. The effect of antioxidants on DPPH radical scavenging was thought to be due to their hydrogen donating ability (Baumann et al., 1979). DPPH is a stable free radical and accepts an electron or hydrogen radical to become a stable diamagnetic molecule (Soares et al., 1997). The reduction capability of DPPH radicals was determined by a decrease in their absorbance at 517 nm induced by antioxidants. The absorption maximum of a stable DPPH radical in ethanol was at 517 nm. The decrease in absorbance of DPPH radical was caused by antioxidants because of the reaction between antioxidant molecules and radical, progresses, which resulted in the scavenging of the radical by hydrogen donation. It is visually noticeable as a discolouration from purple to yellow. Hence, DPPH^• is usually used as a substrate to evaluate antioxidative activity of antioxidants (Duh et al., 1999). In the study, antiradical activities of compounds and standard antioxidants such as BHA, BHT and α-tocopherol were determined by using the DPPH^• method. Scavenging effect values of compounds 4a–g, BHA and α-tocopherol at different concentrations are given in Figs. 2 and 3. The newly synthesized compounds except 4d and 5d showed good activity as a radical scavenger. The radical scavenging effect of the compounds and the standards were found as the following order: α-tocopherol > BHA > compound 4c > 4g > 4f > 4b > 4e > 5g > 4a > BHT > 5e > 5a > 5b > 5c.

Scavenging effect of compounds 4a–g, BHT, BHA and α-tocopherol at different concentrations (12.5–25–37.5 μg/mL).

Scavenging effect of compounds 5a–e, 5g, BHT, BHA and α-tocopherol at different concentrations (12.5–25–37.5 μg/mL).

3.1.3

3.1.3 Ferrous ion chelating activity

The chelating effect towards ferrous ions by the compounds and standards was determined. Ferrozine can quantitatively form complexes with Fe²⁺. In the presence of chelating agents, the complex formation is disrupted with the result that the red colour of the complex is decreased. Measurement of colour reduction therefore allows estimation of the chelating activity of the coexisting chelator (Yamaguchi et al., 2000). Transition metals have a pivotal role in the generation of oxygen free radicals in living organism. The ferric iron (Fe³⁺) is the relatively biologically inactive form of iron. However, it can be reduced to the active Fe²⁺, depending on condition, particularly pH (Strlic et al., 2002) and oxidized back through Fenton type reactions with the production of hydroxyl radical or Haber–Weiss reactions with superoxide anions. The production of these radicals may lead to lipid peroxidation, protein modification and DNA damage. Chelating agents may not activate metal ions and potentially inhibit the metal-dependent processes (Finefrock et al., 2003). Also, the production of highly active ROS such as $O_{2}^{\cdot -}$ , H₂O₂ and OH is also catalysed by free iron though Haber–Weiss reactions: $O_{2}^{\cdot} + H_{2} O_{2} \to O_{2} + {OH}^{-} + {OH}^{\cdot}$ Among the transition metals, iron is known as the most important lipid oxidation pro-oxidant due to its high reactivity. The ferrous state of iron accelerates lipid oxidation by breaking down the hydrogen and lipid peroxides to reactive free radicals via the Fenton reactions: ${Fe}^{2 +} + H_{2} O_{2} \to {Fe}^{3 +} + {OH}^{-} + {OH}^{\cdot}$ Fe³⁺ ion also produces radicals from peroxides, even though the rate is tenfold less than that of Fe²⁺ ion, which is the most powerful pro-oxidant among the various types of metal ions (Calis et al., 1993). Ferrous ion chelating activities of the compounds 4, 5, EDTA and α-tocopherol are shown in Figs. 4 and 5, respectively. It was reported that chelating agents that form σ-bonds with a metal are effective as secondary antioxidants because they reduce the redox potential thereby stabilizing the oxidized form of metal ion (Gordon, 1990).

Metal chelating effect of different amounts of the compounds 4a–g, EDTA and α-tocopherol on ferrous ions.

Metal chelating effect of different amounts of the compounds 5a–e, 5g, EDTA and α-tocopherol on ferrous ions.

It was reported that the compounds with structures containing two or more of the functional groups, such as —OH, —SH, —COOH, —PO₃H₂, C⚌O, —NR₂, —S—, —O— in a favourable structure–function configuration should have chelation activity (Lindsay, 1996; Yuan et al., 2005; Gulcin, 2006 ). In this respect, l-carnitine may chelate the ferrous ions with hydroxyl and carboxylate groups (Gulcin, 2006). In this study; 4 and 5 type compounds contain C⚌O groups.

Low absorbance at 562 nm indicates high metal chelating activity. The data obtained from Figs. 4 and 5 reveal that the metal chelating effects of the compounds 4b, 4g, 5c and 5e were concentration-dependent, the other compounds were not. Thus, the compounds 4b, 4g, 5c and 5e demonstrate a marked capacity for iron binding, suggesting that their action as peroxidation protectors may be related to their iron binding capacity. The metal chelating effect of the compounds and standards decreased in the order of EDTA > 5e > 5c > α-tocopherol > 4g > 4b. On the other hand, free iron is known to have low solubility and a chelated iron complex has greater solubility in solution, which can be contributed solely by the ligand. Furthermore, the compound–iron complex may also be active, since it can participate in iron-catalysed reactions.

3.2

3.2 Potentiometric titrations

In order to determine the pK_a values of the compounds 4a–g, they were titrated potentiometrically with TBAH in four non-aqueous solvents: isopropyl alcohol, tert-butyl alcohol, acetone and DMF. The mV values read in each titration were plotted against 0.05 M TBAH volumes (mL) added, and potentiometric titration curves were obtained for all the cases. From the titration curves, the HNP values were measured, and the corresponding pK_a values were calculated. The data obtained from the potentiometric titrations were interpreted, and the effect of the C-3 substituent in the 4,5-dihydro-1H-1,2,4-triazol-5-one ring as well as solvent effects was studied.

