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Novel 1,8-Naphthyridine Derivatives: Design, Synthesis and in vitro screening of their cytotoxic activity against MCF7 cell line

  • Abeer N. Al-romaizan , Thoraya S. Jaber and Nesreen S. Ahmed EMAIL logo
Published/Copyright: November 6, 2019
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Open Chemistry
From the journal Open Chemistry Volume 17 Issue 1

Abstract

A series of new 2-phenyl-7-methyl-1,8-naphthyridine derivatives with variable substituents at C3 were synthesized for an in vitro evaluation of their anticancer activity against human breast cancer cell line (MCF7). On one hand, compounds 3f, 6f, 8c, and 10b showed IC50 values (6.53, 7.88, 7.89, 7.79 μM, respectively) compared to that of the mentioned drug staurosparine (IC50 = 4.51 μM). On the other hand, derivatives 10c, 8d, 4d, 10f and 8b displayed better activity than staurosporin with IC50 values (1.47, 1.62, 1.68, 2.30, 3.19 μM, respectively).

Keywords: 1,8- naphthyridine; pyrazole; pyrimidine; pyridine; cytotoxic; breast cancer

1 Introduction

Cancer is one of the deadliest diseases affecting public health around the world. The occurrence and death statistics represent that it is on the rise in the developed and economically developing countries [1,2]. Cancer related deaths in females is caused primarily by breast cancer. It constitutes 23% of the total cancer cases, out of which 14% lead to death, the incidence that rises significantly with age [1,2]. On a cellular level, cancer develops as a result of failed cell division and deregulation of signaling cascades. What follows is an uncontrolled cell division, increased cell survival and the development of resistance to anticancer therapies [3].

Even though an early discovery of the disease improves the survival rates through recognized therapeutic routes, metastatic breast malignancy is still the leading cause of breast cancer-related deaths [4]. Noticeably, about 30% of the primarily detected localized malignant masses will progress to an advanced or metastatic disease in 5 years [5,6]. Naphthyridine derivatives are broadly spread in naturally occurring products, principally as tricyclic benzo[f] [1,7] naphthyridines and benzo[c] naphthyridines [2,7]. These derivatives play a vital role in therapeutic products [7, 8, 9]. Naphthyridines derivatives have a wide spectrum of biological effects, for example anti-inflammatory, antimalarial, antifungal, and antibacterial [10, 11, 12]. Moreover, naphthyridine derivatives displayed good HIV-1 integrase inhibitor profiles and cytotoxicity [13,14]. Certain 1,8-naphthyridine derivatives are considered good DNA intercalators. They bind with double stranded DNA (ds-DNA) by intercalating between adjacent base pairs, thus changing the DNA conformation and inhibit DNA duplication or transcription leading to suppression of cancer cell growth [15, 16, 17]. Due to their wide range of biological effects, 1,8-naphthyridine derivatives have been considered promising antitumor agents [18, 19, 20]. Voreloxin (AG-7352, SPC-595, SNS 595, voreloxin) is a naphthyridine analog. It intercalates DNA in the presence of topoisomerase II, resulting in selective, replication-dependent DNA damage, irreversible G2 arrest and rapid apoptosis [21] (Figure 1).

Figure 1 The chemical structure of Voreloxin.
Figure 1

The chemical structure of Voreloxin.

In addition, a novel class of 1,8-naphthyridine-3-carboxamide carrying cyclic and open chain amino acids that were linked at C-3 position had been synthesized. These chemicals were tested for anticancer activity, and the results obtained revealed a promising in vitro cytotoxic activity profile against different human cancer cell lines such as breast, colon, oral [22, 23, 24, 25, 26]. As a continuation of our previous efforts [27, 28, 29], herein, we described the synthetic preparation of a new class of compounds bearing 4-hydroxy-7-methyl-2-phenyl-1,8-naphthyridine scaffold. This new class was hybridized with different heterocylic ring systems known to exhibit anticancer activity such as substituted pyrazole, pyridine and pyrimidine rings [30,31] (Figure 2). The new compounds were evaluated as cytotoxic agents against breast cancer cell lines (MCF7). Some of these compounds displayed a noticeable effect on cancer cells, with IC50 values comparable with the used reference drug.

Figure 2 Design of 1,8-naphtheridine hybrid compounds as anticancer agents.
Figure 2

Design of 1,8-naphtheridine hybrid compounds as anticancer agents.

2 Materials and Methods

Informed consent has been obtained from all individuals included in this study.

Ethical approval: The conducted research is not related to either human or animals use.

2.1 General Information

Commercially available solvents and reagents were purified according to the standard procedures. All melting points were measured on a Barnstead international 1002 melting point apparatus and were calibrated. Thin layer chromatography (TLC) was performed on aluminum silica gel 60 F254 (E-Merk). The spots were detected by iodine and UV light absorption. IR spectra were recorded for the compounds on a FTIR, Perkin Elmer SP 100 spectrometer. 1H NMR and 13C NMR spectra were recorded on Bruker WM 300 and 850 MHz spectrometers using TMS (0.00 ppm) or the signal of the deuterated solvent were used as internal standard. Chemical shift (δ) is given in ppm relative to the signal for TMS as standard, and coupling constant in expressed in Hz. Microanalysis was performed by Perkin Elmer elemental analyzer at the Faculty of Science, King Abdul Aziz University [32].

2.1.1 Synthesis of 4-Hydroxy-7-methyl-2-phenyl-1,8-naphthyridine-3-carbaldehyde (2)

POCl3 (1.86mL, 20 mmol) was added dropwise with stirring to an ice-cooled flask containing N, N-dimethylformamide (20 mL). After a complete addition, the solution was stirred at room temperature for 90 min. Then the flask was cooled again in ice-bath and compound 1 (2.36 g, 10 mmol) was added by portions. The reaction mixture was warmed to at kept at 75○C for 5 h then cooled to room temperature and poured onto an ice water, basified (sat. aqua. K2CO3 solution) and extracted with CHCl3 (120 mL), washed, dried with (MgSO4) and evaporated under vacuo to attained compound 2 (2.55g, 97% yield), yellowish crystals, m.p.114oC. FTIR, cm-1: 3420 (OH); 1661 (C=O). 1H NMR (DMSO-d6) δH: 3.05 (3H, s, CH3), 5.4 (1H, br. s, OH), 7.5 -8.4 (5H, m, Ar-H), 8.6 (1H,d,C6-H, J = 9.2 Hz), 8.8 (1H,d,C5-H, J = 9.2 Hz ), 9.5 (1H, s, CHO). MS (m/z) 264 M+ Found: C, 72.75; H, 4.23; N, 10.27. C16H12N2O2 requires 72.72; H, 4.58; N, 10.60%.

2.1.2 Synthesis of 3-(4-hydroxy-7-methyl-2-phenyl-1,8-naphthyridin-3-yl)-1-arylprop-2-en-1-one (3a-g)

In an Erlenmeyer flask, a solution of aldehyde 2 (0.5 g, 2 mmol) in ethanol (10 mL), acetyl compounds (2 mmol) and Mg-Al- hydrotalcite (0.3g) [33] were refluxed together for appropriate time as examined by TLC. The reaction mixture was filtered to isolate the HT. The filtrate was concentrated under vacuo. The residual solid was crystallized by ethanol to give the title product.

1-Furan-2-yl-3-(4-hydroxy-2-phenyl-[1,8]-naphthyridin-3-yl)-propenone (3a):

Light brown crystals, (89.55%), m.p. 189-190oC. IR: νmax/cm-1 3350 (OH), 1656 (CO).1H NMR (DMSO-d6) δH: 2.08 (3H, s, CH3), 5.79 (1H, s, -OH) , 6.68-7.57 (3H, m, C-H of furan), 7.85 (1H, d, C6-H, J = 9.8 Hz), 8.03 (1H, d, C5-H, J = 9.8 Hz ), 8.30-8.45 (5H, m, Ar-H) 8.38 (1H, d, CH=CHCO, J = 8.4 Hz), 8.58 (1H, d, CH=CHCO, J = 8.4 Hz). 13C-NMR (DMSO-d6) δC: 22.41, 106.10, 113.26, 116.62, 122.53, 123.19, 128.19, 129.39, 130.11, 130.16, 131.06, 137.65, 142.48, 147.50, 152.65, 156.01, 158.48, 159.29, 167.89, 175.29. MS (m/z) 356 M+ Found: C, 74.29; H, 4.42; N, 7.51 C22H16N2O3 requires C, 74.15; H, 4.53; N, 7.86%.

