Synthesis, Characterization, and Cytotoxic Evaluation of Some Newly Substituted Diazene Candidates

El-Naggar, Mohamed; El-Shorbagi, Abdel-Nasser; Elnaggar, Dina H.; Amr, Abd El-Galil E.; Al-Omar, Mohamed A.; Elsayed, Elsayed A.

doi:https://doi.org/10.1155/2018/3626824

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Research Article | Open Access

Volume 2018 | Article ID 3626824 | https://doi.org/10.1155/2018/3626824

Synthesis, Characterization, and Cytotoxic Evaluation of Some Newly Substituted Diazene Candidates

Mohamed El-Naggar,¹Abdel-Nasser El-Shorbagi,^2,3Dina H. Elnaggar,⁴Abd El-Galil E. Amr,^5,6Mohamed A. Al-Omar,⁵and Elsayed A. Elsayed^7,8

Academic Editor: Artur M. S. Silva

Received18 Jun 2018

Revised29 Aug 2018

Accepted16 Sept 2018

Published01 Nov 2018

Abstract

A series of azocompounds containing methyl salicylate 4a–k and 1-naphthyl moiety 6–8 was synthesized and tested as anticancer agents. Nitrosation of methyl 5-amino-2-hydroxybenzoate or 1-aminonaphthalene by using NaNO₂ in the presence of HCl afforded diazonium salt derivatives 2 and 5, which were treated with substituted imino or substituted amino derivatives, to give the corresponding substituted amino-pent-2-en-3-yl-diazenylbenzoate 4a–k or 2-substituted-1-(naphthalen-1-yl)diazene derivatives 6a–h, 7a,b, and 8a,b. All the synthesized compounds were elucidated by elemental analysis and spectroscopic evidence.

1. Introduction

In a previous work, the authors reported that certain synthesized substituted heterocyclic aromatic derivatives showed antiviral activities [1] and alpha reductase inhibition [2]. Also, some of new compounds containing the nitrogen atom have been synthesized and used as antihypertensive α-blocking [3], antiparkinsonian [4], antialzheimer [5], antimicrobial [6–8], and anti-inflammatory [9, 10] agents. There is an increasing and critical demand for more powerful anticancer agents, due to increased detection of cancer resistance [11]. Azocompounds are one of the largest types of organically synthesized compounds, which are effective both as drugs and cosmetics [12]. Also, they are extensively used in the field of dyeing textiles, biomedical studies, advanced applications in organic synthesis, and remarkable biological activities including antibacterial activity [13–20]. A number of azocompounds were synthesized comprising a drug moiety in their skeleton [21]. Salicylates are a class of chemicals with appreciative biological activities. Several biomedical studies have used methyl salicylate derivatives with promising results [22–24]. Aromatic amines such as benzidine, 1-naphthylamine, and 4-methylaniline have been recognized as potential carcinogens [25, 26]. From these observations, we decided to synthesize two series of azocompounds. One of these series contains methyl salicylate moiety, and the other involves 1-naphthyl moiety. All the synthesized compounds were screened as anticancer agents.

2. Experimental

2.1. Chemistry

All reagents and solvents were obtained from the commercial supplier and used without further purification. Melting point is uncorrected and was determined on an electrothermal melting point apparatus (Stuart Scientific, England, UK). Precoated silica gel plates (Kieselgel 0.25 mm, 60G F₂₅₄, Merck, Germany) were used for thin layer chromatography (TLC) for reaction monitoring, and UV light was used for detection. The separation was done using column chromatography with silica gel 60 (Merck) eluted with appropriate solvent. Nuclear magnetic resonance spectra (NMR) were recorded using Bruker 500 MHz instrument. Chemical shifts were reported in ppm, and spectra were corrected using the residual solvent as a reference. Mass spectra were recorded on a Bruker Daltonics spectrometer.

2.1.1. General Procedure for the Synthesis of Compounds 4a–k

A mixture of methyl 5-aminosalicylate 1 (0.56 g, 3.4 mmol) in concentrated hydrochloric acid (5 mL) was stirred with gentle heating until complete dissolving. Then, the mixture was cooled at a temperature from zero to −4°C, sodium nitrite (0.28 g, 4 mmol) in 2 mL of water was added portionwise at a temperature of −4°C to form the corresponding diazonium salt 2, and the diazonium salt formed was added to a mixture of 4-(substituted imino)pentan-2-one derivatives 3 (2 mmol) [27] in ethanol (15 mL) slowly under the same temperature allowing the mixture to stir at room temperature for an additional 3 hours. The solid formed was collected by filtration, washed with cold water several times, and then left to dry. The obtained product was recrystallized from ethanol to give target compounds 4a–k, respectively.

(1) Methyl 5-(4-(benzylamino)-2-oxopent-3-en-3-yl)diazenyl)-2-hydroxybenzoate (4a). Yellow crystalline solid, m.p. 167-168°C, yield = 62%, and ¹H-NMR (DMSO-d₆) δ (ppm) 2.42 (s, 3H, CH₃-CNH), 2.57 (s, 3H, CO-CH₃), 3.93 (s, 3H, OCH₃), 4.82 (s, 2H, Ar-CH₂), 7.05 (d, 1H, J = 8.8 Hz, Ar-H, benzoate ring), 7.36–7.42 (m, 5H, ArH), 7.72 (d, 1H, J = 2.5 Hz, Ar-H, benzoate ring), 7.78 (s, 1H, Ar-H, benzoate ring), 10.50 (br s, 1H, NH), and 14.40 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 16.8, 29.0, 47.6, 53.0, 113.8, 118.9, 123.0, 125.6, 128.1, 128.2, 128.6, 129.4, 137.3, 144.5,159.1, 159.4, 169.3, and 196.4 (20C). ESI-MS: m/z, 368.16 (M⁺ + H). Anal. calcd for C₂₀H₂₁N₃O₄ (367.40): C, 65.38; H, 5.76; and N, 11.44. Found: C, 65.35; H, 5.78; and N, 11.40.

(2) Methyl 5-(2-oxo-4-(phenethylamino)pent-3-en-3-yl)diazenyl)-2-hydroxybenzoate (4b). Yellow crystalline solid, m.p. 131-132°C, yield = 60%, and ¹H-NMR (DMSO-d₆) δ (ppm) 2.39 (s, 3H, CH₃-CNH), 2.52 (s, 3H, CO-CH₃), 2.98 (t, 2H, J = 6.8 Hz, PhCH₂CH₂N), 3.85 (t, 2H, J = 6.7 Hz, ArCH₂CH₂N), 3.95 (s, 3H, OCH₃), 7.03 (d, 1H, J = 8.8 Hz, Ar-H, benzoate ring), 7.34–7.30 (m, 5H, ArH), 7.59 (d, 1H, J = 2.5 Hz, Ar-H, benzoate ring), 7.76 (s, 1H, Ar-H, benzoate ring), 10.50 (br s, 1H, NH), and 13.84 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 16.3, 29.1, 35.0, 44.6, 53.1, 113.8, 118.7, 122.4, 126.6, 127.0, 128.3, 129.0, 129.2, 138.7, 144.9, 159.1, 159.3, 169.5, and 196.3 (21C). ESI-MS: m/z, 382.18 (M⁺ + H). Anal. calcd for C₂₁H₂₃N₃O₄ (381.43): C, 66.13; H, 6.08; and N, 11.02. Found: C, 66.45; H, 6.02; and N, 11.00.

