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Green synthesis and investigation of antioxidant and antimicrobial activity of new schiff base of pyrimidoazepine derivatives: application of Fe3O4/CuO/ZnO@MWCNT MNCs as an efficient organometallic nanocatalyst

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Abstract

In this study, we synthesized schiff base of pyrimidoazepine derivatives in high yields using multicomponent reactions of isatins, alkyl bromides, activated acetylenic compounds, guanidine and aldehydes in the presence of Fe3O4/CuO/ZnO@ Multi Walled Carbon Nanotubes (MWCNT) as a high performance catalyst in water at room temperature. The Fe3O4/CuO/ZnO@MWCNT synthesizes using Petasites hybridus rhizome water extract as a green media and moderate base. As well Fe3O4/CuO/ZnO@MWCNT magnetic nanocomposites show a good improvement in the yield of the product and displayed significant reusable activity. Investigation of antioxidant ability of synthesized compounds using radical trapping of diphenyl-picrylhydrazine and ferric reduction power experiment is another purpose in this research. Also, the antimicrobial activity of some synthesized compounds proved by employing the disk diffusion test on Gram-positive and Gram-negative bacteria. This procedure has some benefits such as short reaction time, product with excellent yields, simple catalyst and products separation.

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Acknowledgements

We thank from Islamic Azad University of Gorgan for their spiritual support.

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Authors and Affiliations

  1. Department of Chemistry, Gorgan Branch, Islamic Azad University, Gorgan, Iran

    Hannaneh Sadat Shirangi, Ali Varasteh Moradi, Maziar Ahmadi Golsefidi & Hamid Reza Jalilian

  2. Department of Chemistry, Qaemshahr Branch, Islamic Azad University, Qaemshahr, Iran

    Zinatossadat Hossaini

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  1. Hannaneh Sadat Shirangi
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Correspondence to Ali Varasteh Moradi.

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Appendix

Appendix

Experimental part

General

All materials employed in this work were purchased from Fluka and Merck with no further purification. The structure of Fe3O4/CuO/ZnO@MWCNT MNCs was confirmed by XRD, SEM, EDX and. X-ray diffraction patterns (XRD) was performed for calculating of the size of prepared Fe3O4/CuO/ZnO@MWCNT MNCs. The Scherrer’s formula; D = 0.9λ/β cosθ used for calculating the average crystallite size of Fe3O4/CuO/ZnO@MWCNT MNCs, where D is the diameter of the nanoparticles, λ (CuKα) = 1.5406 Å and β is the full-width at half-maximum of the diffraction lines. FT-IR spectra were recorded by a Shimadzu IR-460 spectrometer for synthesized compounds. Also, the 1H and 13C NMR spectra are used for the structure confirmation of synthesized compounds by BRUKER DRX-500 AVANCE spectrometer at 500.1 and 125.8 MHz respectively using TMS as the internal standard or 85% H3PO4 as the external standard for solution in CDCl3. A FINNIGAN-MAT 8430 spectrometer with an ionization potential of 70 eV utilized for Mass spectra. The elemental analysis C, H, and N for synthesized compounds was carried out by a Heraeus CHN–O-Rapid analyzer. Energy-dispersive X-ray Spectroscopy (EDX) was performed by Mira 3-XMU FESEM (Tescan Co, Brno, Czech Republic).

Green synthesis of Fe 3 O 4 /CuO/ZnO@MWCNT

Synthesis of Fe3O4/CuO/ZnO@MWCNT MNCs was performed by adding CuCl2 (1 g), Zn(OAC)2 (1 g) and FeCl2.4H2O ( 1.5 g) to 50 mL of Petasites hybridus rhizome water extract to obtain mixed Cu(OH)2, Zn(OH)2 and Fe (OH)2 colloids at room temperature. The colloid was separated utilizing centrifuge, dried and calcined at 350 °C for 2 h for preparation of a gray brown solid ZnO/CuO/Fe3O4 magnetic nanocomposite. Then, prepared Fe3O4/CuO/ZnO MNCs and 0.1 g multi walled carbon nanotubes (MWCNTs) was dispersed in 100 mL Petasites hybridus rhizome water extract at 100 °C. The mixture was sonicated for 30 min and the colloid was separated using centrifuge, dried and calcined at 500 °C for 45 min. After reaching the temperature to r.t., the solid was cleaned several times using water and ethanol. The Fe3O4/CuO/ZnO@MWCNT MNCs magnetic nanoparticles separated with external magnetic field.

