Synthesis, antitumor activity and molecular docking study of some novel 3-benzyl-4(3H)quinazolinone analogues

Article abstract of DOI:10.3109/14756366.2015.1004059

A novel series of 3-benzyl-substituted-4(3H)-quinazolinones were designed, synthesized and evaluated for their in vitro antitumor activity. The results of this study demonstrated that 2-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide, 2-(3-benzyl-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide and 3-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)-propanamide have shown amazing broad spectrum antitumor activity with mean GI₅₀ (10.47, 7.24 and 14.12 μM. respectively), and are nearly 1.5-3.0-fold more potent compared with the positive control 5-FU with mean GI₅₀, 22.60 μM. On the other hand, compounds 6 and 10 yielded selective activities toward CNS, renal and breast cancer cell lines, whereas compound 9 showed selective activities towards leukemia cell lines. Molecular docking methodology was performed for compounds 7 and 8 into ATP binding site of EGFR-TK which showed similar binding mode to erlotinib, while compound 11 into ATP binding site of B-RAF kinase inhibited the growth of melanoma cell lines through inhibition of B-RAF kinase, similar to PLX4032.

Full text of DOI:10.3109/14756366.2015.1004059

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2015 Informa UK Ltd. DOI: 10.3109/14756366.2015.1004059
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RESEARCH ARTICLE
Synthesis, antitumor activity and molecular docking study of some
novel 3-benzyl-4(3H)quinazolinone analogues
Ibrahim A. Al-Suwaidan1, Alaa A.-M. Abdel-Aziz1,2, Taghreed Z. Shawer3, Rezk R. Ayyad3, Amer M. Alanazi1,
Ahmad M. El-Morsy4, Menshawy A. Mohamed4,5, Naglaa I. Abdel-Aziz2, Magda A.-A. El-Sayed6, and
Adel S. El-Azab1,4
1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, 2Department of Medicinal Chemistry,
Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt, 3Department of Pharmaceutical Chemistry, and 4Department of Organic Chemistry,
5
Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt, Department of Pharmaceutical Chemistry, College of Pharmacy, Salman Bin Abdulaziz
University, AlKharj, Saudi Arabia, and 6Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura,
Egypt
Abstract
Keywords
A novel series of 3-benzyl-substituted-4(3H)-quinazolinones were designed, synthesized and
evaluated for their in vitro antitumor activity. The results of this study demonstrated that 2-(3-
benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide,
2-(3-benzyl-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)
acetamide and 3-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxy-
phenyl)-propanamide have shown amazing broad spectrum antitumor activity with mean GI50
(10.47, 7.24 and 14.12 mM. respectively), and are nearly 1.5–3.0-fold more potent compared with
the positive control 5-FU with mean GI50, 22.60 mM. On the other hand, compounds 6 and 10
yielded selective activities toward CNS, renal and breast cancer cell lines, whereas compound 9
showed selective activities towards leukemia cell lines. Molecular docking methodology was
performed for compounds 7 and 8 into ATP binding site of EGFR-TK which showed similar
binding mode to erlotinib, while compound 11 into ATP binding site of B-RAF kinase inhibited
the growth of melanoma cell lines through inhibition of B-RAF kinase, similar to PLX4032.
5-FU, erlotinib, in vitro antitumor evaluation,
molecular docking, NCI, quinazoline
History
Received 31 October 2014
Revised 21 December 2014
Accepted 21 December 2014
Published online 27 March 2015
Introduction
Quinazolines are frequently used in medicine because of their
wide spectrum of biological activities5–11. In the course of
identifying various chemical substances which may serve as leads
for designing novel antitumor agents, we are particularly inter-
ested in the present work with quinazoline derivatives which have
been identified as a new class of cancer chemotherapeutic agents
with significant therapeutic efficacy against solid tumors10,11. It is
well known that quinazoline derivatives are potent inhibitors of
epidermal growth factor receptor (EGFR)12–17. The EGFR is
cellular trans-membrane tyrosine kinases that are over-expressed
in a significant number of human tumors (e.g., breast, ovarian,
colon, renal, and prostate)18,19. Overexpression of EGFR family
receptors have been observed in these tumors, approximately in
60% of all tumors. A number of small molecule EGFR kinase
inhibitors have been evaluated in cancer clinical trials12–19. For
example (Figure 1), anilinoquinazoline-containing compounds
gefitinib (IressaTM),13c–19 erlotinib (TarcevaTM),15a lapatinib
(TykerbTM, also known as GW-572016) and Vandetanib
(ZactimaTM) were recently approved for the treatment of breast
cancer and non-small-cell lung cancer15b–17. On the other hand,
melanoma is the most aggressive type of skin cancer in which
V600E-B-RAF kinase is over-expressed in 63% of all malignant
melanomas20a. Vemurafenib (PLX4032) is a drug which targets
inhibition of V600E-B-RAF kinase20a. In 2011, it was approved
by the U.S. Food and Drug Administration (FDA) for the
treatment of late-stage melanoma, so inhibition of V600E-B-RAF
Cancer is a disease characterized by a shift in the controlled
mechanisms that govern cell proliferation and differentiation1.
Malignancy is caused by abnormalities in cells, which might be
due to inherited genes or caused by outside exposure of the body
to chemicals, radiation, or even infectious agents2,3. Several
techniques have been adopted for the treatment and eradication of
cancerous cells. These techniques involved surgery, radiation,
immunotherapy, chemotherapy and chemoprevention. Ideal antic-
ancer drugs would eradicate cancer cells without harming normal
tissues. Unfortunately, no currently available agents meet this
criterion, and clinical use of drugs involves a weighing of benefits
against toxicity in a search of favorable therapeutic index4. Many
of chemotherapeutic agents currently used in cancer therapy are
agents which inhibit tumor growth by inhibiting the replication
and transcription of DNA. The wide occurrence of the hetero-
cycles in bioactive natural products made them important
synthetic targets. Quinazolines represent a class of heterocyclic
compounds of great importance in biological chemistry5–11
.
Address for correspondence: Adel S. El-Azab, Pharmaceutical Chemistry
Department, College of Pharmacy, P.O. Box 2457, King Saud University,
Riyadh-11451, Saudi Arabia. Tel: +966 14679096. Fax: +966 1 467-
6383. E-mail: adelazaba@yahoo.com

2
I. A. Al-Suwaidan et al.
J Enzyme Inhib Med Chem, Early Online: 1–12
Large fragment
Fragment replacement
O
HN
O
O
N
Small Lipophilic fragment insersion
N
N
S
O
Erlotinib; A
Cl
N
N
Large fragment
F
Fragment replacement
O
N
CH
3
Cl
HN
N
Lipophilic Aromatic insersion
New scaffold for small
molecular antitumor
O
O
N
E; reported quinazoline IC = 3.35 µg/ml (MCF-7)
50
Gefitinib; B
Lead optimization
O
F
Large fragment
Cl
HN
N
O O
S
Fragment insertion
N
O
O
H
N
N
Fragment replacement
N
S
Lapatinib; C
HN
O
n
Cl
O
O
NH
Large fragment insertion
H N
2
O
O
OH
Salicylanilide; D
F; designed quinazolines
Figure 1. Reported and designed quinazoline derivatives as antitumor.
very potential avenue for the treatment of recorded on Bruker 700 MHz or 500 MHz spectrometer using
kinase is
a
melanoma20a. Moreover, a series of salicylanilides were synthe- DMSO-d6 or CDCl3 as solvents at Research Center, King Saud
sized and their inhibitory activity against tyrosine kinases was University, Riyadh, Saudi Arabia. The chemical shifts are expressed
determined. Some of them indeed have proven to be potent and in d ppm using TMS as internal standard. Mass spectra were
selective EGFR tyrosine kinase inhibitors20b (Figure 1). Many recorded on a Perkin-Elmer, Clarus 600T GC/MS, or VarianTQ 320
more compounds are still under evaluation in clinical trials for the GC/MS/MS mass spectrometers at Research Center, King Saud
treatment of cancer18b,19
.
