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Journal of Enzyme Inhibition and Medicinal Chemistry logoLink to Journal of Enzyme Inhibition and Medicinal Chemistry
. 2017 Sep 26;32(1):1229–1239. doi: 10.1080/14756366.2017.1368504

Synthesis, in vitro antitumour activity, and molecular docking study of novel 2-substituted mercapto-3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinone analogues

Adel S El-Azab a,b,✉, Alaa A-M Abdel-Aziz a,c,✉, Hazem A Ghabbour a,c, Manal A Al-Gendy a
PMCID: PMC6010141  PMID: 28948843

Abstract

A novel series of 2-substituted mercapto-3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinones 1–20 was synthesised and evaluated for in vitro antitumour activity. N-(4-Chlorophenyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio)acetamide (7) and N-(3,4,5 trimethoxybenzyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]propanamide (19) exhibited excellent antitumour properties, with mean growth inhibitory concentration (GI50) of 17.90 and 6.33 µΜ, respectively, compared with those of 5-fluorouracil 5-FU, gefitinib, and erlotinib (mean GI50: 18.60, 3.24, and 7.29 µΜ, respectively). Comparison of the GI50 (µM) values of compounds 7 and 19 versus those of 5-FU, gefitinib, and erlotinib against an in vitro subpanel of tumour cells lines showed that compounds 7 and 19 have activities almost equal to or higher than that of those standard drugs, especially against lung, CNS, and breast cancer cells. However, compounds 5, 10, 14, 15, 16, 17, and 20 exhibited effective antitumour activity against the different cell lines tested, with growth inhibition percentage (MGI%) of 19, 24, 19, 17, 16, 15, and 16, respectively. A modelling study was performed for compounds 7 and 19 by docking them into the EGFR kinase enzyme to study their mode of binding with the putative binding site.

Keywords: Quinazoline, in vitro antitumour evaluation, EGFR, molecular docking

Introduction

Cancer refers to an abnormal growth of cells, and is the second leading cause of death worldwide1. Several of the current therapeutic agents have numerous side effects caused by their nonselective activity; therefore, the synthesis of safe and selective agents with a high therapeutic index is a vital research area. Quinazolinone nucleus is a characteristic bioactive scaffold present in several critical agents of biological interest2–29. Gefitinib and erlotinib (Figure 1) are known to contain a quinazoline nucleus and are effective in the treatment of breast and non-small cell lung (NSL) cancer via inhibition of epidermal growth factor receptor-tyrosine kinase (EGFR-TK)30,31. EGFR is over-expressed in numerous human tumours such as prostate, ovarian, breast, colon, and renal31–34. In our previously published studies10,11,15,18,19, the 2-mercaptoquinazoline analogue containing trimethoxyphenyl moiety showed significant antitumour activity such as 2-[(3-benzyl-6,7-dimethoxy-4(3H)-quinazolinon-2-yl)thio]-N-(3,4,5-trimethoxyphenyl)acetamide (A; GI50 = 7.24 µM), 2-[(3-benzyl-6-methyl-4(3H)-quinazolinon-2-yl)thio]-N-(3,4,5-trimethoxyphenyl)acetamide (B; GI50 = 14.12 µM), 2-[(3-phenethyl-4(3H)-quinazolinon-2-yl)thio]-N-(3,4,5-trimethoxyphenyl)acetamide (C; GI50 = 3.16 µM), 3-[(3-benzyl-6-methyl-4(3H)-quinazolinon-2-yl)thio]-N-(3,4,5-trimethoxyphenyl) propanamide (D; GI50 =14.12 µM) compared with that of the reference drug 5-fluorouracil (FU; mean GI50 18.60 µM; Figure 1). In this study, we designed several new 2-substituted mercapto-3-(3,4,5-trimethoxybenzyl)quinazolin-4(3H)-ones containing various alkyl, acetamide, and isopropanamide fragments at position 2 of the quinazoline core, with different electronic environments that would affect lipophilicity. The synthesised molecules 2–20 were evaluated for their in vitro antitumour activities at a single dose (10 µM; Figure 1). These hybrids were synthesised with an aim to develop effective and selective antitumour molecules.

Figure 1.

Figure 1.

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Structures of erlotinib, gefitinib, reported compounds A–D, and designed quinazoline derivatives E–H as antitumour agents.

Experimental

Chemistry

Melting points were recorded on a Barnstead 9100 electrothermal melting apparatus. IR spectra (KBr) were recorded on an FT-IR Perkin-Elmer spectrometer (ν cm−1). 1H and 13C NMR spectra were recorded on Bruker 500 or 700 MHz spectrometers using DMSO-d6 as the solvent. Microanalytical data (C, H, and N) were obtained using a Perkin-Elmer 240 analyser and the proposed structures were within ±0.4% of the theoretical values. Mass spectra were recorded on a Varian TQ 320 GC/MS/MS mass spectrometer. Data of compound 8 were collected on a Bruker APEX-II D8 Venture area diffractometer (Billerica, MA), equipped with graphite monochromatic Mo Kα radiation, λ = 0.71073 Å at 296 (2) K. Cell refinement and data reduction were carried out by Bruker SAINT. SHELXT35,36 was used to solve the structure.

2-Thioxo-3-(3,4,5-trimethoxybenzyl)-2,3-dihydroquinazolin-4(1H)-one (1)

A mixture of 3,4,5-trimethoxybenzyl isothiocyanate (11 mmol, 2.36 g), anthranilic acid (10 mmol, 1.37 g) and triethylamine (15 mmol, 1.51 g), was heated under reflux for 3 h in ethanol (20 ml). The reaction mixture was filtered while hot and the obtained solid was dried.

Yield: 86%; mp: 190–192 °C; IR (KBr, cm−1) ν: 1671 (C=O); 1H NMR (500 MHz, DMSO-d6): δ 13.04 (s, 1H), 7.98 (dd, 1H, J = 7.0 & 1.0 Hz), 7.77–7.70 (m, 1H), 7.42 (d, 1H, J = 8.0 Hz), 7.18 (t, 1H, J = 3.5 & 3.0 Hz), 6.86 (s, 2H), 3.72 (s, 6H), 3.61 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 48.9, 55.8, 59.9, 105.2, 115.4, 115.6, 124.5, 127.3, 132.3, 135.5, 136.7, 139.0, 152.6, 159.4, and 175.6; Anal. calcd. for C18H18N2O4S (%): C, 60.32; H, 5.06; N, 7.82. Found: C, 60.29; H, 5.08; N, 7.84; MS: [m/z, 358].

General procedure for the synthesis of compounds 2–13

A mixture of 2-thioxo-3-(3,4,5-trimethoxybenzyl)-2,3-dihydroquinazolin-4(1H)-one (1) (1 mmol, 358 mg) and appropriate alkylhalides or 2-chloro-N-(substituted)acetamides (1 mmol) in 10 ml acetone containing potassium carbonate (2 mmol, 277 mg) was stirred at room temperature for 10–12 h. The reaction mixture was filtered, the solvent removed, and the obtained solid was washed with water and dried.