General procedure for preparation of compounds 6a–k

The mixture of isatins 1 (2 mmol), electron deficient acetylenic compounds 2 (2 mmol) and bio- Fe3O4/CuO/ZnO@MWCNT MNCs (0.02 g) and Et3N was stirred in water (3 mL) at room temperature for 30 min. After this time \(\alpha\) haloketones 3 (2 mmol) was added to the mixture and new mixture stirred for 15 min. After this time guanidine 4 (2 mmol) was added to previous mixture. Finally, aldehydes were added to latest mixture and new mixture was stirred for 4 h in water at room temperature. The reaction is completed after 2 h and development of the reaction is proved by TLC. The catalyst was separated by external magnet and the solid residue was collected by filtration and washed with EtOH and Et2O to afforded purified compounds 6.

Dimethyl 2-((4-methoxybenzylidene)amino)-4-(4-methoxyphenyl)-7H-benzo[b]pyrimido[4,5-d]azepine-5,6-dicarboxylate (6a): Yellow powder, mp 157–159˚C, Yield: 0.81 g (95%). IR (KBr) (νmax/cm−1): 3193, 1703, 1672, 1531, 1380, 1261 cm−1. 1H NMR (500 MHz, CDCl3): 3.76 (3 H, s, MeO), 3.85 (3 H, s, MeO), 3.89 (3 H, s, MeO), 3.96 (3 H, S, MeO), 7.16 (2 H, d, 3 J = 7.7 Hz, 2 CH), 7.34 (2 H, d, 3 J = 7.7 Hz, 2 CH), 7.49 (1 H, t, 3 J = 7.7 Hz, CH), 7.58 (1 H, t, 3 J = 7.7 Hz, CH), 7.67 (2 H, d, 3 J = 7.7 Hz, 2 CH), 7.86 (2 H, d, 3 J = 7.7 Hz, 2 CH), 7.96 (1 H, d, 3 J = 7.8 Hz, CH), 8.06 (1 H, d, 3 J = 7.8 Hz, CH), 8.39 (1 H, s, CH), 10.25 (1 H, s, NH) ppm. 13C NMR (125.7 MHz, CDCl3): 51.6 (MeO), 52.5 (MeO), 55.6 (MeO), 56.0 (MeO), 110.5 (CH), 113.4 (C), 114.3 (C), 114.9 (2 CH), 115.8 (2 CH), 116.7 (CH), 121.2 (CH), 127.2 (C), 128.6 (CH), 129.3 (C), 132.5 (2 CH), 134.2 (2 CH), 140.2 (C), 142.5 (C), 143.8 (C), 148.3 (C), 149.6 (C), 151.3 (C), 153.6 (C), 158.3 (CH), 159.2 (C), 161.7 (C = O), 162.6 (C = O) ppm. EI-MS: 550 (M+, 15), 396 (84), 31(100). Anal. Calcd for C31H26N4O6 (550.56): C 67.63, H 4.76, N 10.18; Found: C 67.78, H 4.85, N 10.26.

Diethyl 2-((4-methoxybenzylidene)amino)-4-(4-methoxyphenyl)-7H-benzo[b]pyrimido[4,5-d]azepine-5,6-dicarboxylate (6b): Yellow powder, mp 162–164˚C, Yield: 0.84 g (93%). IR (KBr) (νmax/cm−1): 3174, 1708, 1673, 1434, 1381, 1272 cm−1. 1H NMR (500 MHz, CDCl3): 1.14 (3 H, t, 3 J = 7.4 Hz, CH3), 1.28 (3 H, t, 3 J = 7.4 Hz, CH3), 3.85 (3 H, s, MeO), 3.92 (3 H, s, MeO), 4.18 (2 H, q, 3 J = 7.4 Hz, CH2O), 4.26 (2 H, q, 3 J = 7.4 Hz, CH2O), 7.18 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.32 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.47 (1 H, t, 3 J = 7.6 Hz, CH), 7.53 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.62 (1 H, t, 3 J = 7.6 Hz, CH), 7.69 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.77 (1 H, d, 3 J = 7.6 Hz, CH), 7.98 (1 H, d, 3 J = 7.6 Hz, CH), 8.56 (1 H, s, CH), 10.27 (1 H, s, NH) ppm. 13C NMR (125.7 MHz, CDCl3): 13.7 (Me), 14.2 (Me), 55.6 (MeO), 56.2 (MeO), 61.5 (CH2O), 62.7 (CH2O), 110.8 (CH), 113.6 (C), 114.5 (C), 115.2 (2 CH), 116.2 (2 CH), 117.3 (CH), 121.5 (CH), 127.6 (C), 128.5 (C), 129.3 (CH), 132.3 (2 CH), 134.5 (2 CH), 140.7 (C), 143.4 (C), 144.2 (C), 149.5 (C), 150.7 (C), 151.4 (C), 153.5 (C), 157.3 (CH), 158.6 (C), 161.7 (C = O), 163.4 (C = O) ppm. EI-MS: 578 (M+, 15), 412 (68), 45(100). Anal. Calcd for C33H30N4O6 (578.62): C 68.50, H 5.23, N 9.68; Found: C 68.62, H 5.38, N 9.83.