University, Riyadh, Saudi Arabia. Single crystal X-ray crystallog-
Continuing our studies on quinazoline derivatives as attractive raphy was recorded on Bruker APEXII CCD diffractometer at
candidates as antitumor agents10b,11a,20b, we have designed a Chemistry Department, University of Malaya, Kuala Lumpur,
number of new quinazoline derivatives containing benzyl group Malaysia and structure refinement and resolvewas carried out using
with different fragments and biologically evaluated the in vitro SHELXS9721a. Solvent evaporation was performed under reduced
antitumor activities (Figure 1). In the present study, the substitution pressure using Buchan Rotatory Evaporator at the Pharmaceutical
pattern at the 6 and 7 positions of quinazoline pharmacophore was Chemistry Department, King Saud University, Riyadh, Saudi
selected so as to confer different electronic environment that would Arabia. Thin-layer chromatography was performed on precoated
affect the lipophilicity, and hence the activity of the target (0.25 mm) silica gel GF254 plates (E. Merck, Germany); com-
molecules. The objectives of forming these hybrids are an attempt pounds were detected with 254 nm UV lamp. Silica gel (60–230
to reach an active antitumor agent with potentiated activity and mesh) was employed for routine column chromatography separ-
selectivity toward cancerous cells. Molecular docking method- ations. Compounds 1–3 and 14–15 were prepared according to
ology was used to identify the structural features required for the reported procedure11b, while compounds 13 and 21 were prepared
antitumor properties of these new series.
according to the reported method7a,21b respectively.
Materials and methods
General procedure for the synthesis of 3-benzyl-2-mercapto-
substitutedquinazolin-4(3H)-one (1–4)
Chemistry
Melting points were recorded on Barnstead 9100 Electrothermal
melting apparatus at the Pharmaceutical Chemistry Department,
King Saud University, Riyadh, Saudi Arabia. IR spectra (KBr) were
recorded on a FT-IR Perkin-Elmer spectrometer (ꢀ cmꢀ1) at
Research Center, King Saud University, Riyadh, Saudi Arabia.
Nuclear magnetic resonance (1H and 13C NMR) spectra were
A
mixture of substituted anthranilic acid (10 mmol) and
benzylisothiocyanate (10 mmol, 1.49 g) in 30 ml absolute ethanol
containing triethylamine (11 mmol, 1.1 g) was heated under reflux
for 2 h. The reaction mixture was filtered while hot, the solvent
was removed under reduced pressure and the solid obtained was
dried and recrystallized from ethanol.

DOI: 10.3109/14756366.2015.1004059
3-Benzyl-4(3H)quinazolinone analogues
3
3-Benzyl-2-mercaptoquinazolin-4(3H)-one (1)
2-(3-Benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-
ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide (7)
1
Yield 95%, m.p. 240–242 ꢁC, H NMR (700 MHz, DMSO-d6):
ꢁ 13.06 (s, 1H), 7.96 (d, 1H, J ¼ 15.34 Hz), 7.75 (t, 1H, Yield 87%, m.p; 199–200 ꢁC; IR (KBr, cmꢀ1) ꢀ: 3310 (NH),
J ¼ 14.0 Hz), 7.43 (d, 1H, J ¼ 15.34 Hz), 7.34–7.29 (m, 5H), 1685, 1654 (CO); 1H NMR (500 MHz, DMSO-d6): ꢁ 9.94 (s, 1H),
7.24 (d, 1H, J ¼ 12.5 Hz), 5.67 (s, 2H). 13C NMR (175 MHz, 8.13 (s, 1H), 7.62 (s, 2H), 7.38–7.30 (m, 5H), 6.73 (s, 2H), 5.42
DMSO-d6): ꢁ49.2, 115.9, 116.2, 125.0, 127.4, 127.6, 127.8, 128.7, (s, 2H), 3.97 (s, 2H), 3.79 (s, 3H), 3.75 (s, 6H), 2.63 (s, 3H). 13C
136.1, 137.0, 139.6, 159.8, 176.0.
NMR (125 MHz, DMSO-d6): ꢁ 21.3, 36.3, 47.8, 56.0, 61.0, 96.9,
119.3, 124.7, 127.4, 127.8, 128.1, 128.8, 134.1, 134.5, 134.9,
136.3, 137.1, 144.5, 153.3, 157.0, 161.4, 166.4. MS: (M, 505).
3-Benzyl-6-chloro-2-mercaptoquinazolin-4(3H)-one (2)
1
Yield 95%, m.p. 248–251 ꢁC; H NMR (700 MHz, DMSO-d6):
2-(3-Benzyl-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-
2-ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide (8)
ꢁ 13.17 (s, 1H), 7.88 (s, 1H), 7.80 (d, 1H, J ¼ 8.36 Hz), 7.34
(d, 1H, J ¼ 16.73 Hz), 7.33–7.24 (m, 4H), 7.23 (s, 1H), 5.65 (s,
2H). 13C NMR (175 Hz, DMSO-d6): ꢁ 49.3, 117.3, 118.4, 126.7,
127.4, 127.7, 128.6, 128.9, 136.0, 136.8, 138.4, 159.0, 175.9.
Yield 86%, m.p. 205–206 ꢁC; IR (KBr, cmꢀ1) ꢀ: 3304 (NH),
1677, 1656 (CO); 1H NMR (500 MHz, DMSO-d6): ꢁ 9.71 (s, 1H),
7.63 (s, 1H), 7.37–7.34 (m, 5H), 7.04 (s, 1H), 6.73 (s, 2H), 5.42
(s, 2H), 4.00 (s, 2H), 3.98 (s, 6H), 3.78 (s, 3H), 3.74 (s, 6H).13C
NMR (125 MHz, DMSO-d6): ꢁ 36.2, 47.8, 56.0, 56.4, 56.5, 61.0,
97.0, 105.6, 106.6, 112.7, 127.7, 128.0, 128.8, 134.1, 134.7,
135.0, 142.8, 148.9, 153.4, 155.6, 155.7, 160.9, 166.4. MS:
(M, 551).
3-Benzyl-2-mercapto-6-methylquinazolin-4(3H)-one (3)
1
Yield 95%, m.p. 259–261 ꢁC; H NMR (700 MHz, DMSO-d6):
ꢁ 13.01 (s, 1H), 7.75 (s, 1H), 7.58 (d, 1H, J ¼ 15.34 Hz), 7.34–
7.29 (m, 5H), 7.23 (s, 1H), 5.67 (s, 2H), 2.35 (s, 3H). 13C NMR
(175 Hz, DMSO-d6): ꢁ 20.9, 49.1, 115.7, 116.1, 127.1, 127.3,
127.5, 128.6, 134.7, 137.1, 137.2, 137.6, 159.8, 175.5.
3-(3-Benzyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-
trimethoxyphenyl)propanamide (9)
3-Benzyl-2-mercapto-6,7-dimethoxyquinazolin-4(3H)-one (4)
Yield 90%, m.p. 195–196 ꢁC; IR (KBr, cmꢀ1) ꢀ: 3292 (NH),
1685, 1662 (CO); 1H NMR (500 MHz, DMSO-d6): ꢁ 10.40
(s, 1H), 8.12 (d, 1H, J ¼ 7.5 Hz), 7.83 (t, 1H, J ¼ 7.0, 7.5 Hz), 7.61
(d, 1H, J ¼ 8.0 Hz), 7.48 (t, 1H, J ¼ 7.5 Hz), 7.36–7.27 (m, 5H),
7.01 (s, 2H), 5.33(d, 2H, J ¼ 7.0 Hz), 4.74 (d, 1H, J ¼ 6.5 Hz),
3.73 (s, 6H), 3.61 (s, 3H), 1.60 (s, 3H).13C NMR (125 MHz,
DMSO-d6): ꢁ 17.7, 46.7, 47.0, 55.6, 60.0, 97.0, 118.8, 125.8,
126.2, 126.6, 126.7, 127.4, 128.6, 133.6, 134.9, 135.5, 146.7,
152.7, 156.2, 160.8, 169.0. MS: (M, 505).
Yield 82%, m.p. 268–270 ꢁC; IR (KBr, cmꢀ1) ꢀ: 3180 (NH), 1684
(CO), 1251 (CS); 1H NMR (500 MHz, DMSO-d6): ꢁ 12.86
(s, 1H), 7.30–6.94 (m, 7H), 5.66 (s, 2H), 3.85 (s, 6H). 8.04 (d, 1H,
J ¼ 1.5 Hz), 7.82 (d, 2H, J ¼ 8.0 Hz), 7.68 (d, 1H, J ¼ 8.5 Hz),
7.37–7.22 (m, 2H), 2.33 (s, 3H, CH3). 13C NMR (125 MHz,
DMSO-d6): ꢁ 48.6, 55.7, 56.0, 97.7, 106.7, 107.9, 126.8,
127.1, 128.1, 135.0, 136.8, 146.7, 155.3, 158.8, 174.3. MS:
(M, 328).