2-(Methylthio)-3-(3,4,5-trimethoxybenzyl)quinazolin-4(3H)-one (2)

Yield: 93%; mp: 174–175 °C; IR (KBr, cm−1) ν: 1670 (C=O); 1H NMR (500 MHz, DMSO-d6): δ 8.13 (dd, 1H, J = 6.5 & 1.5 Hz), 7.85–7.75 (m, 1H), 7.59 (d, 1H, J = 8.0 Hz), 7.50–7.44 (m, 1H), 6.60 (s, 2H), 5.26 (s, 2H), 3.70 (s, 6H), 3.63 (s, 3H), 2.62 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 14.7, 47.0, 55.9, 59.9, 104.5, 118.6, 125.9, 125.9, 126.6, 131.3, 134.8, 136.9, 146.8, 152.9, 157.6, and 160.9; Anal. calcd. for C19H20N2O4S (%): C, 61.27; H, 5.41; N, 7.52. Found: C, 61.31; H, 5.39; N, 7.53; MS: [m/z, 372].

2-((2-Morpholinoethyl)thio)-3-(3,4,5-trimethoxybenzyl)quinazolin-4(3H)-one (3)

Yield: 88%; mp: 150–1152 °C; IR (KBr, cm−1) ν: 1683 (C=O); 1H NMR (500 MHz, CDCl3): δ 8.23 (d, 1H, J = 8.0 Hz), 7.69 (t, 1H, J = 7.5 Hz), 7.52 (d, 1H, J = 8.0 Hz), 7.38 (t, 1H, J = 7.5 Hz), 6.66 (s, 2H), 5.30 (s, 2H), 3.81 (s, 6H), 3.80 (s, 3H), 3.72–3.70 (m, 4H), 3.46–3.43 (m, 2H), 2.75–2.72 (m, 2H), 2.55–2.49 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 29.3, 40.6, 47.6, 53.5, 53.7, 56.1, 57.4, 60.7, 66.8, 66.9, 105.4, 106.5, 119.3, 125.7, 126.0, 127.1, 131.3, 134.4,137.6, 147.3, 152.9, 153.2, 156.5, and 161.9; MS: [m/z, 471].

2-((2-(Piperidin-1-yl)ethyl)thio)-3-(3,4,5-trimethoxybenzyl)quinazolin-4(3H)-one (4)

Yield: 89%; mp: 162–164 °C; IR (KBr, cm−1) ν: 1680 (C=O); 1H NMR (500 MHz, CDCl3): δ 8.18 (d, 1H, J = 7.0 Hz), 7.635 (d, 1H, J = 6.0Hz), 7.49 (d, 1H, J = 7.0 Hz), 7.33 (d, 1H, J = 6.0 Hz), 6.63 (s, 2H), 5.26 (s, 2H), 3.77 (s, 9H), 3.41 (s, 2H), 2.48 (s, 4H), 1.57 (s, 4H), 1.41 (s, 2H); 13C NMR (125 MHz, CDCl3): 60.7, 57.6, 56.1, 54.3, 47.6, 29.4, 25.7, 24.1, 119.2, 126.0, 125.6, 127.0, 131.3, 134.4, 137.7, 147.3, 152.8, 156.5, and 161.9; MS: [m/z, 469].

2-((4-Chlorobenzyl)thio)-3-(3,4,5-trimethoxybenzyl)quinazolin-4(3H)-one (5)

Yield: 91%; mp: 174–175 °C; IR (KBr, cm−1) ν:, 1671 (C=O); 1H NMR (500 MHz, CDCl3): δ 8.26 (dd, 1H, J = 7.0 & 1.0 Hz), 7.75 (t, 1H, J = 7.0 0 Hz), 7.63 (d, 1H, J = 8.0 Hz), 7.43–7.40 (m, 3H), 7.30 (s, 1H), 7.28 (d, 1H, J = 2.0 Hz), 6.62 (s, 2H), 5.29 (s, 2H), 4.53 (s, 2H), 3.83 (s, 3H), 3.78 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 161.9, 155.7, 153.2, 147.2, 137.6, 135.4, 134.5, 133.4, 131.1, 130.6, 128.7, 127.2, 126.0, 125.9, 119.4, 105.1, 60.8, 56.1, 47.6, and 35.8; Anal. calcd. for C25H23ClN2O4S (%):C, 62.17; H, 7.34; N, 5.80. Found: C, 61.22; H, 7.38; N, 5.78. MS: [m/z, 482; M + 1, 483].

2-((4-Oxo-3-(3,4,5-trimethoxybenzyl)-3,4-dihydroquinazolin-2-yl)thio)acetamide (6)

Yield: 81%; mp: 238–239 °C; IR (KBr, cm−1) ν: 3404 (NH), 1675, 1651 (C=O); 1H NMR (500 MHz, DMSO-d6): 8.30 (s, 1H), 8.12 (s, 1H), 7.81 (d, 1H, J = 5.0 Hz), 7.69 (s, 1H), 7.55 (d, 1H, J = 5.0 Hz), 7.47 (d, 1H, J = 5.5 Hz), 7.240 (d, 1H, J = 2.5 Hz), 6.66 (d, 1H, J = 6.0 Hz), 5.28 (s, 2H), 4.01 (d, 1H, J = 8.5 Hz), 3.73 (s, 6H), 3.66 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 168.5, 160.8, 156.6, 152.9, 146.7, 136.9, 134.7, 131.2, 126.6, 126.0, 118.7, 104.6, 59.9, 55.9, 47.2, and 35.7; MS: [m/z, 415].

N-(4-Chlorophenyl)-2-((4-oxo-3-(3,4,5-trimethoxybenzyl)-3,4-dihydroquinazolin-2-yl)thio)acetamide (7)

Yield: 84%; mp: 250–252 °C; IR (KBr, cm−1) ν: 3295 (NH), 1677, 1655 (C=O); 1H NMR (500 MHz, DMSO-d6): δ 10.47 (s, 1H), 8.10 (dd, 1H, J = 7.0 & 1.0 Hz), 7.70–7.72 (m, 1H), 7.62 (d, 2H, J = 9.0 Hz), 7.48 (d, 1H, J = 8.0 Hz), 7.45–7.40 (m, 1H), 7.30 (d, 2H, J = 8.5 Hz), 6.67 (s, 2H), 5.28 (s, 2H), 4.20 (s, 2H), 3.74 (s, 6H), 3.66 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 36.8, 47.2, 55.8, 59.9, 78.5, 78.8, 79.0, 104.7, 118.7, 120.5, 125.7, 125.8, 126.5, 127.0, 128.5, 131.0, 134.6, 137.0, 137.8, 146.6, 152.8, 156.3, 160.8, ανδ 165.6; Anal. calcd. for C26H24ClN3O5S (%): C, 59.37; H, 4.60; N, 7.99. Found: C, 59.32; H, 4.61; N, 7.80. MS: [m/z, 525, M + 1, 526].

N-(4-Fluorophenyl)-2-((4-oxo-3-(3,4,5-trimethoxybenzyl)-3,4-dihydroquinazolin-2-yl)thio)acetamide (8)

Yield: 83%; mp: 253–255 °C; IR (KBr, cm−1) ν: 3246 (NH), 1677, 1654 (C=O); 1H NMR (500 MHz, CDCl3): δ 9.72 (s, 1H), 8.34 (s, 1H), 7.84–7.28 (m, 5H), 6.96 (d, 2H, J = 5.0 Hz), 6.66 (s, 2H), 5.34 (s, 2H), 4.03 (s, 2H), 3.82 (s, 6H), 3.81 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 166.4, 161.4, 157.7, 153.4, 146.4, 138.0, 135.3, 133.9, 130.4, 127.9, 126.8, 125.0, 121.0, 115.8, 115.6, 105.5, 60.8, 56.2, 48.1, and 36.1; MS: [m/z, 509].

