Design, synthesis and cytotoxic evaluation of quinazoline-2,4,6-triamine and 2,6-diaminoquinazolin-4(3H)-one derivatives

Article abstract of DOI:10.1007/s00044-018-2188-7

A series of quinazoline-2,4,6-triamine (quinazoline) and 2,6-diaminoquinazolin-4(3H)-one (quinazolinone) derivatives were designed, synthesized and evaluated as cytotoxic agents in three cancer cell lines (HCT-15, SKOV-3, and MDA-MB-231) using conventiona

Full text of DOI:10.1007/s00044-018-2188-7

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-018-2188-7
ORIGINAL RESEARCH
Design, synthesis and cytotoxic evaluation of quinazoline-2,4,6-
triamine and 2,6-diaminoquinazolin-4(3H)-one derivatives
2
Audifás S. Matus-Meza1,2 Marco A. Velasco-Velázquez3 Francisco Hernández-Luis
●
●
Received: 24 November 2017 / Accepted: 4 May 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
A series of quinazoline-2,4,6-triamine (quinazoline) and 2,6-diaminoquinazolin-4(3H)-one (quinazolinone) derivatives were
designed, synthesized and evaluated as cytotoxic agents in three cancer cell lines (HCT-15, SKOV-3, and MDA-MB-231)
using conventional MTT assay. Of the tested compounds, only eleven quinazoline derivatives showed activity against all the
tested cell lines, at 24 h of exposure. Among them, the compounds 3e and 3f exhibited the highest cytotoxic activity, with the
most important IC50 values ranging from 4.5 to 15.5 μM. They were more active than the reference drugs (Gefitinib,
PD153035) which showed IC50 values ranging between 19.4 and 48.8 μM. These compounds open new possibilities for
preparing novel analogous of quinazoline as antitumor agents.
●
●
Keywords Quinazoline-2,4,6-triamine 2,6-diaminoquinazolin-4(3H)-one Cytotoxic activity
Introduction
(Monsuez et al. 2010; Curigliano et al. 2010; Hartmann
et al. 2009). So that, there is a growing demand to identify
new agents and new targets for the treatment of neoplastic
diseases.
Cancer is continuing to be a major health problem in
developing as well as undeveloped countries (WHO Media
Center 2017). Despite the extensive research and rapid
progress in cancer treatment, anticancer drugs used along
with conventional radiotherapy and chemotherapy fre-
quently evoke adverse side effects, severe immunosup-
pression and alarming increase in the incidence of drug
resistance (Massagué and Obenauf 2016; Sbeity and
Younes 2015; Dienstmann and Tabernero 2017; Sudhakar
2009; Charlton and Spicer 2016). Additionally, many cases
of cancer generate sequels that affect the quality of life
Over the past years there has been a considerable interest
in the development and pharmacology of heteroaromatic
organic compounds (Kidwai et al. 2002; Asif 2017;
Nikaljea and Bahetia 2017; Cavalli et al. 2009; Welsch et al.
2010). Among these structures both quinazoline and qui-
nazolinone constitute an important class of pharmacophores
in medicinal chemistry because of their potential in H-
bonding and π–π stacking interactions with aromatic amino
acid residues of receptors (Yadav et al. 2013; Ajani et al.
2016). These nuclei are associated with diverse pharmaco-
logical effects, including antiparasitic (Mendoza-Martínez
et al. 2015), antibacterial (Jafari et al. 2016), antifungal
(Khodarahmi et al. 2012), antiinflamatory (Tiwary et al.
2015; Alagarsamy and Saravanan 2013) and anticancer
activities (Alanazi et al. 2014). Taking all the above find-
ings into consideration, many research groups have dedi-
cated efforts in developing molecules with a particular
biological activity. Such is the case for the drugs Gefitinib,
Erlotinib, and PD153035, all of which share the scaffold of
quinazolin-4-amine and they were developed as therapies
for the treatment of cancer by inhibiting the activity of the
epidermal growth factor receptor (EGFR), which is
involved in the regulation of cell growth, differentiation,
and survival.
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00044-018-2188-7) contains supplementary
material, which is available to authorized users.
* Francisco Hernández-Luis
franher@unam.mx
1
Programa de Maestría y Doctorado en Ciencias Químicas, UNAM,
México City 04510, Mexico
2
Departamento de Farmacia, Facultad de Química, UNAM,
México City 04510, Mexico
3
Departamento de Farmacología y Unidad Periférica de
Biomedicina Translacional, Facultad de Medicina, UNAM,
México City 04510, Mexico

Medicinal Chemistry Research
Fig. 1 Design of target compounds 3a–l, 4a–c, and 5a–c analogs to Gefitinib and PD153035
Accordingly, as a part of our ongoing effort to develop
potential anticancer drugs, in the present study we designed,
synthesized, and characterized fifteen compounds derived
from quinazoline-2,4,6-triamine and three compounds
derived from quinazolin-4-(3H)-one. The quinazoline deri-
vatives are structurally related to Gefitinib and PD153035;
and the quinazolinone derivatives were designed in order to
search if compounds with a hydrogen bond acceptor site
favored cytotoxic activity. All compounds were screened
in vitro by MTT assay using three cancer cell lines: HCT-15
(colorectal cancer), SKOV-3 (ovarian cancer), and MDA-
MB-231 (breast cancer).