(3) Methyl 5-(2-oxo-4-(1-phenylethylamino)pent-3-en-3-yl)diazenyl)-2-hydroxybenzoate (4c). Yellow crystalline solid, m.p. 110-111°C, yield = 66%, and ¹H-NMR (DMSO-d₆) δ (ppm) 1.60 (d, 3H, J = 7.6 Hz, ArCH(CH₃)N), 2.41 (s, 3H, CH₃-C), 2.49 (s, 3H, CO-CH₃), 3.94 (s, 3H, OCH₃), 5.17 (q, 1H, J = 6.7 Hz, ArCH(CH₃)N), 7.06 (d, 1H, J = 8.8 Hz, Ar-H, benzoate ring), 7.40–7.45 (m, 5H, ArH), 7.76 (d, 1H, J = 2.5 Hz, Ar-H, benzoate ring), 7.86 (s, 1H, Ar-H, benzoate ring), 10.50 (br s, 1H, NH), and 14.63 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 16.8, 24.0, 29.0, 53.1, 53.7, 114.0, 119.0, 122.2, 126.4, 126.6, 128.2, 128.5, 129.4, 143.0, 144.5, 159.2, 159.4, 169.3, and 196.4 (21C). ESI-MS: m/z, 382.18 (M⁺ + H). Anal. calcd for C₂₁H₂₃N₃O₄ (381.43): C, 66.13; H, 6.08; and N, 11.02. Found: C, 66.04; H, 6.03; and N, 10.98.

(4) Methyl 5-(4-(2-hydroxyethylamino)-2-oxopent-3-en-3-yl)diazenyl)-2-hydroxybenzoate (4d). Yellow crystalline solid, m.p. 187-188°C, yield = 70%, and ¹H-NMR (DMSO-d₆) δ (ppm) 2.42 (s, 3H, CH₃-C), 2.54 (s, 3H, CO-CH₃), 3.59 (t, 2H, J = 5.0 Hz, NCH₂CH₂OH), 3.66 (t, 2H, J = 4.2 Hz, NCH₂CH₂OH), 3.92 (s, 3H, OCH₃), 5.13 (br s, 1H, NCH₂CH₂OH) 7.07 (d, 1H, J = 8.8 Hz, Ar-H, benzoate ring), 7.79 (d, 1H, J = 2.5 Hz, Ar-H, benzoate ring), 8.01 (s, 1H, Ar-H, benzoate ring), and 10.5 (br s, 1H, NH), 14.21 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 16.7, 29.1, 46.0, 53.1, 59.7, 113.9, 118.7, 122.1, 127.0, 128.4, 134.5, 154.1, 159.3, 169.5, and 196.4 (15C). ESI-MS: 322.27 (M⁺ + H). Anal. calcd for C₁₅H₁₉N₃O₅ (321.33): C, 56.07; H, 5.96; and N, 13.08. Found: C, 56.00; H, 5.92; and N, 13.00.

(5) Methyl 5-(4-(isobutylamino)-2-oxopent-3-en-3-yl)diazenyl)-2-hydroxybenzoate (4e). Yellow crystalline solid, m.p. 94–95°C, yield = 75%, and ¹H-NMR (DMSO-d₆) δ (ppm) 1.00 (d, 6H, J = 6.7 Hz, NHCH₂CH(CH₃)₂), 1.95–1.90 (m, 1H, NHCH₂CH(CH₃)₂), 2.42 (s, 3H, CH₃-C), 2.54 (s, 3H, CO-CH₃), 3.39 (dd, 2H, J = 5.4 Hz, NHCH₂CH(CH₃)₂), 3.92 (s, 3H, OCH₃), 7.07 (d, 1H, J = 8.8 Hz, Ar-H, benzoate ring), 7.76 (d, 1H, J = 2.5 Hz, Ar-H, benzoate ring), 7.95 (s, 1H, Ar-H, benzoate ring), 10.50 (br s, 1H, NH), and 14.09 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 16.45, 2.36, 28.3, 29.1, 50.7, 53.1, 114.0, 118.9, 122.0, 126.8, 128.4, 134.5, 145.2, 159.3, 169.4, and 196.2 (17C). ESI-MS: m/z, 334.18 (M⁺ + H). Anal. calcd for C₁₇H₂₃N₃O₄ (333.38): C, 61.25; H, 6.95; and N, 12.60. Found: C, 61.12; H, 6.90; and N, 12.54.

(6) Methyl 5-(4-(isopropylamino)-2-oxopent-3-en-3-yl)diazenyl)-2-hydroxybenzoate (4f). Yellow crystalline solid, m.p. 104-105°C, yield = 61%, and ¹H-NMR (DMSO-d₆) δ (ppm) 1.30 (d, 6H, J = 6.4 Hz, NHCH(CH₃)₂), 2.41 (s, 3H, CH₃-C), 2.56 (s, 3H, COCH₃), 3.92 (s, 3H, OCH₃), 4.15–4.12 (m, 1H, J = 6.4 Hz, NHCH(CH₃)₂), 7.08 (d, 1H, J = 8.8 Hz, Ar-H, benzoate ring), 7.78 (d, 1H, J = 2.5 Hz, Ar-H, benzoate ring), 7.92 (s, 1H, Ar-H, benzoate ring), 10.50 (br s, 1H, NH), and 14.10 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 16.3, 23.2, 29.1, 45.6, 53.1, 114.0, 118.8, 121.8, 127.1, 127.9, 134.5, 145.1, 159.3, 169.4, and 196.1 (16C). ESI-MS: m/z, 320.16 (M⁺ + H). Anal. calcd for C₁₆H₂₁N₃O₄ (319.36): C, 60.17; H, 6.63; and N, 13.16. Found: C, 60.10; H, 6.58; and N, 13.10.

(7) Methyl 5-(4-(butylamino)-2-oxopent-3-en-3-yl)diazenyl)-2-hydroxybenzoate (4g). Yellow crystalline solid, m.p. 131-132°C, yield = 65%, and ¹H-NMR (DMSO-d₆) δ (ppm) 0.97 (t, 3H, J = 7.3 Hz, NHCH₂CH₂CH₂CH₃), 1.43-1.40 (m, 2H, J = 7.6 Hz, NHCH₂CH₂CH₂CH₃), 1.62–1.66 (m, 2H, J = 6.9 Hz, NHCH₂CH₂CH₂CH₃), 2.41 (s, 3H, CH₃-C), 2.53 (s, 3H, COCH₃), 3.52 (t, 2H, J = 6.7 Hz, NHCH₂CH₂CH₂CH₃), 3.91 (s, 3H, OCH₃), 7.07 (d, 1H, J = 8.8 Hz, Ar-H, benzoate ring), 7.72 (d, 1H, J = 2.5 Hz, Ar-H, benzoate ring), 7.93 (s, 1H, Ar-H, benzoate ring), 10.50 (br s, 1H, NH), and 14.05 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 14.0, 16.4, 20.2, 29.0, 31.0, 43.1, 53.1, 113.9, 118.9, 122.6, 126.5, 128.2, 134.5, 145.1, 159.3, 169.4, and 196.2 (17C). ESI-MS: m/z, 334.18 (M⁺ + H). Anal. calcd for C₁₇H₂₃N₃O₄ (333.38): C, 61.25; H, 6.95; and N, 12.60. Found: C, 61.12; H, 6.86; and N, 12.52.

