Design, synthesis, and biological evaluation of triazolyl- and triazinyl-quinazolinediones as potential antitumor agents

Article abstract of DOI:10.1155/2019/9104653

Novel 6(3-1H-1,2,4-triazol-1-yl)-3-phenylquinazoline-2,4(1H,3H)-diones (7a-e) were synthesized from different enaminones (6a-e) with 6-hydrazinyl-3-phenylquinazoline-2,4(1H,3H)-dione. 2,6(4-2-Substituted-1,3,5-triazin-1(2H)-yl)-3-phenylquinazoline-2,4(1H,3H)-diones (8a-k) were synthesized from the reaction of 1-(2,4-dioxo-3-phenyl-1,2,3,4-tetrahydroquinazolin-6-yl)thiourea, urea, or guanidine (3a-c) with enaminones (6a-e), and a series from 3-substituted-2-imino-1,3,5-triazin-1(2H)-yl-sulfonyl-phenyl-1-methylquinazoline-2,4(1H,3H)-dione (12a-j) were obtained from the reaction of N-(diaminomethylene)-4-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzenesulfonamide (11) with the enaminone (6a-j). The antitumor activity of the synthesized compounds was evaluated against two human cell lines: human colon carcinoma HCT116 and human hepatocellular carcinoma HEP-G2. Some of the tested compounds showed significant potency compared to the reference drug staurosporin.

Full text of DOI:10.1155/2019/9104653

Hindawi
Journal of Chemistry
Volume 2019, Article ID 9104653, 12 pages
https://doi.org/10.1155/2019/9104653
Research Article
Design, Synthesis, and Biological Evaluation of Triazolyl- and
Triazinyl-Quinazolinediones as Potential Antitumor Agents
,
,3
Abeer N. Al-Romaizan,1 Nesreen S. Ahmed ,1 2 and Sherin M. Elfeky1
1Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
2Department of %erapeutic Chemistry, Pharmaceutical, and Drug Industries Research Division, National Research Center,
El Buhouth Street, Dokki, Cairo 12622, Egypt
3Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 355516, Egypt
Correspondence should be addressed to Nesreen S. Ahmed; nesreen69eg@yahoo.com
Received 22 October 2018; Revised 12 December 2018; Accepted 25 December 2018; Published 3 February 2019
Academic Editor: Zhong-Wen Liu
Copyright © 2019 Abeer N. Al-Romaizan et al. -is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Novel 6(3-1H-1,2,4-triazol-1-yl)-3-phenylquinazoline-2,4(1H,3H)-diones (7a–e) were synthesized from different enaminones
(6a–e) with 6-hydrazinyl-3-phenylquinazoline-2,4(1H,3H)-dione. 2,6(4-2-Substituted-1,3,5-triazin-1(2H)-yl)-3-phenylquinazoline-
2,4(1H,3H)-diones (8a–k) were synthesized from the reaction of 1-(2,4-dioxo-3-phenyl-1,2,3,4-tetrahydroquinazolin-6-yl)thiourea,
urea, or guanidine (3a–c) with enaminones (6a–e), and a series from 3-substituted-2-imino-1,3,5-triazin-1(2H)-yl-sulfonyl-phenyl-
1-methylquinazoline-2,4(1H,3H)-dione (12a–j) were obtained from the reaction of N-(diaminomethylene)-4-(1-methyl-2,4-dioxo-
1,2-dihydroquinazolin-3(4H)-yl)benzenesulfonamide (11) with the enaminone (6a–j). -e antitumor activity of the synthesized
compounds was evaluated against two human cell lines: human colon carcinoma HCT116 and human hepatocellular carcinoma
HEP-G2. Some of the tested compounds showed significant potency compared to the reference drug staurosporin.
antitumor agents through targeting dihydrofolate reductase
enzyme (DHFR) [3]. A series of 2[(3-substituted-4(3H)-
quinazoline-2-yl-thio]N-(3,4,5)trimethoxy phenyl)acetamides
were reported to act as antitumor agents against a number
of cancer cell lines [4]. Also a series of 6-methyl-2-
thioxoquinazoline-4(1H)-ones were reported to act as anti-
tumor candidates through targeting and inhibiting the epi-
dermal growth factor receptor (EGFR) [5]. EGFR is a
transmembrane protein that is closely related to the receptor
tyrosine kinase. Both play a significant role in cell pro-
liferation differentiation, survival, and metabolism. Over-
expression of EGFR is associated with the development of
various tumors where 30% of breast cancer was reported to
have a correlation with overexpression of the growth factor
receptor ErbB2. Blocking EGFR binding site would thus
prevent EGFR expressing tumors [6, 7]. Erlotinib is an an-
titumor agent that is used for nonsmall cell lung cancer and
pancreatic cancer, and it is reported that it acts through the
inhibition of EGFR [8]. Gefitinib is a marketed antitumor
1. Introduction
Quinazolines are such interesting scaffolds that cover a wide
range of biological activity depending on the nature and
position of substituents and are reported to act as an an-
tidepressant, antipsychotic, sedative, analgesic, antibacterial,
anti-inflammatory, and others [1]. -ere are different classes
of quinazolinones depending on the position of substituents:
2-substituted-4(3H)-quinazolinones, 3-substituted-4(3H)-
quinazolinones, 4-substituted quinazolinones, 2,3-
disubstituted-4(3H)-quinazolinones, and 2,4-disubstituted-
4(3H)-quinazolinones. Depending on the position of the
oxo group, these quinazolinones can be further classified
into three main groups: 2(1H)-quinazolinones, 4(3H)-
quinazolinones, and 2,4(1H,3H)-quinazolinones. -ey
differ in their synthetic approaches and in their starting
materials [2]. Quinazolinones were reported to act as an-
titumor agents through different mechanisms. Methoxylated-
2-benzyl thioquinazoline-4(3H) ones were reported to act as

2
Journal of Chemistry
agent that acts through inhibiting EGFR as well [9]. Both
erlotinib and gefitinib (Figure 1) belong to a class of EGFR
inhibitors that are 4-anilinoquinazolines [10]. Another class of
reported EGFR inhibitors is 2-styryl-4aminoquinazolines (SQ-
I) (Figure 1). -is class was reported to show potent in vitro
antiproliferative activity against different cell lines compared to
gefitinib [11]. In the present work, new compounds of
quinazoline-2,4(1H,3H)-diones were designed through in-
troducing substituted N-containing ring systems: triazole or 2-
oxo-, 2-thia-, 2-imino-triazine moieties at C6, or introduction
of 2- imino-triazine through a phenyl sulfonyl linker at N3 of
the quinazolinone ring (Figure 2). -e antitumor activity of the
new derivatives was evaluated via the MTT assay.
8.53 (s, 1H, C5-H), 7.80 (d, 1H, C8-H), 7.72 (d, 1H, C7-H),
7.27 (m, 4H, Ar-H), 7.21 (m, 1H, Ar-H), 6.51 (s, 1H, -NH),
and 3.48 (m, 3H, -NHNH2).
(3) General Procedure for Synthesis of 3a–c. 6-Bromo-3-
phenylquinazoline-2,4(1H,3H)-dione (1) (1 mmol) was
allowed to reflux with urea, thiourea, or guanidine (1 mmol)
in ethanol (20 ml) for 12 hours. -e reaction was monitored
by TLC until no starting materials were present. -e pre-
cipitate formed on cooling was filtered off and recrystallized
from aqueous ethanol in yields of 90–92%. -e following
compounds were prepared:
1-(2,4-Dioxo-3-phenyl-1,2,3,4-tetrahydroquinazolin-6-
yl)urea (3a). Yield 92% and m.p.:130–132°C; 1H NMR
(DMSO-d6): δ 9.24 (s, 1H, NH), 8.10 (s, 1H, C5-H), 7.82
(m, 4H, Ar-H), 7.74 (d, 1H, C8-H), 7.24 (d, 1H, C7-H), 6.65
(m, 1H, Ar-H), 5.52 (s, 1H, N1-H), and 3.67 (s, 2H, NH2)
2. Experimental
2.1. Chemistry. Melting points were recorded using Stuart
melting apparatus. IR spectra (KBr) were recorded on an
−1
1-(2,4-Dioxo-3-phenyl-1,2,3,4-tetrahydroquinazolin-6-
FT-IR spectrometer (]max/cm ). Nuclear magnetic reso-
1
yl)thiourea ( 3b ). Yield 91% and m.p.: 173–175°C; H
nance (1H NMR and 13C NMR) spectra were recorded on
Bruker 400 MHz and 300 MHz spectrometer using DMSO-
d6 or CDCl3 as solvents; the chemical shifts are expressed
in δ ppm using TMS as an internal standard. Mass spectra
were recorded on Shimadzu QP-GC/MS mass spectrom-
eters at the microanalytical unit of Faculty of Science of
Cairo University. Elemental microanalyses were carried
out, and the results were within 0.3 from the theoretical
values. Solvent evaporation was performed under reduced
pressure using Buchi R-3000 Rotacool Rotary Evaporator,
and thin layer chromatography was performed on pre-
coated (0.25 mm) silica gel GF254 plates (E. Merck, Ger-
many); compounds were detected with 254 nm UV lamp.