3- ( 4-Hydroxy-7-methyl -2-phenyl - [ 1 , 8 ] - naphthyridin-3-yl)-1-thiophen-2-yl-propenone (3b):

Brown crystals, (93.36%), m.p.249-251oC. IR: νmax/cm-1 3470 (OH), 1690 (CO).1H NMR (DMSO-d6) δH: 2.09 (3H, s, CH3), 5.78 (1H, s, -OH), 6.80 (1H, d, C6-H, J = 8.5 Hz), 7.50 (1H, d, C3H of thiophene), 7.60 (1H, dd, C4H of thiophene,), 7.74 (1H, d, C5H of thiophene), 8.09 (1H, d, C5-H, J = 8.5 Hz ), 8.31-8.36 (5H, m, Ar-H), 8.37 (1H, d, CH=CHCO, J = 8.4 Hz), 8.78 (1H, d, CH=CHCO, J = 8.4 Hz). 13C NMR (DMSO-d6) δC: 22.15, 107.11, 116.89, 117.87, 125.19, 127.96, 128.08 ,128.22, 129.43 130.12, 133.49, 134.47, 137.84, 143.25, 146.42,150.58, 156.18, 158.62, 162.82,186.93. MS (m/z) 372 M+ Found: C, 71.29; H, 4.02; N, 7.13. C22H16N2O2S requires C, 70.95; H, 4.33; N, 7.52%.

3- ( 4-Hydroxy-7-methyl -2-phenyl - [ 1 , 8 ] - naphthyridin-3-yl)-1-phenyl-propenon (3c):

Orange crystals, (96.02%), m.p. above 320oC. IR: νmax/ cm-1 3170 (OH), 1696 (CO). 1H NMR ( DMSO-d6) δH:2.73 (3H, s, CH3), 5.79 (1H, s, -OH), 7.75, 8.29 (10H, 2m, Ar-H), 7.62 (1H, d, C6-H, J = 7.7 Hz), 8.30 (1H, d, C5-H, J = 7.7 Hz ), 8.10 (1H, d, CH=CHCO, J = 8.3 Hz), 8.56 (1H, d, CH=CHCO, J = 8.3 Hz). 13C NMR ( DMSO-d6) δC: 22.19, 107.27, 116.89, 119.09, 123.19, 125.96, 127.96, 128.23, 129.12, 130.11, 133.49, 134.47, 137.86, 143.25, 146.42, 150.95, 156.18, 158.76, 162.82 , 168.93. MS (m/z) 366 M+ Found: C, 78.30; H, 4.43; N, 7.26. C24H18N2O2 requires C, 78.67; H, 4.95; N, 7.65%.

3- ( 4-Hydroxy-7-methyl -2-phenyl - [ 1 , 8 ] - naphthyridin-3-yl)-1-p-tolyl-propenone (3d):

Yellow crystals, (91.84%), m.p. 228-230oC. IR: νmax/ cm-1 3457 (OH), 1677 (CO). 1H NMR ( DMSO-d6) δH: 1.50 (3H, s, CH3), 2.08 (3H, s, CH3), 5.80 (1H, s, -OH) ,7.50 (1H, d, C6-H, J = 8.3 Hz), 8.00 (1H, d, C5-H, J = 8.3 Hz ), 8.17 (1H, d, CH=CHCO, J = 7.2 Hz) , 7.51, 8.30 (9H, 2m, Ar-H), 8.34 (1H, d, CH=CHCO, J = 7.2 Hz). 13C NMR (DMSO-d6) δC: 14.79, 22.69, 107.99, 117.91, 124.62, 128.10, 129.18, 129.39, 130.12, 133.72, 135.74, 140.00, 142.84, 145.21, 150.91, 157.42, 158.44, 162.89, 189.03. MS (m/z) 380 M+ Found: C, 78.49; H, 4.92; N, 7.11. C25H20N2O2 requires C, 78.93; H, 5.30; N, 7.36%.

3- ( 4-Hydroxy-7-methyl -2-phenyl - [ 1 , 8 ] - naphthyridin-3-yl)-1-(4-methoxy-phenyl)-propenone (3e):

Dark brown crystals, (86.60%), m.p. 160-162oC. IR: νmax/cm-1 3480 (OH), 1690 (CO). 1H NMR (DMSO-d6) δH: 2.73 (3H, s, CH3), 2.89 (3H, s, -OCH3), 5.78 (1H, s, -OH), 7.55, 8.30 (9H, 2m, Ar-H) ), 8.10 (1H, d, C6-H, J = 8.4 Hz), 8.25 (1H, d, C5-H, J = 8.4 Hz ), 8.38 (1H, d, CH=CHCO, J = 7.4 Hz), 8.54 (1H, d, CH=CHCO, J = 7.4 Hz).13C-NMR (DMSO-d6) δC: 14.65, 55.92, 106.31, 113.16, 116.38, 125.06 , 127.91, 128.24, 128.68, 129.37, 139.01, 140.81, 143.94, 150.14, 158.03, 159.57, 162.76, 169.99, 186.83. MS (m/z) 396 M+ Found: C, 75.46; H, 4.72; N, 6.71. C25H20N2O2 requires C, 75.74; H, 5.08; N, 7.07%.

1-(4-Fluoro-phenyl)-3-(4-hydroxy-7-methyl-2-phenyl-[1,8]-naphthyridin-3-yl)-propenone (3f):

Yellow crystals, (94.23%), m.p. 207-210oC. IR: νmax/ cm-1 3456 (OH), 1697 (CO). 1H NMR (DMSO-d6) δH: 2.89 (3H, s, CH3), 5.78 (1H, s, OH), 7.49, 8.37 (9H, 2m, Ar-H), 7.80 (1H, d, C6-H, J = 9.9 Hz), 8.90 (1H, d, C5-H, J = 9.8 Hz ), 7.93 (1H, d, CH=CHCO, J = 8.4 Hz), 8.45 (1H, d, CH=CHCO, J = 8.4Hz).13C-NMR (DMSO-d6) δC: 22.49, 106.57, 116.30, 117.51, 122.34, 127.14, 128.27, 130.12, 131.69, 135.34, 140.20, 142.03, 150.13, 157.63, 158.84, 162.10, 163.57, 186.22. . MS (m/z) 384 M+ Found: C, 75.36; H, 4.17; N, 6.91. C24H17FN2O2 requires C, 74.99; H, 4.46; N, 7.29%.

3- ( 4-Hydroxy-7-methyl -2-phenyl - [ 1 , 8 ] - naphthyridin-3-yl)-1-(4-nitro-phenyl)-propenone (3g):

Reddish brown crystals, (96.40%), m.p. > 320oC. IR: νmax/cm-1 3345 (OH), 1630 (CO). 1H NMR (DMSO-d6) δH: 2.09 (3H, s, CH3), 5.32 (1H, s, -OH), 7.52 (1H, d, C6-H, J = 7.5 Hz), 7.56 – 7.90 (9H, 2m, Ar-H) 8.33 (1H, d, C5-H, J = 7.5 Hz ), 7.76 (1H, d, CH=CHCO, J = 8.3 Hz), 8.42 (1H, d, CH=CHCO, J = 8.3 Hz). 13C-NMR (DMSO-d6) δC: 21.10, 109.24, 115.62, 118.05, 122.68, 125.12, 127.26, 129.37, 130.84, 132.13, 136.48, 140.59, 143.78, 150.65, 153.27, 156.18, 158.04, 164.93, 189.20. MS (m/z) 411 M+ Found: C, 70.37; H, 3.87; N, 9.94. C24H17FN2O2 requires C, 70.07; H, 4.16; N, 10.21%.

2.1.3 Synthesis of 3-(4,5-dihydro-1-phenyl-3-aryl-1H-pyrazol-5-yl)-7-methyl-2-phenyl-1,8-naphthyridine-4-ol (4d,f, and g)

A mixture from chalcons 4 (10 mmol) and phenylhydrazine (1.2 mL, 12mmol) in 10ml acetic acid were refluxed for 8-10h. The reaction mixture was cooled, poured onto ice water (50mL), and neutralized with cold NH4OH solution. The formed solid product was collected by filtration and crystalized from ethanol to give the title products.

3-(4,5-dihydro-1-phenyl-3-p-tolyl-1H-pyrazol-5-yl)-7-methyl-2-phenyl-1,8-naphthyridine-4-ol (4d):

Dark brown solid, (63%), m.p. 108-110oC. IR: νmax/cm-1 3158 (OH), 1596, 1504 (C=C, C=N). 1H NMR (DMSO-d6) δH: 2.00 (2H, dd, C4-H, J = 9.3 Hz), 2.74, 2.90 (6H, 2s, 2CH3), 5.32 (1H, t, C5-H, J = 9.3 Hz), 5.64 ( 1H, s, -OH), 6.41-8.51 (16H, m, Ar-H). MS (m/z) 470 M+ Found: C, 79.16; H, 5.23; N, 11.46. C31H26N4O requires C, 79.12; H, 5.57; N, 11.91%.

3-[5-(4-Fluoro-phenyl)-2-phenyl-3,4-dihydro-2H-pyrazol-3-yl]-7-methyl-2-phenyl-1,8-naphthyridin-4-ol (4f ):

Yellow solid, (62%), m.p.104-106oC. IR: νmax/cm-1 3210 (OH), 1596, 1560 (C=C, C=N).