removed; both changes increased the number of donor
bonds per hydrogen bond; (c) benzylamine derivatives with
different electron-donating and electron-withdrawing sub-
stituents were added at the 6-position in order that these
substituents had electronic effects on the quinazoline
nucleus and contributed to the modulation of activity; (d)
the 7-position was left unsubstituted to achieve only the
electronic effect of the substituents at 6-position. Addi-
tionally, three quinazoline-2,4,6-triamine with pyridine
substituents at 6-position were proposed (5a–c) with the
intention of analyzing the influence of a benzene ring
change with a heterocycle. Finally, we decided to explore
the relevance of the amino group at the 4-position by
changing it for a carbonyl group to generate the quinazo-
linone derivatives 4a–c.
Chemistry
The synthesis of 3a–l, 4a–c, and 5a–c is shown in
Scheme 1. The starting material, 2-amino-5-nitrobenzoni-
trile, was reacted with guanidine carbonate in a 1:1 ethanol/
propanol mixture at 90 °C and the first intermediate, 6-
nitroquinazoline-2,4-diamine (1), was obtained by a cyclo-
condensation reaction. Subsequently, 1 was subjected to a
hydrogenation under a hydrogen atmosphere using palla-
dium on charcoal (10%) to yield the second intermediate
quinazoline-2,4,6-triamine (2). Reductive amination of this
In our continued exploration for potential anticancer agents
with multi-targeted molecular mechanisms, fifteen com-
pounds were designed as quinazoline derivatives and three
as quinazolinone derivatives (Fig. 1). Within the first group,
twelve molecules (3a–l) were designed with reference to the
drugs Gefitinib and PD153035, considering four modifica-
tions to quinazoline nucleus: (a) an amino group was added
to the 2-position; (b) the phenyl group at the 4-position was

Medicinal Chemistry Research
Scheme 1 Synthetic route for the preparation of the compounds 3a–l, 4a–c, and 5a–c. Reagents and conditions: a EtOH–PrOH, KOH, 1:1, 90 °C,
6 h; b H2, Pd/C 10%, MeOH, 50 min; c DMF–DMA, NaBH4, MeOH 8–12 h; d HCl 6N, 6 h
intermediate with various aryl aldehydes, DMF–DMA,
NaBH4 and MeOH provided amines 3a–l and 5a–c. The
compounds 4a–b were obtained from 3a and 3f, respec-
tively, by refluxing conditions of a solution of HCl (6N) for
4 h; 4c was obtained from 5b under the same reaction
conditions of 4a and 4b. The synthesis of compounds 1 and
2 has been previously reported (Mendoza-Martínez et al.
2015); in this work, the used solvent ratios and reaction
times were modified to try to improve yields.
solubility of the imine intermediate and favor the reduction
of the double bond.
On the other hand, the compounds 4a–c were obtained
directly from the 3a, 3f, and 5b, respectively, because the
reaction between the intermediate 2,6-diaminoquinazolin-4
(3H)-one and the aldehydes generated greater impurities.
Compounds 3a–l and 5a–c had no drawbacks in the reac-
tion mixture; however, their purification was somewhat
laborious.
All the synthesized compounds were characterized by 1H
NMR and 13C NMR, infrared spectroscopy and high-
resolution mass spectrometry (HRMS). All of them pre-
sented signals in common both in the IR and NMR spectra.
In the 1H NMR spectra of the final products, a double signal
that is in the range of 4.21–4.68 ppm, which integrates for
two protons, confirmed the presence of the methylene that
binds the benzylamine substituent to the quinazoline
nucleus. The same signal of the secondary carbon of the
methylene was seen in the 13C NMR spectra at δ value of
41.5–47 ppm for most of the compounds, except for 5c,
which presented it at 59.06 ppm. An important point to note
Result and discussion
Chemistry
The target compounds (3a–l, 4a–c, and 5a–c) were obtained
in yields of moderate to acceptable (50–85%). It is impor-
tant to mention that the target compounds (3a–l and 5a–c)
were synthesized directly without isolating the imine
intermediate; their formation only was monitored by thin
layer chromatography (TLC) and once observed, was added
the NaBH4 with an excess of methanol to increase the
1
in the H NMR of all compounds was that they showed a

Medicinal Chemistry Research
triple common signal corresponding to the amino group at
6-position of the quinazoline nucleus between 5.80 and
6.60 ppm, except for compounds 4a and 5c, (2-amino-6-
(benzylamino)quinazolin-4(3H)-one and 4-(((2,4-diamino-
quinazolin-6-yl)amino)methyl)-6-(hydroxymethyl)-2-
methylpyridin-3-ol), respectively. The amino group at 2-
position was commonly found between 5.49 and 5.57 ppm
for 3b–i, 3k–l, and 5a–c; at 8.61 and 5.78 ppm for 3a and
3j, respectively; and between 5.94 and 6.35 ppm for 4a–c.