All chemicals and starting materials were commercial
chemicals obtained from Sigma-Aldrich.
NMR (DMSO-d6): δ 8.75 (s, 1H, NH), 8.53 (s, 1H,
C5-H), 7.81 (d, 1H, C8-H), 7.73 (d, 1H, C7-H), 7.22 (m,
2H, Ar-H), 7.14 (m, 2H, Ar-H), 7.11 (s, 1H, Ar-H), 6.96
(s, 1H, N1-H), and 4.06 (s, 2H, NH2)
1-(2,4-Dioxo-3-phenyl-1,2,3,4-tetrahydroquinazolin-6-
yl)guanidine ( 3c ). Yield 90%, m.p.: 160–162°C, and IR
−1
(]max/cm ) 1718 and 1679 (C�O), 3423, 3393 and 3383
(NH, NH2); 1H NMR (DMSO-d6): δ 8.61 (s, 1H, NH),
8.40 (s, 1H, C5-H), 8.04 (d, 1H, C8-H), 7.86 (d, 1H, C7-
H), 7.52 (m, 3H, Ar-H), 7.45 (m, 1H, Ar-H), 7.00 (s, 1H,
N1-H), 5.35 (s, 2H, NH2), and 4.04 (s, 1H, NH)
(4) General Procedure for Synthesis of 6a–e. Substituted
acetophenones or 2-acetyl thiophene (furan) (1 mmol) were
refluxed with DMF-DMA (1.2 mmol) for 8–12 hours in
ethanol (20 ml). -e reaction was monitored with TLC till no
starting materials were detectable. -e corresponding enami-
nones derivatives were afforded in yields of 92–97%. -e so-
lutions were evaporated under suction. -e precipitates were
collected and recrystallized from aqueous ethanol. -e following
compounds were prepared:
2.1.1. Synthesis of 6(3-1H-1,2,4-Triazol-1-yl)-3-phenylquinazoline-
2,4(1H,3H)-diones and 6(4-2-Substituted-1,3,5-Triazin-1(2H)-yl)-
3-phenylquinazoline-2,4(1H,3H)-diones
(1) Synthesis of 6-Bromo-3-phenylquinazoline-2,4(1H,3H)-
dione (1). 5-Bromoisatoic anhydride (1 mmol) reacted
with aniline (1 mmol) in ethanol (20 ml) in presence of few
drops of acetic acid under ultrasonic irradiation at 80°C for
25 min to afford only one isolable product examined by TLC.
-e solution was concentrated under suction poured on
crushed ice, filtered off, and recrystallized from aqueous
ethanol to obtain the desired product in yields of 95%
(254–255°C [12], m.p. 249–252°C).
(E)-3-(Dimethylamino)-1-(furan-2-yl)prop-2-en-1-one
°
( 6a ). 92°
C [13], yield: 93%, and m.p.: 95–97 C
(E)-3-(Dimethylamino)-1-(thiophen-2-yl)prop-2-en-1-
one ( 6b ). 147–149°C [14], yield 92%, and m.p.:
140–141°C
(E)-3-(Dimethylamino)-1-phenylprop-2-en-1-one ( 6c ).
92°C [15], yield 95%, and m.p.: 93–95°C
(2) Synthesis of 6-Hydrazinyl-3-phenylquinazoline-2,4(1H,3H)-
dione (2). 6-Bromo-3-phenylquinazoline-2,4(1H,3H)-dione
(1) (1 mmol) was allowed to reflux in neat hydrazine hydrate
(10 ml) for 12 hours, and the reaction was monitored with
TLC. -e solution was poured on ice and allowed to stir till
the hydrazide accumulated and then was filtered off and
recrystallized from aqueous ethanol. Yield: 88%, m.p.:
(E)-3-(Dimethylamino)-1-(4-nitrophenyl)prop-2-en-1-
one ( 6d ). 139–141°C [16], yield: 96%, and m.p.:
151–153°C
(E)-3-(Dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-
one ( 6e ). 94–96°C [16], yield: 97%, and m.p.:100–101°C
−1
150–152°C, and IR (]max/cm ) 1659 and 1639 (2C�O),
(5) General Procedure for Synthesis of 7a–e. Enaminones
(6a–e) (1 mmol) and 6-hydrazinyl-3-phenylquinazoline-
1
3470, 3389, and 3373 (NH, NH2); H NMR (DMSO-d6): δ

Journal of Chemistry
3
F
HN
N
Cl
HN
N
O
O
O
O
O
O
N
N
N
O
(a)
(b)
N
HN
N
Cl
O
(c)
Figure 1: Di›erent EGFR inhibitors: (a) erlotinib; (b) ge¡tinib; (c) SQ-I.
HN
N
O
S
N
N
R3 = H
R2 =
,
O
N
N
N
O
N
X
R3
R2
O
N
N
N
X = O, S, N
N
R1
R1 = H, CH3
Figure 2: Design of new quinazolinones as antitumor agents.
2,4(1H,3H)-dione (2) (1 mmol) were reꢀuxed together in
ethanol (20 ml) for 24 hours. ꢁe reaction was monitored
using TLC till termination. ꢁe solutions were dried under
suction, and the obtained precipitates were recrystallized
from petroleum ether in yields of 93–96%. ꢁe following
compounds were prepared:
3-Phenyl-6-(3-(thiophen-2-yl)-1H-1,2,4-triazol-1-yl)
quinazoline-2,4(1H,3H)-dione ( 7b ). Yield: 94%, m.p.:
160–162°C, and IR (]max/cm−1) 1702 and 1637
1
(2CꢀO), 3375 (NH); H NMR (DMSO-d6): δ 10.00
(s, 1H, C-H trizole), 7.70 (d, 3H, C-H quinazoline),
7.01–7.33 (m, 6H, Ar-H), 6.79 (m, 2H, Ar-H), and
6.43 (s, 1H, N-H quinazoline).
6-(3-(Furan-2-yl)-1H-1,2,4-triazol-1-yl)-3-phenylquinazoline-
2,4(1H,3H)-dione ( 7a ). Yield: 95%, m.p.: 154–156°C, and IR
3-Phenyl-6-(3-phenyl-1H-1,2,4-triazol-1-yl)quinazoline-
−1
1
2,4(1H,3H)-dione ( 7c ). Yield: 93%, m.p.: 80–82°C, and
(]max/cm ) 1707 and 1638 (2CꢀO), 3383 (NH); H
NMR (DMSO-d6): δ 10.07 (s, 1H, C-H trizole), 7.70 (m,
3H, C-H quinazoline), 7.30–7.11 (m, 6H, Ar-H), 6.79 (m,
2H, Ar-H), and 6.43 (s, 1H, N-H quinazoline). Ms: [M+
371] consistent with the molecular formula C20H13N5O3.
−1
IR (]max/cm ) 1712 and 1660 (2CꢀO), 3492 (NH); 1H
NMR (CDCl3): δ 9.88 (s, 1H, C-H trizole), 8.40 (s, 1H,
C5-H), 7.85 (d, 1H, J ꢀ 8.0 Hz, C8-H), 7.64 (d, 1H,
J ꢀ 8.1 Hz, C7-H), 7.62–7.26 (m, 10 H, Ar-H), and 6.38

4
Journal of Chemistry
(s, 1H, N-H quinazoline); 13C NMR (CDCl3): δ 128.2,
128.3, 128.4, 128.5, 128.6, 128.7, 129.5, 129.7, 129.9,
130.1, 133.1, 133.3, 133.5, 134.1, 136.4, 138.2, 146.2,
146.4, 150.0, 152.7, 161.0, and 161.2.