Methyl 2-((4-cyanobenzylidene)amino)-4-(p-tolyl)-7H-benzo[b]pyrimido[4,5-d]azepine-5-carboxylate (6c): Yellow powder, mp 128–130˚C, Yield: 0.65 g (92%). IR (KBr) (νmax/cm−1): 3182, 2198, 1710, 1675, 1492, 1378, 1257 cm−1. 1H NMR (500 MHz, CDCl3): 2.32 (3 H, s, Me), 3.83 (3 H, s, MeO), 7.08 (2 H, d, 3 J = 7.8 Hz, CH), 7.28 (1 H, t, 3 J = 7.6 Hz, CH), 7.38 (1 H, t, 3 J = 7.6 Hz, CH), 7.46 (2 H, d, 3 J = 7.8 Hz, CH), 7.55 (2 H, d, 3 J = 7.8 Hz, CH), 7.67 (1 H, d, 3 J = 7.6 Hz, CH), 7.73 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.93 (1 H, d, 3 J = 7.6 Hz, CH), 8.46 (1 H, s, CH), 8.68 (1 H, s, CH), 10.34 (1 H, s, NH), ppm. 13C NMR (125.7 MHz, CDCl3): 21.3 (Me), 51.7 (MeO), 108.3 (C), 110.5 (CH), 115.3 (C), 116.2 (CN), 117.4 (CH), 118.2 (C), 121.3 (CH), 127.3 (C), 128.2 (2 CH), 129.5 (CH), 130.4 (2 CH), 131.3 (2 CH), 133.4 (2 CH), 138.2 (C), 139.2 (C), 142.3 (C), 144.7 (C), 145.6 (CH), 148.6 (C), 149.6 (C), 151.6 (C), 158.4 (C), 161.7 (C = O) ppm. EI-MS: 471 (M+, 10), 440 (86), 31(100). Anal. Calcd for C29H21N5O2 (471.51): C 73.87, H 4.49, N 14.85; Found: C 73.96, H 4.63, N 14.96.

Methyl 2-((4-cyanobenzylidene)amino)-4-(4-methoxyphenyl)-10-methyl-7H-benzo[b]pyrimido [4,5-d]azepine-5-carboxylate (6d): Yellow powder, mp 133–135 °C, Yield: 0.73 g (95%). IR (KBr) (νmax/cm−1): 3195, 2195, 1718, 1676, 1493, 1374, 1272 cm−1. 1H NMR (500 MHz, CDCl3): 2.25 (3 H, s, Me), 3.78 (3 H, s, MeO), 3.83 (3 H, s, MeO), 7.25 (2 H, d, 3 J = 7.7 Hz, 2 CH), 7.34 (1 H, d, 3 J = 7.5 Hz, CH), 7.45 (1 H, d, 3 J = 7.5 Hz, CH), 7.58 (2 H, d, 3 J = 7.7 Hz, 2 CH), 7.69 (2 H, d, 3 J = 7.7 Hz, 2 CH), 7.79 (1 H, s, CH), 7.86 (2 H, d, 3 J = 7.7 Hz, 2 CH), 8.53 (1 H, s, CH), 8.62 (1 H, s, CH), 10.42 (1 H, s, NH) ppm. 13C NMR (125.7 MHz, CDCl3): 21.2 (Me), 51.5 (MeO), 55.8 (MeO), 108.2 (C), 114.3 (C), 115.3 (2 CH), 115.9 (CN), 116.5 (CH), 118.6 (C), 125.4 (CH), 130.3 (C), 131.6 (2 CH), 132.3 (2 CH), 133.4 (CH), 134.2 (2 CH), 137.6 (C), 138.2 (C), 139.8 (C), 145.3 (CH), 146.2 (C), 148.3 (C), 149.5 (C), 151.3 (C), 152.6 (C), 157.6 (CH), 161.6 (C = O) ppm. EI-MS: 501 (M+, 15), 354 (68), 31(100). Anal. Calcd for C30H23N5O3 (501.54): C 71.84, H 4.62, N 13.96; Found: C 71.93, H 4.78, N 14.12.