General procedure for the synthesis of compounds 5–12
3-(3-Benzyl-6-chloro-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-
(3,4,5-trimethoxyphenyl)propanamide (10)
A mixture of appropriate 2-mercapto-3-benzylquinazolin-4(3H)-
one (1) (2 mmol) and/or the appropriate 2-chloro-N-phenylaceta-
mide and/or phenyl 2-chloroacetate (2 mmol) in 15 ml acetone
containing anhydrous potassium carbonate (3 mmol, 415 mg) was
stirred at room temperature for 10–12 h. The reaction mixture was
filtered, the solvent was removed under reduced pressure and the
solid obtained was dried and recrystallized from ethanol.
Yield 89%, m.p. 196–198 ꢁC; IR (KBr, cmꢀ1) ꢀ: 3307 (NH),
1683, 1663 (CO); 1H NMR (500 MHz, DMSO-d6): ꢁ 10.41
(s, 1H), 8.04 (s, 1H), 7.88 (d, 1H, J ¼ 7.0 Hz), 7.69 (d, 1H,
J ¼ 7.0 Hz), 7.43–7.28 (m, 5H), 7.0 (s, 2H), 5.31 (s, 2H), 4.71
(d, 1H, J ¼ 6.5 Hz), 3.71 (s, 6H), 3.60 (s, 3H), 1.58 (d, 3H,
J ¼ 6.5 Hz). 13C NMR (125 MHz, DMSO-d6): ꢁ 17.6, 48.8, 47.2,
55.6, 60.1, 96.8, 120.0, 125.6, 126.8, 127.5, 128.0, 128.6, 130.2,
133.5, 134.9, 135.0, 135.2, 145.4, 152.7, 157.0, 159.9, 169.0. MS:
(M, 539, M + 2, 541).
2-(3-Benzyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-
trimethoxyphenyl)acetamide (5)
Yield 92%, m.p; 201–203 ꢁC; IR (KBr, cmꢀ1) ꢀ: 3287 (NH),
1674, 1655 (CO); 1H NMR (500 MHz, DMSO-d6): ꢁ 9.88 (s, 1H),
8.34 (d, 1H, J ¼ 7.5 Hz), 7.80 (t, 1H, J ¼ 7.0 Hz), 7.70 (d, 1H,
J ¼ 8.0 Hz), 7.51 (t, 1H, J ¼ 7.0 Hz), 7.40–7.31 (m, 5H), 6.73 (s,
2H), 5.42 (s, 2H), 3.99 (s, 2H), 3.78 (s, 3H), 3.74 (s, 6H). 13C
NMR (125 MHz, DMSO-d6): ꢁ 36.3, 47.8, 56.0, 61.0, 96.8, 119.6,
124.8, 126.7, 127.8, 128.0, 128.1, 128.8, 134.1, 134.5, 134.7,
135.0, 146.4, 153.3, 158.0, 161.3, 166.3. MS: (M, 491).
3-(3-Benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-
(3,4,5-trimethoxyphenyl)propanamide (11)
Yield 85%, m.p 217–219 ꢁC; IR (KBr, cmꢀ1) ꢀ: 3293 (NH), 1686,
1662 (CO); 1H NMR (500 MHz, DMSO-d6): ꢁ 10.42 (s, 1H), 7.91
(s, 1H), 7.62 (d, 1H, J ¼ 7.0 Hz), 7.51 (d, 1H, J ¼ 7.0 Hz), 7.43–
7.25 (m, 5H), 7.01 (s, 2H), 5.30 (s, 2H), 4.72 (d, 1H, J ¼ 6.5 Hz),
3.72 (s, 6H), 3.60 (s, 3H), 2.42 (s, 3H), 1.58 (d, 3H, J ¼ 6.5 Hz).
13C NMR (125 MHz, DMSO-d6): ꢁ 17.6, 20.7, 46.6, 46.8, 55.6,
60.0, 96.8, 118.5, 125.7, 125.9, 126.7, 127.4, 128.6, 133.5, 135.0,
135.6, 136.0, 136.2, 144.9, 152.9, 155.1, 160.7, 169.1. MS:
(M, 519).
2-(3-Benzyl-6-chloro-4-oxo-3,4-dihydroquinazolin-2-
ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide (6)
Yield 88%, m.p. 190–192 ꢁC; IR (KBr, cmꢀ1) ꢀ: 3243 (NH),
1663, 1650 (CO); 1H NMR (500 MHz, DMSO-d6): ꢁ 9.48 (s, 1H),
8.28 (s, 1H), 7.71 (dd, 1H, J ¼ 7.0, 1.5 Hz), 7.62 (d, 1H,
J ¼ 8.5 Hz), 7.37–7.31 (m, 5H), 6.71 (s, 2H), 5.41 (s, 2H), 3.99
(s, 2H), 3.79 (s, 3H), 3.76 (s, 6H). 13C NMR (125 MHz, DMSO-
d6): ꢁ 36.3, 48.0, 56.0, 61.0, 97.0, 120.6, 126.6, 127.2, 127.8,
128.2, 128.8, 132.4, 133.9, 134.5, 134.7, 135.3, 145.0, 153.3,
158.1, 160.4, 166.0. MS: (M, 526 and M + 2, 528).
3-(3-Benzyl-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-
ylthio)-N-(3,4,5-trimethoxyphenyl)propanamide (12)
Yield 84%, m.p; 150–152 ꢁC; IR (KBr, cmꢀ1) ꢀ: 3275 (NH),
1684, 1670 (CO); H NMR (500 MHz, DMSO-d6): ꢁ 10.34 (s,
1
1H), 7.43–7.27 (m, 7H), 7.05 (s, 2H), 5.31 (s, 2H), 4.69 (s, 3H),
3.87 (s, 3H), 3.83 (s, 3H),3.72 (s, 3H), 3.61 (s, 1H), 3.51 (s, 3H),

4
I. A. Al-Suwaidan et al.
J Enzyme Inhib Med Chem, Early Online: 1–12
1.59 (s, 3H).13C NMR (125 MHz, DMSO-d6): ꢁ 17.6, 46.5, 2-(3-Benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N0-
46.8,55.6, 55.7, 60.1, 96.8, 105.6, 106.7, 11.6, 126.7, 127.4, (2-methoxybenzylidene)acetohydrazide (18)
128.5, 133.6, 135.1, 135.7, 143.1, 148.2, 152.7, 154.1, 155.0,
1
Yield 90%; m.p. 203–205 ꢁC; H NMR (700 MHz, DMSO-d6),
160.1, 169.2. MS: (M, 565).
11.79 (s, 0.36 H), 11.60 (s, 0.64 H), 8.61 (s, 0.36 H), 8.40
(s, 0.64 H), 7.90 (s, 1H), 7.82 (d, 0.64 H, J ¼ 11.15 Hz), 7.77 (d,
Ethyl 2-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-
0.36, J ¼ 12.55 Hz), 7.63 (d, 0.36 H, J ¼ 13.94 Hz), 7.60 (d, 0.64
ylthio)acetate (14)
H, J ¼ 13.94 Hz), 7.45 (d, .036, J ¼ 13.94 Hz), 7.40 (d, 0.64 H,
A mixture of 3-benzyl-2-mercapto-6-methylquinazolin-4(3H)-one J ¼ 13.94 Hz), 7.35–7.34 (m, 6H), 7.31 (d, 1H, J ¼ 11.15 Hz), 7.30
(3) (10 mmol, 2.82 g) ethyl 2-bromoacetate (11 mmol, 1.84 g), and (d, 0.36 H, J ¼ 5.76 Hz), 7.29 (d, 0.64, J ¼ 25.1 Hz), 5.36 (s, 2H),
anhydrous potassium carbonate (12 mmol, 1.66 g) in (100 ml) dry 4.55 (s, 1.2 H), 4.06 (s, 0.8 H), 3.86 (s, 3H), 2.42 (s, 3H). 13C
acetone was stirred at room temperature for 6 h. The reaction NMR (175 MHz, DMSO-d6): ꢁ 21.2, 34.3, 47.3, 56.2, 112.3,
mixture was filtered, the solvent was removed under reduced 118.9, 121.1, 122.5, 125.9, 126.3, 127.2, 127.8, 129.0, 131.8,
pressure, and the solid obtained was dried and recrystallized from 132.0, 136.1, 136.6, 139.5, 142.6, 145.3, 155.7, 155.9, 158.1,
ethanol. Yield 95%; m.p; 130–133 ꢁC; 1H NMR (700 MHz, 161.2, 163.8, 169.1.