6-(2-Oxo-4-phenyl-1,3,5-triazin-1(2H)-yl)-3-phenylquinazoline-
2,4(1H,3H)-dione ( 8c ). Yield: 92%, m.p.: 80–82°C, and IR
−1
(]max/cm )1723, 1656 and 1630 (3C�O), 3431 (NH); 1H
NMR (CDCl3): δ 9.08 (s, 1H, C-H triazine), 8.53 (s, 1H,
C5-H),7.87 (d, 1H, J � 8.4 Hz, C8-H), 7.72 (d, 1H, 8.4 Hz.,
C7-H),7.71 (m, 2H, Ar-H), 7.65–7.61 (m, 3H, Ar-H),
7.60–7.20 (m, 5H, Ar-H), and 6.19 (s, 1H, N-H qui-
nazoline); 13C NMR (CDCl3): δ 119.9, 124.3,127.3, 127.7,
128.6, 128.9, 129.5, 129.9, 131.3, 132.4, 132.9, 134.0,
134.3, 135.3, 137.0, 138.1, 142.0, 142.8, 151.2, 157.2,
157.4, 160.5, and 162.4.
6-(3-(4-Nitrophenyl)-1H-1,2,4-triazol-1-yl)-3-phenylquinazoline-
2,4(1H,3H)-dione ( 7d ). Yield: 96%, m.p.: 177–179°C, and IR
−1
1
(]max/cm ) 1706 and 1677 (2C�O), 3430 (NH); H NMR
(CDCl3): δ 9.80 (s, 1H, C-H triazole), 8.33–8.10 (m, 3H, C-H
quinazoline), 8.12 (d, 2H, Ar-H), 7.75 (d, 3H, Ar-H), 7.41 (m,
4H, Ar-H), and 6.38 (s, 1H, N-H quinaozline);13C NMR
(CDCl3): δ 115.7, 122.6, 123.4, 124.8, 126.5, 126.9, 127.8, 129.28,
129.3, 129.4, 129.7, 132.3, 133.6, 135.0, 137.2, 140.2, 146.2,
146.4,149.5, 159.7, 161.1, and 162.1.
6-(4-(4-Nitrophenyl)-2-oxo-1,3,5-triazin-1(2H)-yl)-3-
phenylquinazoline-2,4(1H,3H)-dione ( 8d ). Yield:
−1
95%, m.p.: 168–170°C, and IR (]max/cm ) 1723, 1657
6-(3-(4-Fluorophenyl)-1H-1,2,4-triazol-1-yl)-3-phenylquinazoline-
and 1637, (3C�O), 3431 (NH); 1H NMR (CDCl3): δ 9.11
(s, 1H, C-H triazine), 8.47–8.00 (m, 7H, Ar-H), 7.83–
7.76 (m, 4H, Ar-H), 7.17 (m, 1H, Ar-H), and 6.99 (s, 1H,
N-H quinazoline); 13C NMR (CDCl3): δ 118.8, 120.3,
120.9, 123.5, 123.9, 124.0, 124.2, 128.3, 130.2, 130.6,
130.7, 134.0, 135.9, 137.4, 138.6, 139.8, 140.8, 150.5,
151.3, 153.9, 156.4, 158.4, and 164.7.
2,4(1H,3H)-dione ( 7e ). Yield: 96%, m.p.: 110–112°C, and IR
−1
1
(]max/cm ) 1701 and 1675 (2C�O), 3433 (NH); H NMR
(CDCl3): δ 9.96 (s,1H, C-H triazole), 8.12 (s, 1H, C5-H),
7.74 (d, 1H, J � 8.3 Hz, C8-H), 7.56 (d, 1H, J � 8.3 Hz, C7-
H), 7.52–7.42 (m, 6H, Ar-H), 7.41–7.14 (m, 3H, Ar-H),
and 6.40 (s, 1H, N-H quinazoline); 13C NMR (CDCl3):
δ 115.2, 117.9, 123.4, 124.4, 126.5, 126.9, 128.5, 129.3,
129.7, 131.3, 132.1, 133.9, 133.9, 134.7, 137.1, 138.2,
139.0, 140.0, 146.8, 159.7, 161.2, 162.6, and 171.2.
6-(4-(4-Fluorophenyl)-2-oxo-1,3,5-triazin-1(2H)-yl)-3-
phenylquinazoline-2,4(1H,3H)-dione ( 8e ). Yield: 96%,
−1
m.p.: 115–117°C, and IR (]max/cm ) 1722, 1682 and
1642 (3C�O), 3441 (NH); 1H NMR (CDCl3): δ 9.02 (s,
1H, C-H triazine), 8.33–7.90 (m, 4H, Ar-H), 7.89 (d,
1H, J � 8.5 Hz., C8-H), 7.83 (d, 1H, J � 8.5 Hz., C7-H),
7.80–7.23 (m,6H, Ar-H), and 6.85 (s, 1H, N-H qui-
nazoline); 13C NMR (CDCl3): δ 115.7, 115.9, 115.9,
116.1, 119.6, 129.2, 129.3, 130.0, 130.3, 130.8, 131.1,
132.5, 132.6, 132.8, 133.3, 133.7, 134.3, 138.2, 138.3,
151.0, 159.3, 164.4, 165.5, and 171.2.
(6) General Procedure for Synthesis of 8a–k. Enaminones
(6a–e) (1 mmol) and 1-(2,4-dioxo-3-phenyl-1,2,3,4-
tetrahydroquinazolin-6-yl)thiourea, urea, or guanidine (3a–
c) (1 mmol) were refluxed in ethanol (20 ml) for 24 hours. -e
reaction was monitored using TLC till termination. -e so-
lutions were dried under suction. -e obtained precipitates
were recrystallized from petroleum ether to obtain products
in yields of 92–97%. -e following compounds were
prepared:
6-(4-(Furan-2-yl)-2-thioxo-1,3,5-triazin-1(2H)-yl)-3-
phenylquinazoline-2,4(1H,3H)-dione ( 8f ). Yield: 94%,
−1
m.p.: 146–148°C, and IR (]max/cm ) 1732 and 1629
6-(4-(Furan-2-yl)-2-oxo-1,3,5-triazin-1(2H)-yl)-3-
phenylquinazoline-2,4(1H,3H)-dione ( 8a ). Yield: 92%,
m.p.: 83–85°C, and IR (]m1ax/cm−1) 1707, 1688 and
1631 (3C�O), 3432 (NH); H NMR (CDCl3): δ 9.40
(s, 1H, C-H triazine), 8.09 (s, 1H, C5-H), 7.82 (d, 1H,
J � 8.3 Hz, C8-H), 7.72 (d, 1H, J � 8.3 Hz, C7-H), 7.70–
7.34 (m, 5H, Ar-H), 6.99 (s, 1H, N-H quinazoline), and
6.64–6.59 (m, 3H, Ar-H); 13C NMR (CDCl3): δ 108.7,
111.2, 112.6, 117.7, 120.7, 122.0, 124.8, 126.7, 129.5,
130.4, 131.9, 132.8, 136.4, 137.7, 144.6, 147.1, 151.2,
153.3, 157.9, 162.8, and 164.5.
(2C�O), 3436 (NH); 1H NMR (CDCl3): δ 8.81 (s, 1H,
C-H triazine), 8.09 (s, 1H, C5-H), 7.92–7.42 (m, 6H,
Ar-H), 7.23 (m, 1H, Ar-H), 6.95–6.89 (m, 3H, Ar-H),
and 6.66 (s, 1H, N-H quinazoline); 13C NMR
(CDCl3): δ 111.7, 113.0, 116.0, 119.0, 121.1, 123.3,
124.6, 126.1, 127.1, 128.2, 129.5, 134.2, 138.1, 141.1,
142.6, 146.7, 149.5, 150.3, 164.3, 165.6, and 180.8. Ms:
[M+ 415]. Consistent with the molecular formula
C21H13N5O3S.