(8) Methyl 5-(4-(3-hydroxypropylamino)-2-oxopent-3-en-3-yl)diazenyl)-2-hydroxybenzoate (4h). Yellow crystalline solid, m.p. 135-136°C, yield = 63%, and ¹H-NMR (DMSO-d₆) δ (ppm) 1.80–1.75 (m, 2H, J = 6.3 Hz, NHCH₂CH₂CH₂OH), 2.41 (s, 3H, CH₃-C), 2.54 (s, 3H, CO-CH₃), 3.54 (br t, 2H, J = 5.7 Hz, NHCH₂CH₂CH₂OH), 3.59 (br t, 2H, J = 6.7 Hz, NHCH₂CH₂CH₂OH), 3.91 (s, 3H, OCH₃), 4.70 (br s, 2H, NHCH₂CH₂CH₂OH), 7.07 (d, 1H, J = 8.8 Hz, Ar-H, benzoate ring), 7.77 (d, 1H, J = 2.5 Hz, Ar-H, benzoate ring), 7.98 (s, 1H, Ar-H, benzoate ring), and 10.50 (br s, 1H, NH), 13.95 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 16.3, 29.1, 32.2, 40.0, 53.1, 58.4, 113.9, 118.7, 122.0, 127.1, 128.3, 134.5, 145.2, 159.3, 169.5, and 196.2 (16C). ESI-MS): m/z, 336.16 (M⁺ + H). Anal. calcd for C₁₆H₂₁N₃O₅ (335.36): C, 57.30; H, 6.31; and N, 12.53. Found: C, 57.10; H, 6.22; and N, 12.42.

(9) Methyl 5-(2-oxo-4-(pentylamino)pent-3-en-3-yl)diazenyl)-2-hydroxybenzoate (4i). Yellow crystalline solid, m.p. 127-128°C, yield = 72%, and ¹H-NMR (DMSO-d₆) δ (ppm) 0.92 (t, 3H, J = 6.9 Hz, NHCH₂CH₂CH₂CH₂CH₃), 1.40–1.45 (m, 4H, NHCH₂CH₂CH₂CH₂CH₃), 1.66–1.62 (m, 2H, NHCH₂CH₂CH₂CH₂CH₃), 2.41 (s, 3H, CH₃-C), 2.54 (s, 3H, CO-CH₃), 3.53 (t, 2H, J = 6.7 Hz, NHCH₂CH₂CH₂CH₂CH₃), 3.91 (s, 3H, OCH₃), 7.06 (d, 1H, J = 8.8 Hz, Ar-H, benzoate ring), 7.78 (d, 1H, J = 2.5, Ar-H, benzoate ring), 7.93 (s, 1H, Ar-H, benzoate ring), 10.50 (br s, 1H, NH), and 14.05 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 14.3, 16.4, 22.3, 28.6, 29.2, 30.7, 43.4, 53.0, 113.8, 118.9, 122.7, 126.3, 128.2, 134.5, 145.1, 159.4, 169.4, and 196.2 (18C). ESI-MS: m/z, 348.19 (M⁺ + H). Anal. calcd for C₁₈H₂₅N₃O₄ (347.41): C, 62.23; H, 7.25; and N, 12.10. Found: C, 62.05; H, 7.16; and N, 12.05.

(10) Methyl 5-(4-(ethylamino)-2-oxopent-3-en-3-yl)diazenyl)-2-hydroxybenzoate (4j). Yellow crystalline solid, m.p. 106-107°C, yield = 75%, and ¹H-NMR (DMSO-d₆) δ (ppm) 1.27 (t, 3H, J = 7.2 Hz, NHCH₂CH₃), 2.41 (s, 3H, CH₃-C), 2.54 (s, 3H, CO-CH₃), 3.55 (q, 2H, NHCH₂CH₃), 3.91 (s, 3H, OCH₃), 7.07 (d, 1H, J = 8.8 Hz, Ar-H, benzoate ring), 7.78 (d, 1H, J = 2.5 Hz, Ar-H, benzoate ring), 7.93 (s, 1H, Ar-H, benzoate ring), 10.50 (br s, 1H, NH), and 13.88 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 14.8, 16.3, 29.1, 38.3, 53.1, 113.9, 118.8, 122.3, 126.9, 128.1, 134.5, 145.3, 159.4, 169.5, and 196.1 (15C). ESI-MS): m/z, 306.15 (M⁺ + H). Anal. calcd for C₁₅H₁₉N₃O₄ (305.33): C, 59.01; H, 6.27; and N, 13.76. Found: C, 58.86; H, 6.20; and N, 13.70.

(11) Methyl 5-(2-oxo-4-(propylamino)pent-3-en-3-yl)diazenyl)-2-hydroxybenzoate (4k). Yellow crystalline solid, m.p. 137-138°C, yield = 69%, and ¹H-NMR (DMSO-d₆) δ (ppm) 0.99 (t, 3H, J = 7.3 Hz, NHCH₂CH₂CH₃), 1.68–1.64 (m, 3H, J = 7.2 Hz, NHCH₂CH₂CH₃), 2.41 (s, 3H, CH₃-C), 2.54 (s, 3H, CO-CH₃), 3.50 (q, 2H, J = 6.9 Hz, NHCH₂CH₃), 3.92 (s, 3H, OCH₃), 7.08 (d, 1H, J = 8.8 Hz, Ar-H, benzoate ring), 7.77 (d, 1H, J = 2.5 Hz, Ar-H, benzoate ring), 7.96 (s, 1H, Ar-H, benzoate ring), 10.52 (br s, 1H, NH), and 13.98 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 11.8, 16.4, 22.5, 29.1, 45.1, 53.1, 114, 118.8, 122.2, 126.9, 128.3, 134.5, 145.2, 159.3, 169.4, and 196.2 (16C). ESI-MS: m/z, 320.14 (M⁺ + H). Anal. calcd for C₁₆H₂₁N₃O₄ (319.36): C, 60.17; H, 6.63; and N, 13.16. Found: C, 60.00; H, 6.56; and N, 13.10.