N-(4-Methoxyphenyl)-2-((4-oxo-3-(3,4,5-trimethoxybenzyl)-3,4-dihydroquinazolin-2-yl)thio)acetamide (9)

Yield: 85%; mp: 210–211 °C; IR (KBr, cm−1) ν: 3260 (NH) 1682, 1662 (C=O); 1H NMR (500MHz, CDCl3): δ 9.52 (s, 1H), 8.32 (d, 1H, J = 7.0 Hz), 7.82 (s, 1H), 7.66 (d, 1H, J = 7.5 Hz), 7.51 (d, 1H, J = 6.5 Hz), 7.34 (d, 2H, J = 8.5 Hz), 6.80 (d, 2H, J = 8.5 Hz), 6.66 (s, 2H), 5.33 (s, 2H), 4.03 (s, 2H), 3.82 (s, 6H), 3.80 (s, 3H), 3.76 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 166.1, 161.4, 157.6, 156.3, 153.4, 146.5, 137.9, 135.2, 131.0, 130.5, 127.8, 126.7, 125.1, 121.0, 119.5, 114.2, 105.4, 60.8, 56.2, 55.4, 48.1, and 36.1; MS: [m/z, 521].

2-((4-Oxo-3-(3,4,5-trimethoxybenzyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(3,4,5-trimethoxyphenyl)acetamide (10)

Yield: 83%; mp: 230–231 °C; IR (KBr, cm−1) ν: 3335 (NH), 1681, 1652 (C=O); 1H NMR (500 MHz, DMSO-d6): δ 8.27 (s, 1H), 8.15–8.10 (m, 1H), 7.80–7.76 (m, 1H), 7.58–7.53 (m, 1H), 7.46–7.42 (m, 1H), 7.01 (d, 2H, J = 20.5 Hz), 6.67 (d, 2H, J = 20.5 Hz), 5.29 (d, 2H, J = 19.0 Hz), 4.19 (d, 2H, J = 20.5 Hz), 3.78–3.63 (m, 18H); 13C NMR (125 MHz, DMSO-d6): δ 36.8, 47.2, 55.6, 55.8, 59.9, 60.0, 78.5, 78.84, 9.1, 96.8, 104.8, 118.8, 125.8, 126.6, 131.1, 133.5, 134.6, 134.9, 137.0, 146.7, 152.6, 152.9, 156.3, 160.8, and 165.2; MS: [m/z, 581].

2-((4-Oxo-3-(3,4,5-trimethoxybenzyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(4-sulfamoylbenzyl)acetamide (11)

Yield: 81%; mp: 288–290 °C; IR (KBr, cm−1) ν: 3327, 3236 (NH), 1693 (C=O); 1H NMR (500 MHz, DMSO-d6): δ 10.78 (s, 1H), 8.11–8.10 (m, 1H), 7.80–7.76 (m, 5H), 7.47–7.43 (m, 2H), 7.26 (s, 2H), 6.69 (s, 2H), 5.29 (s, 2H), 4.26 (s, 2H), 3.74 (s, 6H), 3.65 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 36.9, 47.3, 55.9, 59.9, 104.7, 118.6, 118.7, 125.7, 126.1, 126.6, 126.7, 131.2, 134.8, 136.9, 138.4, 141.8, 146.6, 152.9, 156.5, 160.8, and 166.3; MS: [m/z, 570].

2-((4-Oxo-3-(3,4,5-trimethoxybenzyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(3,4,5-trimethoxybenzyl)acetamide (12)

Yield: 84%; mp: 203–205 °C; IR (KBr, cm−1) ν: 3260 (NH), 1682, 1662 (C=O); 1H NMR (500 MHz, DMSO-d6): δ 8.72 (t, 1H, J = 7.5 & 0.5 Hz(, 8.10 (d, 1H, J = 8.0 Hz), 7.73 (t, 1H, J = 7.5 & 0.5 Hz), 7.48–7.44 (m, 2H), 6.65 (s, 2H), 6.55 (s, 2H), 5.28 (s, 2H), 4.25 (d, 2H, J = 6.0 Hz), 4.09 (s, 2H), 3.71 (s, 6H), 3.64 (s, 6H), 3.62 (s, 3H), 3.61 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 35.7, 42.9, 47.1, 55.6, 55.8, 59.9, 104.6, 104.7, 118.6, 125.9, 126.0, 126.5, 131.2, 134.7, 136.4, 136.9, 146.6, 152.7, 152.9, 156.5, 160.8, ανδ 166.7; Anal. calcd. for C30H33N3O8S (%):C, 60.49; H, 5.58; N, 7.05. Found: C, 60.51; H, 5.60; N, 7.03; MS: [m/z, 595].

2-((4-Oxo-3-(3,4,5-trimethoxybenzyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(4-sulfamoylbenzyl)propanamide (13)

Yield: 81%; mp: 278–280 °C; IR (KBr, cm−1) ν: 3308, 3200 (NH), 1676, 1656 (C=O); 1H NMR (500 MHz, DMSO-d6): δ 8.86 (s, 1H), 8.13 (d, 1H, J = 7.0 Hz), 7.82–7.29 (m, 9H), 6.65 (s, 2H), 5.29 (s, 2H), 4.40 (s, 2H), 4.04 (d, 2H, J = 4.0 Hz), 3.70 (s, 6H), 3.64 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 35.6, 42.2, 47.2, 55.8, 59.9, 104.6, 118.7, 125.5, 125.9, 126.1, 126.6, 127.2, 131.2, 134.8, 136.9, 142.5, 143.2, 146.6, 152.9, 156.5, 160.1, and 166.9; MS: [m/z, 584].

General procedure for the synthesis of compounds 14–20

A mixture of 2-thioxo-3-(3,4,5-trimethoxybenzyl)-2,3-dihydroquinazolin-4(1H)-one (1) (1 mmol, 358 mg) and appropriate 2-chloro-N-(substituted)propanamides (1 mmol) in 10 ml acetone containing potassium carbonate (2 mmol, 277 mg) was heated under reflux for 6–9 h. The reaction mixture was filtered while hot, the solvent was removed, and the obtained solid was washed with water and dried.

N-(4-Chlorophenyl)-2-((4-oxo-3-(3,4,5-trimethoxybenzyl)-3,4-dihydroquinazolin-2-yl)thio)propanamide (14)

Yield: 83%; mp: 222–224 °C; IR (KBr, cm−1) ν: 3253 (NH), 1685, 1655 (C=O); 1H NMR (500 MHz, DMSO-d6): δ 10.56 (s, 1H), 8.11 (dd, 1H, J = 7.0 & 1.0 Hz), 7.80 (t, 1H, J = 7.0 Hz), 7.66 (d, 2H, J = 9.0 Hz), 7.54 (d, 1H, J = 8.5 Hz), 7.46 (t, 1H, J = 7.0 Hz), 7.37 (d, 2H, J = 9.0 Hz), 6.64 (s, 2H), 5.24 (s, 2H), 4.76 (q, 1H, J = 9.0 Hz), 3.71 (s, 6H), 3.63 (s, 3H), 1.62 (d, 3H, J = 7.5 Hz); 13C NMR (125 MHz, DMSO-d6): δ 17.3, 46.5, 47.2, 52.0, 55.8, 59.9, 104.6, 118.8, 120.7, 125.7, 126.1, 126.6, 127.0, 128.6, 131.1, 134.8, 136.9, 137.8, 146.7, 152.9, 156.1, 160.7, and 169.5; MS: [m/z, 539, M + 1, 540].