The protons of the aromatic ring of quinazoline were
commonly found overlapped with the amino group at 4-
position. In the 13C NMR for compounds 3e–f and 3k, C–F3
couplings were observed as quartets, and C–F for 3j as
doublets (see Supplementary material).
indispensable to keep in this group of compounds amino
groups in 2-positions and 4-positions, and benzylamine
substituted in 6-position of the quinazoline nucleus. The
isosters did not presented good biological activity at the
tested concentration, and the biological activity can be
modulated with the presence of different groups both
electron-withdrawing and electron-donating on the aromatic
ring.
Given these results, the compounds 3a–g and 3i–l were
evaluated for the determination of IC50 at 24 h of exposure
and this was calculated via a sigmoid curve fitting using
GraphPad Prism 6.0 from at least three independent deter-
mination SD. The results are shown in Table 1.
Compounds 3e–f have potent cytotoxic activity, showing
a significant difference with Gefitinib and PD153035 in the
Cytotoxic activity
Table 1 IC50 values of 3a–l against MDA-MB-231, SKOV-3, and
HCT-15 cell lines
All target compounds (3a–l, 4a–c, and 5a–c) and positive
controls (Gefitinib and PD153035) were tested for their
in vitro cytotoxic activity against the HCT-15 (human colon
adenocarcinoma), MDA-MB-231 (human breast adeno-
carcinoma) and SKOV-3 (ovarian adenocarcinoma) cell
lines through two-stage screening process. First, cells were
exposed to a single concentration of each compound (50
µM) during 24 h. The effect on cell viability was estimated
by MTT assay. The results from single concentration
screening (Fig. 2) showed that quinazoline derivatives (3a–
g and 3i–l) reduced cell viability in 80%. On the other hand,
the quinazolinone derivatives (4a–c) and the compounds
(3h, 5a–c) did not show a percentage of growth inhibition
greater than 50%.
The quinazoline derivatives (3a–g and 3i–l), that showed
an excellent percentage of growth inhibition, have a ben-
zylamine substituent at 6-position and amino group in the 2-
positions and 4-positions. The exception the derivative 3h
which has a benzylamine substitutes with a hydroxyl group
at the position meta. Both the quinazolinone derivatives
(4a–c) and the quinazoline derivatives with a pyridine
group at 6-position (5a–c) did not decrease cell growth by
more than 50%. With these results, we can argue that it is
Compounds
IC50 (μM) SD
MDA-MB-231
SKOV-3
HCT-15
3a
21.81 6.5*
14.82 4.3*
10.61 2.8*+
8.89 1.9*+
9.03 2.9*+
15.51 7.2*
19.54 2.9*
10.76 1.1*+
13.72 0.7*+
14.69 9.6*
26.20 2.4*
38.73 3.0
29.34 1.5*+
16.70 2.3*
14.32 0.2*
14.05 0.7*
10.58 3.2*+
10.38 3.5*+
22.97 6.1*
14.62 0.1*
13.20 3.7*
14.40 1.0*
31.93 1.3*+
48.76 3.6
25.64 1.7
3b
13.32 2.7*+
10.57 0.9*+
11.40 0.3*+
4.56 0.4*+
6.23 0.5*+
22.87 5.1*
11.53 0.6*+
12.62 1.3*+
8.19 2.8*+
23.79 5.2
3c
3d
3e
3f
3g
3i
3j
3k
3l
Gefitinib*
PD153035+
29.89 2.8
25.35 2.4
19.40 1.3
25.58 1.6
IC50: concentration of compound (μM) producing 50% cell growth
inhibition after 24 h of exposure
Statistical analyses were performed using ANOVA followed by
Turkey’s multiple comparison test, when comparing the IC50 of
Gefitinib or PD153035 with each of the compounds (3a–l) with *p <
0.05 vs. Gefitinib; +p < 0.05 vs. PD153035
Fig. 2 Activity of compounds
3a–l, 4a–c, and 5a–c on cell
growth of MDA-MB-231,
SKOV-3, and HCT-15 cell lines
to 24 h of exposition. Cell
viability was measured by MTT
assay from at least two
independent determination SD

Medicinal Chemistry Research
three cell lines (MDA-MB-231, SKOV-3 and HCT-15).
With exception of 3a and 3l, all other compounds only
showed significant reductions vs. Gefitinib in the HCT-15
cell line. The result of cytotoxic activity appears to be
related to the electronic effects of the substituents on the
benzene group which connects through a methyl amine
group with the quinazoline nucleus. In Table 1 it can be
seen that most of the compounds have an IC50 below 20 µM
except for 3a, 3g, and 3l. The presence of an electro-
attractant group, such as the nitro group, decreased cyto-
toxicity; however, the trifluoromethoxy group favored the
cytotoxic activity, mainly when they are in the ortho posi-
tion of the benzene ring, probably due to the electronegative
and reactive nature of the fluorine atoms, which also is
appreciated in the cytotoxic activities of compounds 3f, 3j,
and 3k.