2.1.2. General Procedure for the Synthesis of Compounds 6–8

A mixture of 1-aminonaphthalene (0.48 g, 3.4 mmol) and conc. HCl (5 mL) was stirred with gentle heating until complete dissolving. The reaction mixture was cooled at a temperature from zero to −4°C in an ice bath, and then sodium nitrite (0.28 g, 4 mmol) in water (2 mL) was added portionwise to the reaction mixture at the same temperature to form the diazonium salt 5. To the diazonium salt 5, a solution of appropriate amide or iminoderivatives [27], namely, N-substituted 3-oxo-butanamide, ethyl 3-(substituted imino)butanoate, or N-alkyl-3-(alkyl imino)-butanamide in absolute ethanol (10 mL), was added while stirring at a temperature of −4°C, and the mixture was stirred at room temperature for an additional 3 hours. The solid formed was collected by filtration, washed with cold water several times, dried, and crystallized from dimethylformamide/ethanol to give the corresponding 6a–h, 7a,b, and 8a,b, respectively.

(1) 2-(Naphthalen-1-yl-diazenyl)-3-hydroxy-N-phenethylbut-2-enamide (6a). Brownish crystalline solid, m.p. 141-142°C, yield = 70%, and ¹H-NMR (DMSO-d₆) δ (ppm) 2.50 (s, 3H, C-CH₃), 2.88 (t, 2H, J = 7.2 Hz, ArCH₂CH₂NH), 3.62 (q, 2H, J = 7.0 Hz, ArCH₂CH₂NH), 7.23–7.20 (m, 1H, Ar), 7.33–7.30 (m, 4H, ArH), 7.63–7.60 (m, 2H, naphthyl-H), 7.74–7.70 (m, 1H, naphthyl-H), 7.78 (d, 1H, J = 8.1 Hz, naphthyl-H), 7.83 (d, 1H, J = 6.7 Hz, naphthyl-H), 7.91 (d, 1H, J = 8.4 Hz, naphthyl-H), 8.04 (d, 1H, J = 7.9 Hz, naphthyl-H), 9.40 (br s, 1H, NHCO), and 15.67 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 26.4, 35.2, 40.7, 110.9, 119.8, 123.1, 125.1, 126.8, 126.9, 127.2, 127.5, 128.1, 128.9, 129.2, 129.3, 134.2, 136.9, 139.5, 164.9, and 198.7 (22C). ESI- MS: m/z, 360.17 (M⁺ + H). Anal. calcd for C₂₂H₂₁N₃O₂ (359.42): C, 73.52; H, 5.89; and N, 11.69. Found: C, 73.45; H, 5.80; and N, 11.60.

(2) 2-(Naphthalen-1-yl-diazenyl)-3-hydroxy-N-methylbut-2-enamide (6b). Brownish crystalline solid, m.p. 175-176°C, yield = 71%, and ¹H-NMR (DMSO-d₆) δ (ppm) 2.52 (s, 3H, C-CH₃), 2.88 (d, 3H, J = 4.9 Hz, CONHCH₃), 7.63–7.60 (m, 2H, naphthyl-H), 7.72–7.68 (m, 1H, naphthyl-H), 7.77 (d, 1H, J = 8.2 Hz, naphthyl-H), 7.83 (d, 1H, J = 7.6 Hz, naphthyl-H), 7.92 (d, 1H, J = 8.0 Hz, naphthyl-H), 8.02 (d, 1H, J = 8.1 Hz, naphthyl-H), 9.23 (br s, 1H, NHCO), and 15.72 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 25.8, 26.4, 110.8, 119.8, 123.0, 124.9, 126.9, 127.1, 127.5, 128.3, 129.3, 134.2, 136.9, 165.5, and 198.5 (15C). ESI-MS: m/z, 270.12 (M⁺ + H). Anal. calcd for C₁₅H₁₅N₃O₂ (269.30): C, 66.90; H, 5.61; and N, 15.60. Found: C, 66.80; H, 5.50; and N, 15.52.

(3) 2-(Naphthalen-1-yl-diazenyl)-N-tert-butyl-3-hydroxybut-2-enamide (6c). Brownish crystalline solid, m.p. 126-127°C, yield = 59%, and ¹H-NMR (DMSO-d₆) δ (ppm) 1.43 (s, 9H, C(CH₃)₃), 2.52 (s, 3H, C-CH₃), 7.63–7.60 (m, 2H, naphthyl-H), 7.74–7.40 (m, 1H, naphthyl-H), 7.78 (d, 1H, J = 8.1 Hz, naphthyl-H), 7.83 (d, 1H, J = 7.6 Hz, naphthyl-H), 7.90 (d, 1H, J = 8.4 Hz, naphthyl-H), 8.02 (d, 1H, J = 8.1 Hz, naphthyl-H), 9.42 (s, 1H, NHCO), and 15.69 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 26.5, 28.8, 51.3, 111.0, 119.7, 123.1, 125.1, 126.9, 127.1, 127.6, 128.4, 129.2, 134.2, 136.9, 164.7, and 199.3 (18C). ESI-MS: m/z, 312.17 (M⁺ + H). Anal. calcd for C₁₈H₂₁N₃O₂ (311.38): C, 69.43; H, 6.80; and N, 13.49. Found: C, 69.30; H, 6.75; and N, 13.40.

(4) 2-(Naphthalen-1-yl-diazenyl)-3-hydroxy-N-isopropylbut-2-enamide (6d). Brownish crystalline solid, m.p. 124-125°C, yield = 62%, and ¹H-NMR (DMSO-d₆) δ (ppm) 1.23 (d, 6H, J = 6.6 Hz, CH(CH₃)₂), 2.52 (s, 3H, C-CH₃), 4.11–4.00 (m, 1H, CH(CH₃)₂), 7.65–7.60 (m, 2H, naphthyl-H), 7.74–7.70 (m, 1H, naphthyl-H), 7.78 (d, 1H, J = 8.1 Hz, naphthyl-H), 7.83 (d, 1H, J = 6.8 Hz, naphthyl-H), 7.90 (d, 1H, J = 8.3 Hz, naphthyl-H), 8.02 (d, 1H, J = 8.1 Hz, naphthyl-H), 9.26 (br s, 1H, NHCO), and 15.71 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 22.6, 40.8, 49.1, 110.9, 119.7, 123.1, 125.1, 127.0, 127.1, 127.5, 128.1, 129.3, 134.2, 136.9, 164.2, and 199.0 (17C). ESI-MS: m/z, 280.15 (M⁺ + H). Anal. calcd for C₁₇H₁₉N₃O₂ (297.35): C, 68.67; H, 6.44; and N, 14.13. Found: C, 68.60; H, 6.34; and N, 14.00.

(5) 2-(Naphthalen-1-yl-diazenyl)-N-ethyl-3-hydroxybut-2-enamide (6e). Brownish crystalline solid, m.p. 130–131°C, yield = 75%, and ¹H-NMR (DMSO-d₆) δ (ppm) 1.17 (t, 3H, J = 7.2 Hz, NHCH₂CH₃), 2.52 (s, 3H, C-CH₃), 3.38–3.34 (m, 2H, NHCH₂CH₃), 7.64–7.60 (m, 2H, naphthyl-H), 7.74–7.70 (m, 1H, naphthyl-H), 7.77 (d, 1H, J = 8.1 Hz, naphthyl-H), 7.82 (d, 1H, J = 7.6 Hz, naphthyl-H), 7.91 (d, 1H, J = 8.4 Hz, naphthyl-H), 8.02 (d, 1H, J = 8.1 Hz, naphthyl-H), 9.33 (br s, 1H, NHCO), and 15.72 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 14.9, 26.5, 33.60, 110.9, 119.8, 123.0, 125.0, 126.9, 127.1, 127.5, 128.2, 129.3, 134.2, 136.9, 164.8, and 198.7 (16C). ESI-MS: m/z, 284.14 (M⁺ + H). Anal. calcd for C₁₆H₁₇N₃O₂ (283.33): C, 67.83; H, 6.05; and N, 14.83. Found: C, 67.74; H, 6.00; and N, 14.78.