N-(4-Fluorophenyl)-2-((4-oxo-3-(3,4,5-trimethoxybenzyl)-3,4-dihydroquinazolin-2-yl)thio)propanamide (15)

Yield: 82%; mp: 216–217 °C; IR (KBr, cm−1) ν: 3302 (NH), 1685, 1661 (C=O); 1H NMR (500 MHz, DMSO-d6): δ 10.50 (s, 1H), 8.10 (d, 1H, J = 9.0 Hz), 7.79 (d, 1H, J = 7.5 Hz), 7.65 (q, 2H, J = 5.0 & 4.0 Hz), 7.56 (d, 1H, J = 8.0 Hz), 7.46 (d, 1H, J = 7.5 Hz), 7.13 (t, 2H, J = 9.0 & 8.5 Hz), 6.65 (s, 2H), 5.25 (s, 2H), 4.76 (dd, 1H, J = 7.0 Hz), 3.71 (s, 6H), 3.64 (s, 3H), 1.63 (d, 3H, J = 7.0 Hz); [m/z, 523].

N-(4-Methoxyphenyl)-2-((4-oxo-3-(3,4,5-trimethoxybenzyl)-3,4-dihydroquinazolin-2-yl)thio)propanamide (16)

Yield: 84%; mp: 202–203 °C; IR (KBr, cm−1) ν: 3275 (NH), 1683, 1654 (C=O); 1H NMR (500 MHz, DMSO-d6): δ 10.29 (s, 1H), 7.81 (s, 1H), 8.11 (s, 1H), 7.57.47 (m, 3H), 6.89 (d, 2H, J = 4.0 Hz), 6.65 (d, 2H, J = 5.0 Hz), 5.25 (s, 2H), 4.76 (dd, 1H, J = 6.5 & 4.5 Hz), 3.71–3.64 (m, 12H), 1.62 (d, 3H, J = 6.5 Hz); 13C NMR (125 MHz, DMSO-d6): δ 17.6, 46.5, 47.2, 55.1, 55.9, 59.9, 104.6, 113.9, 118.8, 120.7, 120.9, 125.8, 126.1, 126.6, 131.1, 131.9, 134.8, 137.0, 146.7, 152.9, 155.4, 156.2, 160.7, and 168.7; MS: [m/z, 535].

2-((4-Oxo-3-(3,4,5-trimethoxybenzyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(3,4,5-trimethoxyphenyl)propanamide (17)

Yield: 83%; mp: 206–207 °C; IR (KBr, cm−1) ν: 3324 (NH), 1684, 1664(C=O); 1H NMR (500 MHz, CDCl3-DMSO-d6): δ 10.32 (s, 1H), 8.20 (s, 1H), 8.09 (d, 1H, J = 8.0 Hz), 7.76 (d, 1H, J = 8.0 Hz), 7.56 (d, 1H, J = 8.0 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.98 (s, 2H), 6.63 (s, 2H), 5.23 (s, 2H), 4.76 (dd, 1H, J = 7.5 Hz), 3.72 (s, 12H), 3.65 (s, 3H), 3.62 (s, 3H), 1.62 (d, 3H, J = 7.0 Hz); 13C NMR (125 MHz, CDCl3-DMSO-d6): δ 17.3, 46.4, 47.1, 55.5, 55.7, 59.8, 59.9, 96.8, 96.9, 104.6, 118.8, 125.7, 125.9, 126.5, 131.0, 133.5, 134.5, 134.8, 136.9, 146.7, 152.6, 152.8, 156.1, 158.3, 158.5, 160.7, and 169.0; MS: [m/z, 595].

2-((4-Oxo-3-(3,4,5-trimethoxybenzyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(4-sulfamoylphenyl)propanamide (18)

Yield: 81%; mp: 218–220 °C; IR (KBr, cm−1) ν: 3360, 3297 (NH), 1687, 1664 (C=O); 1H NMR (500 MHz, DMSO-d6): δ 10.78 (s, 1H), 8.10 (d, 1H, J = 7.0 Hz), 7.87–7.78 (m, 5H), 7.52 (d, 1H, J = 8.5 Hz), 7.46 (t, 1H, J = 7.5 & 8.0 Hz), 7.27 (s, 2H), 6.65 (s, 2H), 5.24 (d, 2H, J = 5.5 Hz), 4.78 (d, 1H, J = 7.0 Hz), 3.72 (s, 6H), 3.65 (s, 3H), 1.63 (d, 3H, J = 7.5 Hz); 13C NMR (125 MHz, DMSO-d6): δ 17.1, 46.6, 47.2, 55.8, 59.9, 104.6, 118.7, 120.7, 125.7, 126.1, 126.4, 126.6, 126.7, 131.1, 134.8, 136.9, 138.6, 139.8, 146.6, 152.9, 156.1, 160.7, and 170.0; [m/z, 584].

2-((4-Oxo-3-(3,4,5-trimethoxybenzyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(3,4,5-trimethoxybenzyl)propanamide (19)

Yield: 83%; mp: 262–264 °C; IR (KBr, cm−1) ν: 3237 (NH), 1684, 1663 (C=O); 1H NMR (700 MHz, DMSO-d6): δ 8.84–8.77 (m, 2Η), 8.11 (d, 0.5H, J = 5.5 Hz), 7.76 (t, 0.5H, J = 5.5 Hz), 7.51–7.45 (m, 1H), 6.62 (s, 1H), 6.59 (s, 2H), 6.53 (s, 1H), 5.24 (s, 1H), 4.73–4.70 (m, 0.4H), 4.60–4.57 (m, 0.6H), 4.32–4.20 (m, 3H), 3.75–3.60 (m, 18H), 1.59–1.57 (m, 3H); 13C NMR (175 MHz, DMSO-d6): δ 18.4, 21.7, 42.8, 43.1, 46.1, 47.6, 54.8, 55.9, 56.1, 56.2, 60.3, 60.4, 104.6, 104.7, 104.8, 119.2, 126.4, 126.6, 127.0, 131.7, 134.9, 135.1, 135.2, 136.7, 136.8, 137.3, 147.2, 153.2, 153.3, 153.4, 156.6, 161.3, 169.2, and 170.9; MS: [m/z, 609]. Anal. calcd. for C31H35N3O8S (%): C, 61.07; H, 5.79; N, 6.89.Found: C, 61.12; H, 5.81; N, 6.91.

2-((4-Oxo-3-(3,4,5-trimethoxybenzyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(4-sulfamoylbenzyl)propanamide (20)

Yield: 81%; mp: 174–175 °C; IR (KBr, cm−1) ν: 3371, 3253 (NH), 1685, 1663 (C=O); 1H NMR (500 MHz, DMSO-d6): δ 8.93 (s, 1H), 8.11 (d, 1H, J = 1.0 Hz), 7.82–7.80 (m, 1H), 7.64 (d, 2H, J = 8.5 Hz), 7.55–7.49 (m, 2H), 7.38 (d, 2H, J = 8.5 Hz), 7.29 (s, 2H), 6.61 (s, 2H), 5.24 (s, 2H), 4.69 (d, 1H, J = 7.5 Hz), 4.40–4.35 (m, 2H), 3.68 (s, 6H), 3.63 (s, 3H), 1.57 (d, 3H, J = 7.5 Hz); 13C NMR (125 MHz, DMSO-d6): δ 17.8, 42.1, 45.6, 47.1, 55.8, 59.9, 104.4, 118.7, 125.5, 125.7, 125.9, 126.2, 126.5, 127.2, 127.3, 131.2, 134.8, 136.8, 142.5, 143.1, 146.7, 152.8, 156.1, 160.8, and 170.7; MS: [m/z, 598].