Dimethyl 2-((4-chlorobenzylidene)amino)-4-(4-methoxyphenyl)-10-methyl-7H-benzo[b] pyrimido[4,5-d]azepine-5,6-dicarboxylate (6e): Yellow powder, mp 161–163 °C, Yield: 0.84 g (95%). IR (KBr) (νmax/cm−1): 3371, 1718, 1673, 1374, 1210 cm−1. 1H NMR (500 MHz, CDCl3): 2.27 (3 H, s, Me), 3.76 (3 H, s, MeO), 3.85 (3 H, s, MeO), 3.98 (3 H, s, MeO), 7.25 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.38 (1 H, d, 3 J = 7.5 Hz, CH), 7.49 (1 H, d, 3 J = 7.5 Hz, CH), 7.56 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.68 (2 H, d, 3 J = 7.6 Hz, 2 CH), 7.75 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.83 (1 H, s, CH), 8.46 (1 H, s, CH), 10.36 (1 H, s, NH) ppm. 13C NMR (125.7 MHz, CDCl3): 21.5 (Me), 51.3 (MeO), 52.5 (MeO), 55.7 (MeO), 112.3 (C), 114.5 (C), 115.4 (2 CH), 116.7 (CH), 125.5 (CH), 128.6 (2 CH), 130.5 (C), 131.2 (2 CH), 132.7 (CH), 133.6 (C), 134.6 (2 CH), 136.2 (C), 138.3 (C), 139.5 (C), 143.6 (C), 144.8 (C), 148.5 (C), 149.7 (C), 151.6 (C), 152.7 (C), 158.3 (CH), 161.3 (C = O), 162.6 (C = O) ppm. EI-MS: 569 (M+, 10), 410 (64), 31(100). Anal. Calcd for C31H25N4ClO5 (569.00): C 65.44, H 4.43, N 9.85; Found: C 65.63, H 4.62, N 9.98.

Dimethyl -2-((4-cyanobenzylidene)amino)-4-(p-tolyl)-7H-benzo[b]pyrimido[4,5-d]azepine-5,6-dicarboxylate (6f): Yellow powder, mp 141–143 °C, Yield: 0.74 g (90%). IR (KBr) (νmax/cm−1): 3322, 2202, 1703, 1672, 1531, 1380, 1261 cm−1. 1H NMR (500 MHz, CDCl3): 2.25 (3 H, s, Me), 3.75 (3 H, s, MeO), 3.87 (3 H, s, MeO), 7.32 (1 H, t, 3 J = 7.6 Hz, CH), 7.43 (1 H, t, 3 J = 7.6 Hz, CH), 7.54 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.65 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.73 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.83 (1 H, d, 3 J = 7.6 Hz, CH), 7.92 (2 H, d, 3 J = 7.8 Hz, 2 CH), 8.02 (1 H, d, 3 J = 7.8 Hz, CH), 8.53 (1 H, s, CH), 10.52 (1 H, s, NH) ppm. 13C NMR (125.7 MHz, CDCl3): 20.5 (Me), 51.3 (MeO), 52.6 (MeO), 111.3 (CH), 113.2 (C), 114.5 (C), 116.3 (CH), 118.3 (CN), 121.4 (CH), 127.3 (2 CH), 128.2 (C), 129.4 (CH), 131.2 (2 CH), 132.4 (2 CH), 133.5 (2 CH), 137.4 (C), 138.2 (C), 142.3 (C), 143.8 (C), 144.5 (C), 149.2 (C), 150.2 (C), 151.3 (C), 158.3 (CH), 161.5 (C = O), 162.7 (C = O) ppm. EI-MS: 529 (M+, 10), 380 (48), 31(100). Anal. Calcd for C31H23N5O4 (529.55): C 70.31, H 4.38, N 13.23; Found: C 70.52, H 4.54, N 13.38.