3-Phenyl-6-(4-(thiophen-2-yl)-2-thioxo-1,3,5-triazin-1(2H)-
yl)quinazoline-2,4(1H,3H)-dione ( 8g ). Yield: 93%, m.p.:
6-(2-Oxo-4-(thiophen-2-yl)-1,3,5-triazin-1(2H)-yl)-3-
−1
111–113°C, and IR (]max/cm ) 1721 and 1641 (2C�O),
phenylquinazoline-2,4(1H,3H)-dione ( 8b ). Yield: 93%,
3431 (NH); 1H NMR (CDCl3): δ 9.02 (s, 1H, C-H triazine),
8.53–7.72 (m, 7H, Ar-H), 7.21–7.09 (m, 4H, Ar-H), and
6.76 (s, 1H, N-H quinazoline); 13C NMR (CDCl3): δ 125.3,
128.1, 128.2, 128.3, 128.4, 128.5, 128.7, 129.4, 130.9, 131.1,
132.5, 132.6, 132.7, 135.4, 135.4, 135.5, 138.8, 142.5, 157.9,
159.5, and 186.2. Ms: [M+ 431]. Consistent with the mo-
lecular formula C21H13N5O2S2.
−1
m.p.: 96–98°C, and IR (]max/cm ) 1711, 1682 and
1642 (3C�O), 3454 (NH); 1H NMR (CDCl3): δ 9.06 (s,
1H, C-H triazine), 8.53 (s, 1H, C5-H), 8.20 (d, 1H,
J � 8, C8-H), 7.79 (d, 1H, J � 8.2 Hz., C7-H), 7.77–7.50
(m, 8H, Ar-H), and 6.77 (s, 1H, N-H quinazoline);
13C NMR (CDCl3): δ 118.3, 126.4, 128.2, 128.4, 129.6,
131.5, 132.5, 134.7, 134.8, 135.3, 135.4, 137.5, 138.9,
142.6, 143.2, 143.7, 150.3, 154.1, 155.4, 167.0, and
169.8.
3-Phenyl-6-(4-phenyl-2-thioxo-1,3,5-triazin-1(2H)-yl)
quinazoline-2,4(1H,3H)-dione ( 8h ). Yield: 93%, m.p.:

Journal of Chemistry
5
−1
110–112°C, and IR (]max/cm ) 1653 and 1717 (2C�O),
reaction was monitored with TLC till no starting materials were
detectable. -e solution was poured on crushed ice. -e pre-
cipitate was collected by filtration and recrystallized from
1
3431 (NH); H NMR (CDCl3): δ 9.07 (s, 1H, C-H tri-
azine), 8.71 (s, 1H, C5-H), 8.03 (d, 1H, J � 7.6 Hz, C8-H),
7.53 (d, 1H, J � 7.6 Hz., C7-H) 7.53–7.47 (m, 4H, Ar-H),
7.47–7.07 (m,6H, Ar-H), and 6.99 (s, 1H, N-H quina-
zoline); 13C NMR (CDCl3): δ 120.1, 122.8, 124.6, 125.4,
127.2, 128.70, 128.9, 130.1, 131.4, 133.7, 134.5, 135.7,
138.3, 139.7, 141.1, 142.4, 143.1, 143.8, 145.5, 146.5,
158.3, 167.4, and 178.5. Ms: [M+ 425]. Consistent with
the molecular formula C23H15N5O2S.
aqueous ethanol. Yield (97%), m.p.: 172–174°C, and IR (]max
/
−1
cm ) 1705 and 1632 (2C�O), 3431, 3345 and 3240 (NH, NH2);
1H NMR (DMSO-d6): δ 10.33 (s, 1H, NH), 7.84 (d, 2H, Ar- H),
7.40 (m, 4H, Ar-H), 6.75 (m, 2H, Ar-H), 5.71 (s, 2H, NH2), 2.81
(s, 3H, CH3), and 1.92 (s, 1H, NH). Ms: [M+ 373]. Consistent
with the molecular formula C16H15N5O4S.
(2) General Procedure for Synthesis of 6f–j. Different
substituted acetophenones (1 mmol) were refluxed with
DMF-DMA (1.2 mmol) for 8–12 hours. In ethanol (20 ml),
reaction was monitored with TLC till no starting materials
were detectable. -e corresponding enaminones derivatives
were afforded in yields of 92–97%. -e solutions were
evaporated under suction. -e precipitates were collected
and recrystallized from aqueous ethanol. -e following
compounds were prepared:
6-(4-(4-Nitrophenyl)-2-thioxo-1,3,5-triazin-1(2H)-yl)-3-
phenylquinazoline-2,4(1H,3H)-dione ( 8i ). Yield: 95%,
−1
m.p.: 198–200°C, and IR (]max/cm ) 1708 and 1625
1
(2C�O), 3430 (NH); H NMR (CDCl3): δ 9.11 (s, 1H,
C-H triazine), 8.82 (s, 1H, C5-H), 8.80 (d, 1H, J � 8.2 Hz,
C8-H), 8.72 (d, 1H, J � 8.2 Hz, C7-H), 8.31 (d, 2H,
J � 6.8 Hz, Ar-H),8.03 (d, 2H, J � 6.8 Hz, Ar-H) 7.55–
7.20 (m, 5H, Ar-H), and 6.99 (s, 1H, N-H quinazoline);
13C NMR (CDCl3): δ 120.3, 122.1, 123.6, 124.1, 124.8,
127.4, 128.2, 130.3, 131.2, 133.8, 135.7, 137.4, 138.8,
141.4, 143.2, 147.4, 148.8, 149.9, 153.3, 159.1, 162.2,
164.8, and 177.8. Ms: [M+ 470]. Consistent with the
molecular formula C23H14N6O4S.
(E)-1-(2-Bromophenyl)-3-(dimethylamino)prop-2-en-1-
one ( 6f ). Liq. [17]; yield: 92% and liq.
(E)-3-(Dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-
1-one ( 6g ). Liq. [18]; yield 92% and liq.
6-(4-(4-Fluorophenyl)-2-thioxo-1,3,5-triazin-1(2H)-yl)-
3-phenylquinazoline-2,4(1H,3H)-dione ( 8j ). Yield:
(E)-3-(Dimethylamino)-1-(p-tolyl)prop-2-en-1-one ( 6h ).
m.p.: 112–114°C [19]; yield 94% and m.p.: 115–117°C
−1
97%, m.p.:118–120°C, and IR (]max/cm ) 1704 and
(E)-3-(Dimethylamino)-1-(pyridin-2-yl)prop-2-en-1-one
( 6i ). m.p.: 135–136°C [20]; yield 97% and m.p.:
136–138°C
(E)-3-(Dimethylamino)-1-(4-methoxyphenyl)prop-2-en-
1-one ( 6j ). m.p.:98–100°C [21]; yield 96% and m.p.:
104–106°C
1
1657 (C�O), 3393 (NH); H NMR (CDCl3): δ 9.00 (s,
1H, C-H triazine), 8.60 (d, 2H, J � 5.2 Hz., Ar-H), 8.53
(s, 1H, C5-H), 8.06 (d, 2H, J � 5.2 Hz., Ar-H), 7.89 (d,
1H, J � 8.3 Hz, C8-H),7.78 (d, 1H, J � 8.3 Hz., C7-H)
7.42–7.23 (m, 1H, Ar-H), 7.21–7.09 (m, 5H, Ar-H), and
6.99 (s, 1H, N-H quinazoline); 13C NMR (CDCl3): δ
111.2, 113.0, 116.2, 117.7, 122.0, 127.1, 129.3, 131.6,
133.8, 136.2, 138.5, 139.4, 143.9, 145.6, 148.4, 151.4,
154.6, 157.0, 158.3, 161.7, 164.1, 165.2, 171.2, and 178.9.
(3) General Procedure for Synthesis of 12a–j. N-(Diamino-
methylene)-4-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3
(4H)-yl)benzenesulfonamide (11) (1 mmol) and (E)-3-
(dimethylamino)-1-arylprop-2-en-1-ones (6a–j) (1 mmol)
in DMF/ethanol were refluxed for 8–12 hours. -e reaction
was monitored with TLC till no starting materials were de-
tectable. -e solutions were concentrated under suction.