X-ray crystallography

Data of compound 8 were collected on a Bruker APEX-II D8 Venture area diffractometer, equipped with graphite monochromatic Mo Kα radiation, λ = 0.71073 Å at 296 (2) K. Cell refinement and data reduction were carried out by Bruker SAINT. SHELXT35,36 was used to solve the structure. The final refinement was carried out by full-matrix least-squares techniques with anisotropic thermal data for non-hydrogen atoms on F. CCDC 1534954 contains the supplementary crystallographic data for this compound and can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Antitumour screening

The antitumour evaluation was performed in nearly 60 human tumour cell lines obtained from nine organs, according to the rules of the Drug Evaluation Branch, NCI, Bethesda, MD37–41.

Docking methodology

All modelling experiments were conducted with MOE 2007.9 of the Chemical Computing Group Inc. (Montreal, Canada)42,43. The starting coordinates of the X-ray crystal structure of the EGFR enzyme in complex with erlotinib (pdb code 1M17) were obtained from the RCSB Protein Data Bank44.

Results and discussion

Chemistry

2-thioxo-3-(3,4,5-trimethoxybenzyl)-2,3-dihydroquinazolin-4(1H)-one (1) was obtained at 86% yield by heating 2-aminobenzoic acid with 3,4,5-trimethoxybenzyl isothiocyanate in ethanol containing triethylamine (Scheme 1). The confirmation of compound 1 exists as thione tautomer in the solid-state according to X-ray of quinazoline analogue45,46 due to the dimeric aggregates are connected into layers by C=H···O interactions, involving the bifurcated carbonyl-O atom, and C—H···S interactions45,46.

Scheme 1.

Scheme 1.

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Synthesis of new quinazoline conjugates 1–20.

The thione tautomer was confirmed by presence of singlet signal at 13.04ppm, corresponding to NH group and unique signal at 175.6 ppm related to C=S according to 1H NMR and 13C NMR spectra. Additionally, NMR spectra of compound 1 revealed three characteristic signals related to trimethoxybenzyl group at 59.9, 55.8, 48.9, 5.60, 3.72, and 3.68 ppm. Accordingly, compound 1 was stirred at room temperature with various halides (such as methyl iodide, 4-(2-chloroethyl)morpholine, 1-(2-chloroethyl)piperidine, and 4-chlorobenzylchloride) in acetone containing potassium carbonate to give 2-(substituted alkylthio)-3-(3,4,5-trimethoxybenzyl)quinazolin-4(3H)-ones 2–5 analogues at 88–93% yield (scheme 1). The 1H NMR spectra of compounds 2–5 showed loss of the NH group of the parent compound at 13.04 ppm, and a new signal related to s-alkyl moiety was observed at 4.61–2.62 ppm in the 1H NMR spectra and at 14.7–35.8 ppm in the 13C NMR spectra of these compounds.

Compound 1 was also stirred with various 2-chloro-N-(substituted)acetamides and 2-chloro-N-(substituted)propanamides in acetone containing potassium carbonate to give N-(substituted)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)quinazolinon-2-yl)thio]acetamides 6–13 and N-(substituted)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)quinazolinon-2-yl)thio]propanamides 14–20 at 81–86% yield (Scheme 1).

Compounds 6–13 were confirmed based on their 1H NMR spectra, which showed the presence of singlet signals at 10.78–8.30 ppm and 4.26–4.01 ppm attributable to –SCH2CONH– and –SCH2CONH– groups, respectively, in addition to characteristic signals of trimethoxybenzyl moieties at 5.34–5.28 ppm and 3.82–3.61 ppm. Similarly, 13C NMR spectra showed the presence of signals for –SCH2CONH– at 36.9–35.6 ppm and –SCH2CONH– groups at 168.5–165.2 ppm, accompanied by the characteristic signals of a trimethoxybenzyl moiety at 60.8–47.1 ppm and the carbonyl group of the parent quinazoline moiety at 161.4–160.1 ppm.

Based on the 1H NMR spectra, compounds 14–20 were recognised by the presence of signals for SCH2CONH– at 10.78–8.93 ppm, –SCH(CH3)CONH– groups at 4.78–4.69 ppm, and a typical peak for a SCH(CH3)CONH– moiety at 1.63–1.57 ppm, in addition to the classic signal of a trimethoxybenzyl moiety at 5.25–3.62 ppm. Simultaneously, these compounds were confirmed based on their 13C NMR spectra, which showed signals of –SCH(CH3)CONH–, –SCH(CH3)CONH–, and SCH(CH3)CONH– groups at 45.6–46.6, 17.1–17.8, and 169.0–170.8ppm, respectively, as well as the definitive signals of the trimethoxybenzyl and carbonyl groups of the parent quinazoline moiety at 47.1–59.9 and 160.6–160.8, respectively.

X-ray crystallography

The crystallographic data and refinement information of compound 8 are summarised in Tables S1–S3. The asymmetric unit is comprised of one independent molecule as shown in Figures S1 and S2. All the bond lengths and angles are in normal ranges47. In the crystal structure, the central quinazolin-4(3H)-one plane makes dihedral angles of 62.97° and 68.48° with the trimethoxybenzyl and flurophenyl groups, respectively, in different directions. The crystal packing was formed by three intermolecular interactions between N3=H1N3•••O2, C9=H9A•••O1, and C9=H9B•••O2 with bond lengths 2.07 (3), 2.35, and 2.31 Å and bond angles 158(3)°, 143°, and 144°, respectively.

Antitumour activity

Evaluation of the in vitro antitumour activity of the new synthesised compounds indicated in Table 1 was performed by the National Cancer Institute, Bethesda, MA. A single dose (10 µM) of the test compounds 2–20 was used in the full NCI 60 Human Tumor Cell Line Panel assay37–41.

Table 1.

Percentage growth inhibition (GI %) of in vitro subpanel tumour cell lines at 10 µM concentration.

  % Growth Inhibition (GI %)
                        