(6) 2-(Naphthalen-1-yl-diazenyl)-N-butyl-3-hydroxybut-2-enamide (6f). Brownish crystalline solid, m.p. 142-143°C, yield = 71%, and ¹H-NMR (DMSO-d₆) δ (ppm) 0.93 (t, 3H, J = 7.3 Hz, NHCH₂CH₂CH₂CH₃), 1.38–1.35 (m, 2H, J = 7.6 Hz, NHCH₂CH₂CH₂CH₃), 1.57–1.54 (m, 2H, J = 7.3 Hz, NHCH₂CH₂CH₂CH₃) 2.53 (s, 3H, C-CH₃), 3.36 (q, 2H, J = 7.0 Hz, NHCH₂CH₂CH₂CH₃), 7.65–1.62 (m, 2H, naphthyl-H), 7.75–7.71 (m, 1H, naphthyl-H), 7.77 (d, 1H, J = 8.1 Hz, naphthyl-H), 7.82 (d, 1H, J = 7.5 Hz, naphthyl-H), 7.91 (d, 1H, J = 8.4 Hz, naphthyl-H), 8.02 (d, 1H, J = 8.1 Hz, naphthyl-H), 9.36 (br s, 1H, NHCO), and 15.72 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 14.1, 20.2, 26.5, 31.3, 38.3, 110.9, 119.8, 123.1, 125.1, 126.9, 127.1, 127.5, 128.2, 129.3, 134.2, and 136.9, 164.9, 198.8 (18C). ESI-MS: m/z, 312.17 (M⁺ + H). Anal. calcd for C₁₈H₂₁N₃O₂ (311.38): C, 69.43; H, 6.80; and N, 13.49. Found: C, 69.35; H, 6.72; and N, 13.40.

(7) 2-(Naphthalen-1-yl-diazenyl)-N-sec-butyl-3-hydroxybut-2-enamide (6g). Yellow crystalline solid, m.p. 105-106°C, yield = 55%, and ¹H-NMR (CDCl₃) δ (ppm) 1.01 (t, 3H, J = 7.4 Hz, CH₃CH₂CH(NH)CH₃), 1.28 (d, 3H, J = 6.6 Hz, CH₃CH₂CH(NH)CH₃), 1.66–1.60 (m, 2H, CH₃CH₂CH(NH)CH₃), 2.62 (s, 3H, C-CH₃), 4.12–4.08 (m, 1H, CH₃CH₂CH(NH)CH₃) 7.56–7.52 (m, 3H, naphthyl-H), 7.68 (d, 1H, J = 8.0 Hz, naphthyl-H), 7.82 (d, 1H, J = 8.0 Hz, naphthyl-H), 7.90 (d, 1H, J = 7.6 Hz naphthyl-H), 8.07 (d, 1H, J = 7.9 Hz naphthyl-H), 9.40 (br s, 1H, NHCO), and 15.81 (s, 1H, OH); ¹³C-NMR (CDCl₃) δ (ppm). 10.4, 20.3, 26.2, 29.4, 46.0, 110.7, 120.2, 123.5, 124.8, 126.1, 126.4, 126.7, 127.6, 128.6, 134.1, 137.2, 164.7, and 199.4 (18C). ESI-MS: m/z, 312.16 (M⁺ + H). Anal. calcd for C₁₈N₂₁N₃O₂ (311.38): C, 69.43; H, 6.80; and N, 13.49. Found: C, 69.35; H, 6.72; and N, 13.40.

(8) 2-(Naphthalen-1-yl-diazenyl)-3-hydroxy-N-propylbut-2-enamide (6h). Brownish crystalline solid, m.p. 157-158°C, yield = 65%, and ¹H-NMR (CDCl₃) δ (ppm) 1.04 (t, 3H, J = 7.4 Hz, CONHCH₂CH₂CH₃), 1.68–1.63 (m, 2H, J = 7.3 Hz, CONHCH₂CH₂CH₃), 2.62 (s, 3H, C-CH₃), 3.42 (q, 2H, J = 7.0 Hz, CONHCH₂CH₂CH₃), 7.57–7.53 (m, 3H, naphthyl-H), 7.68 (d, 1H, J = 8.1 Hz, naphthyl-H), 7.82 (d, 1H, J = 7.5 Hz, naphthyl-H), 7.90 (d, 1H, J = 7.5 Hz, naphthyl-H), 8.07 (br d, 1H, J = 8.5 Hz, naphthyl-H), 9.54 (br s, 1H, NHCO), and 15.79 (s, 1H, OH); ¹³C-NMR (CDCl₃) δ (ppm) 11.6, 22.6, 26.2, 40.4, 110.7, 120.2, 123.5, 124.9, 126.1, 126.4, 126.7, 127.6, 128.6, 134.1, 137.1, 165.3, and 199.4 (17C). ESI-MS: m/z, 298.15 (M⁺ + H). Anal. calcd for C₁₇H₁₉N₃O₂ (297.35): C, 68.67; H, 6.44; and N, 14.13. Found: C, 68.55; H, 6.36; and N, 14.04.

(9) Ethoxy 3-(benzylimino)-2-(naphthalen-1-yl-diazenyl)but-1-en-1-ol (7a). Brownish crystalline solid, m.p. 110-111°C, yield = 77%, and ¹H-NMR (DMSO-d₆) δ (ppm) 1.32 (t, 3H, J = 7.1 Hz, OCH₂CH₃), 2.59 (s, 3H, C-CH₃), 4.27 (q, 2H, J = 7.1 Hz, OCH₂CH₃), 4.83 (s, 2H, J = 3.4 Hz, ArCH₂N), 7.50–4.46 (m, 9H, naphthyl-H and ArH), 7.65 (d, 1H, J = 7.5 Hz, naphthyl-H), 7.72 (d, 1H, J = 8.1 Hz, naphthyl-H), 7.88 (d, 1H, J = 8.2 Hz, naphthyl-H), and 14.90 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 14.9, 17.2, 50.2, 60.3, 111.2, 121.9, 124.1, 126.1, 126.4, 126.4, 126.6, 127.2, 128.1, 128.5, 129.3, 129.5, 134.3, 136.9, 137.9, 166.7, and 198.7 (23C). ESI-MS: m/z, 374.19 (M⁺ + H). Anal. calcd for C₂₃H₂₃N₃O₂ (373.45): C, 73.97; H, 6.21; and N, 11.25. Found: C, 73.85; H, 6.12; and N, 11.20.