400 MHz) δ ppm, 9.07 (1H, d, J = 2.50 Hz, Ar–H), 8.21
(1H, dd, J = 9.2 Hz, 2.50 Hz, Ar–H), 7.83 (2H, s, Ar–NH2),
7.21 (1H, d, J = 9.20 Hz, Ar–H), 6.76 (2H, s, Ar–NH2); 13
C
NMR (DMSO-d6, 101 MHz), δ ppm, 163.23, 162.97,
157.24, 139.13, 126.58, 124.85, 121.88, 108.82 (Ar–C);
MS: m/z (M + H) 206.
Preparation of quinazoline-2,4,6-triamine (2)
A mixture of 3.00 g (17.12 mmol) of 1, 0.33 g (10%) of Pd/
C in 270 mL of methanol were placed in a Parr hydro-
genation flask at a pressure of 60 lb/in2 for 1 h; the reaction
end was consumed at 85 lb/in2. The suspension was then
filtered to remove Pd/C catalyst and the filtrate was eva-
porated in vacuo to yield 0.24 g (yield: 94%) of a light
yellow solid, mp: 250–252 °C; IR (νmax, cm−1): 3399, 3326,
1
3146 (NH), 1559 (C=N), 1520 (C=C); H NMR (DMSO-
d6, 300 MHz), δ ppm, 7.01 (1H, d, J = 9.5 Hz, Ar–H),
6.95–6.98 (1H, m, Ar–H), 6.94 (1H, s, Ar–H), 6.87 (2H, s,
NH2), 5.48 (2H, s, NH2), 4.77 (2H, s, NH2); 13C NMR
(DMSO-d6, 101 MHz), δ ppm, 104.00, 110.95, 123.52,
125.08, 142.14, 145.03, 158.31, 161.40 (Ar–C); MS: m/z
(M + H) 176.
Materials and methods
Melting points were determined in open capillary tubes with
an IA9000 Series Melting Point Apparatus and they were
uncorrected. The reactions were monitored by TLC on
0.2 mm precoated silica gel 60 F254 plates (E. Merck) and
visualized by irradiation with a UV lamp Spectroline Model
ENF-240C. The mass spectrometry was performed by ESI-
MS positive ion detection on a computer. The IR spectra
were obtained on a spectrophotometer Pelkin ATX-Elmer.
1H NMR spectra and 13C NMR were acquired in DMSOd6
on a Varian 300 and 400 MHz equipment; chemical shifts
were obtained in parts per million (ppm), by using the
deuterated solvent itself as reference. Splitting patterns have
been designated as follows: s, singlet; d, doublet; q, quartet;
dd, doublet of doublet; t, triplet; m, multiplet; br s, broad
singlet. Catalytic hydrogenations were carried out in a Parr
Shaker Hydrogenation apparatus. The starting materials 2-
amine-5-nitrobenzonitrile, guanidine carbonate, and alde-
hydes are commercially available (Sigma Aldrich).
PD153035 was synthetized following the synthesized
reported by VanBrocklin et al. 2005 and Gefitinib was
purchased of Santa Cruz Biotechnology (SC-202166).
General procedures for the synthesis of compounds 3a–l
and 5a–c
To a solution of 0.50 g (2.85 mmol) of 2 in 15 mL of
methanol was added 1.2 equivalents of the corresponding
aryl aldehyde with ten drops of DMF-DMA. The mixture of
the reaction was heated to 40 °C for 12 h. After cooling to
room temperature, NaBH4 (11.4 mmol) in 50 mL of
methanol were added and then stirred for an additional 12 h.
The mixture of the reaction was poured into a solution of
NaHCO3; the solid formed was filtered off and washed
subsequent with water. After dried under vacuum condition,
the crude product was purified by recrystallization from a
methanol/water mixture.
General procedures for the synthesis of compounds 4a–c
Compounds 3a or 3f or 5b, (0.43 mmol) were placed in
15 mL of HCl (6N) and stirred for 4 h to 90 °C. When
reaction was completed, the mixture was cooled to 5 °C and
neutralized by adding an appropriate amount of aqueous
solution of NaOH (1 M). The precipitated solid formed was
collected by filtration, washed with water, dried, and crys-
tallized from a methanol/water mixture.