DMSO-d6), ꢁ 7.90 (s, 1H), 7.64 (d, 1H, J ¼ 12.55 Hz), 7.38
(d, 1H, J ¼ 12.55 Hz), 7.34 (d, 2H, J ¼ 9.76 Hz), 7.428 (s, 3H,),
2-(3-Benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-
(4-oxo-2-phenylthiazolidin-3-yl)acetamide (19)
5.33 (s, 2H), 4.13 (q, 3H, J ¼ 9.76 Hz), 4.08 (s, 2H), 2.43 (s, 3H),
1.19 (s, 3H). 13C NMR (175 MHz, DMSO-d6): ꢁ 14.6, 21.2, 34.6,
A solution of 2-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-
47.4, 61.5, 118.8, 126.2, 126.4, 127.2, 127.9, 129.0, 136.0, 136.4,
136.7, 145.2, 155.5, 161.2, 168.7. MS: (M, 368).
2-ylthio)-N0-benzylideneacetohydrazide (16) (0.5 mmol, 221 mg)
in acetic acid (10 ml) was refluxed for 12 h with thiglycolic acid
(3 mmol, 271 mg). The reaction mixture was cooled, the solvent
was removed under reduced pressure; the residue was neutralized
2-(3-Benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)
acetohydrazide (15)
with 10% sodium carbonate solution. The solid obtained was
filtered, dried and recrystallized from acetic acid. Yield 61%; m.p.
A solution of the ethyl 2-(3-benzyl-6-methyl-4-oxo-3,4-dihydro-
quinazolin-2-ylthio)acetate (14) (3.68 g, 0.01 mol) and hydrazine
hydrate (85 %, 3 ml) in ethanol (40 ml) was heated under reflux
for 2 h. The obtained solid was filtered, dried, and recrystallized
1
207–209 ꢁC; H NMR (700 MHz, DMSO-d6), 11.44 (s, 1H), 7.95
(d, 1H, J ¼ 8.36 Hz), 7.64 (d, 1H, J ¼ 13.95 Hz), 7.52–7.11 (m,
11H), 5.34 (s, 2H), 5.09 (s, 2 H), 4.38–4.30 (m, 1H), 3.94–3.88
(m, 1H), 3.76–3.59 (m, 1H), 2.46 (s, 3H). 13C NMR (175 MHz,
DMSO-d6): 20.7, 21.2, 25.3, 43.6, 46.7, 114.0, 115.6, 120.0,
126.1, 126.7, 126.9, 127.1, 127.3, 127.4, 127.5, 127.7 127.9,
128.7, 128.8, 129.4, 136.2, 136.6, 137.0, 137.7, 137.9, 145.6,
150.6, 154.6, 161.9, 162.4. MS: (M, 516).
1
from ethanol. Yield 95%, m.p. 207–210 ꢁC; H NMR (700 MHz,
DMSO-d6): ꢁ 9.36 (s, 1H), 7.91 (s, 1H), 7.66 (d, 1H,
J ¼ 13.94 Hz), 7.50 (d, 1H, J ¼ 15.34 Hz), 7.38–7.27 (m, 5H),
5.34 (s, 2H), 4.35 (s, 2H), 3.93 (s, 2H), 2.44 (s, 3H).13C NMR
(175 MHz, DMSO-d6) ꢁ21.2, 35.0, 47.3, 118.9, 126.3, 126.4,
127.2, 127.9, 129.0, 136.1, 136.3, 136.6, 145.2, 155.5, 161.3,
166.6. MS: (M, 354).
2-Mercapto-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-5-one (20)
2-(3-Benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N0-
substituted benzylideneacetohydrazide (16–18)
A solution of 3-benzyl-2-mercaptoquinazolin-4(3H)-one (13)
(354 mg, 1 mmol), carbon disulphide (760 mg, 10 mmol) and
potassium hydroxide (170 mg, 3 mol) in ethanol (10 ml) was
stirred at room temperature for 4 h the reaction mixture was
heated under reflux for 6 h. The reaction mixture was cooled and
the solvent was evaporated under reduced pressure. The solid
obtained was dissolved in water, acidified with concentrated
hydrochloric acid; the solid obtained was filtered, washed with
water, dry and crystallized from ethanol. Yield 90%; m.p. 198–
A solution of acid hydrazide 15 (1 mmol, 354 mg) in methanol
(10 mL) and the appropriate aldehyde (1 mmol) was stirred at
room temperature for 12–15 h. The reaction mixture was washed
with hexane, filtered and dried.
2-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N’-
benzylideneacetohydrazide (16)
1
200 ꢁC; H NMR (500 MHz, DMSO-d6): ꢁ 14.72 (s, 1H), 7.55 9
1
Yield 92%; m.p. 225–227 ꢁC; H NMR (700 MHz, DMSO-d6): ꢁ
(d, 1H, J ¼ 7.5 Hz), 7.28 (t, 1H, J ¼ 7.0 Hz), 6.90 (d, 1H,
J ¼ 8.0 Hz), 6.68 (t, 1H, J ¼ 7.5 Hz), 13C NMR (125 MHz,
DMSO-d6): ꢁ 101.1, 113.7, 114.0, 125.0, 130.7, 145.1, 158.6,
173.8. MS: (M, 235).
11.81 (s, 0.37 H), 11.65 (s, 0.63 H), 8.27 (s, 0.37 H), 8.07 (s, 0.63
H), 7.90 (s, 1H), 7.70 (s, 2H), 7.63–7.59 (m, 1H), 7.45–7.41
(m, 3H), 7.35–7.32 (m, 6H), 5.36 (s, 2H), 4.56 (s, 1.2 H), 4.09
(s, 0.8 H), 2.41 (s, 3H). 13C NMR (175 MHz, DMSO-d6) ꢁ21.2,
34.3, 47.3, 118.9, 126.3, 126.4, 127.2, 127.3, 127.5, 127.9, 129.0,
129.3, 130.5, 134.6, 136.1, 136.3, 136.6, 143.8, 145.3, 147.1,
155.7, 161.1, 164.0, 169.0, MS: (M, 422).
2-(Methylthio)-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-
5-one (21)
A solution of 2-mercapto-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-
5-one (20) (470 mg, 2 mmol), in 10 ml acetone containing
anhydrous potassium carbonate (3 mmol, 415 mg) was stirred
with iodomethane (426 mg, 3 mmol) at room temperature for 6 h.
The reaction mixture was filtered, the solvent was removed under
reduced pressure, and the solid obtained was washed with water,
dried and recrystallized from ethanol. Yield 76%; m.p. 96–98 ꢁC;
1H NMR (500 MHz, CDCl3): ꢁ 8.42 (d, 1H, J ¼ 7.5 Hz), 7.79
(t, 1H, J ¼ 7.0 Hz), 7.63 (d, 1H, J ¼ 8.0 Hz), 7.49 (t, 1H,
J ¼ 7.0 Hz), 2.84 (s, 3H), 13C NMR (125 MHz, CDCl3):
ꢁ ¼ 15.3, 118.9, 126.2, 127.6, 134.8, 147.2, 156.2, 157.1, 158.5.
MS: (M, 249).
2-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N0-
(2-fluorobenzylidene)acetohydrazide (17)
1
Yield 92%; m.p. 219–221 ꢁC; H NMR (700 MHz, DMSO-d6): ꢁ
11.95 (s, 0.33 H), 11.76 (s, 0.67 H), 8.50 (s, 0.33 H), 8.28 (s, 0.67
H), 7.90 (s, 2H), 7.63–7.59 (m, 1H), 7.47–7.45 (m, 1H), 7.35–7.20
(m, 8H), 5.36 (s, 2H), 4.56 (s, 1.2 H), 4.08 (s, 0.8 H), 2.41 (s, 3H).