(10) Ethoxy 2-(naphthalen-1-yl-diazenyl)-3-(phenethylimino)but-1-en-1-ol (7b). Brownish crystalline solid, m.p. 142-143°C, yield = 72%, and ¹H-NMR (DMSO-d₆) δ (ppm) 1.30 (t, 3H, J = 7.1 Hz, OCH₂CH₃), 2.48 (s, 3H, C-CH₃), 3.08 (t, 2H, J = 7.1 Hz, ArCH₂CH₂N), 3.89 (t, 2H, J = 6.9 Hz, ArCH₂CH₂N), 4.23 (q, 3H, J = 7.1 Hz, OCH₂CH₃), 7.20–7.15 (m, 1H, naphthyl-H), 7.28–7.24 (m, 2H, naphthyl-H), 7.32–7.28 (m, 2H, naphthyl-H), 7.58–7.55 (m, 4H, ArH), 7.78–7.74 (m, 1H, naphthyl-H), 7.96–7.92 (m, 1H, naphthyl-H), and 14.59 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm). 14.9, 16.5, 35.9, 46.4, 60.1, 111.9, 122.6, 125.1, 126.3, 126.5, 126.7, 126.9, 127.5, 128.6, 128.9, 129.2, 129.2, 134.4, 136.9, 138.9, 166.7, and 198.7 (24C). ESI-MS: m/z, 388.19 (M⁺ + H). Anal. calcd for C₂₄H₂₅N₃O₂ (387.47): C, 74.39; H, 6.50; and N, 10.84. Found: C, 74.18; H, 6.42; and N, 10.76.

(11) 1-(Butylamino)-3-(butylimino)-2-[(1-(naphthalen-1-yl)diazene]but-1-en-1-ol (8a). Brownish crystalline solid, m.p. 91-92°C, yield = 71%, and ¹H-NMR (DMSO-d₆) δ (ppm). 0.93 (t, 3H, J = 6.4 Hz, NHCH₂CH₂CH₂CH₃), 0.96 (t, 3H, J = 7.3 Hz, NCH₂CH₂CH₂CH₃), 1.46–1.40 (m, 4H, J = 7.7 Hz, NHCH₂CH₂CH₂CH₃ and NCH₂CH₂CH₂CH₃), 1.61 (q, 2H, NHCH₂CH₂CH₂CH₃), 1.67–1.64 (m, 2H, NCH₂CH₂CH₂CH₃), 2.62 (s, 3H, C-CH₃), 3.39 (q, 2H, J = 6.4 Hz, NHCH₂CH₂CH₂CH₃), 3.65 (q, 2H, J = 6.8 Hz, NCH₂CH₂CH₂CH₃), 7.56–7.52 (m, 4H, naphthyl-H), 7.76 (d, 1H, J = 8.2 Hz, naphthyl-H), 7.95–7.90 (m, 1H, naphthyl-H), 8.4 (d, 1H, J = 7.4 Hz, naphthyl-H), 11.3 (br s, 1H, NH), and 15.37 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm) 14.1, 14.2, 14.7, 20.0, 20.4, 31.4, 31.7, 37.9, 44.0, 111.3, 121.3, 122.8, 126.0, 126.3, 126.8, 126.8, 128.6, 129.0, 134.5, 148.7, 165.9, and 172.7 (22C). ESI-MS: m/z, 367.25 (M⁺ + H). Anal. calcd for C₂₂H₃₀N₄O (366.50): C, 72.10; H, 8.25; and N, 15.29. Found: C, 72.00; H, 8.18; and N, 15.20.

(12) N-(2-hydroxyethyl imino)-3-(2-hydroxyethylamino)-2-(naphthalen-1-yldiazenyl)but-2-en-2-ol (8b). Brownish crystalline solid, m.p. 157-158°C, yield = 70%, and ¹H-NMR (DMSO-d₆) δ (ppm) 2.64 (s, 3H, C-CH₃), 3.47 (q, 3H, J = 5.3 Hz, CONHCH₂CH₂OH), 3.62–3.66 (m, 6H, CONHCH₂CH₂OH and CNCH₂CH₂OH), 4.95 (t, 1H, J = 4.6 Hz, CONHCH₂CH₂OH), 5.08 (t, 1H, J = 4.4 Hz, CNCH₂CH₂OH), 7.54–7.50 (m, 4H, naphthyl-H), 7.74 (d, 1H, J = 7.8 Hz, naphthyl-H), 7.94–7.88 (m, 1H, naphthyl-H), 8.74–8.70 (m, 1H, naphthyl-H), 11.40 (br s, 1H, NH), and 15.37 (s, 1H, OH); ¹³C-NMR (DMSO-d₆) δ (ppm).15.0, 41.1, 47.1, 60.0, 60.5, 111.1, 121.3, 123.9, 126.3, 126.4, 126.7, 126.8, 128.2, 129.2, 134.5, 148.8, 165.8, and 172.8 (18C). ESI-MS: m/z, 343.18 (M⁺ + H). Anal. calcd for C₁₈H₂₂N₄O₃ (342.39): C, 63.14; H, 6.48; and N, 16.36. Found: C, 63.00; H, 6.40; and N, 16.30.

2.2. Cytotoxicity Assay

Three cancer cell lines were used in the current study: MCF-7 (human breast adenocarcinoma), A549 (lung carcinoma), and HT-29 (human colorectal adenocarcinoma). Cancer cell lines were obtained from Sigma-Aldrich Chemical Company, USA, and were seeded in Dulbecco’s Modified Eagle Media (DMEM) supplemented with 10% heat-inactivated fetal bovine serum (FBS), 100 IU/mL penicillin, 100 mg/mL streptomycin, and 2 mM glutamine. The cells were maintained in a humidified atmosphere with 5% CO₂ at 37°C.

2.2.1. Antiproliferative Activity

The antiproliferative activity of the tested compounds was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay as mentioned before [28–30]. In brief, cells were seeded in 96-well plates 24 h before different treatments. Test compounds were dissolved in dimethyl sulfoxide (DMSO) and further diluted with the cultivation medium. All target compounds (1–23) were preliminary evaluated in vitro at the single concentration of 5 μM against different cancer cell lines. Doxorubicin was used in parallel as a positive control drug at the single concentration of 2 μM. Different tested samples were added to the wells, and the cells were incubated at 37°C in a 5% CO₂-humidified incubator for 48 h. After treatment, 10 μL of the MTT solution (5 mg/mL) was added to each well, and the plates were further incubated for 2 h. The media along with the MTT solution was removed and replaced by 100 μL of the DMSO solution to dissolve the precipitating formazan crystals. The intensity of the developed color was measured at 570 nm with an automatic multiwell plate reader (Varioskan™ LUX multimode microplate reader, Thermo Fisher Scientific, USA). Percentage inhibition of proliferation was calculated as a fraction of the vehicle control.