Subpanel tumour cell lines 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 5-FU
Leukaemia
CCRF-CEM 12 – – 24 – 17 – – – – – – 21 14 23 – – 65 – 57.1
K-562 27 nt 13 38 – 55 14 21 – 21 nt – 37 30 29 15 12 92 nt 42.3
MOLT-4 12 17 – 51 – 54 – 32 11 12 – – 38 51 39 22 – 82 – 43.1
PRMI-8226 30 – – 42 – 72 – 14 – – – – 33 26 17 13 – 61 – 41.4
SR 17 – – 44 – 54 – 18 34 12 – – 39 44 24 37 20 89 – 24.8
Non-small cell lung cancer
 A549/ATCC – – – 15 – 36 – – 38 – – – 19 17 15 14 14 65 14 34.2
 HOP-62 35 13 – 11 – 46 36 – 58 – – 16 15 18 16 21 – 71 64 47.8
 NCI-H226 26 13 12 37 13 L – 12 43 34 – 12 18 21 23 27 21 30 21 69.5
 HOP-92 – – – 24 – 61 – 42 61 – – – 36 45 40 41 43 56 39 50.6
 NCI-H23 – – – 15 11 28 38 – 23 – – – 13 – 11 – – 49 – 39.0
 NCI-H322M – – – – – 36 – – 18 – – – 28 19 13 11 – 40 – 59.5
 NCI-H460 – – –   – 83 – – 43 – – – – – – – – 87 20 13.0
 NCI-H522 29 22 32 49 11 60 27 44 67 30 19 17 51 47 40 32 30 90 62 58.0
Colon cancer
 COLO 205 – – – 27 – – – – – – – – – – – – – 75 – 40.2
 HCC-2998 – nt – – – – – – – – – – – – – – – 14 21 >100
 HCT-116 18 – – 44 – 65 – 11 42 14 – – 44 35 31 16 24 84 – 17.8
 HCT-15 – – – 31 – 28 – 11 – – – – 27 21 24 12 – 83 – 26.5
 HT29 – – – 41 – 13 – – – – – – 13 14 – – – 88 – 27.1
 KM12 – – – – – 21 – – – – – – – – – – – 83 – 40.7
 SW-620 – – – 12 – 23 – – – – – – – – – – – 77 – 50.1
CNS cancer
 SF-268 – – 14 – – 44 13 15 46 – – 18 23 20 19 12 – 50 18 59.0
 SF-295 23 – – – – 38 –   15 – –   16 12 – – – 64 – 69.1
 SF-539 13 – – – – L – 22 34 – – – 14 16 16 – – 75 42 >100
 SNB-19 – – – 19 – 37 –   26 16 – – 21 20 23 18 17 45 33 65.9
 SNB-75 22 15 27 34 12 73 52 34 L 27 11 21 26 20 36 34 36 83 77 65.9
 U251 – – – – – 25 – – 48 – – – 12 – – – – 62 14 50.3
Melanoma
 LOX IMVI – – – 13 – 44 – – – – – – 12 – – – – 56 – 30.4
 MALME-3M – – – – – 91 – 14 18 12 – – 17 – – 17 13 60 13 58.2
 M14 – – – 14 – 26 – – – – – – 14 – – 11 – 94 – –
 MDA-MB-435 – – – – – 31 – – – – – – – – – – – L – 36.6
 SK-MEL-2 – – – 25 – 19 – – 25 – – – 19 19 17 – – L 15 95.5
 SK-MEL-28 – – – – – 17 12 – – – – – – – – 13 – 45 – –
 SK-MEL-5 20 – – 15 – 51 11 13 – – – – 12 16 18 20 18 88 21 33.7
 UACC-257 – – – – – 27 – – – – – – – – – 15 13 41 13 19.5
 UACC-62 25 – – 32 – 37 15 26 16 23 14 – 31 24 32 27 26 64 21 39.7
Ovarian cancer
 IGROV1 – – – 24 – 59 – – 28 11 – – 14 23 23 22 24 49 – 51.2
 OVCAR-4 34 – 30 37 – 47 28 18 11 15 – – 23 15 30 26 23 42 12 59.4
 OVCAR-5 – – – – – 18 – – 12 – – – – – – – – 32 – 44.3
 OVCAR-8 – – 15 15 – 38 20 – 20 – – 13 15 16 14 – 14 52 – –
 NCI/ADR-RES 22 – – 22 – 49 – 17 – – – – 19 17 14 – – 83 – 47.6
 SK-OV-3 – – – – – 32 13 – 49 – – – – – – – – 73 43 77.5
Renal cancer
 786-0 – – – – – L –   27 – – – 11 – – – – 44 – 48.7
 A498 – – – – 18 59 – 13 38 20 12 – 36 37 29 29 – 79 – >100
 ACHN 19 – 13 15 – 82 17 20 67 – – – 16 19 15 15 18 52 13 39.3
 CAKI-1 25 – – 22 – 29 – – – – – – 29 26 14 11 – 66 – 39.4
 RXF 393 – – – – – 81 22 18 39 – – – 23 26 22 26 – 47 34 34.3
 SN12C 20 – 12 31 – 29 – 21 18 12 – – 28 18 25 18 16 50 15 54.0
 TK-10 – – – 0 – 33 16 – 33 – – – – – – – – 38 – 66.9
 UO-31 41 32 16 48 27 83 20 27 20 25 28 13 52 47 46 49 31 53 17 41.3
Prostate cancer
 PC-3 18 – – 41 13 35 – 15 13 – – – 28 25 25 17 19 51 – 58.2
 DU-145 – – – – – 34 – – – – – – – – –   – 42 – 35.5
Breast cancer
 MCF7 – – – 21 – 23 13 – – – – – 16 – 13 11 18 85 17 11.5
 MDA-MB-231/ATCC 25 14 11 36 13 51 14 27 42 19 – 19 36 35 37 37 30 54 35 78.1
 HS 578T – – 13   – 93 13 – 52 – – – 20 14 12 20 – 43 22 >100
 BT-549 – – –   – 25 – 11 35 – – – 19 – – 12 – 52 30 37.8
 T-47D 14 – 15 36 – 55 – 16 23 – 11 – 15 23 32 24 – 91 36 56.7
 MDA-MB-468 30 – – 24 – 53 15 – 28 16 – 12 – 12 15 48 38 99 61 –
 MGI% 11 2 4 19 2 47 7 10 24 7 2 1 19 17 16 15 10 65 16  
 PCE 24/57 7/55 13/57 36/57 8/57 55/57 20/57 26/57 38/57 17/57 6/56 9/57 44/57 37/57 38/57 36/57 23/57 57/57 29/56 55/59
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PCE: positive cytotoxic effect; the ratio between the number of cell lines with percentage growth inhibition >10% and total number of cell lines. MGI%: mean growth inhibition percentage; nt = not tested; L= >100%

The in vitro screening of compounds 2–20 at 10 µM showed that compounds 2, 4, 5, 7–11, and 14–20 exhibited remarkable antitumour activities against the tested cell lines with positive cytotoxic effects (PCE) of 24/57, 13/57, 36/57, 55/57, 20/57, 26/57, 38/57, 17/57, 44/57, 37/57, 38/57, 36/57, 57/57, 23/57, and 29/56, respectively, compared with that of 5-FU (55/59) (Table 1). Conversely, compounds 3, 6, 12, and 13 showed weak activities against the tested cell lines with PCE of 7/55, 8/57, 6/56, and 9/57, respectively (Table 1).

2-(Substituted alkylthio)-3-(3,4,5-trimethoxybenzyl)quinazolin-4(3H)-ones 2–5 and 2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]acetamide (6) showed variable antitumour activities with MGI % of 2–19 (Table 1).

N-(Substituted)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]acetamides 7–13 showed mild to potent antitumour activities with MGI % ranging from 7 to 47, while N-(substituted)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)quinazolinon-2-yl)thio]propanamides 14–20 showed potent antitumour activities with MGI % ranging from 10 to 65 (Table 1).

Compounds 3, 4, 6, 8, 11, 12, and 13 showed selective activity against different cancer cell lines. Compounds 3, 4, 11, 12, and 13 showed selective activity against the NCI-H522 cancer cell line, with a range of growth inhibition percentage (RGI %) of 17–32, while compounds 3, 6, 11, and 12 had selectivity against the UO-31 cancer cell line with RGI % of 25–32. The SNB-75 cancer cell line was sensitive to compounds 4, 11, and 12 with RGI % of 21–27, whereas the MDA-MB-468 cancer cell line was sensitive to compounds 11 and 13 with RGI % of 16–19. The A498 cancer cell line was sensitive to compounds 6 and 11 with RGI % of 18–20, while the K-562, NCI-H226, UACC-62, and MDA-MB-231/ATCC cancer cell lines were susceptible to compound 11 with RGI % of 19–34. The MOLT-4, OVCAR-4, and SF-268 cancer cell lines were susceptible to compounds 3, 4, and 13 with RGI % of 17–30. The prostate cancer cell line PC-3 showed selective sensitivity to compounds 2, 5, 7, and 14–18 with RGI % of 18–51; whereas compounds 7 and 19 showed selective activities with RGI % of 34–42 against the DU-145 prostate cell line (Table 1).