Dimethyl 10-nitro-2-((4-nitrobenzylidene)amino)-4-(p-tolyl)-7H-benzo[b]pyrimido[4,5-d] azepine-5,6-dicarboxylate (6 g): Yellow powder, mp 171–173 °C, Yield: 0.79 g (87%). IR (KBr) (νmax/cm−1): 3189, 1711, 1677, 1488, 1377, 1211 cm−1. 1H NMR (500 MHz, CDCl3): 2.32 (3 H, s, Me), 3.78 (3 H, s, MeO), 3.85 (3 H, s, MeO), 7.56 (2H, d, 3 J = 7.8 Hz, 2 CH), 7.63 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.78 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.86 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.97 (1 H, d, 3 J = 7.6 Hz, CH), 8.07 (1 H, d, 3 J = 7.6 Hz, CH), 8.36 (1 H, s, CH), 8.68 (1 H, s, CH), 10.32 (1 H, s, NH) ppm. 13C NMR (125.7 MHz, CDCl3): 21.6 (Me), 51.7 (MeO), 52.4 (MeO), 113.5 (CH), 114.3 (C), 115.6 (C), 124.8 (2 CH), 125.2 (CH), 126.7 (CH), 127.3 (2 CH), 128.3 (C), 131.5 (2 CH), 132.2 (2 CH), 137.6 (C), 138.5 (C), 140.2 (C), 141.4 (C), 143.6 (C), 144.8 (C), 148.3 (C), 153.2 (C), 154.8 (C), 158.4 (C), 159.3 (CH), 160.5 (C = O), 162.8 (C = O) ppm. EI-MS: 594 (M+, 15), 563 (56), 31(100). Anal. Calcd for C30H22N6O8 (594.53): C 60.61, H 3.73, N 14.14; Found: C 60.72, H 3.87, N 14.28.

Dimethyl 10-methyl-2-((4-nitrobenzylidene)amino)-4-(4-nitrophenyl)-7H-benzo[b]pyrimido [4,5-d]azepine-5,6-dicarboxylate (6 h): Yellow powder, mp 169–171 °C, Yield: 0.79 g (87%). IR (KBr) (νmax/cm−1): 3321, 1712, 1674, 1488, 1384, 1273 cm−1. 1H NMR (500 MHz, CDCl3): 2.32 (3 H, s, Me), 3.75 (3 H, s, MeO), 3.85 (3 H, s, MeO), 7.26 (1 H, d, 3 J = 7.6 Hz, CH), 7.38 (1 H, d, 3 J = 7.6 Hz, CH), 7.68 (1 H, s, CH), 7.75 (2 H, d, 3 J = 7.8 Hz, 2 CH), 8.05 (2 H, d, 3 J = 7.8 Hz, 2 CH), 8.23 (2 H, d, 3 J = 7.8 Hz, 2 CH), 8.43 (2 H, d, 3 J = 7.8 Hz, 2 CH), 8.74 (1 H, s, CH), 10.43 (1 H, s, NH) ppm. 13C NMR (125.7 MHz, CDCl3): 20.8 (Me), 51.3 (MeO), 52.7 (MeO), 109.2 (C), 114.5 (C), 117.2 (CH), 124.6 (2 CH), 125.4 (CH), 126.8 (2 CH), 130.6 (C), 131.8 (2 CH), 132.4 (CH), 137.6 (C), 138.2 (2 CH), 139.2 (C), 142.3 (C), 144.2 (C), 145.3 (C), 147.3 (C), 148.6 (C), 154.2 (C), 156.4 (C), 158.4 (C), 159.4 (CH), 162.5 (C = O), 163.8 (C = O) ppm. EI-MS: 594 (M+, 15), 563 (64), 31(100). Anal. Calcd for C30H22N6O8 (594.53): C 60.61, H 3.73, N 14.14; Found: C 60.76, H 3.92, N 14.32.