13C NMR (175 MHz, DMSO-d6) ꢁ21.2, 34.2, 37.3, 116.5, 118.9,
122.1, 125.3, 125.4, 126.4, 126.7, 126.8, 127.2, 127.8, 127.9,
129.1, 132.2, 136.1, 136.2, 136.6, 155.8, 160.5, 161.9, 164.1,
169.3. MS: (M, 460).

DOI: 10.3109/14756366.2015.1004059
3-Benzyl-4(3H)quinazolinone analogues
5
Antitumor screening
dihydroquinazolin-2-ylthio)acetate (14), which was treated with
hydrazine hydrate in ethanol at room temperature to fur-
nish 2-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)
acetohydrazide (15) as key intermediate in 90% yield. Schiff’s
bases 16–18 were obtained in 90–92% yields, by reaction of the
acid hydrazide 15 with various aldehydes in methanol at room
temperature, compound 16 was subjected cyclization via boiling
with acetic acid containing thioglycolic acid to give 2-phenylthia-
A primary anticancer assay was performed for an approximately
60 human tumor cell line panel derived from nine neoplastic
diseases, in accordance with the protocol of the Drug Evaluation
Branch, National Cancer Institute, Bethesda, MD22–26
.
Docking methodology
Docking studies have been performed using MOE 2008.10 zolidin-4-one 19 in 61% yield. Reaction of 3-amino-2-mercapto-
(2008). Docking procedure was followed using the standard quinazolin-4(3H)-one (13) with carbon disulfide in ethanol
protocol implemented in MOE 2008.10 and the geometry of containing potassium hydroxide gave 2-mercapto-5H-[1,3,4]thia-
resulting complexes was studied using the MOE’s Pose Viewer diazolo[2,3-b]quinazolin-5-one (20) in 90% yield, the last com-
utility27.
pound was alkylated by stirring with iodomethane in acetone
containing potassium carbonate to yield 2-(methylthio)-5H-
[1,3,4]thiadiazolo[2,3-b]quinazolin-5-one (21) in 76% yield. The
structure of compound 21 was also confirmed by X-ray crystal-
lography analysis21b (Scheme 2) and the molecular solid state
Results and discussion
Chemistry
Synthesis of 2-mercapto-3-benzylquinazolin-4(3H)-one deriva- structure and numbering system are indicated in Figure 2.
tives (1–4) as key intermediates was achieved by the reaction of
various anthranilic acid with benzylisothiocyanate in absolute
Antitumor activity
ethanol in 82–88% yield. Compounds 1–4 were treated with
In vitro antitumor evaluation of eight compounds indicated in
Table 1 was selected by National Cancer Institute, Bethesda,
Maryland, USA, on the basis of degree of the structure variation
and computer modeling techniques for evaluation of their
anticancer activity.
A single dose (10 mM) of the test compounds 5–11 and 21 was
used in the full NCI 60 cell lines panel assay22–26. The data
reported as mean-graph of the percent growth of the treated cells,
and presented as percentage growth inhibition (GI %) caused by
the test compounds (Table 1).
2-chloro-N-(3,4,5-trimethoxyphenyl)acetamide or 3-chloro-N-
(3,4,5-trimethoxyphenyl)propanamide in anhydrous acetone in
the presence of potassium carbonate to give the corresponding
2-(quinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide or
2-(quinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)propanamide
5–12 in 84–92% yield (Scheme 1).
On the other hand, 3-benzyl-2-mercapto-6-methylquinazolin-
4(3H)-one (3) was reacted with ethyl 2-bromoacetate in dry
acetone in the presence of potassium carbonate at room
temperature to afford ethyl 2-(3-benzyl-6-methyl-4-oxo-3,4-
S
C
N
O
O
X
X
OH +
NH
N
EtOH, TEA
reflux
2
SH
N
1; X=H
2; X=6-Cl
3; X=6-CH
4; X=6,7-di-OCH3
O
3
O
O
O
, r.t.
3
O
O
Cl
NH
CO
2
O
NH
Cl
acetone, K
O
O
N
O
X
N
X
N
S
N
S
O
HN
O
O
O
HN
O
O
9; X=H
10; X=6-Cl
11; X=6-CH
5; X=H
6; X=6-Cl
7; X=6-CH
3
3
O
12; X=6,7-di-OCH3
8; X=6,7-di-OCH3
O
Scheme 1
Scheme 1. Reactions of 2-mercapto-3-benzylquinazolin-4(3H)-one (1) with 2-chloro-N-(3,4,5-trimethoxyphenyl)acetamide and 3-chloro-N-(3,4,5-
trimethoxyphenyl)propanamide.

6
I. A. Al-Suwaidan et al.
J Enzyme Inhib Med Chem, Early Online: 1–12
O
N
O
O
N
O
O
Br
X
R
O
N
O
S
N
N
O
S
H N NH
2
2
acetone, K CO , r.t
2
3
EtOH, r.t
N
SH
HN
NH
2
3; X=CH ,R=Bn
13; X=H, R=NH
3
14
15
2
CS , KOH, EtOH, reflux
2
O
X
O
N
N
MeOH, r.t.
SH
S
N
20
O
O
N
N
CH I, acetone, K CO
3
3
2
S
N
N
O
N
O
S
N
X
OH
O
HS
O
N
HN
HN
O
N
N
benzene, reflux
S
S
S
16;X=H
17;X=F
21
19
18;X=OCH
3
Scheme 2
Scheme 2. Synthesis, reactions of 3-benzyl-2-mercaptoquinazolin-4(3H)-one and 2-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)
acetohydrazide.
With regard to broad spectrum antitumor activity, close
examination of the data presented in Table 1, revealed that
compounds 7, 8 and 11 are the most active members of this study,
showing effectiveness toward numerous cell lines belong to
different tumor subpanels. Consequently, compounds 7, 8 and 11
were selected and tested against a panel of 60 different tumor cell
lines at a 5-log dose range22–26. Three response parameters, GI50,
TGI, and LC50 were calculated for each cell line, using the known
drug 5-Fluorouracil (5-FU) as a positive control. Compounds 7, 8
and 11 exhibited remarkable growth inhibitory activity pattern
against renal cancer (GI50 ¼ 4.26, 3.47 and 12.30, mM), non-small
cell lung cancer (GI50 ¼ 5.65, 3.92 and 7.83 mM), breast cancer
Figure 2. X-ray crystal structure and numbering system of compound 21.
(GI50 ¼ 4.16, 4.16 and 6.16 mM), ovarian cancer (GI50 ¼ 9.54,
6.30 and 10.23 mM) and melanoma cancer (GI50 ¼ 6.58, 4.24 and
3.70 mM), CNS (GI50 ¼ 5.43, 2.50 and 3.38 mM), prostate cancer
(GI50 ¼ 27.22, 4.89 and 18.8 mM), respectively. Compounds 7, 8
The compounds 5–11 displayed significant activities in the
and 11 are almost 1.5–3.0 fold more active than the positive
in vitro screening on the tested cell lines in 10 mM concentration
control 5-FU, with GI50, (10.47, 7.24 and 14.12 mM), TGI (58.8,
36.30 and 60.25 mM) and LC50 (4100, 87.09 and 95.49 mM)
values, respectively (Table 3). Comparison of the antitumor
activities of compounds 7, 8 and 11 with the activities of Gefitinib
and Erlotinib showed that compounds 7, 8 and 11 (Table 4)
possess activities almost equal to or higher than those of gefitinib
and erlotinib against most cell lines except non-small lung
(EKVX and NCI-H522), melanoma (SK-MEL-28), ovarian
cancer (IGROV1 and SK-OV-3) renal cancer (ACHN and
TK-10) and breast cancer (MDA-MB-468). On the other hand,
with positive cytotoxic effect (PCE) of 23/53, 52/53, 52/53, 49/49,
41/57, 46/57 and 46/58, respectively, whereas 7/58 for compound
21 (Table 2). Compounds 5–11 showed cytotoxic effects on the
most of the cancer cell lines with mean growth inhibition
percentages (MGI %) of 10%, 35%, 44%, 50%, 19%, 29% and
34%, respectively (Table 2). Compound 21 showed slight
selective activity against HOP-62, NCI-H226, NCI-H522, SNB-
75, OVCAR-4, PC-3 and MCF7 cancer cell lines with GI values
of 13%, 20%, 11%, 28%, 11%, 11% and 21%, respectively
(Table 1).