1H NMR (DMSO-d6) δH: 1.98 (2H, dd, C4-H, J = 9.3 Hz), 2.58 (3H, s, CH3), 5.32 (1H, t, C5-H, J = 9.3 Hz), 5.85 (1H, s, -OH), 6.38-8.57 (16H, m, Ar-H). MS (m/z) 474 M+ Found: C, 75.46; H, 4.41; N, 11.39. C30H23FN4O requires C, 75.93; H, 4.89; N, 11.81%.

7-Methyl-3-[5-(4-nitro-phenyl)-2-phenyl-3,4-dihydro-2H-pyrazol-3-yl]-2-phenyl-1,8-naphthyridin-4-ol (4g):

Orange solid, (78%), m.p. 160-162oC. IR: νmax/cm-1 3130 (OH), 1620,1597 (C=C, C=N).

1H NMR (CDCl3) δH: 2.02 (2H, dd, C4-H, J = 9.3 Hz), 2.70 (3H, s, CH3), 5.35 (1H, t, C5-H, J = 9.3 Hz), 5.85 (1H, s, -OH), 6.70-8.37 (16H, m, Ar-H). 13C NMR (CDCl3) δC: 22.49, 38.10, 43.24, 107.14, 111.43, 116.90, 125.58, 126.56, 127.44, 128.45, 129.62, 130.41, 135.11, 137.37, 140.14, 140.46, 150.14, 154.43, 157.63, 168.65, 165.11. MS (m/z) 501 M+ Found: C, 72.06; H, 4.23; N, 13.49. C30H23N5O3 requires C, C, 71.84; H, 4.62; N, 13.96%.

2.1.4 Synthsis of 6-(4-Hydroxy-7-methyl-2-phenyl-[1,8] naphthyridin-3-yl)-4-aryl-5,6-dihydro-1H-pyrimidin-2-one (5d,f, and g)

Chalcons 4 (10 mmol) were added to a mixture made from urea ( 1g, 15mmol) in 20 mL of ethanol and few drops of conc. HCl. The mixture was refluxed for 10h. The reaction was concentrated, cooled, poured onto ice water (50mL), and neutralized with cold NH4OH solution. The solid product formed was collected by filtration and then crystalized from ethanol to give the products 5d,g, and f.

6- ( 4-Hydroxy-7-methyl -2-phenyl - [ 1 , 8 ] naphthyridin-3-yl)-4-p-tolyl-5,6-dihydro-1H-pyrimidin-2-one (5d):

White crystals, (51%), m.p. 290-292oC. IR: νmax/cm-1 3230 (OH), 1711 (C=O).1H NMR (DMSO-d6) δH: 1.97 (2H, dd, C5-H, J = 12.7 Hz), 2.73, 2.90 (6H, 2s, 2CH3), 5.31 (1H, t, C6-H, J =12.7 Hz), 5.78 (1H, s, -OH), 6.92-8.62 (12H, m, Ar-H , NH). 13C NMR (DMSO-d6) δC: 22.49, 38.10, 43.24, 107.14, 111.43, 116.90, 125.58, 126.56, 127.44, 128.45, 129.62, 130.41, 135.11, 137.37, 150.30, 158.19, 159.40, 163.04, 164.44, 168.28. MS (m/z) 422 M+ Found: C, 73.06; H, 4.93; N, 13.03. C25H22N4O2 requires C, 73.92; H, 5.25; N, 13.26%.

4-(4-Fluoro-phenyl)-6-(4-hydroxy-7-methyl-2-phenyl-[1,8]naphthyridin-3-yl)-5,6-dihydro-1H-pyrimidin-2-one (5f):

Yellow crystals, (53%), m.p.115-117oC. IR: νmax/cm-1 3119 (OH), 1764 (C=O).1H NMR (DMSO-d6) δH: 1.98 (2H, dd, C5-H, J = 11.9 Hz), 2.71 (3H, s, CH3), 5.32 (1H, t, C6-H, J = 11.9 Hz), 5.43 (1H, s, -OH), 6.67-8.35 (12H, m, Ar-H , NH). 13C NMR (DMSO-d6) δC: 13.26, 22.45, 29.10, 101.21, 115.30, 116.31, 121.19, 125.01, 127.03, 128.11, 129.25, 129.33, 135.32, 139.57, 150.44, 151.57, 154.36, 161.64, 164.45, 166.07. MS (m/z) 426 M+ Found: C, 70.96; H, 4.21; N, 12.99. C25H19 FN4O2 requires C, 70.41; H, 4.49; N, 13.14%.

6- ( 4-Hydroxy-7-methyl -2-phenyl - [ 1 , 8 ] naphthyridin-3-yl)-4-(4-nitro-phenyl)-5,6-dihydro-1H-pyrimidin-2-one (5g):

Brown solid, (67%), m.p. > 300oC. IR: νmax/cm-1 3162 (OH), 1718 (C=O). 1H NMR (DMSO-d6) δH: 2.00 (2H, dd, C5-H, J =10.2 Hz), 2.74 (3H, s, CH3), 5.33 (1H, t, C6-H, J =10.2 Hz), 5.77 (1H, s, -OH), 7.53-8.82 (12H, m, Ar-H, NH). 13C NMR (DMSO-d6) δC: 22.45, 29.52, 42.48, 107.82, 123.38, 124.20, 125.01, 126.05, 128.16, 129,67, 135.64, 138.34, 140.55, 150.92, 152.52, 158.33, 159.40, 163.21, 164.68, 167.60. MS (m/z) 453 M+ Found: C, 66.61; H, 4.01; N, 15.01.

C25H19N5O4 requires C, C, 66.22; H, 4.22; N, 15.44%.

2.1.5 Synthesis of 5,6-dihydro-6-(4-Hydroxy-7-methyl-2-phenyl-1,8-naphthyridin-3-yl)-4-aryl-2-(1H)-thione (6d,f, and g)

A mixture of chalcons 4 (10 mmol), thiourea (1.1 mL, 14mmol) and NaOH (0.1 g) in 25 mL ethanol were refluxed for 10h. The reaction mixture was concentrated, cooled, and the formed solid product was collected by filtration, then crystalized from ethanol to give the title products 5d,g, and f.

5,6-dihydro-6-(4-Hydroxy-7-methyl-2-phenyl-1,8-naphthyridin-3-yl)-4-p-tolylpyrimidine-2-(1H)-thione (6d).

Yellow crystals (64 %), m.p. > 300oC. IR: νmax/cm-1 3342 (OH).1H NMR (DMSO-d6) δH: 1.97 (2H, dd, C5-H, J = 9.3 Hz), 2.08 (1H, s, -NH ), 2.69 (6H, s, 2CH3), 5.31 (1H, t, C6-H, J = 9.3 Hz), 5.45 (1H, s, -OH), 6.45-8.74 (11H, m, Ar-H). 13C NMR (DMSO-d6) δC: 22.35, 34.93, 41.06, 106.42, 122.75, 124.45, 126.65, 129.15, 130.12, 135.12, 139.37, 150.29, 158.33, 159.19, 162.54, 165.66, 187.51. MS (m/z) 438 M+ Found: C, 71.46; H, 4.83; N, 12.36. C26H22N4O2S requires C, 71.21; H, 5.06; N, 12.78%.

4-(4-Fluoro-phenyl)-5,6-dihydro-6-(4-hydroxy-7-methyl-2-phenyl-1,8-naphthyridin-3-yl) pyrimidine-2(1H)-thione (6f):

White solid (37 %), m.p. 286- 288 oC. IR: νmax/cm-1 3452 (OH).1H NMR (DMSO-d6) δH: 1.98 (2H, dd, C5-H, J = 9.1 Hz), 2.09 ( 1H, s, -NH ), 2.71 (3H, s, CH3), 5.31 (1H, t, C6-H, J = 9.1 Hz), 5.40 ( 1H, s, -OH), 6.89-8.71 (11H, m, Ar-H ) . MS (m/z) 442 M+ Found: C, 68.26; H, 4.01; N, 12.32. C25H19 FN4O requires: C, 67.86; H, 4.33; N, 12.66%.

5,6-dihydro- 6-(4-Hydroxy-7-methyl-2-phenyl-1,8-naphthyridin-3-yl)-4-(4-nitro-phenyl) pyrimidine-2-(1H)-thione (6g):

Yellow crystal (46%), m.p. 243-245oC. IR: νmax/cm-1 3343 (OH).1H NMR (DMSO-d6) δH: 2.00 (2H, dd, C5-H, J = 8.5 Hz), 2.10 (1H, s, -NH ), 2.74 (3H, s, CH3), 5.33 (1H, t, C6-H, J = 8.5 Hz), 5.77 (1H, s, -OH), 7.53-8.52 (11H, m, Ar-H). 13C NMR (DMSO-d6) δC: 22.94, 35.40, 40.47, 107.82, 116.14, 122.23, 124.20, 125.01, 127.43, 128.74, 130.06, 135.93, 137.26, 141.01, 150.92, 151.91, 156.57, 157.00, 160.66, 161.08, 187.34. MS (m/z) 469 M+ Found: C, 63.48; H, 3.98; N, 14.59. C25H19N5O3S requires: C, 63.95; H, 4.08; N, 14.92%.