Ethyl 10-chloro-2-((4-chlorobenzylidene)amino)-4-(p-tolyl)-7H-benzo[b]pyrimido[4,5-d]azepine -5-carboxylate (6i): Yellow powder, mp 153–155 °C, Yield: 0.64 g (85%). IR (KBr) (νmax/cm−1): 3278, 1708, 1673, 1434, 1381, 1272 cm−1. 1H NMR (500 MHz, CDCl3): 1.25 (3 H, t, 3 J = 7.4 Hz, CH3), 2.34 (3 H, s, Me), 4.23 (2 H, q, 3 J = 7.4 Hz, CH2O), 7.24 (2 H, d, 3 J = 7.8 Hz, 2 CH),7.32 (1 H, d, 3 J = 7.7 Hz, CH), 7.48 (1 H, d, 3 J = 7.7 Hz, CH), 7.56 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.65 (2 H, d, 3 J = 7.7 Hz, 2 CH), 7.72 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.83 (1 H, s, CH), 7.92 (1 H, s, CH), 8.38 (1 H, s, CH), 10.52 (1 H, s, NH) ppm. 13C NMR (125.7 MHz, CDCl3): 13.8 (Me), 23.4 (Me), 62.5 (CH2O), 108.5 (C), 115.2 (C), 117.6 (CH), 124.2 (CH), 125.3 (C), 126.0 (C), 126.8 (2 CH), 127.8 (2 CH), 128.6 (CH), 129.6 (2 CH), 130.8 (2 CH), 133.2 (C), 136.4 (C), 138.3 (C), 142.5 (C), 144.5 (C), 145.7 (CH), 149.2 (C), 150.4 (C), 151.3 (C), 158.2 (CH), 162.3 (C = O) ppm. EI-MS: 529 (M+, 15), 356 (58), 45(100). Anal. Calcd for C29H22Cl2N4O2 (529.42): C 65.79, H 4.19, N 10.58; Found: C 65.93, H 4.32, N 10.72.

4-Ethyl-5,6-dimethyl 2-((4-cyanobenzylidene)amino)-10-methyl-7H-benzo[b]pyrimido[4,5-d] azepine-4,5,6-tricarboxylate (6j): Pale yellow powder, mp 117–119 °C, Yield: 0.74 g (97%). IR (KBr) (νmax/cm−1): 3174, 2198, 1708, 1673, 1434, 1381, 1272 cm−1. 1H NMR (500 MHz, CDCl3): 1.28 (3 H, t, 3 J = 7.4 Hz, CH3), 2.25 (3 H, s, Me), 3.78 (3 H, s, MeO), 3.85 (3 H, s, MeO), 4.18 (2 H, q, 3 J = 7.4 Hz, CH2O), 7.34 (1 H, d, 3 J = 7.7 Hz, CH), 7.46 (1 H, d, 3 J = 7.7 Hz, CH), 7.63 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.75 (2 H, d, 3 J = 7.8 Hz, 2 CH), 7.83 (1 H, s, CH), 8.64 (1 H, s, CH), 10.64 (1 H, s, NH) ppm. 13C NMR (125.7 MHz, CDCl3): 14.2 (Me), 21.7 (Me), 51.6 (MeO), 52.5 (MeO), 62.3 (CH2O), 113.4 (C), 114.8 (C), 115.6 (CH), 116.3 (C), 118.6 (CN), 125.3 (CH), 131.6 (2 CH), 132.6 (2 CH), 133.2 (CH), 134.2 (C), 135.6 (C), 136.8 (C), 142.3 (C), 144.3 (C), 148.2 (C), 156.3 (C), 157.2 (C), 158.6 (CH), 160.4 (C = O), 161.5 (C = O), 162.8 (C = O) ppm. EI-MS: 525 (M+, 15), 376 (86), 31(100). Anal. Calcd for C28H23N5O6 (525.51): C 63.99, H 4.41, N 13.33; Found: C 64.12, H 4.58, N 13.52.