Poured on ice, the precipitates formed were collected by
filtration and recrystallized from aqueous ethanol, and the
products were obtained in yields of 93–98%. -e following
compounds were prepared:
6-(2-Imino-4-(thiophen-2-yl)-1,3,5-triazin-1(2H)-yl)-3-
phenylquinazoline-2,4(1H,3H)-dione ( 8k ). Yield: 94%,
−1
m.p.:172–174°C, and IR (]max/cm ) 1708 and 1638
1
(2C�O), 3240 and 3434 (2NH); H NMR (CDCl3): δ
9.26 (s, 1H, C-H triazine), 8.53 (s, 1H, C5-H), 7.85 (d,
1H, J � 8.4 Hz., C8-H), 7.80 (d, 1H, J � 8.4 Hz., C7-H),
7.73–7.45 (m, 3H, Ar-H), 7.22–7.13 (m, 5H, Ar-H), 6.99
(s, 1H, N-H quinazoline), and 6.74 (s, 1H, NH); 13C
NMR (CDCl3): δ 111.7, 116.4, 119.2, 124.1, 128.4, 129.7,
132.5, 133.4, 135.4, 135.4, 137.2, 138.9, 140.2, 142.6,
144.5, 146.2, 149.9, 152.7, 155.9, 164.9, and 166.4. Ms:
[M+ 414]. Consistent with the molecular formula
C21H14N6O2S.
3-(4-((4-(Furan-2-yl)-2-imino-1,3,5-triazin-1(2H)-yl)
sulfonyl)phenyl)-1-methylquinazoline-2,4(1H,3H)-dione
( 12a ). Yield 95%, m.p.: 230–232°C, and IR (]max
/
cm ) 1707 and 1660 (C�O), and 3345 (NH); 1H
NMR (CDCl3): δ 10.30 (s, 1H, NH), 8.09 (d, 2H, Ar-
H), 8.02 (d, 2H, Ar-H), 7.87 (m, 3H, Ar-H), 7.76 (s,
1H, C-H triazine), 7.74–7.38 (m, 4H, C-H quinazo-
line), and 3.64 (s, 3H, CH3); 13C NMR (CDCl3): δ
29.7, 108.8, 111.3, 115.9, 117.8, 118.9, 123.8, 125.1,
127.7, 128.6, 129.1, 131.2, 133.9, 135.8, 136.7, 140.8,
145.7, 147.9, 152.0, 153.9, 160.1, and 162.5. Ms: [M+
476]. Consistent with the molecular formula
C22H16N6O5S.
−1
2.1.2. Synthesis of 3-Substituted-2-Imino-1,3,5-triazin-1(2H)-
yl-sulfonyl-phenyl-1-methylquinazoline-2,4(1H,3H)-dione
(12a–j)
(1) Synthesis of N-(Diaminomethylene)-4-(1-methyl-2,4-
dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzenesulfonamide
(11 ). N-methyl isatoic anhydride (9) (2 mmol) was refluxed
with sulfaguanidine (10) (2 mmol) in glacial acetic acid
(30 ml) under ultrasound irradiation at 80°C for 90 min. -e

6
Journal of Chemistry
3-(4-((2-Imino-4-(thiophen-2-yl)-1,3,5-triazin-1(2H)-yl)
sulfonyl)phenyl)-1-methylquinazoline-2,4(1H,3H)-dione
128.6, 130.1, 131.9, 132.8, 133.3, 135.5, 137.6, 143.4,
148.4, 149.3, 149.4, 150.9, 152.0, 156.3, and 160.9. Ms:
[M+ 564]. Consistent with the molecular formula
C24H17BrN6O4S.
−1
(12b ). Yield 94%, m.p.: 257–259°C, and IR (]max/cm )
1701 and 1631 (2C�O), and 3347 (NH); 1H NMR
(DMSO-d6): δ 10.30 (s, 1H, NH), 7.84–7.71 (m, 5H, Ar-
H), 7.69 (s, 1H, C-H triazine), 7.41–7.36 (m, 6H, Ar-H),
and 3.35 (s, 3H, CH3); 13C NMR (DMSO-d6): δ 29.3,
110.7, 114.0, 115.1, 119.7, 120.3, 121.4, 122.5, 123.8,
126.2, 127.2, 129.0, 129.8, 133.0, 134.8, 136.4, 138.9,
141.6, 150.1, 158.0, 166.7, and 168.25. Ms: [M+ 492].
Consistent with the molecular formula C22H16N6O4S2.
3-(4-((4-(2-Hydroxyphenyl)-2-imino-1,3,5-triazin-1(2H)-
yl)sulfonyl)phenyl)-1-methylquinazoline-2,4(1H,3H)-dione
−1
( 12g ). Yield 93%, m.p.: 252–254°C, and IR (]max/cm )
1705 and 1632 (2C�O) and 3349 (NH); 1H NMR
(DMSO-d6): δ 10.30 (s, 1H, NH), 7.85–7.65 (m, 4H, Ar-
H),7.65 (s, 1H, C-H triazine), 7.61–7.30 (m, 4H, C-H
quinazoline), 6.72–6.64 (m, 6H, Ar-H), 5.67 (br, 1H,
OH), and 3.34 (s, 3H, CH3); 13C NMR (DMSO-d6): δ
29.4, 110.7, 114.0, 114.2, 115.2, 118.8, 119.8, 121.9, 122.3,
124.1, 126.3, 127,5, 129.0, 130.5, 133.1, 134.5, 138.9, 141.7,
150.2, 152.2, 155.6, 158.0, 162.4, and 168.2. Ms: [M+ 502].
Consistent with the molecular formula C24H18N6O5S.
3-(4-((2-Imino-4-phenyl-1,3,5-triazin-1(2H)-yl)sulfonyl)
phenyl)-1-methylquinazoline-2,4(1H,3H)-dione ( 12c ).
−1
Yield 94%, m.p.: 255–257°C, and IR (]max/cm ) 1704
and 1631 (C�O) and 3347 (NH); 1H NMR (DMSO-d6):
δ 10.30 (s, 1H, NH), 7.85–7.70 (m, 4H, Ar-H),7.69 (s,
1H, C-H triazine), 7.40 (m, 3H, Ar-H), 6.72–6.64 (m,
6H, Ar-H), and 3.37 (s, 3H, CH3); 13C NMR (DMSO-
d6): δ 29.3, 110.7, 114.0, 115.1, 117.2, 119.7,120.3, 122.4,
123.6, 126.2, 126.2, 127.1, 129.0, 130.1, 133.0, 133.2,
134.7, 138.9, 141.6, 150.1, 158.0, 160.3, 166.0, and 168.2.
Ms: [M+ 486]. Consistent with the molecular formula
C24H18N6O4S.
3-(4-((2-Imino-4-(p-tolyl)-1,3,5-triazin-1(2H)-yl)sulfonyl)
phenyl)-1-methylquinazoline-2,4(1H,3H)-dione ( 12h ).
−1
Yield 94%, m.p.: 277–279°C, and IR (]max/cm ) 1702
and 1631 (C�O) and 3348 (NH); 1H NMR (DMSO-d6): δ
10.30 (s, 1H, NH), 7.84 (d, 2H, Ar-H), 7.68 (m, 2H, Ar-
H), 7.67 (s, 1H, C-H triazine),7.66–7.30 (m, 4H, C-H
quinazoline), 6.72–6.64 (m, 4H, Ar-H), 3.36 (s, 3H, CH3),
and 2.90 (s, 3H, CH3); 13C NMR (DMSO-d6): δ 20.9, 29.4,
110.7, 114.1, 115.1, 119.8, 121.2, 123.3, 124,4, 126.3, 127.2,
128.1, 129.0, 130.1, 131.4, 133.1, 134.3, 138.9, 140.5, 141.7,
146.2, 150.2, 152.2, 158.0, and 168.2. Ms: [M+ 500].
Consistent with the molecular formula C25H20N6O4S.
3-(4-((2-Imino-4-(4-nitrophenyl)-1,3,5-triazin-1(2H)-yl)
sulfonyl)phenyl)-1-methylquinazoline-2,4(1H,3H)-dione
−1
( 12d ). Yield 93%, m.p.: 262–264°C, and IR (]max/cm )
1705 and 1632 (2C�O) and 3350 (NH); 1H NMR
(DMSO-d6): δ 10.30 (s, 1H, NH), 8.36 (m, 4H, Ar-H),
7.96–7.74 (m, 4H, Ar-H),7.72 (s, 1H, C-H triazine), 7.39
(m, 1H, C8-H), 7.31 (m, 1H, C5-H), 6.69 (m, 2H, C-H
quinazoline), and 3.40 (s, 3H, CH3); 13C NMR (DMSO-
d6): δ 29.3, 110.7, 114.0, 115.1, 119.8, 124.0, 124.3, 126.2,
126.8, 128.9, 129.1, 130.2, 133.1, 137.9, 138.9, 141.6,
144.5, 145.9, 150.1, 152.04, 154.4, 155.8, 158.0, and
168.2. Ms: [M+ 531]. Consistent with the molecular
formula C24H17N7O6S.