As an example for the potentiometric titration curves for 0.001 M solutions of compounds 4a titrated with 0.05 M TBAH in isopropyl alcohol, tert-butyl alcohol, DMF and acetone are shown in Fig. 6.

Potentiometric titration curves of 0.001 M solutions of compound 4a titrated with 0.05 M TBAH in DMF, acetone, tert-butyl alcohol and isopropyl alcohol at 25 °C.

When the dielectric permittivity of solvents is taken into consideration, the acidity order can be given as follows: DMF (ε = 36.7) > acetone (ε = 36) > isopropyl alcohol (ε = 19.4) > tert-butyl alcohol (ε = 12). As seen in Table 1, the acidity order for compound 4a is: DMF > acetone, for compound 4b it is: DMF > acetone > tert-butyl alcohol, for compounds 4c and 4f it is: tert-butyl alcohol > DMF > acetone, for compound 4d it is: isopropyl alcohol > DMF > acetone, for compound 4e it is: isopropyl alcohol > tert-butyl alcohol > DMF > acetone, while the order for compound 4g is: DMF > tert-butyl alcohol > acetone. Moreover, as seen in Table 1, for compounds 4a in isopropyl alcohol and tert-butyl alcohol, for compounds 4b, 4c, 4f and 4g in isopropyl alcohol and for compounds 4d in tert-butyl alcohol the HNP values and the corresponding pK_a values were not obtained.

Table 1 The HNP and the corresponding pK_a values of compounds 4a–g in DMF, acetone, tert-butyl alcohol and isopropyl alcohol.

Compd.	Isopropyl alcohol		tert-Butyl alcohol		DMF		Acetone
Compd.	HNP (mV)	pK_a	HNP (mV)	pK_a	HNP (mV)	pK_a	HNP (mV)	pK_a
4a	–	–	–	–	−335	13.37	−483	16.30
4b	–	–	−525	15.91	−397	14.61	−427	14.94
4c	–	–	−428	11.81	−350	13.73	−495	16.15
4d	−339	13.03	–	–	−333	13.36	−478	16.01
4e	−191	10.56	−382	14.02	−453	15.56	−566	17.53
4f	–	–	−591	13.80	−416	14.92	−576	17.79
4g	–	–	−380	13.60	−330	13.34	−577	17.96

As it is well known, the acidity of a compound depends on some factors. The two most important factors are the solvent effect and molecular structure (Arslantas et al., 2012; Gursoy-Kol et al., 2012). Table 1 and Fig. 6 show that the HNP values and corresponding pK_a values obtained from the potentiometric titrations depend on the non-aqueous solvents used and the substituents at C-3, in the 4,5-dihydro-1H-1,2,4-triazol-5-one ring.

4 Conclusion

The synthesis and in vitro antioxidant evaluation of new 4,5-dihydro-1H-1,2,4-triazol-5-one derivatives are described. Compound 4g demonstrates a marked capacity for antioxidant activity. The data reported with regard to the observed radical scavenging and metal chelating activities of the studied compounds could prevent redox cycling. Design and synthesis of novel small molecules can play specifically a protective role in biological systems and in modern medicinal chemistry. These results may also provide some guidance for the development of novel triazole-based therapeutic target.

Acknowledgements

This work was supported by the Scientific Research Projects Coordination Unit of Kafkas University (Project Number: 2013-FEF-74). The authors thank Dr. Zafer Ocak for the determination of pK_a values and Dr. Mustafa Calapoglu for antioxidant activities.

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Introduction

Materials and methods

Chemical reagents and apparatus
General procedure for the synthesis of compounds 4
General procedure for the synthesis of compounds 5
Antioxidant activity: chemicals
Potentiometric titrations

Results and discussion

Antioxidant activity
Potentiometric titrations

Conclusion

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Antioxidant activities and acidic properties of some novel 4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one derivatives

Abstract

Keywords

1,2,4-Triazol-5-one

Schiff base

Synthesis

Antioxidant activity

Acidity

1 Introduction

2 Materials and methods

2.1 Chemical reagents and apparatus

2.2 General procedure for the synthesis of compounds 4

2.2.1 3-Methyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (4a)

2.2.2 3-Ethyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (4b)

2.2.3 3-Benzyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (4c)

2.2.4 3-p-Methylbenzyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (4d)

2.2.5 3-p-Chlorobenzyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (4e)

2.2.6 3-m-Chlorobenzyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (4f)

2.2.7 3-Phenyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (4g)

2.3 General procedure for the synthesis of compounds 5

2.3.1 1-Acetyl-3-methyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (5a)

2.3.2 1-Acetyl-3-ethyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (5b)

2.3.3 1-Acetyl-3-benzyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (5c)

2.3.4 1-Acetyl-3-p-methylbenzyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (5d)

2.3.5 1-Acetyl-3-p-chlorobenzyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (5e)

2.3.6 1-Acetyl-3-phenyl-4-[3,4-di-(4-nitrobenzoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one (5g)

2.4 Antioxidant activity: chemicals

2.4.1 Reducing power

2.4.2 Free radical scavenging activity

2.4.3 Metal chelating activity

2.5 Potentiometric titrations

3 Results and discussion

3.1 Antioxidant activity

3.1.1 Total reductive capability using the potassium ferricyanide reduction method

3.1.2 DPPH• radical scavenging activity

3.1.3 Ferrous ion chelating activity

3.2 Potentiometric titrations

4 Conclusion

Acknowledgements

References

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3.1.2 DPPH^• radical scavenging activity