DOI: 10.3109/14756366.2015.1004059
3-Benzyl-4(3H)quinazolinone analogues
7
Table 1. Percentage growth inhibition (GI %) of in vitro subpanel tumor Table 2. Mean growth inhibition percentage and positive cytotoxic effect
cell lines at 10 mM concentration. of quinazoline derivatives.
% Growth inhibition (GI %)a
60 cell lines assay in one dose 10.0 mM concentration
Subpanel tumor cell lines
5
6
7
8
9
10
11
21
Compd No
MGI%
PCE
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
PRMI-8226
SR
Non-small cell lung cancer
A549/ATCC
EKVX
HOP-62
NCI-H226
HOP-92
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
CNS cancer
SF-268
SF-295
5
6
7
8
10
35
44
50
19
29
34
0
23/53
52/53
52/53
49/49
41/57
46/57
46/58
7/58
nt
nt
nt
nt
nt
nt
nt
nt
nt
nt
nt
nt
nt
nt
nt
nt
nt
nt
nt
nt
nt
nt
nt
nt
26
ꢀ
22
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
nt
19
31
44
nt
33
40
58
34
23
ꢀ
9
17
ꢀ
10
11
20
13
11
35
45
10
ꢀ
33
17
ꢀ
34
16
55
L
76
26
37
43
69
72
25
nt
55
nt
31
35
32
nt
28
nt
41
nt
43
69
nt
58
nt
91
73
nt
ꢀ
nt
PCE: Positive cytotoxic effect; the ratio between number of cell lines with
percentage growth inhibition 410% and total number of cell lines.
MGI%: Mean growth inhibition percentage.
ꢀ
13
20
ꢀ
54
nt
nt
46
11
25
ꢀ
24
18
36
43
ꢀ
ꢀ
ꢀ
11
ꢀ
17
19
L
29
52
35
ꢀ
compounds 6 and 10 yielded selective activities toward CNS,
renal and breast cancer cell lines, compound 9 showed selective
activities toward leukemia cell lines, whereas compound 5
possessed moderate antitumor activity.
Regarding the activity toward individual cell lines, compounds
9 and 10 showed selective activity against leukemia cell lines
CCRF-CEM, K-562, MOLT-4 and PRMI-8226 with GI values of
26%, 22%, 19%, 23%, 31%, 40% and 44%, 58% respectively.
Compound 10 revealed selective activities towards SR leukemia
cell lines with GI values of 34%, whereas compound 11 disclosed
weak activity against K-562 and PRMI-8226 cell lines with GI
values of 23% and 17%.
ꢀ
30
96
11
ꢀ
ꢀ
14
ꢀ
ꢀ
ꢀ
ꢀ
17
10
49
12
44
49
19
12
25
57
16
30
43
19
ꢀ
23
48
10
39
23
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
17
ꢀ
48
28
24
nt
66
24
22
nt
ꢀ
13
ꢀ
14
16
14
ꢀ
41
16
L
12
47
45
31
21
89
11
L
61
55
94
37
L
19
25
28
16
45
20
ꢀ
34
74
ꢀ
60
41
67
27
L
ꢀ
ꢀ
ꢀ
ꢀ
28
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
SF-539
SNB-19
SNB-75
U251
46
ꢀ
In non-small cell lung, A549/ATCC cell line proved to be
selectively sensitive to 6, 7, 8, 9, 10 and 11 with GI values of 33%,
34%, 72%, 28%, 41% and 58%, respectively. In addition,
compounds 5, 10 and 11 proved to susceptible to the HOP-62,
NCI-H226 and NCI-H522 cell lines with GI values of 35%, 43%,
91%, 45%, 69%, 73%, 30%, lethal and 35%, respectively.
Compounds 6, 7 and 8 have dedicated activity against NCI-
H226, NCI-H23, NCI-H322M and NCI-H460 cell lines with GI
values of 54%, lethal, 55%, 24%, 26%, 31%, 18%, 37%, 35%, 36%,
43% and 32% respectively. Compounds 7 and 9 showed strong
activity against HOP-92 and NCI-H522 cell lines in 76%, 46%,
69% and 96% respectively, Meanwhile, compounds 10 and 11
showed certain activity against NCI-H322M and NCI-H460 cell
lines in 17%, 29%, 19% and 52% respectively, whereas com-
pounds 7, 8 and 9 showed activity in 55%, 25% and 25% against
HOP-62, EKVX and NCI-H322M cancer cells respectively.
In activity against colon cancer, compounds 6, 7, 8, 10 and 11
showed GI values of 49%, 57%, 48%, 48%, 66%, 44%, 30%, 39%,
24% and 22% with colon HCT-116 and HT29 cell lines,
respectively, while compounds 7 and 8 demonstrated moderate
activities against HCC-2998 cancer cell line with GI value 25%
and 23%, respectively. On the other hand, compounds 10 and 11
verified sensitivity in 28% and 24% to colon HCT-15 cancer cells,
compounds 6, 7 and 8 displayed modest activities against KM12
cancer cell with GI value 49%, 43% and 23% respectively.
In investigation of activity toward CNS cancer, compounds 5,
6, 7, 8, 9, 10 and 11 showed strong potency against CNS cancer
SF-539, SNB-75 and U251 cell lines with GI values of 46%,
lethal, 89%, 94%, 28%, 74%, 67%, 23%, 47%, lethal, lethal, 45%,
74%, lethal, 25%, 45%, 43%, 94%, 20%, 30 and 56%, respectively.
Compounds 7, 8, 9 and 11 showed GI values of 31%, 61%, 19%,
60%, 21%, 55%, 25% and 41% to CNS cancer SF-268 and SF-295
cell lines, respectively. CNS cancer SNB-19 proved to be
sensitive to compounds 8 and 11 with GI values of 37% and
27%, while compounds 6 and 10 showed certain potency to
SF-268, and SF-295 cancer cells with GI values of 41% and 34%
respectively.
23
25
74
30
43
94
56
Melanoma
LOX IMVI
MALME-3 M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
Ovarian cancer
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
Renal cancer
786-0
ꢀ
17
22
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
26
39
27
22
23
22
55
31
57
39
51
35
33
43
25
61
39
47
32
55
61
24
55
40
33
80
24
18
19
ꢀ
ꢀ
29
67
13
ꢀ
16
25
12
27
30
26
39
47
11
16
ꢀ
48
27
10
43
15
13
11
34
ꢀ
ꢀ
16
23
19
15
32
33
28
26
57
77
ꢀ
25
31
52
ꢀ
ꢀ
12
37
ꢀ
ꢀ
ꢀ
ꢀ
33
L
ꢀ
ꢀ
11
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
39
12
27
16
19
ꢀ
ꢀ
55
ꢀ
59
34
61
L
21
18
ꢀ
71
17
70
nt
53
28
ꢀ
17
ꢀ
42
89
43
24
70
12
28
38
57
86
63
18
76
17
45
29
L
L
17
36
22
28
ꢀ
ꢀ
65
55
37
43
21
ꢀ
28
33
47
35
64
11
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
A498
ACHN
CAKI-1
RXF 393
SN12C
TK-10
34
16
64
31
L
12
29
ꢀ
18
ꢀ
ꢀ
UO-31
23
52
55
26
29
Prostate cancer
PC-3
DU-145
Breast cancer
MCF7
MDA-MB-231/ATCC
HS 578T
BT-549
T-47D
MDA-MB-468
ꢀ
ꢀ
29
28
26
20
65
46
34
ꢀ
57
ꢀ
17
17
10
ꢀ
ꢀ
15
45
28
ꢀ
30
56
53
69
45
nt
30
65
56
47
88
nt
18
59
76
87
27
nt
16
36
23
12
22
ꢀ
30
49
60
27
36
ꢀ
23
48
94
ꢀ
21
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
65
32
nt
nt ¼ not tested; –, GI510%; L, compound proved lethal to the cancer cell
line.

8
I. A. Al-Suwaidan et al.
J Enzyme Inhib Med Chem, Early Online: 1–12
Table 3. Compounds 7, 8 and 11 median growth inhibitory (GI50, mM), total growth inhibitory (TGI, mM) and median lethal (LC50, mM) concentration
of in vitro subpanel tumor cell lines.
Subpanel tumor cell lines
NSC lung
cancer
Colon
cancer
CNS
cancer
Ovarian
cancer
Renal
cancer
Prostate
cancer
Breast
cancer
Compd.