2.1.6 Synthesis of 1-{4-[(4-Hydroxy-7-methyl-2-phenyl-[1,8]naphthyridin-3-ylmethylene)-amino]-phenyl}-ethanone (7)

A solution of aldehyde 2 (5 g, 20 mmol) and p-aminoacetophenone (2.7g, 20mmol) in ethanol (30 mL) were refluxed together for 2h. The reaction was concentrated, cooled, and the formed preciptate was recrystallized from dilute ethanol to give the title compound as orange crystal in 84% yield, m.p.137-139oC. IR: νmax/cm-1 3463 (OH), 1659 (C=O), 1621 (C=N).1H NMR (CDCl3) δH: 2.19, 2.52 (6H, 2s, 2CH3), 5.50 (1H, s, -OH), 7.53-8.52 (11H, m, Ar-H ), 7.55 (1H, s, CH=N). 13C NMR (CDCl3) δC: 22.70, 26.11, 108.35, 113.74, 117.88, 121.29, 124.46, 128.75, 129.62, 130.46, 130.67, 135.95, 138.56, 141.05, 151.11, 158.60, 161.07, 164.48, 166.92, 196.57. MS (m/z) 381 M+ Found: C, 75.91; H, 4.88; N, 10.86. C24H19N3O2 requires: C, 75.57; H, 5.02; N, 11.02%.

2.1.7 Synthesis of 4-(aryl)-6-{4-[(4-hydroxy-7-methyl-2-phenyl-[1,8]naphthyridin-3-ylmethylene)-amino]-phenyl}-2-oxo-1,2-dihydro-pyridine-3-carbonitrile 8a-d

A mixture made from 7 (0.8g, 2mmol), aldehyde ( 2 mmol), ethylcyanoacetate ( 0.21mL, 2 mmol) were refluxed for 2-4h. in a 10 mL absolute ethanol. The reaction mixture was allowed to cool and the resulting solid precipitate was filtered and recrystallized from ethanol to obtain the title product 8a-d.

4-(4-Chloro-phenyl)-6-{4-[(4-hydroxy-7-methyl-2-phenyl-[1,8]naphthyridin-3-ylmethylene)-amino]-phenyl}-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (8a):

Brownish crystal (83%), m.p. 209-211oC. IR: νmax/cm-1 3159 (OH), 2226 (CN), 1712 (C=O). 1H NMR (DMSO-d6) δH: 2.60 (3H, s, CH3), 5.61 (1H, s, -OH), 6.80 (1H, s, C5-H of pyridone), 7.40-8.60 (16H, m, Ar-H, NH), 7.54 (1H, s, CH=N). 13C NMR (DMSO-d6) δC: 22.93, 96.08, 101.31, 107.41, 111.05, 117.39, 121.37, 122.11, 123.19, 127.41, 129.26, 129.69, 131.01, 131.60, 134.72, 135.52, 136.01, 137.95, 148.75, 154.51, 158.05, 162.63, 163.44, 167.41, 169.71. MS (m/z) 567 M+, 569 M++2 Found: C, 71.43; H, 3.68; N, 11.99. C34H22ClN5O2 requires: C, 71.89; H, 3.90; N, 12.33%.

6-{4-[(4-Hydroxy-7-methyl-2-phenyl-[1,8] naphthyridin-3-ylmethylene)-amino]-phenyl}-4-(4-nitro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (8b):

Reddish crystal (88%), m.p. 179-181oC. IR: νmax/cm-1 3315 (OH), 2220 (CN), 1695 (C=O). 1H NMR (DMSO-d6) δH: 2.37 (3H, s, CH3), 5.62 (1H, s, -OH), 7.01 (1H, s, C5-H of pyridone), 6.72-8.59 (16H, m, Ar-H, NH), 7.60 (1H, s, CH=N). MS (m/z) 578 M+ Found: C, 70.79; H, 3.38; N, 14.09. C34H22N6O4 requires: C, 70.58; H, 3.83; N, 14.53%.

4-(4-Fluoro-phenyl)-6-{4-[(4-hydroxy-7-methyl-2-phenyl-[1,8]naphthyridin-3-ylmethylene)-amino]-phenyl}-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (8c):

Green crystal (78%), m.p. 188-190oC. IR: νmax/cm-1 3150 (OH), 2140 (CN), 1736 (C=O). 1H NMR (DMSO-d6) δH: 2.60 (3H, s, CH3), 5.60 (1H, s, -OH), 6.76 (1H, s, C5-H of pyridone), 7.19-8.62 (16H, m, Ar-H, NH), 7.30 (1H, s, CH=N). 13C NMR (DMSO-d6) δC: 22.65, 95.41, 100.33, 107.41, 112.47, 115.70, 119.12, 122.17, 123.19, 128.11, 128.42, 129.65, 129.86, 131.02, 139.30, 139.44, 137.55, 140.18, 148.13, 158.80, 161.62, 162.83, 166.45, 167.08, 169.91. MS (m/z) 551 M+ Found: C, 74.48; H, 3.63; N, 12.41. C34H22FN5O2 requires: C, 74.04; H, 4.02; N, 12.70%.

4-(4-Bromo-phenyl)-6-{4-[(4-hydroxy-7-methyl-2-phenyl-[1,8]naphthyridin-3-ylmethylene)-amino]-phenyl}-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (8d):

Light brown crystal (76%), m.p. 151-153oC. IR: νmax/ cm-1 3256 (OH), 2132 (CN), 1736 (C=O). 1H NMR (DMSO-d6) δH: 2.30 (3H, s, CH3), 5.59 (1H, s, -OH), 6.81 (1H, s, C5-H of pyridone), 7.33-8.42 (16H, m, Ar-H, NH), 7.59 (1H, s, CH=N). 13C NMR (DMSO-d6) δC: 22.69, 95.08, 100.63, 108.21, 112.21, 112.61, 120.96, 122.17, 123.94, 128.09, 128.24, 129.62, 129.66, 130.11, 133.01, 135.27, 136.51, 139.55, 140.54, 149.24, 158.95, 162.61, 164.05,165.06 167.01, 178.11. MS (m/z) 612 M+, 614 M++2 Found: C, 66.93; H, 3.18; N, 11.22. C34H22BrN5O2 requires: C, 66.67; H, 3.62; N, 11.43%.

2.1.8 Synthesis of 2-(4-Hydroxy-7-methyl-2-phenyl-[1,8] naphthyridin-3-ylmethylene)-malononitrile 9

A mixture of aldehyde 2 (2.5g, 10 mmol) and malononitrile (0.66g, 10 mmol) were stirred together at room temperature for 24h in a 20mL ethanol in the presence of few drops of piperidine. The formed precipitate was filtered, dried, and recrystallized from n-butanol to give 9 as a light green crystal in 89%, m.p. 253-255oC. IR: νmax/cm-1 3345 (OH), 2166 (CN). 1H NMR (CDCl3) δH: 2.19 (3H, s, CH3), 5.37 (1H, s,-OH), 7.59 (5H, m, -Ph), 8.03 (1H, s, -CH=C), 8.52 (1H, d, C6-H, J = 8.5), 9.62 (1H, d, C5-H, J = 8.5). 13C-NMR (CDCl3) δC: 22.79, 84.64, 116.80, 119.24, 127.85, 129.24, 143.19, 146.95, 150.57, 154.53, 158.82, 161.20, 163.99. MS (m/z) 312 M+ Found: C, 72.84; H, 3.41; N, 17.56. C19H12N4O requires: C, 73.07; H, 3.87; N, 17.94%.

2.1.9 Synthesis of 2-Ethoxy-4-(4-hydroxy-7-methyl-2-phenyl-[1,8]naphthyridin-3-yl)-6-aryl-2-yl-nicotinonitrile (10 a-f)

A mixture of equimolar amounts of 9 (0.3 g, 10 mmol) and methyl aryl ketones (10 mmol) was stirred at room temperature (25–30oC) for the proper time controlled by Thin-layer chromatography (TLC), in the alcohol (20 mL) containing sodium (0.46 g, 20 mmol). The separated solid was collected, washed with water and crystallized from n-butanol to obtain the title compounds 10a–f.