3. Results and Discussion

3.1. Chemistry

In the present work, a series of methyl 2-hydroxy-5-4-oxo-2-(substituted amino)pent-2-en-3-yl)diazenyl)benzoate 4a–k were synthesized via the diazotization of methyl 5-amino-2-hydroxybenzoate 2 as the starting material. Nitrosation of methyl 5-amino-2-hydroxybenzoate 1 by using NaNO₂ in the presence of HCl afforded the corresponding diazonium salt derivative 2. Treatment of 2 with 4-(substituted amino)pent-3-en-2-one derivatives 3 [31] in absolute ethanol with stirring at room temperature gave the corresponding methyl 2-hydroxy-5-(4-oxo-2-(substituted amino)pent-2-en-3-yl)diazenyl)benzoate 4a-k, respectively (Scheme 1).

Additionally, nitrosation of 1-aminonaphthalene by using NaNO₂ in the presence of HCl afforded the corresponding diazonium salt of naphthalen-1-amine 5. Treatment of diazonium compound 5 with N-substituted 3-oxo-butanamides (A) or ethyl 3-(substituted imino)butanoates (B) gave the corresponding azocompounds 6a–h and 7a,b, respectively. Finally, compound 5 was reacted with N-alkyl-3-(alkyl imino)butanamides (C) in the presence of sodium acetate to afford the corresponding compounds 8a,b, respectively (Scheme 2).

3.2. Anticancer Activity

The results of the antiproliferative activity of the synthesized compounds (Table 1, Figure 1) clearly showed that the synthesized compounds greatly varied in their effects on the tested cell lines. All the evaluated 23 compounds showed variable effects on MCF-7 cells. On the contrary, compounds 4f, 6f, 6g, 8a, and 8b were not effective against A549 and HT-29 cells. For MCF-7 cells, the most effective compounds are 4c, 4a, and 8a, whereas their toxicities were moderate on cells and reached 35, 23, and 22%, respectively. Compounds 6f, 4i, 6b, 4k, 6a, 4j, 6d, and 7a showed lower anticancer activities, and their toxicities obtained at the tested dose recorded 20, 16, 15, 13, 12, 11, 11, and 11%, respectively. The rest of the synthesized compounds showed weak anticancer activities, where they maximally reduced cell viabilities by 10%. Concerning A549 cells, compounds 4a and 6b showed a maximal potent effect, and their percentages of inhibition of cancer cells were obtained as 34 and 25%, respectively. On the contrary, compounds 7a, 4i, 4j, and 4h showed lower anticancer activities, and their maximal cytotoxicities reached 17, 15, 13, and 11%, respectively. For HT-29 cells, it can be seen that the most potent compound (compound 7b) against HT-29 cells reduced cell growth by about 39%. On the contrary, compounds 4f, 4d, and 7a showed weaker cytotoxic activities ranging only from 13 to 11%. It can be generally concluded that the most potent synthesized compounds are 7b against HT-29 cells, compound 4a against A549 cells, and compound 4c against MCF-7 cells.

The abovementioned results showed that different cell lines varied greatly in their response against different synthesized compounds. This correlates well with previously reported results [32, 33], where this can be attributed to the inherent differences between different cells in their specific membrane structure and organization. For the synthesized derivatives, our results are in good agreement with those previously reported by Jakopec et al. [34], who reported on the cytotoxic activities of diazenes on several tumor cell lines. They attributed their results to both (1) the attachment of unsubstituted benzene on the amide nitrogen and (2) the extent of compound basicity. Moreover, the length of the conjugation plays a crucial role in the activity of the synthesized derivatives [34].

Generally, it can be observed that the obtained anticancer activities of the newly synthesized diazene candidates are not promising as expected; therefore, the future work is planned to investigate further structural modifications of the prepared derivatives.

Data Availability

All data used to support the findings of this study are included within the article.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

The authors are grateful to the Deanship of Scientific Research, King Saud University, for funding this work through research group project “RGP-1435-047.”