Activity
Leukemia
Melanoma
MG-MIDa
7
GI50
TGI
LC50
GI50
TGI
LC50
GI50
TGI
LC50
GI50
TGI
84.5
b
b
86.09
b
b
b
b
b
15.1
b
5.65
42.65
b
3.92
35.89
71.03
7.83
40.36
94.40
b
51.9
b
b
36.43
72.21
93.32
63.09
b
5.43
33.65
97.72
2.50
84.7
56.75
3.38
18.28
69.50
72.1
b
6.56
19.85
b
4.24
45.47
b
3.70
79.03
b
70.6
b
9.54
60.25
b
6.30
26.0
93.11
10.23
87.09
b
4.26
39.81
b
27.22
b
b
4.89
b
4.16
67.09
b
4.16
27.28
70.79
6.16
57.32
b
10.47
58.8
b
8
3.47
26.76
98.0
12.30
45.49
97.72
45.6
b
7.24
36.30
87.09
14.12
60.25
95.49
22.60
b
b
11
18.80
b
b
22.7
b
b
8.4
b
5-FU
61.4
b
76.4
b
b
LC50
b
b
b
b
b
b
b
b
b
b
aFull panel mean-graph midpoint (mM).
bCompounds showed values 4100 mM.
Table 4. GI50 values (mM) of compounds 7, 8, 11, Gefitinib and Erlotinib
over the most cell lines of non-small lung cancer, colon cancer, CNS
cancer, melanoma, Ovarian Cancer, Renal Cancer and breast cancer
subpanels.
Table 4. Continued
GI50 (mM)
Subpanel tumor cell lines
7
8
11
Erlotinib Gefitinib
GI50 (mM)
NCI/ADR-RES
SK-OV-3
Renal cancer
786-0
A498
ACHN
CAKI-1
RXF 393
SN12C
TK-10
UO-31
Breast cancer
MCF7
8.97
3.06
3.30
2.91
9.25
4.75
6.30
0.39
12.58
0.63
Subpanel tumor cell lines
7
8
11
Erlotinib Gefitinib
Non-small cell lung cancer
A549/ATCC
EKVX
HOP-62
NCI-H226
NCI-H23
NCI-H460
NCI-H522
HOP-92
NCI-H322M
NCI-H460
Colon cancer
COLO 205
HCC-2998
HCT-116
3.20
1.01
3.49
5.08
2.24
25.4
5.58
5.97
3.51
1.75 15.8
4.63
3.05 4100
2.55
4.70 78.0
4.17
5.01
1.58
0.15
0.10
6.30
6.3
7.94
0.40
0.20
0.16
5.01
6.30
0.10
1.25
10.5
8.59
5.13
5.12
2.03
2.66
8.08
nt
2.94
2.66
7.94
0.05
12.58
6.30
19.95
5.01
1.00
6.30
0.05
5.01
7.94
0.05
10.00
15.84
15.84
6.30
6.30
7.94
0.08
6.30
3.72
2.30
3.20
8.30
7.24
4.63
nt
3.48
4.17 26.6
6.72 nt
3.65 11.3
4.06
1.95 11.6
7.43
0.10
1.99
nt
nt
nt
1.90
70.4
5.31
nt
nt
9.98
3.42
3.23
2.98
4.01
4.11
7.93 32.0
100
10.00
12.58
10.00
7.94
6.30
0.01
MDA-MB-231/ATCC
HS 578T
BT-549
T-47D
MDA-MB-468
3.73
2.46
2.02
6.57
5.72
4.20
1.99
6.30
39.81
3.16
0.20
2.18
5.02
7.04
5.39
4100 15.3 4100
4100 50.6 4100
31.62
79.34
5.01
6.30
10.00
7.94
3.38
6.74
4.35
HT29
KM12
4100 16.6 4100
29.9 4100 4100
50.11
63.09
3.98
7.94
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
Melanoma
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
Ovarian cancer
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
6.91
7.01
3.46
21.4
1.82
3.93
3.57
1.94
2.37
2.93
1.57
3.18
4.21
nt
2.50
3.17
1.90
7.06
19.95
15.84
12.58
3.98
12.58
19.95
7.94
1.99
10.00
12.58
6.30
In activity against melanoma, compounds 6, 7 and 8 are active
against LOX IMVI, MALME-3M, M14, MDA-MB-435, MDA-
MB-435, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257 and
UACC-62 cell lines with GI values from 22% to 80%. Compound
5 showed moderate activities against M14 cell line in 22% and
25%, whilst compounds 9 and 10 possessed activity against
UACC-62 cell line with GI values of 34% and 47%. Melanoma
SK-MEL-2, SK-MEL-28 and UACC-257 cell lines were sensitive
to compounds 10 and 11 in 27%, 48%, 30%, 27%, 39% and 43%,
respectively, at the same time as compound 11 was active to LOX
IMVI and MALME-3M cell lines in 29% and 67%, while
compound 10 had slight activity against SK-MEL-5 cell line with
GI value of 26%.
In investigation of activity toward ovarian cancer, compounds
5, 6 and 7 showed moderate activities against ovarian OVCAR-8
and SK-OV-3 cell lines with GI values of 55%, 32%, 59%, 28%,
28% and 61% respectively. Ovarian OVCAR-3 and OVCAR-4
cell lines were responsive to compounds 6, 7 and 8 with GI
values of 23%, 57%, 31%, 19%, 77% and 52% respectively,
while compounds 9 and 10 were active against OVCAR-8 and
OVCAR-4 cell lines with GI values of 21%, 27%, 37% and 39%,
10.00
55.0
4.07
8.38 16.1
9.55
3.38
7.04
3.67
4.86
2.93
4.71
3.30
6.40
4.73
24.4
5.01
5.01
6.30
15.84
12.58
31.62
15.84
7.94
3.16
5.01
3.16
12.58
0.31
3.98
6.30
5.01
4.91 4100
3.41
3.02
-
3.55
2.35 15.7
4.40
6.30
32.4
4.96 100
1.25
32.5
9.36
3.41
58.0 4100 4100
4.42 3.46 5.01
7.34 27.7
7.68
2.11
0.25
3.16
19.95
19.95
7.94
0.20
5.01
7.94
10.00
10.00
5.05
3.95
(continued )

DOI: 10.3109/14756366.2015.1004059
3-Benzyl-4(3H)quinazolinone analogues
9
Figure 3. The antitumor activity correlation
of the newly synthesized compounds.
O
N
O
N
N
X
Fragment insersion
S
N
S
O
O
increase activity
HN
O
O
HN
O
O
O
O
6; X=6-Cl, MGI%: 35%
5; MGI%:10%
7; X=6-CH , MGI%:44%
3
8; X=6,7-di-OCH3, MGI%: 50%
O
N
O
N
Fragment insersion
Increase activity
X
N
S
N
S
HN
O
O
HN
O
O
O
O
O
O
10; X=6-Cl, MGI%: 29%
9; MGI%:19%
11; X=6-CH , MGI%:34%
3
MGI%: Mean growth inhibition percentage
respectively. Ovarian NCI/ADR-RES and IGROV1 cell lines were moderate antitumor potency. The introduction of 6-Cl, 6-CH3 or
receptive to compounds 6, 7 and 7, 8 with GI values of 33%, 34% 6,7-dimethoxy groups at quinazoline moiety of compound 5
and 26%, 25%, respectively, additionally compounds 8 and 11 produced compounds 6–8 with dramatically increased the
demonstrated lethal activities to OVCAR-8 and OVCAR-4 cell antitumor activity, also the induction of chloro or methyl function
lines, respectively. OVCAR-3, OVCAR-8, SK-OV-3 cell lines at position 6 of quinazoline nucleus of compound 9 produced
were sensitive to compound 11 with GI values of 33%, 71% and compounds 10, 11 with remarkable improved antitumor potency.