4-Ethyl 5-methyl 2-((4-nitrobenzylidene)amino)-7H-benzo[b]pyrimido[4,5-d]azepine-4,5-dicarboxylate (6 k): Yellow powder, mp 128–132 °C, Yield: 0.57 g (85%). IR (KBr) (νmax/cm−1): 3182, 1710, 1675, 1492, 1378, 1257 cm−1. 1H NMR (500 MHz, CDCl3): 1.32 (3 H, t, 3 J = 7.4 Hz, CH3), 3.85 (3 H, s, MeO), 4.26 (2 H, q, 3 J = 7.4 Hz, CH2O), 7.34 (1 H, t, 3 J = 7.6 Hz, CH), 7.42 (1 H, t, 3 J = 7.6 Hz, CH), 7.58 (1 H, d, 3 J = 7.6 Hz, CH), 7.72 (1 H, s, CH),7.86 (1 H, d, 3 J = 7.6 Hz, CH), 7.95 (2 H, d, 3 J = 7.8 Hz, 2 CH), 8.12 (2 H, d, 3 J = 7.8 Hz, 2 CH), 8.57 (1H, s, CH), 10.62 (1 H, s, NH) ppm. 13C NMR (125.7 MHz, CDCl3): 14.3 (Me), 51.8 (MeO), 62.3 (CH2O), 107.6 (C), 108.6 (CH), 115.2 (CH), 116.3 (C), 121.5 (CH), 125.6 (2 CH), 129.2 (CH), 131.3 (2 CH), 133.5 (C), 135.7 (C), 144.2 (C), 145.3 (CH), 146.2 (C), 149.2 (C), 156.2 (C), 157.3 (C), 158.3 (CH), 162.3 (C = O), 165.6 (C = O) ppm. EI-MS: 473 (M+, 15), 304 (68), 31(100). Anal. Calcd for C24H19N5O6 (473.44): C 60.89, H 4.05, N 14.79; Found: C 61.06, H 4.18, N 14.93.

4-ethyl 5-methyl -2-((thiophen-2-ylmethylene)amino)-7H-benzo[b]pyrimido[4,5-d]azepine-4,5-dicarboxylate (6 l): Yellow powder, mp 145–147 °C, Yield: 0.74 g (85%). IR (KBr) (νmax/cm−1): 3387, 1735, 1712, 1695, 1587, 1496, 1287 cm−1. 1H NMR (500 MHz, CDCl3): 1.26 (3 H, t, 3 J = 7.4 Hz, CH3), 3.87 (3 H, s, MeO), 4.23 (2 H, q, 3 J = 7.4 Hz, CH2O), 6.86 (1 H, t, 3 J = 7.6 Hz, CH), 7.12 (1 H, d, 3 J = 7.6 Hz, CH), 7.25 (1 H, d, 3 J = 7.6 Hz, CH), 7.34 (1 H, t, 3 J = 7.6 Hz, CH), 7.46 (1 H, d, 3 J = 7.7 Hz, CH), 7.53 (1 H, d, 3 J = 7.7 Hz, CH), 7.64 (1 H, t, 3 J = 7.7 Hz, CH), 7.49 (1H, s, CH), 8.35 (1 H, s, CH), 10.78 (1 H, s, NH) ppm. 13C NMR (125.7 MHz, CDCl3): 14.2 (Me), 52.3 (MeO), 62.5 (CH2O), 107.8 (C), 108.5 (CH), 115.3 (CH), 119.2 (C), 120.5 (CH), 121.7 (CH), 126.2 (CH), 127.5 (C), 128.6 (CH), 130.2 (CH), 143.2 (C), 144.7 (CH), 145.7 (C), 146.4 (C), 151.2 (C), 153.4 (CH), 158.2 (C), 165.4 (C = O), 168.2 (C = O) ppm. EI-MS: 434 (M+, 15), 403 (78), 31(100). Anal. Calcd for C22H18N4O4S (434.47): C 60.82, H 4.18, N 12.90; Found: C 60.93, H 4.27, N 13.06.

4-Ethyl 5-methyl -2-((furan-2-ylmethylene)amino)-7H-benzo[b]pyrimido[4,5-d]azepine-4,5-dicarboxylate (6 m): Yellow powder, mp 137–139˚C, Yield: 0.71 g (85%). IR (KBr) (νmax/cm−1): 3374, 1742, 1724, 1696, 1576, 1487, 1295 cm−1. 1H NMR (500 MHz, CDCl3): 1.25 (3 H, t, 3 J = 7.4 Hz, CH3), 3.83 (3 H, s, MeO), 4.18 (2 H, q, 3 J = 7.4 Hz, CH2O), 6.92 (1 H, t, 3 J = 7.6 Hz, CH), 7.16 (1 H, d, 3 J = 7.6 Hz, CH), 7.22 (1 H, d, 3 J = 7.6 Hz, CH), 7.35 (1 H, t, 3 J = 7.6 Hz, CH), 7.43 (1 H, d, 3 J = 7.7 Hz, CH), 7.52 (1 H, t 3 J = 7.7 Hz, CH), 7.74 (1 H, d, 3 J = 7.7 Hz, CH), 7.63 (1H, s, CH), 8.42 (1 H, s, CH), 10.84 (1 H, s, NH) ppm. 13C NMR (125.7 MHz, CDCl3): 14.5 (Me), 51.6 (MeO), 62.3 (CH2O), 107.6 (CH), 108.7 (C), 109.6 (CH), 110.3 (CH), 114.6 (CH), 119.2 (C), 121.4 (CH), 127.2 (C), 129.2 (CH), 143.2 (C), 144.6 (C), 145.7 (CH), 146.8 (CH), 151.3 (C), 158.6 (C), 159.4 (CH), 160.2 (C), 165.8 (C = O), 169.3 (C = O) ppm. EI-MS: 418 (M+, 15), 387 (78), 31(100). Anal. Calcd for C22H18N4O5 (418.40): C 63.15, H 4.34, N 13.39; Found: C 63.26, H 4.47, N 13.48.