Preparation of 6-nitroquinazoline-2,4-diamine (1)
A mixture of 5.00 g (30.64 mmol) of 2-amino-5-nitro-
benzonitrile, 4.17 g (23.03 mmol) guanidine carbonate and
2.05 g (36.77 mmol) of KOH in 25 mL of ethanol and
50 mL propanol was refluxed for 6 h. The warm suspension
was separated by filtration and the solid collected was
washed successively with water and methanol to obtain
5.35 g (yield: 85%) of an orange solid; mp: 359–362 °C; IR
(νmax, cm−1): 3463, 3440, 3106 (NH), 1614, 1460 (C=C),
N6-benzylquinazoline-2,4,6-triamine (3a) Yield: 70%, mp:
299–302 °C; IR (νmax, cm−1): 3317, 3148 (NH), 1633, 1588
1
(C=C aromatic), 1588, 1536 (C=N); H NMR (DMSO-d6,
1
1661 (C=N), 1325, 1295 (C–NO2); H NMR (DMSO-d6,
400 MHz), δ ppm, 8.61 (2H, s, Ar–NH2), 7.42 (2H, d, J =

Medicinal Chemistry Research
7.4 Hz, Ar–H), 7.37 (2H, s, Ar–NH2), 7.33–7.28 (2H, m,
Ar–H), 7.32 (1H, d, J = 1.9 Hz, Ar–H), 7.25 (1H, dd, J =
9.0, 2.1 Hz, Ar–H), 7.24–7.19 (1H, m, Ar–H), 7.20 (1H, d,
J = 8.93 Hz, Ar–H), 6.56 (1H, t, J = 6.1 Hz, NH), 4.35 (2H,
d, J = 6.1 Hz, CH2); 13C NMR (DMSO-d6, 101 MHz), δ
ppm, 162.47, 153.65, 145.75, 139.56, 131.12, 128.21,
127.70, 126.76, 124.15, 117.82, 110.12, 101.72 (Ar–C),
46.51 (Ar–CH2–NH); ESI-MS m/z: calcd for C15H16N5 [M
+ H]+ 266.1400, found 266.1404.
N6-(2-(trifluoromethoxy)benzyl)quinazoline-2,4,6-triamine
(3e) Yield: 82%, decomp. point: 300.1–301.5 °C; IR (νmax
,
cm−1): 3629, 3444, 3428, 3356, 3112 (NH), 2817 (C–H),
1673, 1616 (C=C aromatic), 1569, 1526 (C=N), 1244,
1
1201, 1179, 1155, 815, 760 (C–F3); H NMR (DMSO-d6,
400 MHz), δ ppm, 7.51–7.56 (1H, ddd, J = 7.3, 1.8, 0.6 Hz,
Ar–H), 7.32–7.42 (3H, m, Ar–H), 7.03–7.18 (2H, d, Ar–H),
6.97 (s, 3H, NH2, Ar–H), 5.87 (t, 1H, J = 6.1 Hz, NH), 5.57
(s, 2H, NH2), 4.37 (d, 2H, J = 6.0 Hz, CH2); 13C NMR
(DMSO-d6, 101 MHz), δ ppm, 161.49, 158.38 (Ar–C),
146.72 (q, J = 1.5 Hz, Ar–C), 145.08, 142.62, 132.40,
129.81, 128.60, 127.33, 125.08, 123.15, 120.44 (Ar–C),
120.33 (q, J = 256.5 Hz, O–CF3), 110.78, 100.52, 41.54
(Ar–CH2–NH); ESI-MS m/z: calcd for C16H15N5OF [M +
H]+ 350.1223, found 350.1222.
N6-(2-chlorobenzyl)quinazoline-2,4,6-triamine (3b) Yield:
75%, mp: 72.7–74.1 °C; IR (νmax, cm−1): 3336, 3110 (NH),
1627 (C=C aromatic), 1543, 1521 (C=N), 1036, 740
(C–Cl); 1H NMR (DMSO-d6, 300 MHz,), δ ppm, 7.43–7.47
(2H, m, Ar–H), 7.24–7.31 (2H, m, Ar–H), 7.08–7.11 (1H,
dd, J = 9.1, 1.9 Hz, Ar–H), 7.05–7.08 (1H, d, J = 8.8 Hz,
Ar–H), 7.01 (2H, s, NH2), 6.96 (1H, s, Ar–H), 5.92 (1H, t,
J = 6.1 Hz, NH), 5.57 (2H, s, NH2), 4.38 (2H, d, J = 6.1 Hz,
CH2); 13C NMR (DMSO-d6, 75 MHz), δ ppm, 161.52,
158.46, 145.26, 142.65, 137.20, 132.69, 129.29, 129.22,
128.48, 127.06, 125.24, 123.24, 110.85, 100.41 (Ar–C),
44.89 (Ar–CH2–NH); ESI-MS m/z: calcd for C15H15N5Cl
[M + H]+ 300.1010, found 300.1011.