2-Ethoxy-4-(4-hydroxy-7-methyl-2-phenyl-[1,8] naphthyridin-3-yl)-6-thiophen-2-yl-nicotinonitrile (10a):

Yellow crystal (82%), m.p. 227-229oC. IR: νmax/cm-1 3256 (OH), 2182 (CN).1H NMR (CDCl3) δH: 0.88 (3H, t, -CH2CH3, J = 7.6), 2.17 (3H, s, CH3), 4.03 ( 2H, q, -CH2CH3, J = 7.6), 5.26 ( 1H, s, -OH), 7.26 (1H, s, C5-H of pyridine ), 7.38-8.89 (10H, m, Ar-H). 13C NMR (CDCl3) δC: 14.12, 22.40, 65.24, 97.05, 107.29, 109.39, 114.32, 120.11, 122.91, 124.20, 126.62, 127.02, 129.42, 135.94, 140.05, 142.63, 150.74, 152.14, 156.62, 158.23, 159.25, 165.32, 166.16. MS (m/z) 464 M+ Found: C, 69.45; H, 3.88; N, 11.79. C27H20N4O2S requires: C, 69.81; H, 4.34; N, 12.06%.

2-Ethoxy-4-(4-hydroxy-7-methyl-2-phenyl-[1,8] naphthyridin-3-yl)-6-phenyl-nicotinonitrile (10b):

Brown crystal (85%), m.p. 279-281oC. IR: νmax/cm-1 3332 (OH), 2132 (CN).1H NMR (DMSO-d6) δH: 0.86 (3H, t, -CH2CH3, J = 6.8), 2.58 (3H, s, CH3), 4.07 (2H, q, -CH2CH3, J = 7.6), 5.42 ( 1H, s, -OH), 7.28 (1H, s, C5-H of pyridine), 7.52-8.34 (12H, m, Ar-H). 13C NMR (DMSO-d6) δC: 14.36, 22.40, 64.73, 97.20, 107.00, 109.02, 117.21, 119.11, 119.51, 121.01, 127.58, 128.35, 129.30, 129.81, 130.11, 131.94, 142.50, 150.93, 151.81, 156.56, 158.11, 159.19, 160.46, 164.05, 169.21. MS (m/z) 458 M+ Found: C, 75.42; H, 4.36; N, 11.79. C29H22N4O2 requires: C, 75.97; H, 4.84; N, 12.22%.

2-Ethoxy-4-(4-hydroxy-7-methyl-2-phenyl-[1,8] naphthyridin-3-yl)-6-p-tolyl-nicotinonitrile (10c):

Yellow crystal (79%), m.p. 293-295oC. IR: νmax/cm-1 3343 (OH), 2199 (CN).1H NMR (DMSO-d6) δH: 1.05 (3H, t, -CH2CH3, J = 7.6), 2.54, 2.75 (6H, 2s, 2CH3), 5.43 (2H, q, -CH2CH3, J = 7.6), 5.83 (1H, s, -OH), 7.56-8.57 (12H, m, Ar-H). 13C NMR (DMSO-d6) δC: 14.36, 17.45, 22.65, 64.21, 99.10, 107.21, 108.22, 116.65, 118.51, 119.65, 119.82, 120.62, 127.93, 128.03, 129.41, 135.91, 136.34, 137.61, 139.37, 150.29, 151.20, 158.37, 159.29, 160.61, 163.38, 169.91. MS (m/z) 472 M+ Found: C, 67.69; H, 4.83; N, 11.59. C30H29N4O2 requires: C, 76.25; H, 5.12; N, 11.86%.

2-Ethoxy-4-(4-hydroxy-7-methyl-2-phenyl-[1,8] naphthyridin-3-yl ) -6-(4-methoxy-phenyl ) - nicotinonitrile (10d):

Brown crystal (68%), m.p. 269-271oC. IR: νmax/cm-1 3326 (OH), 2183 (CN).1H NMR (CDCl3) δH: 0.89 (3H, t, -CH2CH3, J = 7.6), 2.56 (3H, s, CH3), 3.87(3H, s, -OCH3), 4.06 ( 2H, q, -CH2CH3, J = 7.6), 5.27 (1H, s, -OH), 6.91-8.51 (12H, m, Ar-H). 13C NMR (CDCl3) δC: 14.52, 22.68, 46.47, 63.42, 97.45, 107.38, 108.60, 113.48, 119.24, 127.42, 129.48, 129.72, 129.77, 130.35, 130.60, 131.60, 132.48, 139.77, 150.94, 151.91, 156.92, 158.82, 161.27, 162.29.163.48, 171.46. MS (m/z) 488 M+ Found: C, 73.26; H, 4.66; N, 11.19. C30H24N4O3 requires: C, 73.76; H, 4.95; N, 11.47%.

2-Ethoxy-6-(4-fluoro-phenyl)-4-(4-hydroxy-7-methyl-2-phenyl-[1,8]naphthyridin-3-yl)-nicotinonitrile; compound with methane (10e):

Brown crystal (76%), m.p. 278-280oC. IR: νmax/cm-1 3333 (OH), 2213 (CN).1H NMR (CDCl3) δH: 1.44 (3H, t, -CH2CH3, J = 6.8), 2.55 (3H, s, CH3), 4.09 (2H, q, -CH2CH3, J = 6.8), 5.25 (1H, s, -OH), 7.96-8.21 (12H, m, Ar-H). 13C NMR (CDCl3) δC: 14.69, 22.63, 63.74, 96.03, 107.94, 108.80, 114.01, 115.01, 119.25, 123.34, 127.02, 129.23, 129.92, 130.26, 130.60, 131.60, 135.65, 136.76, 139.85, 150.03, 152.56, 158.41, 159.29, 162.91, 170.39. MS (m/z) 492 M+ Found: C, 73.48; H, 4.83; N, 11.06. C30H25FN4O2 requires: C, 73.16; H, 5.12; N, 11.37%.

2-Ethoxy-4-(4-hydroxy-7-methyl-2-phenyl-[1,8] naphthyridin-3-yl)-6-(4-nitro-phenyl)-nicotinonitrile (10f):

brown crystal (93%), m.p. 244-246oC. IR: νmax/cm-1 3331 (OH), 2229 (CN). 1H NMR (CDCl3) δH: 0.87 (3H, t, -CH2CH3, J = 7.6), 2.68 (3H, s, CH3), 4.08 (2H, q, -CH2CH3, J = 7.6), 5.24 (1H, s, -OH), 7.26-8.51 (12H, m, Ar-H). 13C NMR (CDCl3) δC: 14.12, 22.68, 63.62, 97.05, 107.18, 108.39, 114.07, 115.24, 123.89, 127.82, 128.23, 129.32, 131.65, 136.76, 140.62, 145.27, 147.70, 150.23, 157.14, 158.23, 162.18, 164.72, 170.59. MS (m/z) 503 M+ Found: C, 68.78; H, 3.97; N, 13.48. C29H21N5O4 requires: C, 69.18; H, 4.20; N, 13.91%.

Antitumor activity: To evaluate the antitumor efficacy of the new compounds’ contrary to MCF7 cell line, a standard MTT technique was applied. The numerical assess rest on the capacity of the mitochondrial dehydrogenase of feasible cells to slash the tetrazolium ring of MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide). The fashioned purple dye is measured spectrophotometrically and therefore the intensification or reduction in cell amount can specify the antitumor action of verified compounds. The antitumor efficacy was determined as the concentration of the compound that produced 50% growing embarrassment (IC50, mean ±SEM) in contrast to the development of raw cells. Cells for Cell Line were gotten from American Type Culture Collection, and cultivated by DMEM (Invitrogen) complemented by 10% FBS (Hyclone,), 10 ug/ml of insulin (Sigma), and 1% penicillin-streptomycin. 96-well dish was utilized for the test. Cells were preserved with sequential concentrations of test compounds and hatched for 48 hours at 370C. The dish was then studied utilizing an overturned microscope earlier the MTT assess. The cultures stayed detached from incubator to a laminar stream top and MTT was added as a 10% of culture medium volume formerly incubated for 2-4 hours. Afterwards elimination from incubator, the fashioned Formazan crystals were dissolved by means of MTT solubilizing solution. The absorbance was measured at a wavelength of 570 nm. [33,34].

Ethical approval: The conducted research is not related to either human or animal use.

3 Results and Discussion

3.1 Chemistry

Synthetic methodology to attain target compounds is clarified in Scheme 1 and 2. Formylation of 7-methyl-2-phenyl-1,8-naphthyridin-4-ol 1 via Vilsmeier–Haack reaction, afforded the vital starting compound in our study: the 4-hydroxy-7-methyl-2-phenyl-1,8-naphthyridine-3-carbaldehyde 2 [35]. The structure of aldehyde 2 was identified based on microanalysis and spectral data. The IR spectra showed the absorption band at ν = 1661 cm−1due to aldehydic carbonyl group. Its 1H NMR spectrum showed the disappearance of C3-H at δ = 6.30 ppm and a characteristic singlet signal at δ = 9.56 ppm for –CHO group proton. 13C NMR spectrum for 2 displayed the presence of carbon of a carbonyl group at δ = 190.05 ppm. The formed aldehyde derivative 2 was treated with different acetyl compounds in the presence of MgAl-hydrotalcite (HT) [36] in refluxing ethanol and it produced only one isolable product (as examined by TLC) identified as the chalcones derivatives 3a-g (Scheme 1). As a descriptive example, the 1H NMR spectrum of 3a displays a characteristic signal at δ = 8.38 and 8.58 ppm as a pair of doublet referring to the two olefinic protons. 13C NMR spectrum of 3e shows the existence of the carbon of methoxide group at δ = 55.9 ppm. The signals for the two olefinic carbons appeared at δ = 128 and 143 ppm, respectively. Treatment of chalcone 3 with different binuclophilic agents, namely phenylhydrazine, urea, and thiourea afforded in each case one isolable product (examined by TLC) corresponding to pyrazoline 4d,f,g, dihydropyrimidinone 5d,f,g, and dihydropyrimidinethione 6d,f,g derivatives (Scheme 1).