70%, respectively, just as SK-OV-3 cell line was perceptive to Additionally, replacement of the 6-Cl function at quinazoline ring
compound 8 with GI values of 53%.
of compounds 6 and 10 by 6-CH3 group produced compounds 7
In renal cancer, compounds 6, 7, 8 and 11 were active against and 11 with significant enhanced antitumor activity, as well
786-0, A498, ACHN, CAKI-1, RXF 393, SN12C, TK-10 and substitution of the 6-Cl-function at quinazoline nucleus of
UO-31cell lines with GI values from 24%-lethal. Renal A498, compound 6 with 6,7-dimethoxy functions gave compound 8
ACHN, CAKI-1, SN12C and UO-31 cell lines were sensitive to with advanced antitumor achievement, which implied that elec-
compounds 9 and 10 with GI values of 36%, 65%, 22%, 55%, tron donating functions favor the activity rather than electron
28%, 37%, 18%, 21%, 55% and 26%, respectively, whereas RXF withdrawing moieties. Moreover, changeover of the 6-CH3 group
393 cell line was responsive to compounds 5 and 10 with GI of quinazoline ring of compound 7 with 6,7-dimethoxy group
values of 29% and 43%, respectively.
enhanced the antitumor activity of compound 8. On the other
Prostate PC-3 and DU-145 cell lines proved to be selectively hand, replacement of acetamide function of compounds 6–8 by
sensitive to compounds 6, 7 and 8 with GI value of 29%, 26%, propanamide function produced compounds 9–11 with reduction
65%, 28%, 20% and 46%, respectively, while compounds 9 and 10 of the antitumor activity, which indicated that the length of the
possessed selective activity towards PC-3 cell line with GI value carbon chain linking is a vital factor for the antitumor activity.
of 34% and 57%, respectively.
Accordingly, the N-substituted phenylacetamides with one carbon
Activity against breast cancer; breast MCF7, MDA-MB-231/ length favor the activity (compounds 6–8) rather than the
ATCC, HS 578T, BT-549, T-47D cell lines possessed convinced propanamides with two carbon lengths (compounds 9–11).
response to compounds 6, 7, 8, 9, 10 and 11 with GI values from
23% to 94%. Compound 5 showed GI effectiveness against breast
Molecular docking studies
HS 578T and BT-549 cell lines with values of 45% and 28%,
additionally compound 11 had selective activity against breast
MDA-MB-468 cell line with GI value of 32%.
The level of antitumor activities of the compounds 7 and 8 over
breast cancer, colon, renal and small lung cancer cells, in which
EGFR kinase is highly expressed18,19,27, prompted us to perform
molecular docking into the ATP binding site of EGFR kinases to
Structure activity relationship
The antitumor activity correlation of the newly synthesized predict if these compounds had analogous binding mode to the
compounds (Figure 3) revealed that compound 5 showed EGFR kinase inhibitor. We assumed that the active target

10 I. A. Al-Suwaidan et al.
J Enzyme Inhib Med Chem, Early Online: 1–12
Figure 4. Docking of the erlotinib inhibitor (Upper panel in yellow), compounds 7 (Lower left panel in blue) and 8 (Lower right panel in cyan) into the
active site of epidermal growth factor receptor. Hydrogen bonds are shown in red.
˚
compounds 7 and 8 might demonstrate antiproliferative activity bonds with Met-769- (2.94–2.98A) and HOH-10 (2.70–2.71A and
˚
˚
against breast cancer, colon, renal and small lung cell lines 2.98–2.99A)-mediated hydrogen bonding interaction with Thr-
through inhibition of EGFR. Compounds 7 and 8 were docked 830 and Thr-766 side chain. Moreover, the anilide trimethox-
into receptor active site of EGFR along with their inhibitor. All yphenyl fragment showed two additional hydrogen bonds with
calculations were performed using MOE 2008.10 software28 Gly-695 (2.74–2.73A and 2.85–2.92A).
˚
˚
installed on 2.0G Core 2 Duo. The crystal structure of EGFR with
On the other hand, the level of antitumor activities of the
erlotinib (TarcevaÔ) (PDB code: 1M17)18,19,29–31 was obtained compound 11 over melanoma cancer cells, in which V600E-
from protein data bank (PDB). The automated docking program B-RAF kinase is highly expressed18,19,28, prompted us to perform
of MOE 2008.10 was used to dock compounds 7 and 8 along with molecular docking into the ATP binding site of V600E-B-RAF
the inhibitor erlotinib into ATP binding site of EGFR. The kinase to predict if this compound 11 has analogous binding mode
complexes were energy-minimized with a MMFF94 force field31 to the V600E-B-RAF kinase inhibitors. The crystal structure of
till the gradient convergence 0.01 kcal/mol was reached. The V600E-BRAF kinase in complex with PLX4032 (PDB code:
binding energies of compounds 7, 8 and erlotinib docked into the 3OG7)28,32,33 was obtained from protein data bank (PDB). The
active site of EGFR were ꢀ21.04, ꢀ22.56 and ꢀ24.00 kcal/mol, binding energies of compound 11 and PLX4032 docked into
respectively (Figure 4). These docking studies have revealed that the active site of V600E-BRAF kinase were ꢀ30.65 and
the quinazoline ring binds to a narrow hydrophobic pocket in the ꢀ36.11 kcal/mol, respectively (Figure 5). The docking study has
N-terminal domain of EGFR-TK where N-1 of the quinazoline revealed that the ligand 11 has bound in the active site of one of
ring interacts with the backbone NH of Met-769 via a hydrogen the protomers in the protein dimer through the formation of four
˚
˚
bond, and similarly, a water (HOH-10) molecule-mediated hydrogen bonds with Gln-530 (2.85A), Cys-532 (2.92A), Leu-505
˚
˚
hydrogen bonding interaction is observed among the N-3 and (2.13A) and Thr-529 (2.20A). Moreover, there was one arene ꢂ–ꢂ
S-atom of the quinazoline ring and the Thr-830 and Thr-766 interaction between the binding site and the ligand which
side chain. These interactions revealed the importance of occurred between quinazoline fragment and Trp-531. The results
quinazoline ring for binding and the subsequent inhibitory of this molecular docking study can support the postulation that
capacity. Compounds 7, 8 complexed with EGFR-TK in a fashion our active compound may inhibit the growth of melanoma cell
similar to erlotinib and showed the occurrence of three hydrogen lines through inhibition of B-RAF kinase, similar to PLX403233.

DOI: 10.3109/14756366.2015.1004059
3-Benzyl-4(3H)quinazolinone analogues 11
Figure 5. Docking of the PLX4032 inhibitor (Upper panel in green) and compound 11 (Lower panel in yellow) into the V600E-B-RAF kinase domain.
Hydrogen bonds are shown in red.
5. (a) El-Azab AS, Kamal EH. Synthesis and anticonvulsant evaluation
of some new 2,3,8-trisubstituted-4(3H)-quinazoline derivatives.
Bioorg Med Chem Lett 2012;22:327–33.
Conclusion
A
new derivatives of 3-benzyl-4(3H)-quinazolinones were
(b) Alanazi AM, Abdel-Aziz A-MA, Al-Suwaidan I, et al. Design,
synthesis and biological evaluation of some novel substituted
quinazolines as antitumor agents. Eur J Med Chem 2014;79:446–54.
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ones. Indian J Heterocycl Chem 1996;6:25–30.
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nazoline analogs as potential antimicrobial agents. Phosphorus
Sulfur Silicon Relat Elem 2007;183:333–48.
synthesized and evaluated for their in vitro antitumor activity.
The results of this study indicated that compounds 7, 8 and 11
possess amazing broad spectrum antitumor activity with mean
GI50 (10.47, 7.24 and 14.12 mM respectively) and are nearly 1.5–
3.0 fold more potent compared with the positive control 5-FU
with mean GI50 22.60 mM.
Declaration of interest
6. (a) Habib NS, Ismail KA, El-Tombary AA, Abdel-Aziem T.
Antilipidemic agents, Part. IV: synthesis and antilipidemic testing
of some heterocyclic derivatives of hexadecyl and cyclohexyl
hemisuccinate esters. Pharmazie 2000;55:495–9.
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. RGP-VPP-163. The authors would like to
express their gratitude and thanks to the National Cancer Institute (NCI),
Bethesda Maryland, USA, for doing the antitumor testing of the new
compounds.
(b) Al-Omar MA, El-Azab AS, El-Obeid HA, Abdel Hamide SG.
Synthesis of some new 4(3H) quinazoline analogs as potential
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(c) Alafeefy AM, Kadi AA, El-Azab AS, et al. Synthesis, analgesic
and anti-inflammatory evaluation of some new 3H-quinazolin-4-one
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Supplementary material available online
NMR Chart for the synthesized compounds