N6-(4-(trifluoromethoxy)benzyl)quinazoline-2,4,6-triamine
(3f) Yield: 85%, mp: 213.0–214.1 °C; IR (νmax, cm−1):
3630, 3445, 3351, 3109 (NH), 2852 (C–H), 2060, 1896
(overtone = CH2), 1673, 1621 (C=C aromatic), 1570, 1522
1
(C=N), 1288, 1257, 1216, 1196, 1158, 822 (C–F3); H
NMR (DMSO-d6, 400 MHz), δ ppm, 7.54 (2H, d, J =
8.7 Hz, Ar–H), 7.31 (2H, d, J = 7.9 Hz, Ar–H), 7.04 (2H, s,
Ar–H), 6.96 (3H, s, NH2, Ar–H), 6.01 (1H, t, J = 6.2 Hz,
N6-(3-chlorobenzyl)quinazoline-2,4,6-triamine (3c) Yield:
80%, mp: 98.6–101.4 °C; IR (νmax, cm−1): 3441, 3351,
3132 (NH), 2817 (C–H), 1656, 1623 (C=C aromatic),
1574, 1523 (C=N), 1076, 830, 771 (C–Cl); 1H NMR
(DMSO-d6, 400 MHz), δ ppm, 7.44–7.50 (1H, m, Ar–H),
7.36–7.39 (1H, dt, J = 7.7, 1.5 Hz, Ar–H), 7.34 (1H, t, J =
7.6 Hz, Ar–H), 7.26–7.29 (1H, dt, J = 7.5, 1.7 Hz, Ar–H),
7.05 (1H, s, Ar–H), 7.04 (1H, s, Ar–H), 6.99 (2H, s, NH2),
6.94 (1H, s, Ar–H), 6.06 (1H, t, J = 6.3 Hz, NH), 5.57 (2H,
s, NH2), 4.31 (2H, d, J = 6.3 Hz, CH2); 13C NMR
(101 MHz, DMSO-d6), δ ppm, 158.29, 144.80, 143.07,
142.47, 132.94, 130.06, 127.38, 126.59, 126.31, 124.96,
123.36, 110.72, 100.58 (Ar–C), 46.17 (Ar–CH2–NH); ESI-
MS m/z: calcd for C15H15N5Cl [M + H]+ 300.1010, found
300.1011.
NH), 5.53 (2H, s, NH2), 4.33 (2H, d, J = 6.2 Hz, CH2); 13
C
NMR (DMSO-d6, 101 MHz), δ ppm, 161.42, 158.43
(Ar–C), 147.11 (q, J = 1.8 Hz, Ar–C), 145.30, 142.51,
139.82, 129.39, 125.19, 123.33, 120.80 (Ar–C), 120.12 (d,
J = 255.8 Hz, OCF3), 110.74, 100.46, 46.16 (Ar–
CH2–NH); ESI-MS m/z: calcd for C16H15N5OF [M + H]+
350.1223, found 350.1223.
N6-(4-nitrobenzyl)quinazoline-2,4,6-triamine (3g) Yield:
70%, mp: 299.4–302.0 °C; IR (νmax, cm−1): 3456, 3320,
3105 (NH), 1623, 1604 (C=C aromatic), 1564, 1506
(C=N), 1338, 821 (C–NO2); 1H NMR (DMSO-d6,
400 MHz), δ ppm, 8.19 (2H, d, J = 8.7 Hz, Ar–H), 7.66
(2H, d, J = 8.7 Hz, Ar–H), 7.05 (2H, s, Ar–H), 6.94 (2H, s,
NH2), 6.91 (1H, s, Ar–H), 6.20 (1H, t, J = 6.4 Hz, NH),
5.54 (2H, s, NH2), 4.46 (2H, d, J = 6.3 Hz, CH2); 13C NMR
(DMSO-d6, 101 MHz), δ ppm, 161.39, 158.40, 148.94,
146.35, 145.20, 142.18, 128.43, 125.19, 123.31, 123.21,
110.70, 100.61 (Ar–C), 46.19 (Ar–CH2–NH); ESI-MS m/z:
calcd for C15H15N6O2 [M + H]+ 311.1251, found 311.1253.
N6-(4-chlorobenzyl)quinazoline-2,4,6-triamine (3d) Yield:
80%, mp: 128.6–131.8 °C; IR (νmax, cm−1): 3348, 3115
(NH), 1621, 1566 (C=C aromatic), 1522 (C=N), 1013,
1089, 808 (C–Cl); 1H NMR (DMSO-d6, 400 MHz), δ ppm,
7.43 (2H, d, J = 8.6 Hz, Ar–H), 7.36 (2H, d, J = 8.5 Hz,
Ar–H), 7.06–7.03 (1H, dd, 1H, J = 9.9, 2.7 Hz, Ar–H), 7.02
(1H, d, J = 7.6 Hz, Ar–H), 6.93 (1H, d, J = 1.3 Hz, Ar–H),
6.92 (2H, s, NH2), 5.98 (1H, t, J = 6.3 Hz, NH), 5.49 (2H, s,
NH2), 4.29 (2H, d, J = 62 Hz, CH2); 13C NMR (DMSO-d6,
101 MHz), δ ppm, 161.43, 158.44, 145.26, 142.49, 139.33,
131.15, 129.50, 128.13, 125.17, 123.37, 110.75, 100.56
(Ar–C), 46.17 (Ar–CH2–NH); ESI-MS m/z: Calcd for
C15H15N5Cl [M + H]+ 300.1010, found 300.1011.