Scheme 1
Scheme 1
Scheme 2
Scheme 2

The established structures of all new chemical entities 4-6 were verified by their spectral data and microanalyses. The IR spectra of pyrazoline derivatives showed the disappearance of the carbonyl group of chalcones. The 1H NMR spectrum of 4d displayed two signals, at δ = 2.00 ppm as a doublet of doublet and a triplet signal at δ = 5.32 ppm for the protons at C4 and C5 of pyrazoline ring, respectively. 1H NMR spectrum of 5f revealed multiplet signal at δ = 1.98 and triplet signal at 5.32 ppm for protons at C5 and C6 of hydropyrimidinone derivative. Reaction of aldehyde 2 with p-aminoacetophenone in ethanol under reflux gave 1-{4-[(4-Hydroxy-7-methyl-2-phenyl-[1, 8] naphthyridin-3-ylmethylene)-amino]-phenyl}-ethanone 7 (Scheme 2). Its structure was confirmed through microanalysis and spectral data. The IR spectra of 7 revealed a strong absorption peak at ν = 1659 cm-1 for C=O group, 1H NMR spectrum of 7 displayed two singlet signals at δ = 2.19 and 7.55 ppm due to COCH3 and CH=N- respectively, in addition to multiplet signals due to aromatic protons. Furthermore, treatment of 7 with different aromatic aldehyde, ethylcyanoacetate, and excess ammonium acetate in EtOH under reflux (Scheme 2), afforded only one isolable product (examined by TLC) identified as 4-(substituted)-6-{4-[(4-hydroxy-7-methyl-2-phenyl-[1,8]

naphthyridin-3-ylmethylene)-amino]-phenyl}-2-oxo-1,2-dihydro-pyridine-3-carbonitrile 8a-d. The structures of 8a-d were established based on elemental analysis and spectral data. The IR spectra revealed the absorption band at ν = 2132- 2226 cm−1due to CN group, the 1H NMR spectrum of 8a displays a singlet signal at δ = 6.80 ppm referring to C5-H of pyridone. The carbaldehyde 2 which reacted with malononitrile in refluxing ethanol, gave 1-{4-[(4-Hydroxy-7-methyl-2-phenyl-[1,8]naphthyridin-3-ylmethylene)-amino]-phenyl}-ethanone 9. According to the cited procedure [37], the required 2-Ethoxy-4-(4-hydroxy-7-methyl-2-phenyl-[1,8]naphthyridin-3-yl)-6-aryl-2-yl-nicotinonitrile 10a-f were obtained from the reaction of ylidenemalononitrile 9 with different ketones catalyzed by sodium ethoxide (Scheme 2). The structure of compounds 10a-f was confirmed in the same way as the previous compounds. An IR spectrum of compound 10a shows a characteristic stretching vibration band at ν = 2182 cm−1 for CN group. Its 1H NMR spectrum displays two signals at δ = 0.88 and 4.03 ppm characteristic for the ethoxide group, while a singlet peak at δ = 7.26 ppm for pyridinyl H-5 appears. 13C NMR spectrum of 10a shows the presence of ethoxide carbons at δ = 14.12 and 65.24 ppm, C-3, C-5 of pyridine and the carbon of nitrile group appears at δ = 97.05, 107.92, and 114.32 ppm, respectively. The mass spectrum (EI) of 10a displays a peak at 482.27 with relative intensity value 30.7% for the molecular ion.

3.2 Biological Evaluation

The antitumor activity of compounds 3b, f, g, 4d, g, 5f, 6f, 7, 8a-d, and 10a-f was examined and compared with staurosporin as a standardized medicine antagonizing human breast cancer cell lines (MCF-7) using standard MTT assay process [35]. Cancer cells were either isolated separately as a control or with a range of concentrations of the compounds tested (100, 25, 6.25, 1.56, 0.39 μM). Results obtained were presented as IC50 (μM) values, which is the average of minimally three independent trials shown in Table 1. Results showed that compounds 10c, 8d, 4d, 10f and 8b produced strongest cytotoxic effects at IC50 ranges from 1.47 to 3.19 μM vs staurosporin of IC50; 4.51 μM. The changes in the kinds of aryl substituents in the heterocyclic rings attached to the parent 1,8-naphthyridine scaffold significantly impacted the antitumor activity of the tested compounds. The conjugation of 4-tolyl and 4-bromophenylcyanopyridine entity to the 1,8-naphthyridine ring in 10c, 8d and 3-tolylpyrazoline 4d, resulted in an approximately 3-fold development in the growth inhibition of the cancer cell lines of IC50; 1.47, 1.62, and 1.68 μM. The increase was larger in comparison with staurosporin. On the other hand, cytotoxic potency was completely eliminated due the replacement of the 4-tolyl moiety in compound 10c with thiophenyl ring as compound 10a, IC50; 136.82 μM. On the contrary, the replacement of 3-tolyl moiety in pyrazoline conjugated with 1,8-naphthyridine scaffold 4d with p-nitrophenyl in 4f reduced the cytotoxicity from 1.68 to 8.17 μM.

Table 1

The cytotoxic activity of several newly synthesized compounds against human breast cancer cell lines (MCF7).

CompoundsMWIC50 μM
3c46627.19 ±1.13
3f3847.88 ±0.33
3g3939.10 ±0.34
4d4701.68 ±0.05
4g5018.17 ±0.29
5f42635.33 ±1.75
6f4426.53 ±0.25
738110.13 ±0.41
8a567.516.15 ±0.77
8b5783.19 ±0.12
8c5517.89 ±0.33
8d6121.62 ±0.05
10a464136.82 ±6.22
10b4587.97 ±0.24
10c4721.47 ±0.04
10d4888.80 ±0.28
10e47621.41 ±0.92
10f5032.30 ± 1.17
Staurosporin466.534.51 ±0.16

In summary, breast malignant tumors MCF-7 cell lines were viciously inhibited by 1,8-naphthyridine scaffold showing its significant antitumor activity. Variation in the types of heterocyclic rings conjugated with it considerably affected the observed activity. In general, 1,8-napthyridine conjugated with pyridine and pyrazoline, specially 4-bromophenyl pyridine, 4-tolyl pyridine and 3-tolylpyrazoline, introduced novel candidates which could serve as key templates to fight against antitumor effects on breast cancer cells.

4 Conclusions

In this article, a novel series of 2-phenyl-7-methyl-1,8-naphthyridine derivatives with variable substituents at C-3 were synthesized. Most of the synthesized derivatives showed potential as anticancer agents against breast cancer cell line MCF7. Compounds 10c, 8d, 4d, 10f and 8b displayed better activity with an IC50 values (1.47, 1.62, 1.68, 2.30, 3.19 μM, respectively) compared with the reference drug staurosporin (IC50 = 4.51 μM).

Acknowledgments

The project was funded by the Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, under grant no. J-739-247-38. The authors, therefore, acknowledge with thanks DSR for technical and financial support.

  1. Supplementary Materials: Supplementary materials are available online.

  2. Author Contributions The listed authors contributed to this work as described in the following. Nesreen S. Ahmed and Thoraya S. J carried out the synthesis work, interpreted the results and Abeer N.Al-romaizan and Nesreen S. Ahmed interpreted the results and cooperated in the preparation of the manuscript. All authors read and approved the final manuscript.

  3. Conflict of interest

    Conflicts of Interest: The authors declare no conflicts of interest

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Received: 2018-12-06
Accepted: 2019-03-11
Published Online: 2019-11-06

© 2019 Abeer N. Al-romaizan et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 Public License.