Furthermore, compounds 2, 5, 7, 9, 10, and 14–20 showed potent activity against leukaemia, NSL cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, and breast cancer cell lines with RGI % of 12–92, 16 –>100, 18–88, 13 –>100, 16 –>100, 16–83, 16 –>100, and 14–99, respectively (Table 1).

The MGI% data revealed that compounds 7 and 19 were the most active, with antitumour activity against numerous cell lines belonging to diverse tumour subpanels (Table 1). Therefore, these compounds were tested against a panel of 57 tumour cell lines at a 5-log dose range37–41 and the median growth inhibitory (GI50), total growth inhibitory (TGI), and median lethal (LC50) concentrations were calculated for each cell line (Table 2).

Table 2.

Median growth inhibitory (GI50, μM), total growth inhibitory (TGI, μM), and median lethal (LC50, μM) concentrations of compounds 7 and 19 on in vitro subpanel tumour cell lines.

  Subpanel tumour cell lines
  
Compd. Activity Leukaemia NSC lung cancer Colon cancer CNS cancer Melanoma Ovarian cancer Renal cancer Prostate cancer Breast cancer MG-MIDa
7 GI50 68.28 8.11 30.82 4.33 12.26 8.86 5.76 17.40 5.30 17.90
  TGI b 40.56 85.81 15.28 57.06 37.30 30.41 b 30.46 55.20
  LC50 b 80.22 89.76 46.10 78.12 80.95 64.80 b 84.75 80.52
19 GI50 4.57 8.95 5.47 4.62 5.25 8.07 6.62 9.03 4.47 6.33
  TGI 93.44 63.45 73.35 63.85 49.74 56.50 65.06 b 70.50 70.65
  LC50 b 96.36 88.55 64.62 b 92.75 b b b 93.58
5-FU GI50 15.10 b 8.40 72.10 70.60 61.40 45.60 22.70 76.40 18.60
  TGI b b b b b b b b b b
  LC50 b b b b b b b b b b
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a

Full panel mean-graph midpoint (μM).

b

Compounds showed values >100 μM.

Compounds 7 and 19, compared with 5-FU, exhibited remarkable GI50 activities against leukaemia (68.28, 4.57, and 15.10 µM, respectively), NSL cancer (8.11, 8.95, and 100 µM), colon cancer (30.82, 5.47, and 8.40 µM), CNS cancer (4.33, 4.62, and 72.10 µM), melanoma cancer (12.26, 5.25, and 70.60 µM), ovarian cancer (8.86, 8.07, and 61.40 µM), renal cancer (5.76, 6.62, and 45.60 µM), prostate cancer (17.40, 9.03, and 22.70 µM), and breast cancer (5.30, 4.47, and 76.40 µM) (Table 2).

Additionally, comparing the median GI50 values (µM) of compounds 7 and 19 with those of 5-FU, gefitinib, and erlotinib against an in vitro subpanel of tumour cell lines showed that compounds 7 and 19 had activities almost equal to or higher than these known drugs against most cell lines (Table 3).

Table 3.

GI50 values (μM) of compounds 7 and 19 compared with those of erlotinib, gefitinib, and 5-FU on in vitro subpanel tumour cell lines.

Subpanel tumour cell lines     GI50 (μM)    
  7 19 Erlotinib Gefitinib 5-FU
Leukaemia
CCRF-CEM 4.91 >100 15.84 5.01 31.62
HL-60(TB( 3.57 >100 5.01 5.01 19.95
MOLT-4 7.38 >100 5.01 3.98 12.58
RPMI-8226 4.00 22.90 5.01 1.58 5.01
SR 3.01 18.05 6.30 3.16 3.98
Non-small cell lung cancer
 A549/ATCC 6.33 4.66 7.94 7.94 1.99
 HOP-62 4.36 3.10 12.58 10.00 19.95
 HOP-92 5.70 2.26 6.30 7.94 >100
 NCI-H226 14.60 4.00 6.30 15.84 >100
 NCI-H23 6.87 16.5 19.95 15.84 12.58
 NCI-H322M 23.00 19.1 0.05 0.08 19.95
 NCI-H460 4.19 10.4 5.01 6.30 1.00
 NCI-H522 6.55 4.89 1.00 6.30 39.81
Colon cancer
 COLO 205 5.32 73.20 31.62 6.30 nt
 HCC-2998 13.00 26.60 79.34 10.00 nt
 HCT-116 3.76 4.04 5.01 7.94 nt
 HCT-15 2.47 17.00 3.16 5.01 nt
 KM12 3.98 32.30 63.09 7.94 nt
 SW-620 4.31 31.80 5.01 7.94 nt
CNS cancer
 SF-268 7.13 6.62 19.95 7.94 nt
 SF-295 4.36 5.55 15.84 1.99 nt
 SF-539 2.86 2.29 12.58 10.00 nt
 SNB-19 6.00 6.80 3.98 12.58 nt
 SNB-75 2.06 1.58 12.58 6.30 nt
 U251 5.34 3.14 19.95 10.00 79.43
Melanoma
 LOX IMVI 7.05 13.50 5.01 7.94 6.30
 M14 2.23 16.50 6.30 5.01 50.11
 MDA-MB-435 1.15 22.80 15.84 3.16 10.00
 SK-MEL-2 2.82 15.20 12.58 12.58 >100
 SK-MEL-28 6.69 11.40 31.62 0.31 50.11
 SK-MEL-5 2.85 6.38 15.84 3.98 12.58
 UACC-257 16.30 6.04 100 6.30 >100
 UACC-62 2.92 6.29 1.25 5.01 12.58
Ovarian cancer
 IGROV1 13.20 19.00 0.25 0.20 15.84
 OVCAR-3 4.23 7.86 3.16 5.01 25.11
 OVCAR-4 10.80 3.01 19.95 7.94 79.43
 OVCAR-5 9.38 14.80 19.95 10.00 >100
 OVCAR-8 10.00 4.82 7.94 10.00 19.95
 NCI/ADR-RES 3.59 8.37 6.30 12.58 39.81
 SK-OV-3 5.34 4.20 0.39 0.63 >100
Renal cancer
 786-0 5.10 3.37 5.01 7.94 12.58
 A498 4.05 2.42 1.58 0.40 10.00
 ACHN 8.09 3.15 0.15 0.20 10.00
 CAKI-1 5.46 11.30 0.10 0.16 5.01
 RXF 393 5.31 2.59 6.30 5.01 50.11
 SN12C 8.10 16.90 6.3 6.30 25.11
 TK-10 11.00 2.63 0.10 0.10 >100
 UO-31 5.90 3.75 1.99 1.25 5.01
Prostate cancer
 PC-3 10.80 16.70 50.11 0.79 5.11
 DU-145 7.27 18.10 1.58 2.51 50.11
Breast cancer
 MCF7 3.46 8.97 100 10.00 1.99
 MDA-MB-231/ATCC 5.36 3.08 1.99 12.58 >100
 HS 578T 5.24 3.95 6.30 10.00 >100
 BT-549 4.90 6.42 39.81 7.94 100
 T-47D 5.52 2.16 3.16 6.30 79.43
 MDA-MB-468 2.35 7.22 0.20 0.01 31.62
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nt: not tested.