3-(4-((2-Imino-4-(pyridin-2-yl)-1,3,5-triazin-1(2H)-yl)
sulfonyl)phenyl)-1-methylquinazoline-2,4(1H,3H)-dione
−1
(12i ). Yield 98%, m.p.: 253–255°C, and IR (]max/cm )
1631 and 1705 (2C�O), 3347 (NH); 1H NMR (DMSO-
d6): δ 10.30 (s, 1H, NH), 7.85 (d, 2H, Ar-H), 7.79–7.70
(m, 2H, Ar-H),7.68 (s, 1H, C-H triazine) 7.65–7.30 (m,
4H, Ar-H), 6.72–6.64 (m, 4H, Ar-H), and 3.36 (s, 3H,
CH3); 13C NMR (DMSO-d6): δ 29.4, 110.7, 114.1,
115.1, 118.2, 119.8, 121.2, 123.1, 123.2, 124.2, 126.3,
129.0, 130.1, 131.3, 133.1, 135.2, 137.5, 138.9, 141.7,
146.3, 150.2, 158.1, and 168.2. Ms: [M+ 487]. Con-
sistent with the molecular formula C23H17N7O4S.
3-(4-((4-(4-Fluorophenyl)-2-imino-1,3,5-triazin-1(2H)-yl)
sulfonyl)phenyl)-1-methylquinazoline-2,4(1H,3H)-dione
−1
( 12e ). Yield 96%, m.p.: 248–250°C, and IR (]max/cm )
1717 and 1631 (2C�O) and 3350 (NH); 1H NMR
(CDCl3): δ 10.03 (s, 1H, NH), 8.09 (d, 2H, J � 8.3 Hz., Ar-
H), 7.92 (d, 2H, J � 8.3 Hz, Ar-H), 7.89–7.38 (m, 8H, Ar-
3-(4-((2-Imino-4-(4-methoxyphenyl)-1,3,5-triazin-1(2H)-
yl)sulfonyl)phenyl)-1-methylquinazoline-2,4(1H,3H)-dione
−1
( 12j ). Yield 97%, m.p.: 271–273°C, and IR (]max/cm )
H), 7.07 (s, 1H, C-H triazine), and 3.55 (s, 3H, CH3); 13
C
1631 and 1705 (2C�O) and 3345 (NH); 1H NMR
(DMSO-d6): δ 10.30 (s, 1H, NH), 7.85 (d, 2H, J � 8.2 Hz.
Ar-H), 7.74 (d, 2H, J � 8.2 Hz., Ar-H),7.69 (s, 1H, C-H
triazine), 7.61–7.31 (m, 4H, C-H quinazoline), 6.72–6.64
(m, 4H, Ar-H), 3.84 (s, 3H, CH3), and 3.34 (s, 3H, CH3);
13C NMR (DMSO-d6): δ 29.3, 54.8, 110.7, 112.8, 113.1,
114.0, 115.1, 115.7, 119.7, 122.4, 126.2, 129.0, 132.3, 133.0,
134.2, 137.3, 138.4, 138.9, 141.6, 147.4, 150.1, 157.5, 158.0,
167.2, and 168.2. Ms: [M+ 516]. Consistent with the
molecular formula C25H20N6O5S.
NMR (CDCl3): δ 30.9, 115.6, 117.4, 119.3, 123.8, 124.9,
126.2, 127.2, 128.0, 128.6, 129.0, 130.0, 131.3, 133.1, 137.2,
139.8, 143.6, 147.5, 150.0, 153.9, 157.4, 159.1, 165.7, 167.9,
and 171.2. Ms: [M+ 504]. Consistent with the molecular
formula C24H17FN6O4S.
3-(4-((4-(2-Bromophenyl)-2-imino-1,3,5-triazin-1(2H)-
yl)sulfonyl)phenyl)-1-methylquinazoline-2,4(1H,3H)-dione
−1
( 12f ). Yield 93%, m.p.:220–222°C, and IR (]max/cm )
1702 and 1632 (2C�O) and 3342 (NH); 1H NMR
(CDCl3): δ 10.17 (s, 1H, NH), 8.11 (d, 2H, J � 8.8 Hz,
Ar-H), 8.01 (d, 2H, J � 8.8 Hz, Ar-H), 7.84–7.77 (m, 4H,
Ar-H), 7.61 (s, 1H, C-H triazine), 7.60–7.30 (m, 4H, Ar-
H), and 3.52 (s, 3H,CH3); 13C NMR (CDCl3): δ 29.7,
117.2, 118.8, 121.5, 122.3, 123.2, 125.2, 126.9, 128.1,
2.2. Antitumor Activity. Standard MTT method was used to
evaluate the antitumor activity of the synthesized com-
pounds against HepG2 and HCT116 human tumor cell lines.

Journal of Chemistry
7
1
-e quantitative assay depends on the ability of the mito-
chondrial dehydrogenase of viable cells to cleave the tet-
razolium ring of MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-
diphenyl-2H-tetrazolium bromide). -e produced purple
color is measured spectrophotometrically, and thus the in-
crease or decrease in the cell number can indicate the anti-
tumor activity of tested compounds. -e antitumor activity
was conveyed as the concentration of the compound that
caused 50% growth inhibition (IC50, mean SEM) in com-
parison to the growth of untreated cells. Cells for cell line were
obtained from American Type Culture Collection and cul-
tured using DMEM (Invitrogen) supplemented with 10% FBS
(Hyclone,), 10 μg/ml of insulin (Sigma), and 1% penicillin-
streptomycin. 96-well plate was used for the test. Cells were
treated with serial concentrations of test compounds and
incubated for 48 hours at 37°c, and then the plate was ex-
amined under inverted microscope before the MTTassay. -e
cultures were removed from the incubator to laminar flow
hood, and MTT was added as 10% of the culture medium
volume and then incubated for 2–4 hours. After removal from
the incubator, the formed formazan crystals were dissolved;
using MTT solubilizing solution, the absorbance was mea-
sured at a wavelength of 570 nm [22, 23].
characterized by three peaks in H NMR at 4.0 ppm corre-
sponding to two protons of the thiourea’s NH2 group, at
8.7 ppm corresponding to one proton of thiourea’s NH
proton, and at 6.9 ppm corresponding to the NH proton of
the quinazoline ring. Guanidine derivative (3c), on the other
hand, was characterized by IR spectrum that showed two
−1
−1
carbonyl stretching bands at 1679 cm and 1718 cm , two
NH stretching bands at 3383 and 3393, and NH2 stretching
band at 3423 cm . It was also characterized by 1H NMR that
−1
showed four peaks that were exchangeable with the D2O one
peak downfield at 8.6 ppm and another at 7.0 ppm. Each
corresponds to one proton: one of the guanidine NH group
and the other for the NH proton of the quinazoline ring. A
peak appeared downfield at 5.3 ppm corresponding to two
protons of the terminal amino group of the guanidine, while a
peak appeared upfield at 4.0 ppm corresponding to one
proton of the guanidine NH group. Dimethylformamide
dimethyl acetal (DMF-DMA) is a very valuable reagent for
organic synthesis. It has an electrophilic site represented by
the carbon atom carrying two methoxy groups and nucleo-
philic site represented by dimethyl amino carrying a lone pair
of electrons. -us, DMF-DMA is involved in two types of
reactions: methylation and formylation. Methylation involves
the synthesis of methyl esters from acids. Formylation in-
volves the formation of enaminones from active methylenes.
It can be further cyclized into heterocyclic ring systems, where
enaminones can react with hydrazides to afford the corre-
sponding azoles. It can react with urea, thiourea, and gua-
nidine to afford the corresponding triazines [25, 26]. In the
current work, differently substituted acetophenones or 2-
acetyl thiophene (furan) reacted with DMF-DMA to prepare
the corresponding enaminone derivatives. -is was taken to
the next step, where enaminones (6a–e) in a cyclization re-
action with 6-hydrazinyl-3-phenylquinazoline-2,4(1H,3H)-
dione (2) afforded the corresponding 6(3-1H-1,2,4-triazol-
1-yl)-3-phenylquinazoline-2,4-(1H,3H)-diones (7a–e), as
shown in Scheme 1.