3-(((2,4-diaminoquinazolin-6-yl)amino)methyl)phenol
(3h) Yield: 50%, mp: 180.2–182.7 °C; IR (νmax, cm−1):
3372 (NH), 3147 (OH), 1656, 1619 (C=C aromatic), 1574,
1
1525 (C=N), 1252, 818, 782 (C–O); H NMR (DMSO-d6,
400 MHz), δ ppm, 9.32 (1H, s, OH), 7.10 (1H, t, J = 7.7 Hz,
Ar–H), 7.06 (1H, dd, J = 9.0, 2.1 Hz, Ar–H), 7.03 (1H, d, J
= 8.8 Hz, Ar–H), 6.95 (1H, d, J = 1.8 Hz, Ar–H), 6.93 (2H,
s, NH2), 6.79–6.86 (2H, m, Ar–H), 6.62 (1H, ddd, J = 8.1,

Medicinal Chemistry Research
2.3, 1.0 Hz, Ar–H), 5.84 (1H t, J = 6.1 Hz, NH), 5.49 (2H,
s, NH2), 4.21 (2H, d, J = 6.0 Hz, CH2); 13C NMR (DMSO-
d6, 101 MHz), δ ppm, 161.42, 158.33, 157.35, 145.11,
142.91, 141.65, 129.11, 125.05, 123.34, 118.28, 114.45,
113.62, 110.79, 100.38 (Ar–C), 47.04 (Ar–CH2–NH); ESI-
MS m/z: calcd for C15H16N5O [M + H]+ 282.1349, found
282.1353.
132.56 (q, J = 32.1 Hz, Ar–CF), 130.48 (q, J = 31.1 Hz,
Ar–CF), 127.35 (q, J = 5.7 Hz, Ar–CF), 125.97 (q, J =
3.5 Hz, Ar–CF), 125.46 (Ar–C), 124.37 (q, J = 3.6 Hz, Ar–
CF), 122.92 (Ar–C), 122.47–125.20 (d, J = 275.94, Ar–
CF), 122.15–124.87 (d, J = 274.07 Hz, Ar–CF), 110.79,
100.73 (Ar–C), 43.00–44.90 (m, Ar–CH2–NH); ESI-MS m/
z: calcd for C17H14N5F6 [M + H]+ 402.1148, found
402.1149.
N6-(4-methylbenzyl)quinazoline-2,4,6-triamine (3i) Yield:
85%, mp: 209.7–211.3 °C; IR (νmax, cm−1): 3634, 3439,
3346, 3114 (NH), 2974, 2922, 2853 (C–H), 2049, 1890
(overtone =CH2), 1671, 1618 (C=C aromatic), 1565, 1515
(C=N), 1489, 1440, 1341, 820, 799 (CH3); 1H NMR
(DMSO-d6, 400 MHz), δ ppm, 7.30 (2H, d, J = 8.0 Hz,
Ar–H), 7.12 (2H, d, J = 7.8 Hz, Ar–H), 7.05 (1H, dd, J =
9.0, 2.2 Hz, Ar–H), 7.02 (1H, d, J = 8.6 Hz, Ar–H), 6.95
(1H, d, J = 1.8 Hz, Ar–H), 6.94 (2H, s, NH2), 5.84 (1H, t, J
= 6.1 Hz, NH), 5.50 (2H, s, NH2), 4.24 (2H, d, J = 6.0 Hz,
CH2), 2.26 (3H, s, CH3); 13C NMR (DMSO-d6, 101 MHz),
δ ppm, 161.45, 158.37, 145.13, 142.84, 137.02, 135.70,
128.78, 127.75, 125.04, 123.48, 110.77, 100.50 (Ar–C),
46.85 (Ar–CH2–NH), 20.73 (CH3); ESI-MS m/z: calcd for
C16H18N5 [M + H]+ 280.1557, found 280.1558.
N6-(2-nitrobenzyl)quinazoline-2,4,6-triamine
(3l) Yield:
70%, mp: 186.9–189.0 °C; IR (νmax, cm−1): 3423, 3322,
3178 (NH), 1630 (C=C aromatic), 1560, 1513 (C=N),
1
1326, 821 (C–NO2); H NMR (DMSO-d6, 400 MHz), δ
ppm, 8.07–8.13 (1H, m, Ar–H), 7.64–7.68 (1H, m, Ar–H),
7.63 (1H, dd, J = 7.8, 2.0 Hz, Ar–H), 7.50 (1H, ddd, J =
8.7, 6.5, 2.3 Hz, Ar–H), 7.09 (1H, dd, J = 8.9, 2.3 Hz,
Ar–H), 7.06 (1H, d, J = 8.8 Hz, Ar–H), 6.87 (2H, s, NH2),
6.77 (1H, d, J = 2.0 Hz, Ar–H), 6.14 (1H, t, J = 6.2 Hz,
NH), 5.49 (2H, s, NH2), 4.68 (2H, d, J = 6.2 Hz, CH2); 13
C
NMR (DMSO-d6, 101 MHz), δ ppm, 161.38, 158.49,
148.23, 145.38, 142.08, 136.14, 133.72, 129.26, 127.93,
125.35, 124.93, 123.21, 110.72, 100.24 (Ar–C), 44.37 (Ar–
CH2–NH); ESI-MS m/z: calcd for C15H15N6O2 [M + H]+
311.1251, found 311.1252.