Structure-activity relationships

Structure activity relationships for antitumour activities with MGI % indicated that (i) 2-benzylmercapto-4(3H)-quinazolinone 5 showed higher antitumour activity (MGI%: 19%) than did the 2-alkylmercapto-4(3H)-quinazolinone derivatives such as compounds 2–4 (MGI%: 2–11%); (ii) N-(substituted phenyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]acetamide analogues 7–11 (MGI%: 7–47%) and N-(substituted)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]propanamide analogues 14–20 are more active than unsubstituted 2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]acetamide (6); (iii) the antitumour activity of N-(substituted)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]propanamide analogues 14–20 is improved compared to that of N-(substituted)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]acetamide analogues 6–13 except compounds 7 and 10; (iv) the structure-activity correlation of N-(substituted)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]acetamide analogues 6–13 revealed that N-(4-chlorophenyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]acetamide (7) (MGI%; 47%) is more active than the corresponding N-(4-flourophenyl)acetamide 8 (MGI%; 7%); similarly, N-(3,4,5-trimethoxyphenyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]acetamide (10) (MGI%; 24%) is more active than the corresponding N-(4-methoxyphenyl)acetamide 9 (MGI%; 10%). In addition, N-(4-methoxyphenyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]acetamide (9) (MGI%: 10%) is more active than the corresponding N-(4-sulfamoylphenyl)acetamide 11 (MGI%: 7%); (v) The less active compounds in this series are N-(3,4,5-trimethoxybenzyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]acetamide (12) (MGI%; 2%) and N-(4-sulfamoylbenzyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]acetamide (13) (MGI%: 1%). Additionally, structure-activity correlation of N-(substituted)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]propanamide analogues 14–20 indicates that: (i) N-(4-chlorophenyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]propanamide (14) (MGI%: 19%) is more active than the corresponding N-(4-flourophenyl)propanamide 16 (MGI%: 17%); (ii) N-(3,4,5-trimethoxyphenyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]propanamide (17) (MGI%: 15%) has the same antitumour activity as the corresponding N-(4-methoxyphenyl)propanamide 16 (MGI%: 16%); (iii) N-(4-methoxyphenyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]propanamide (16) (MGI%: 16%) is more active than the corresponding N-(4-sulfamoylphenyl)propanamide 18 (MGI%: 10%); (iv) N-(3,4,5-trimethoxybenzyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]propanamid (19) (MGI%: 65%) is more active than the corresponding N-(4-sulfamoylbenzyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]propanamid (20) (MGI%: 16%).

Molecular docking results

EGFR are tyrosine kinase enzymes that are overexpressed in numerous tumours such as colon, prostate, breast, ovarian, renal, and NSL cancers31–34,48. The inhibition of tyrosine kinase by quinazoline derivatives such as gefitinib and erlotinib (Figure 1) is well documented30,31. Accordingly, the antitumour activity of the target compounds against colon, prostate, breast, ovarian, renal, and NSL cancers encouraged us to study the molecular docking of the compounds into the putative binding site on EGFR kinase. In this study, the most active compounds 7 (mean GI50: 17.90 µΜ) and 19 (mean GI50:6.33 µΜ) were docked into the putative active site of EGFR kinase, as well as the reference inhibitor erlotinib (mean GI50: 7.29 µΜ)44. All docking calculations were performed using MOE 2007.09 software (MOE of Chemical Computing Group Inc., Montreal, Canada)42.

The binding energies of the docked compounds 7, 19, and erlotinib (PDB code; 1M17)44 into the putative binding site of EGFR were −22.11, −25.21, and −26.99 kcal/mol, respectively (Figure 2). The molecular docking of the most active compound 19 revealed that it had similar orientation to erlotinib inside the receptor pocket, as well as additional bonding interactions. The docking results showed six typical and atypical hydrogen bonds with surrounding amino acids as shown in Figure 2. The trimethoxybenzyl fragment at C-3 of the quinazoline core formed bifurcated hydrogen bonds with amino acids Lys721. Moreover, the 4-quinazolinone ring uniquely formed two hydrogen bonds with the distinctive residues Met769 and Thr766, similar to that observed in erlotinib (Figure 2). Additionally, the carbonyl group of the acetanilide fragment of compound 19 formed bifurcated hydrogen bonds with the amino acid residue Cys773 and Gly772 augmenting the recognition within the enzyme binding site (Figure 2 and Table 4).

Figure 2.

Figure 2.

Open in a new tab

Three-dimensional (3D) interactions of erlotinib (upper panel), compounds 19 (middle panel) and 7 (lower panel) with the receptor pocket of EGFR kinase. Hydrogen bonds are shown with a green line.

Table 4.

Results of the docking of compounds 7 and 19 into EGFR (pdb: 1m17), in comparison to the co-crystallised ligand (erlotinib).

Ligand no. No. of HBsa Atoms in H-bonding in the ligand Atoms in H-bonding in protein Lengthb (Å)
7 4 O of 3,4,5-timethoxyphenyl NH of Lys721 2.65, 2.82
    O of quinazoline-4-one HOH10 linked to Thr766 2.70
    O of carbonyl anilide NH of Gly772 2.74
19 6 O of 3,4,5-timethoxyphenyl NH of Lys721 2.70, 2.71
    O of quinazoline-4-one HOH10 linked to Thr766 2.75
    O of carbonyl anilide NH of Gly772 2.90
    O of carbonyl anilide SH of Cys773 3.26
    Ar-H of quinazoline O of Pro770 3.04
Erlotinib 4 N1 of quinazoline NH of Met769 2.90
    N3 of quinazoline HOH10 linked to Thr766 2.83
    Ar-H of quinazoline NH of Leu768 3.42
    6-ring of anilino group NH of Lys721 4.58
Open in a new tab
a

HBs: hydrogen bonds;

b

Length among acceptor and donner atoms in angstrom (Å).

Similar to compound 19, compound 7 binds with four hydrogen bonds. It was found that the trimethoxybenzyl group at C-3 of the quinazoline core was clearly recognised with hydrogen bonding to the amino acid residue Lys721 similar to compound 19, while the quinazoline core was shifted away from the distinctive amino acid residue Met769 (Figure 2). Additionally, two hydrogen bonds with the amino acid residue Gly772 and the distinctive residue Thr766 were found (Figure 2). It is obvious that the molecular docking results can be used to design novel quinazoline derivatives with potential binding to EGFR kinase and antitumour activity (Table 4).

Conclusions

A novel series of 2-substituted mercapto-3-[3,4,5-trimethoxybenzyl]-4(3H)-quinazolinones 1–20, was synthesised and evaluated for in vitro antitumour activity. Compounds 7 and 19 showed strong antitumour activities with mean GI50 values of 17.90 and 6.33 µM, TGI of 55.20 and 70.65 µM, and LC50 of 80.52 and 93.58 µM; these values were compared with the reference drug 5-FU (GI50: 22.60 µM, TGI: 100 µM, and LC50: 100 µM). Comparing the median GI50 (µM) of 5-FU, gefitinib, and erlotinib with that of compounds 7 and 19 showed that compounds 7 and 19 showed antitumour activities almost equal to or higher than that of the known drugs against most subpanel tumour cell lines. A molecular docking study for compounds 7 and 19 into the ATP binding site of EGFR-TK showed similar binding as that of erlotinib.

Supplementary Material

IENZ_1368504_Supplementary_Material.pdf
IENZ_A_1368504_SM9929.pdf (576.7KB, pdf)

Funding Statement

The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through the research group project No. RG-1435–046.

Disclosure statement

No potential conflict of interest was reported by the authors.

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Supplementary Materials

IENZ_1368504_Supplementary_Material.pdf
IENZ_A_1368504_SM9929.pdf (576.7KB, pdf)

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