3. Results and Discussion
3.1. Chemistry
3.1.1. Synthesis of 6(3-1H-1,2,4-Triazol-1-yl)-3-phenylquinazoline-
2,4(1H,3H)-diones and 6(4-2-Substituted-1,3,5-Triazin-1(2H)-yl)-
3-phenylquinazoline-2,4(1H,3H)-diones. Synthesis of quina-
zolinones involves different starting materials: one of which
is isatoic anhydride derivatives. In the present work,
6-bromo-3-phenylquinazoline-2,4(1H,3H)-dione (1) was
prepared. Adapting the procedure of Niranjan et al. [24]
where 5-bromoisatoic anhydride reacted with aniline in
ethanol in presence of few drops of acetic acid under ul-
trasonic irradiation, the intermediate was taken to the next
step, where it reacted with hydrazine hydrate to afford 6-
hydrazinyl-3-phenylquinazoline-2,4(1H,3H)-dione (2). -e
intermediate was characterized by IR spectrum that showed
-e series was characterized by 13C NMR where two
carbonyl peaks appeared downfield at above 160 ppm. In 1H
NMR, the characteristic peaks of NH and NH2 of the hy-
drazine moiety disappeared indicating the cyclization to
triazole. -e compounds were also characterized by mass
spectrometry, IR spectroscopy showed characteristic carbonyl
−1
−1
two carbonyl bands at 1639 cm and 1659 cm ; two NH
−1
−1
broad bands appeared at 3373 cm and 3389 cm and a
−1
−1
spike characteristic for NH2 at 3470 cm . -e hydrazinyl
bands at above 1600 cm , and the stretching bands of NH
derivative was also characterized by 1H NMR where 4
protons exchangeable with D2O appeared at 6.5 ppm and
3.4 ppm corresponding to the proton at NH of the quina-
zoline ring and the three hydrazine protons, respectively.
6-Bromo-3-phenylquinazoline-2,4(1H,3H)-dione (1) also
reacted with urea, thiourea, or guanidine in ethanol to afford
1-(2,4-dioxo-3-phenyl-1,2,3,4-tetrahydroquinazolin-6-yl)
thiourea, urea, or guanidine (3a–c). Urea derivative (3a)
and NH2 disappeared. Enaminones (6a–e) also reacted with
1-(2,4-dioxo-3-phenyl-1,2,3,4-tetrahydroquinazolin-6-yl)
thiourea, urea, or guanidine (3a–c) to afford the corre-
sponding
6(4-2-substituted-1,3,5-triazin-1(2H)-yl)-3-
phenylquinazoline-2,4-(1H,3H)-diones (8a–k) through a
cyclization reaction as shown in Scheme 1. -e series were
1
characterized by mass spectrometry, IR spectroscopy, H
NMR, and 13C NMR. -e 2-oxo-1,3,5-triazinyl derivatives
(8a–e) showed three characteristic carbonyl stretching
1
was characterized by H NMR that showed three peaks
−1
exchangeable with D2O: one peak was upfield at 3.6 ppm
corresponding to two protons of the urea’s NH2 group,
and the other was downfield at 9.2 ppm corresponding to
one proton of the urea’s NH group. -e third peak was at
5.5 ppm corresponding to one proton of NH of the quina-
zoline ring. Similarly, thiourea derivative (3b) was
bands above 1600 cm in the IR spectrum with only one
secondary amine stretching band above 3200 cm corre-
sponding to NH of the quinazoline ring, and the stretching
bands of the terminal urea moiety disappeared indicting
cyclization. In 13C NMR, the compounds showed three
peaks downfield at above 160 ppm corresponding to carbonyl
−1

8
Journal of Chemistry
O
Br
N
(NH2)2CX
NH2-NH2
N
H
O
1
O
O
H
NHNH2
N
X
N
N
CH3
OCH3
OCH3
N
H
O
N
H
NH2
+
Ar
O
N
O
3(a–c)
2
X = O, S, NH
4
5(a–e)
+
+
N
Ar
O
6(a–e)
X
NH2
O
NH2
N
O
H
N
O
N
N
N
N
N
Ar
Ar
Ar
N
H
O
N
H
H
O
O
Ar
X
O
N
O
N
N
N
N
N
N
N
H
O
N
H
O
8(a–k)
7(a–e)
O
S
8g X = S, Ar =
8a X= O, Ar =
8b X = O, Ar =
O
S
S
Ar=
,
, Ph, 4-NO2-Ph, 4-F-Ph
8h X = S, Ar = Ph
8i X = S, Ar = 4-NO2-Ph
8j X = S, Ar = 4-F-Ph
8c X = O, Ar = Ph
8d X = O, Ar = 4-NO2-Ph
8e X = O, Ar = 4-F-Ph
S
8k X = NH, Ar =
O
8f X = S, Ar =
Scheme 1: Synthesis of 6(3-1H-1,2,4-triazol-1-yl)-3-phenylquinazoline-2,4(1H,3H)-diones and 6(4-2-substituted-1,3,5-triazin-1(2H)-yl)-
3-phenylquinazoline-2,4(1H,3H)-dione.
carbons. ꢁe 2-thioxo-1,3,5-triazinyl derivatives (8f–8j), on
above 170 ppm. ꢁe 2-imino-1,3,5-triazinyl derivative (8k)
the other hand, showed only two carbonyl stretching bands
showed two characteristic carbonyl bands in the IR spectrum
−1
−1
above 1600 cm , where the thioxo group shows no char-
above 1600 cm and two characteristic secondary amine
−1
acteristic stretching bands. And only one stretching band of
bands above 3200 cm one for NH of the quinazoline ring
−1
the NH secondary amine is above 3200 cm . In 13C NMR, the
and the other for the 2-imino group of the substituting tri-
azine ring at C6. ꢁe imino group appeared as a singlet
compounds showed two down¡eld peaks at above 160 ppm
corresponding to carbonyl carbons and one thioxo carbon at
1
down¡eld at 9.2 ppm in H NMR.

Journal of Chemistry
9
O
NH2
NH2
O
S
O
O
N
+
N
O
H2N
9
10
O
O
O
O
S
NH2
NH2
S
NH
O
N
O
N
HN
N
NH2
N
N
O
O
11
CH3
OCH3
OCH3
N
Ar
+
N
O
Ar
O
4
5(a–j)
6(a–j)
HN
NH2
H
O
S
O
N
O
N
O
N
Ar
N
O
HN
N
Ar
O
S
N
N
O
N
O
N
O
12(a–j)
, Ph, 4-NO2-Ph, 4-F-Ph, 2-Br-Ph, 2-OH-Ph, 4-CH3-Ph,
N
O
S
,
, 4-OCH3-Ph
Ar =
Scheme 2: Synthesis of 3-substituted-2-imino-1,3,5-triazin-1(2H)-yl-sulfonyl-phenyl-1-methylquinazoline-2,4(1H,3H)-dione (12a–j).
3.1.2. Synthesis of 3-Substituted-2-Imino-1,3,5-triazin-
1(2H)-yl-sulfonyl-phenyl-1-methylquinazoline-2,4(1H,3H)-
dione (12a–j). N-methyl isatoic anhydride (9) reacted with
sulfaguanidine (10) in glacial acetic acid under ultrasound
irradiation to a›ord synthesis of N-(diaminomethylene)-
4-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)
benzenesulfonamide (11). ꢁe intermediate was char-
acterized by mass spectrometry, IR, and 1H NMR
spectroscopy. ꢁe IR spectrum showed two carbonyl
−1
stretching bands at above 1600 cm and two secondary
amines stretching bands at 3240 cm−1 and 3345 cm−1 and one
−1
1
primary amine stretching band at 3431 cm . In H NMR
spectrum, the compound showed a singlet up¡eld at 2.8 ppm
corresponding to three protons of the N-methyl. It also
showed three peaks exchangeable with D2O: one down¡eld at
10.3 ppm corresponding to the imino group proton, at

10
Journal of Chemistry
Table 1: In vitro antitumor activity of the tested compounds.