References

N. M. Khalifa, M. A. Al-Omar, A. E. Amr, and M. E. Haiba, “HIV-1 and HSV-1 virus activities of some new polycyclic nucleoside pyrene candidates,” International Journal of Biological Macromoleculesd, vol. 54, pp. 51–56, 2013.
View at: Publisher Site | Google Scholar
A. E. Amr, N. A. Abdel-Latif, and M. M. Abdalla, “Synthesis of some new testosterone derivatives fused with substituted pyrazoline ring as 5α-reductase inhibitors,” Acta Pharmaceutica (Zagreb, Croatia), vol. 56, no. 2, pp. 203–218, 2006.
View at: Google Scholar
B. F. Abdel Wahab, S. F. Mohamed, A. E. Amr, and M. M. Abdalla, “Synthesis and reactions of some newly synthesized thiosemicarbazides, triazoles and Schiff bases as antihypertensive α-blocking agents,” Monatshefte für Chemie - Chemical Monthly, vol. 139, no. 9, pp. 1083–1090, 2008.
View at: Publisher Site | Google Scholar
N. O. Al-Harbi, S. A. Bahashwan, A. A. Fayed, M. S. Aboonq, and A. E. Amr, “Anti-parkinsonism, hypoglycemic and anti-microbial activities of some new poly ring heterocyclic candidates,” International Journal of Biological Macromolecules, vol. 57, pp. 165–173, 2013.
View at: Publisher Site | Google Scholar
M. M. Abdalla, M. A. Al-Omar, R. A. Al-Salahi, A. E. Amr, and N. M. Sabry, “A new investigation for some steroidal derivatives as anti-alzheimer agents,” International Journal of Biological Macromolecules, vol. 51, no. 2, pp. 56–63, 2012.
View at: Publisher Site | Google Scholar
L. Yurttaş, Y. Özkay, H. K. Gençer, and U. Acar, “Synthesis of some new thiazole derivatives and their biological activity evaluation,” Journal of Chemistry, vol. 2015, Article ID 464379, 7 pages, 2015.
View at: Publisher Site | Google Scholar
K. A. Khan, H. M. Faidallah, and A. M. Asiri, “Synthesis and biological evaluation of new N,N′-Bis(1-substituted-ethylidene)-ethane1,2-diamine and their acetyl and trifluoroacetyl derivatives as cytotoxic and antimicrobial agents,” Journal of Chemistry, vol. 2013, Article ID 478635, 9 pages, 2013.
View at: Publisher Site | Google Scholar
Z. A. Kaplancıklı, M. D. Altıntop, B. Sever, Z. Cantürk, and A. Özdemir, “Synthesis and in vitro evaluation of new thiosemicarbazone derivatives as potential antimicrobial agents,” Journal of Chemistry, vol. 2016, Article ID 1692540, 7 pages, 2016.
View at: Publisher Site | Google Scholar
A. E. Amr and M. M. Abdulla, “Synthesis and anti-inflammatory activities of new cynopyrane derivatives fused with steroidal nuclei,” Archiv der Pharmazie, vol. 339, no. 2, pp. 88–95, 2006.
View at: Publisher Site | Google Scholar
L. Pan, N. Hang, C. Zhang et al., “Synthesis and biological evaluation of novel benzimidazole derivatives and analogs targeting the NLRP3 inflammasome,” Molecules, vol. 22, no. 2, p. 213, 2017.
View at: Publisher Site | Google Scholar
C. Holohan, S. Van Schaeybroeck, D. B. Longley, and P. G. Johnston, “Cancer drug resistance: an evolving paradigm,” Nature Reviews Cancer, vol. 13, no. 10, pp. 714–726, 2013.
View at: Publisher Site | Google Scholar
D. M. Marmion, Hand Book of Colorant, Wiley, Hoboken, NJ, USA, 1999.
S. Piotto, S. Concilio, L. Sessa et al., “Synthesis and antimicrobial studies of new antibacterial azo-compounds active against Staphylococcus aureus and Listeria monocytogenes,” Molecules, vol. 22, p. 1372, 2017.
View at: Publisher Site | Google Scholar
S. Concilio, P. Iannelli, L. Sessa et al., “Biodegradable antimicrobial films based on poly (lactic acid) matrices and active azo compounds,” Journal of Applied Polymer Science, vol. 132, no. 33, Article ID 42357, 2015.
View at: Publisher Site | Google Scholar
S. Piotto, S. Concilio, L. Sessa et al., “Novel antimicrobial polymer films active against bacteria and fungi,” Polymer Composites, vol. 34, no. 9, pp. 1489–1492, 2013.
View at: Publisher Site | Google Scholar
S. Piotto, S. Concilio, L. Sessa et al., “Small azobenzene derivatives active against bacteria and fungi,” European Journal of Medicinal Chemistry, vol. 68, pp. 178–184, 2013.
View at: Publisher Site | Google Scholar
L. Sessa, S. Concilio, P. Iannelli, F. De Santis, A. Porta, and S. Piotto, “Antimicrobial azobenzene compounds and their potential use in biomaterials,” in Proceedings of the AIP Conference, pp. 16–19, Oudeniz, Turkey, April 2015.
View at: Google Scholar
I. M. Awad, A. A. Aly, A. M. Abdel Alim, R. A. Abdel, and S. H. Ahmed, “Synthesis of some 5-azo(4'-substituted benzene-sulphamoyl)-8-hydroxyquinolines with antidotal and antibacterial activities,” Journal of Inorganic Biochemistry, vol. 33, no. 2, pp. 77–89, 1998.
View at: Google Scholar
S. A. Ibrahim, M. A. Gahami, Z. A. Khafagi, and S. A. Gyar, “Structure and antimicrobial activity of some new azopyrazolone chelates of Ni(II) and Cu(II) acetates, sulfates, and nitrates,” Journal of Inorganic Biochemistry, vol. 43, no. 1, pp. 1–7, 1991.
View at: Publisher Site | Google Scholar
A. A. Jarahpour, M. Motamedifar, K. Pakshir, N. Hadi, and Z. Zarei, “Synthesis of novel azo Schiff bases and their antibacterial and antifungal activities,” Molecules, vol. 9, no. 10, pp. 815–824, 2004.
View at: Google Scholar
K. M. Rathod and N. S. Thakre, “Synthesis and antimicrobial activity of azo compounds containing m-cresol moiety,” Chemical Science Transactions, vol. 2, no. 1, pp. 25–28, 2013.
View at: Publisher Site | Google Scholar
S. Samadhiya and H. Halve, “Synthetic utility of schiff bases as potential herbicidal agents,” Oriental Journal of Chemistry, vol. 17, pp. 119–122, 2001.
View at: Google Scholar
P. Mao, Z. Liu, M. Xie et al., “Naturally occurring methyl salicylate glycosides,” Mini-Reviews in Medicinal Chemistry, vol. 14, no. 1, pp. 56–63, 2014.
View at: Publisher Site | Google Scholar
W. Xin, C. Huang, X. Zhang et al., “Methyl salicylate lactoside inhibits inflammatory response of fibroblast-like synoviocytes and joint destruction in collagen-induced arthritis in mice,” British Journal of Pharmacology, vol. 171, no. 14, pp. 3526–3538, 2014.
View at: Publisher Site | Google Scholar
X. Zhang, J. Sun, W. Xin et al., “Anti-inflammation effect of methyl salicylate 2-O-β-D-lactoside on adjuvant induced-arthritis rats and lipopolysaccharide (LPS)-treated murine macrophages RAW264.7 cells,” International Immunopharmacology, vol. 25, no. 1, pp. 88–95, 2015.
View at: Publisher Site | Google Scholar
A. L. Walpole and M. H. C. Williams, “Aromatic amines as carcinogens in industry,” British Medical Bulletin, vol. 14, no. 2, pp. 141–145, 1958.
View at: Publisher Site | Google Scholar
R. Sirgamalla, A. Kommakula, S. Banoth et al., “Synthesis of amides from aliphatic acids and amines by using of I2/TBHP at room temperature,” Chemistry Select, vol. 3, no. 4, pp. 1062–1065, 2018.
View at: Publisher Site | Google Scholar
H. A. Omar, S. A. Arafa, I. A. Maghrabi, and J. R. Weng, “Sensitization of hepatocellular carcinoma cells to Apo2L/TRAIL by a novel Akt/NF-kappaB signalling inhibitor,” Basic & Clinical Pharmacology & Toxicology, vol. 114, no. 6, pp. 464–471, 2014.
View at: Publisher Site | Google Scholar
H. A. Omar, W. R. Mohamed, S. A. Arafa et al., “Hesperidin alleviates cisplatininduced hepatotoxicity in rats without inhibiting its antitumor activity,” Pharmacological Reports, vol. 68, no. 2, pp. 349–356, 2016.
View at: Publisher Site | Google Scholar
J. J. Wu, H. A. Omar, Y. R. Lee et al., “6-Shogaol induces cell cycle arrest and apoptosis in human hepatoma cells through pleiotropic mechanisms,” European Journal of Pharmacology, vol. 762, pp. 449–458, 2015.
View at: Publisher Site | Google Scholar
A. Dib, “Synthesis and characterization of schiff bases derived from acetylacetone and their theoretical study,” International Journal of ChemTech Research, vol. 5, no. 1, pp. 204–211, 2013.
View at: Google Scholar
E. A. Elsayed, M. A. Sharaf-Eldin, and M. Wadaan, “In vitro evaluation of cytotoxic activities of essential oil from Moringa oleifera seeds on HeLa, HepG2, MCF-7, CACO-2 and L929 cell lines,” Asian Pacific Journal of Cancer Prevention, vol. 16, no. 11, pp. 4671–4675, 2015.
View at: Publisher Site | Google Scholar
E. A. Elsayed, M. Farooq, D. Dailin et al., “In vitro and in vivo biological screening of kefiran polysaccharide produced by Lactobacillus kefiranofaciens,” Biomedical Research, vol. 28, no. 2, pp. 594–600, 2017.
View at: Google Scholar
S. Jakopec, K. Dubravcic, A. Brozovic, S. Polanc, and M. Osmak, “Structurally similar diazenes exhibit significantly different biological activity,” Cell Biology and Toxicology, vol. 22, no. 1, pp. 61–71, 2006.
View at: Publisher Site | Google Scholar

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Copyright © 2018 Mohamed El-Naggar et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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