Study of schiff base of Pyrimidoazepines antioxidant activity utilizing DPPH radical trapping test.

The DPPH radical scavenging experiment was utilized for investigation of some generated schiff base of pyrimidoazepines antioxidant ability such as 6b–6e like the method reported by Shimada et. al. [92]. For obtaining to this object, various concentrations (200–1000 ppm) of schiff base of Pyrimidoazepines 6b–6e were added to equal volume of DPPH methanolic solution (1 mmol/L). The mixture was stirred for 30 min at environmental temperature and putted in a dark room after this time and the absorbance of mixture was recorded at 517 nm. The schiff base of pyrimidoazepines 6b–6e was replaced with standard type of methanol (3 mL). In this procedure, Butylated hydroxytoluene (BHT) and 2-tertbutylhydroquinone (TBHQ) are standard antioxidants. The percentage of inhibition for the radical of DPPH calculated by utilizing Yen and Duh [93] formula.

Study of reducing ability for synthesized schiff base of pyrimidoazepines

The ability of iron (III) reducing by the schiff base of pyrimidoazepines 6b-6e was investigated utilizing Yildirim et al. method [91]. For this object, the samples (1 mL), potassium ferricyanide (K3Fe(CN)6; 2.5 mL, 10 g/L) and buffer of phosphate (2.5 mL, 0.2 mol/L, pH 6.6) were combined together and maintained for 30 min at 50 °C. Then, trichloroacetic acid (2.5 mL, 10% w/v) was added to the previous solution and centrifuged for 10 min. Finally, the supernatant (2.5 mL), distilled water (2.5 mL) and FeCl3 (0.5 mL, 1 g/L) mixed together and the absorbance of samples was measured at 700 nm. The higher absorbance of sample show higher reducing power of it. For accuracy of calculating, each measuring was carried out in three times. One way study of variance (ANOVA) that was used for data analyzing of compounds is running the SPSS software version 18.0 that proved difference of samples and control. Duncan multiple range experiments was employed for separation mean with the importance quantity of 95% (P < 0.05).

Study of prepared schiff base of pyrimidoazepines antibacterial ability

Gram-positive and Gram-negative bacteria were utilized for investigation of antibacterial effect of synthesized schiff base of pyrimidoazepines against two standards such as Streptomycin and Gentamicin with a concentration 40 μg/mL by employing the disk diffusion procedure. Two types of bacteria that are used in this experiment were produced from the Persian type culture collection (PTCC), Tehran, Iran. The bacteria were cultured for 16 to 24 h at 37 °C for preparing the turbidity equivalent bacteria to McFarland Standard No. 0.5. The bacterial suspension was produced according to the turbidity of the 0.5 McFarland (About 1.5 × 108 CFU/mL) standards and cultured with a sterile swab on Mueller Hinton agar. For valuation of their antibacterial activity of schiff base of pyrimidoazepines with concentration of 25 µg/ml were poured on sterile blank disks. The plates were incubated in an incubator at 37 °C for 24 h. The inhibition zone diameter was measured and compared to with the standard.

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Shirangi, H.S., Moradi, A.V., Golsefidi, M.A. et al. Green synthesis and investigation of antioxidant and antimicrobial activity of new schiff base of pyrimidoazepine derivatives: application of Fe3O4/CuO/ZnO@MWCNT MNCs as an efficient organometallic nanocatalyst. Mol Divers 26, 3003–3019 (2022). https://doi.org/10.1007/s11030-021-10349-6

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