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https://doi.org/10.1515/chem-2019-0097
Keywords for this article
1,8- naphthyridine; pyrazole; pyrimidine; pyridine; cytotoxic; breast cancer
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Articles in the same Issue

  1. Regular Articles
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  10. Thermodynamic properties of the bubble growth process in a pool boiling of water-ethanol mixture two-component system
  11. Critical Roles of the PI3K-Akt-mTOR Signaling Pathway in Apoptosis and Autophagy of Astrocytes Induced by Methamphetamine
  12. Characteristics of Stable Hydrogen and Oxygen Isotopes of Soil Moisture under Different Land Use in Dry Hot Valley of Yuanmou
  13. Specific, highly sensitive and simple spectrofluorimetric method for quantification of daclatasvir in HCV human plasma patients and in tablets dosage form
  14. Chromium-modified cobalt molybdenum nitrides as catalysts for ammonia synthesis
  15. Langerhans cell-like dendritic cells treated with ginsenoside Rh2 regulate the differentiation of Th1 and Th2 cells in vivo
  16. Identification of Powdery Mildew Blumeria graminis f. sp. tritici Resistance Genes in Selected Wheat Varieties and Development of Multiplex PCR
  17. Computational Analysis of new Degree-based descriptors of oxide networks
  18. The Use Of Chemical Composition And Additives To Classify Petrol And Diesel Using Gas Chromatography–Mass Spectrometry And Chemometric Analysis: A Uk Study
  19. Minimal Energy Tree with 4 Branched Vertices
  20. Jatropha seed oil derived poly(esteramide-urethane)/ fumed silica nanocomposite coatings for corrosion protection
  21. Calculating topological indices of certain OTIS interconnection networks
  22. Energy storage analysis of R125 in UIO-66 and MOF-5 nanoparticles: A molecular simulation study
  23. Velvet Antler compounds targeting major cell signaling pathways in osteosarcoma - a new insight into mediating the process of invasion and metastasis in OS
  24. Effects of Azadirachta Indica Leaf Extract, Capping Agents, on the Synthesis of Pure And Cu Doped ZnO-Nanoparticles: A Green Approach and Microbial Activity
  25. Aqueous Micro-hydration of Na+(H2O)n=1-7 Clusters: DFT Study
  26. A proposed image-based detection of methamidophos pesticide using peroxyoxalate chemiluminescence system
  27. Phytochemical screening and estrogenic activity of total glycosides of Cistanche deserticola
  28. Biological evaluation of a series of benzothiazole derivatives as mosquitocidal agents
  29. Chemical pretreatments of Trapa bispinosa's peel (TBP) biosorbent to enhance adsorption capacity for Pb(ll)
  30. Dynamic Changes in MMP1 and TIMP1 in the Antifibrotic Process of Dahuang Zhechong Pill in Rats with Liver Fibrosis
  31. The Optimization and Production of Ginkgolide B Lipid Microemulsion
  32. Photodynamic Therapy Enhanced the Antitumor Effects of Berberine on HeLa Cells
  33. Chiral and Achiral Enantiomeric Separation of (±)-Alprenolol
  34. Correlation of Water Fluoride with Body Fluids, Dental Fluorosis and FT4, FT3 –TSH Disruption among Children in an Endemic Fluorosis area in Pakistan
  35. A one-step incubation ELISA kit for rapid determination of dibutyl phthalate in water, beverage and liquor
  36. Free Radical Scavenging Activity of Essential Oil of Eugenia caryophylata from Amboina Island and Derivatives of Eugenol
  37. Effects of Blue and Red Light On Growth And Nitrate Metabolism In Pakchoi
  38. miRNA-199a-5p functions as a tumor suppressor in prolactinomas
  39. Solar photodegradation of carbamazepine from aqueous solutions using a compound parabolic concentrator equipped with a sun tracking system
  40. Influence of sub-inhibitory concentration of selected plant essential oils on the physical and biochemical properties of Pseudomonas orientalis
  41. Preparation and spectroscopic studies of Fe(II), Ru(II), Pd(II) and Zn(II) complexes of Schiff base containing terephthalaldehyde and their transfer hydrogenation and Suzuki-Miyaura coupling reaction
  42. Complex formation in a liquid-liquid extraction-chromogenic system for vanadium(IV)
  43. Synthesis, characterization (IR, 1H, 13C & 31P NMR), fungicidal, herbicidal and molecular docking evaluation of steroid phosphorus compounds
  44. Analysis and Biological Evaluation of Arisaema Amuremse Maxim Essential Oil
  45. A preliminary assessment of potential ecological risk and soil contamination by heavy metals around a cement factory, western Saudi Arabia
  46. Anti- inflammatory effect of Prunus tomentosa Thunb total flavones in LPS-induced RAW264.7 cells
  47. Collaborative Influence of Elevated CO2 Concentration and High Temperature on Potato Biomass Accumulation and Characteristics
  48. Methods of extraction, physicochemical properties of alginates and their applications in biomedical field – a review
  49. Characteristics of liposomes derived from egg yolk
  50. Preparation of ternary ZnO/Ag/cellulose and its enhanced photocatalytic degradation property on phenol and benzene in VOCs
  51. Influence of Human Serum Albumin Glycation on the Binding Affinities for Natural Flavonoids
  52. Synthesis and antioxidant activity of 2-methylthio-pyrido[3,2-e][1,2,4] triazolo[1,5-a]pyrimidines
  53. Comparative study on the antioxidant activities of ten common flower teas from China
  54. Molecular Properties of Symmetrical Networks Using Topological Polynomials
  55. Synthesis of Co3O4 Nano Aggregates by Co-precipitation Method and its Catalytic and Fuel Additive Applications
  56. Phytochemical analysis, Antioxidant and Antiprotoscolices potential of ethanol extracts of selected plants species against Echinococcus granulosus: In-vitro study
  57. Silver nanoparticles enhanced fluorescence for sensitive determination of fluoroquinolones in water solutions
  58. Simultaneous Quantification of the New Psychoactive Substances 3-FMC, 3-FPM, 4-CEC, and 4-BMC in Human Blood using GC-MS
  59. Biodiesel Production by Lipids From Indonesian strain of Microalgae Chlorella vulgaris
  60. Miscibility studies of polystyrene/polyvinyl chloride blend in presence of organoclay
  61. Antibacterial Activities of Transition Metal complexes of Mesocyclic Amidine 1,4-diazacycloheptane (DACH)
  62. Novel 1,8-Naphthyridine Derivatives: Design, Synthesis and in vitro screening of their cytotoxic activity against MCF7 cell line
  63. Investigation of Stress Corrosion Cracking Behaviour of Mg-Al-Zn Alloys in Different pH Environments by SSRT Method
  64. Various Combinations of Flame Retardants for Poly (vinyl chloride)
  65. Phenolic compounds and biological activities of rye (Secale cereale L.) grains
  66. Oxidative degradation of gentamicin present in water by an electro-Fenton process and biodegradability improvement
  67. Optimizing Suitable Conditions for the Removal of Ammonium Nitrogen by a Microbe Isolated from Chicken Manure
  68. Anti-inflammatory, antipyretic, analgesic, and antioxidant activities of Haloxylon salicornicum aqueous fraction
  69. The anti-corrosion behaviour of Satureja montana L. extract on iron in NaCl solution
  70. Interleukin-4, hemopexin, and lipoprotein-associated phospholipase A2 are significantly increased in patients with unstable carotid plaque
  71. A comparative study of the crystal structures of 2-(4-(2-(4-(3-chlorophenyl)pipera -zinyl)ethyl) benzyl)isoindoline-1,3-dione by synchrotron radiation X-ray powder diffraction and single-crystal X-ray diffraction
  72. Conceptual DFT as a Novel Chemoinformatics Tool for Studying the Chemical Reactivity Properties of the Amatoxin Family of Fungal Peptides
  73. Occurrence of Aflatoxin M1 in Milk-based Mithae samples from Pakistan
  74. Kinetics of Iron Removal From Ti-Extraction Blast Furnace Slag by Chlorination Calcination
  75. Increasing the activity of DNAzyme based on the telomeric sequence: 2’-OMe-RNA and LNA modifications
  76. Exploring the optoelectronic properties of a chromene-appended pyrimidone derivative for photovoltaic applications
  77. Effect of He Qi San on DNA Methylation in Type 2 Diabetes Mellitus Patients with Phlegm-blood Stasis Syndrome
  78. Cyclodextrin potentiometric sensors based on selective recognition sites for procainamide: Comparative and theoretical study
  79. Greener synthesis of dimethyl carbonate from carbon dioxide and methanol using a tunable ionic liquid catalyst
  80. Nonisothermal Cold Crystallization Kinetics of Poly(lactic acid)/Bacterial Poly(hydroxyoctanoate) (PHO)/Talc
  81. Enhanced adsorption of sulfonamide antibiotics in water by modified biochar derived from bagasse
  82. Study on the Mechanism of Shugan Xiaozhi Fang on Cells with Non-alcoholic Fatty Liver Disease
  83. Comparative Effects of Salt and Alkali Stress on Antioxidant System in Cotton (Gossypium Hirsutum L.) Leaves
  84. Optimization of chromatographic systems for analysis of selected psychotropic drugs and their metabolites in serum and saliva by HPLC in order to monitor therapeutic drugs
  85. Electrocatalytic Properties of Ni-Doped BaFe12O19 for Oxygen Evolution in Alkaline Solution