5.7 ppm corresponding to two NH2 protons, and one upfield
at 1.9 ppm corresponding to the NH proton. -at in-
termediate reacted in the cyclization reaction with different
enaminones to afford 3-substituted-2-imino-1,3,5-triazin-
1(2H)-yl-sulfonyl-phenyl-1-methylquinazoline-2,4(1H,3H)-
dione (12a–j), as shown in Scheme 2. -e compounds were
IC50 µM
Compound number
HepG2
HCT116
7a
9.24 0.33
3.20 0.11
4.53 0.12
23.72 .1.9
2.63 0.13
118.1 5.6
2.52 0.69
13.53 0.71
24.54 1.6
14.39 0.8
7.18 0.32
99.43 4.2
11.74 0.67
2.21 0.09
4.75 0.18
1.57 0.06
206.6 9.5
30.93 1.41
6.59 0.27
7.70 0.38
109.3 7.1
11.26 0.81
7c
8a
1
characterized by mass spectrometry, IR, H NMR, and 13C
8b
NMR spectroscopy. -e primary amine stretching bands and
one of the secondary amine stretching bands disappeared in
the IR spectrum, indicating the cyclization. And two of the
D2O exchangeable peaks disappeared in 1H NMR: the one at
1.9 ppm, and the peak of NH2 at 5.7 ppm as additional
evidence that the cyclization reaction took place to yield the
desired products.
8c
8f
8j
12d
12e
12g
Staurosporin
linker to the quinazoline ring-N3 as compounds 12d, 12e, and
12f led to 2-3-fold reduction in the cytotoxic potency of IC50
values of 13.53, 24.54, and 14.39 µM, respectively, in com-
parison to staurosporin.
3.2. Antitumor Screening against HEP-G2 and HCT116 Cell
Lines. -e antitumor activity of compounds 7a, 7b, 8a, 8b,
8c, 8f, 8j, 12d, 12e, and 12j was investigated compared to
staurosporin as a reference drug against human hepato-
cellular carcinoma cell line (HEP-G2) and human colon
carcinoma cell line (HCT116) using the standard MTT
assay method [22]. Tumor cells were incubated either
alone (negative control) or with different concentrations
of the test compounds (100, 25, 6.25, 1.56, and 0.39 μg).
According to Table 1, the tested compounds exhibited
cytotoxic activity of variant degrees depending upon the
substituted heterocyclic ring hybridized with the quinazoline
scaffold. With respect to HepG-2 cancer cell lines, the de-
rivatives 2-oxo-4-phenyl-1,3,5-triazinylquinazoline 8c and 2-
thioxo-4-p-fluorophenyl-1,3,5-triazinylquinazoline 8j repre-
sented significant potency of about 2.6 folds higher than that
of the reference drug (IC50; 2.68, 2.52 µM, respectively vs IC50
staurosporin; 7.18 µM). Slight reduction in the activity was
detected by the 4-furan-2-oxo-1,3,5-triazine analogue 8a but
still was 1.5 fold more potent than staurosporin (IC50,
4.53 µM). An observable decrease in the potency was detected
upon replacement of the furan heterocyclic ring with thio-
phene core as compound 8b (IC50; 23.72 µM). Unfortunately,
drastic drop in the sensitivity of the cancer cells was observed
by the 2-thioxo-4-furan analogue 8f (IC50; 118.1 µM). It could
be noted that the conjugation of aromatic homocyclic sub-
stituents at triazine-C4 produces greater cytotoxic activity
against liver cancer cell (HepG-2) than that obtained by the
heterocyclic moieties. Similarly, the five-membered hetero-
cyclic triazole derivative 7c bearing a phenyl ring at triazole-
C3 represented about 2.1 folds more potent cytotoxic activity
against HepG-2 cancer cell lines than that of the standard
drug of IC50; 3.20 µM, while the activity slightly decreased
upon the attachment of a furan moiety at the triazole-C3
instead of the aromatic homocyclic ring as compound 7a
(IC50; 9.24 µM). It could be noted that the attachment of
aromatic homocyclic moieties to the triazine/triazole rings
enhances the cytotoxic activity of the compounds more than
that of the heterocyclic moieties, which can be explained due
to the increase in the hydrophobicity of the derivatives which
enables them to cause a rapid membrane disruption mech-
anism to kill varying cancer cells [27]. On the other hand, the
attachment of the 2-imino-triazine ring via sulfonylphenyl
With respect to HCT116 cancer cell lines, interestingly,
the compound 8c produced the most potent activity against
the tested cancer cells of the IC50 value: 1.57 µM vs IC50
staurosporin; 11.26 µM, followed by 8a and 8b of IC50 2.21,
4.75 µM. -e activity is about 11-fold greater than the ref-
erence drug. -e sensitivity of colon cancer cells observably
decreased against 8j (IC50; 30.93 µM), while dramatic drop
in the sensitivity was detected against compound 8f of IC50
(206.6 µM). -e triazole derivative 7c produced equipotent
activity to that of the reference drug, while 7a exhibited a
great decrease in the potency of IC50 (99.43 µM). Despite the
activity of the sulphonyl derivatives 12d and 12e being 2–3
folds less than staurosporin in case of HepG-2 cancer cells,
their potency increased to about 1.5 folds higher than that of
the reference drug in case of HCT116 cancer cells (IC50: 6.59
and 7.70 µM), while 12f produced dramatic drop in the
activity (IC50: 109.3 µM). It could be concluded the new
compounds are promising cytotoxic agents; the six-
membered triazine derivatives 8 produced potent broad
cytotoxic activity against the two tested cancer cell lines
followed by the triazole analogues 7a and 7c and then the
sulphonyl derivatives 12d and 12e. Further derivatization is
required for the previous compounds to optimize the an-
ticancer activity.
4. Conclusion
In this study, novel quinazoline-2,4(1H,3H)-diones (7a–e),
(8a–k), and (12a–j) were developed for cytotoxic evaluation
against liver Hep-G2 and colon HCT116 cell lines. -e new
compounds are promising cytotoxic agents. Among the
tested compounds, the six-membered triazine derivatives 8
produced potent broad cytotoxic activity against Hep-G2
and HCT116 cancer cell lines compared to staurosporin
followed by the triazole analogues 7a and 7c and then the
sulphonyl derivatives 12d and 12e.
Data Availability
All data are available as data file in the website of the journal.

Journal of Chemistry
11
“Synthesis and biological evaluation of 2-styrylquinolines as
antitumour agents and EGFR kinase inhibitors: molecular
docking study,” Journal of enzyme inhibition and medicinal
chemistry, vol. 33, no. 1, pp. 199–209, 2017.
Conflicts of Interest
-e authors declare that there are no conflicts of interest.
[12] A. S. Shestakov, O. E. Sidorenko, I. S. Bushmarinov,
K. S. Shikhaliev, and M. Y. Antipin, “3-aryl(alkyl)quinazoline-
2,4(1H,3H)-diones and their alkyl derivatives,” Russian
Journal of organic chemistry, vol. 45, no. 11, pp. 1691–1696,
2009.
[13] K. Al-Zaydi and R. Borik, “Microwave assisted condensation
reactions of 2-aryl hydrazonopropanals with nucleophilic
reagents and dimethyl acetylenedicarboxylate,” Molecules,
vol. 12, no. 8, pp. 2061–2079, 2007.
Acknowledgments
-e project was funded by the Deanship of Scientific Re-
search (DSR) at King Abdulaziz University, Jeddah, under
grant no. G-130-247-39. -e authors, therefore, acknowl-
edge with thanks DSR for technical and financial support.
Supplementary Materials
[14] A. O. Abdelhamid and A. A. Al-Atoom, “Reactions with
hydrazonoyl halides 45: synthesis of some new triazolino[4,3-
a]pyrimidines, pyrazolo[3,4-d]pyridazines, isoxazolo[3,4-d]
pyridazines, and thieno[2,3-b]pyridines,” Synthetic Commu-
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-e supplementary materials are the PDF files for the
original spectroscopic date in the following order (13C NMR,
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[15] N. A. Larina, V. Lokshin, J. Berthet, S. Delbaere,
G. Vermeersch, and V. Khodorkovsky, “Synthesis and pho-
tochromism of a series of new 2-unsubstituted 3-(2-benzyl-
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