  86. Study on the removal of high contents of ammonium from piggery wastewater by clinoptilolite and the corresponding mechanisms
  87. Phytochemistry and toxicological assessment of Bryonia dioica roots used in north-African alternative medicine
  88. The essential oil composition of selected Hemerocallis cultivars and their biological activity
  89. Mechanical Properties of Carbon Fiber Reinforced Nanocrystalline Nickel Composite Electroforming Deposit
  90. Anti-c-myc efficacy block EGFL7 induced prolactinoma tumorigenesis
  91. Topical Issue on Applications of Mathematics in Chemistry
  92. Zagreb Connection Number Index of Nanotubes and Regular Hexagonal Lattice
  93. The Sanskruti index of trees and unicyclic graphs
  94. Valency-based molecular descriptors of Bakelite network BNmn
  95. Computing Topological Indices for Para-Line Graphs of Anthracene
  96. Zagreb Polynomials and redefined Zagreb indices of Dendrimers and Polyomino Chains
  97. Topological Descriptor of 2-Dimensional Silicon Carbons and Their Applications
  98. Topological invariants for the line graphs of some classes of graphs
  99. Words for maximal Subgroups of Fi24‘
  100. Generators of Maximal Subgroups of Harada-Norton and some Linear Groups
  101. Special Issue on POKOCHA 2018
  102. Influence of Production Parameters on the Content of Polyphenolic Compounds in Extruded Porridge Enriched with Chokeberry Fruit (Aronia melanocarpa (Michx.) Elliott)
  103. Effects of Supercritical Carbon Dioxide Extraction (SC-CO2) on the content of tiliroside in the extracts from Tilia L. flowers
  104. Impact of xanthan gum addition on phenolic acids composition and selected properties of new gluten-free maize-field bean pasta
  105. Impact of storage temperature and time on Moldavian dragonhead oil – spectroscopic and chemometric analysis
  106. The effect of selected substances on the stability of standard solutions in voltammetric analysis of ascorbic acid in fruit juices
  107. Determination of the content of Pb, Cd, Cu, Zn in dairy products from various regions of Poland
  108. Special Issue on IC3PE 2018 Conference
  109. The Photocatalytic Activity of Zns-TiO2 on a Carbon Fiber Prepared by Chemical Bath Deposition
  110. N-octyl chitosan derivatives as amphiphilic carrier agents for herbicide formulations
  111. Kinetics and Mechanistic Study of Hydrolysis of Adenosine Monophosphate Disodium Salt (AMPNa2) in Acidic and Alkaline Media
  112. Antimalarial Activity of Andrographis Paniculata Ness‘s N-hexane Extract and Its Major Compounds
  113. Special Issue on ABB2018 Conference
  114. Special Issue on ICCESEN 2017
  115. Theoretical Diagnostics of Second and Third-order Hyperpolarizabilities of Several Acid Derivatives
  116. Determination of Gamma Rays Efficiency Against Rhizoctonia solani in Potatoes
  117. Studies On Compatibilization Of Recycled Polyethylene/Thermoplastic Starch Blends By Using Different Compatibilizer
  118. Liquid−Liquid Extraction of Linalool from Methyl Eugenol with 1-Ethyl-3-methylimidazolium Hydrogen Sulfate [EMIM][HSO4] Ionic Liquid
  119. Synthesis of Graphene Oxide Through Ultrasonic Assisted Electrochemical Exfoliation
  120. Special Issue on ISCMP 2018
  121. Synthesis and antiproliferative evaluation of some 1,4-naphthoquinone derivatives against human cervical cancer cells
  122. The influence of the grafted aryl groups on the solvation properties of the graphyne and graphdiyne - a MD study
  123. Electrochemical modification of platinum and glassy carbon surfaces with pyridine layers and their use as complexing agents for copper (II) ions
  124. Effect of Electrospinning Process on Total Antioxidant Activity of Electrospun Nanofibers Containing Grape Seed Extract
  125. Effect Of Thermal Treatment Of Trepel At Temperature Range 800-1200˚C
  126. Topical Issue on Agriculture
  127. The effect of Cladophora glomerata exudates on the amino acid composition of Cladophora fracta and Rhizoclonium sp.
  128. Influence of the Static Magnetic Field and Algal Extract on the Germination of Soybean Seeds
  129. The use of UV-induced fluorescence for the assessment of homogeneity of granular mixtures
  130. The use of microorganisms as bio-fertilizers in the cultivation of white lupine
  131. Lyophilized apples on flax oil and ethyl esters of flax oil - stability and antioxidant evaluation
  132. Production of phosphorus biofertilizer based on the renewable materials in large laboratory scale
  133. Human health risk assessment of potential toxic elements in paddy soil and rice (Oryza sativa) from Ugbawka fields, Enugu, Nigeria
  134. Recovery of phosphates(V) from wastewaters of different chemical composition
  135. Special Issue on the 4th Green Chemistry 2018
  136. Dead zone for hydrogenation of propylene reaction carried out on commercial catalyst pellets
  137. Improved thermally stable oligoetherols from 6-aminouracil, ethylene carbonate and boric acid
  138. The role of a chemical loop in removal of hazardous contaminants from coke oven wastewater during its treatment
  139. Combating paraben pollution in surface waters with a variety of photocatalyzed systems: Looking for the most efficient technology
  140. Special Issue on Chemistry Today for Tomorrow 2019
  141. Applying Discriminant and Cluster Analyses to Separate Allergenic from Non-allergenic Proteins
  142. Chemometric Expertise Of Clinical Monitoring Data Of Prolactinoma Patients
  143. Chemomertic Risk Assessment of Soil Pollution
  144. New composite sorbent for speciation analysis of soluble chromium in textiles
  145. Photocatalytic activity of NiFe2O4 and Zn0.5Ni0.5Fe2O4 modified by Eu(III) and Tb(III) for decomposition of Malachite Green
  146. Photophysical and antibacterial activity of light-activated quaternary eosin Y
  147. Spectral properties and biological activity of La(III) and Nd(III) Monensinates
  148. Special Issue on Monitoring, Risk Assessment and Sustainable Management for the Exposure to Environmental Toxins
  149. Soil organic carbon mineralization in relation to microbial dynamics in subtropical red soils dominated by differently sized aggregates
  150. A potential reusable fluorescent aptasensor based on magnetic nanoparticles for ochratoxin A analysis
  151. Special Issue on 13th JCC 2018
  152. Fluorescence study of 5-nitroisatin Schiff base immobilized on SBA-15 for sensing Fe3+
  153. Thermal and Morphology Properties of Cellulose Nanofiber from TEMPO-oxidized Lower part of Empty Fruit Bunches (LEFB)
  154. Encapsulation of Vitamin C in Sesame Liposomes: Computational and Experimental Studies
  155. A comparative study of the utilization of synthetic foaming agent and aluminum powder as pore-forming agents in lightweight geopolymer synthesis
  156. Synthesis of high surface area mesoporous silica SBA-15 by adjusting hydrothermal treatment time and the amount of polyvinyl alcohol
  157. Review of large-pore mesostructured cellular foam (MCF) silica and its applications
  158. Ion Exchange of Benzoate in Ni-Al-Benzoate Layered Double Hydroxide by Amoxicillin
  159. Synthesis And Characterization Of CoMo/Mordenite Catalyst For Hydrotreatment Of Lignin Compound Models
  160. Production of Biodiesel from Nyamplung (Calophyllum inophyllum L.) using Microwave with CaO Catalyst from Eggshell Waste: Optimization of Transesterification Process Parameters
  161. The Study of the Optical Properties of C60 Fullerene in Different Organic Solvents
  162. Composite Material Consisting of HKUST-1 and Indonesian Activated Natural Zeolite and its Application in CO2 Capture
  163. Topical Issue on Environmental Chemistry
  164. Ionic liquids modified cobalt/ZSM-5 as a highly efficient catalyst for enhancing the selectivity towards KA oil in the aerobic oxidation of cyclohexane
  165. Application of Thermal Resistant Gemini Surfactants in Highly Thixotropic Water-in-oil Drilling Fluid System
  166. Screening Study on Rheological Behavior and Phase Transition Point of Polymer-containing Fluids produced under the Oil Freezing Point Temperature
  167. The Chemical Softening Effect and Mechanism of Low Rank Coal Soaked in Alkaline Solution
  168. The Influence Of NO/O2 On The NOx Storage Properties Over A Pt-Ba-Ce/γ-Al2O3 Catalyst
  169. Special Issue on the International conference CosCI 2018
  170. Design of SiO2/TiO2 that Synergistically Increases The Hydrophobicity of Methyltrimethoxysilane Coated Glass
  171. Antidiabetes and Antioxidant agents from Clausena excavata root as medicinal plant of Myanmar
  172. Development of a Gold Immunochromatographic Assay Method Using Candida Biofilm Antigen as a Bioreceptor for Candidiasis in Rats
  173. Special Issue on Applied Biochemistry and Biotechnology 2019
  174. Adsorption of copper ions on Magnolia officinalis residues after solid-phase fermentation with Phanerochaete chrysosporium
  175. Erratum
  176. Erratum to: Sand Dune Characterization For Preparing Metallurgical Grade Silicon
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