N6-(2,4-difluorobenzyl)quinazoline-2,4,6-triamine
(3j)
Yield: 85%, mp: 183.1–184.8 °C; IR (νmax, cm−1): 3479,
3423, 3319 (NH), 1614 (C=C aromatic), 1558, 1520
(C=N), 1295, 1264, 1243 (CF) 1H; NMR (DMSO-d6,
300 MHz), δ ppm, 7.47 (1H, td, J = 8.7, 7.0 Hz, Ar–H),
7.19–7.28 (1H, m, Ar–H), 7.15 (2H, s, NH2), 7.01–7.10
(3H, m, Ar–H), 6.98 (1H, s, Ar–H), 5.96 (1H, t, J = 6.1 Hz,
2-amino-6-(benzylamino)quinazolin-4(3H)-one (4a) Yield:
60%, mp: 267.8–268.5 °C; IR (νmax, cm−1): 3470, 3431,
3321 (NH), 3028 C–H), 1656 (C=O), 1615 (C=C aro-
1
matic), 1493 (C=N); H NMR (DMSO-d6, 400 MHz), δ
ppm, 7.36 (2H, d, J = 7.1 Hz, Ar–H), 7.30 (2H, t, J =
7.2 Hz, Ar–H), 7.20 (1H, t, J = 6.7 Hz, Ar–H), 7.05 (2H, s,
Ar–H), 6.95 (1H, s, Ar–H), 6.35 (2H, s, NH2), 4.28 (2H, s,
CH2); 13C NMR (DMSO-d6, 101 MHz), δ ppm, 163.97
(O=C–NH), 150.30 (N=C–NH), 144.34, 140.38, 140.13,
128.47, 127.28, 126.82, 123.38, 122.49, 117.67, 104.86
(Ar–C), 47.01 (Ar–CH2–NH); ESI-MS m/z: calcd for
C15H15N4O [M + H]+ 267.1240, found 267.1241.
NH), 5.78 (2H, s, NH2), 4.31 (2H, d, J = 6.0 Hz, CH2); 13
C
NMR (DMSO-d6, 75 MHz), δ ppm, 161.52 (Ar–C),
159.81–163.05 (d, J = 244.7 Hz, Ar–CF), 159.66–162.89
(d, J = 244.3 Hz, Ar–CF), 158.52, 145.39, 142.47 (Ar–C),
130.66–130.87 (dd, J = 9.7, 6.3 Hz, Ar–CF), 125.26,
123.37 (Ar–C), 122.92–123.17 (dd, J = 15.2, 3.5 Hz, Ar–
CF), 110.78–111.24 (dd, J = 20.8, 3.3 Hz, Ar–CF), 110.78
(Ar–C), 103.69 (t, J = 25.8 Hz, Ar–CF), 100.53 (Ar–C),
40.45 (d, J = 3.2 Hz, Ar–CH2–NH); ESI-MS m/z: calcd for
C15H14N5F2 [M + H]+ 302.1212, found 302.1214.
2-amino-6-((4-(trifluoromethoxy)benzyl)amino)quinazolin-4
(3H)-one (4b) Yield: 58%, mp: 335.6–336.0 °C; IR (νmax
,
cm−1): 3321, 3148 (NH), 2850 (C–H), 1643 (C=O), 1616
(C=C aromatic), 1551, 1532 (C=N), 1256, 1218, 1200,
1156, 820 (C–F); 1H NMR (DMSO-d6, 400 MHz), δ
ppm, 10.80 (1H, s, NH), 7.48 (2H, d, J = 8.6 Hz, Ar–H),
7.31 (2H, d, J = 8.0 Hz, Ar–H), 7.02 (2H, s, Ar–H),
6.90 (1H, s, Ar–H), 6.30 (1H, t, J = 6.0 Hz, NH), 5.95 (2H,
s, NH2), 4.31 (2H, d, J = 5.9 Hz, CH2); 13C NMR (DMSO-
N6-(2,5-bis(trifluoromethyl)benzyl)quinazoline-2,4,6-tria-
mine (3k) Yield: 60 %, mp: 92.1–93.0 °C IR (νmax, cm−1):
3345, 3136 (NH), 1659, 1625 (C=C aromatic), 1594, 1565
(C=N), 1309, 1165, 1120, 1087, 836, 818 (C–F); 1H NMR
(DMSO-d6, 400 MHz), δ ppm, 7.99 (1H, d, J = 8.2 Hz,
Ar–H), 7.96 (1H, s, Ar–H), 7.86 (1H, d, J = 8.1 Hz, Ar–H),
7.08 (1H, d, J = 8.9 Hz, Ar–H), 7.05 (1H, dd, J = 9.0,
2.2 Hz, Ar–H), 6.97 (1H, d, J = 1.8 Hz, Ar–H), 6.94 (2H, s,
NH2), 6.09 (1H, t, J = 6.1 Hz, NH), 5.53 (2H, s, NH2), 4.54
(2H, d, J = 5.8 Hz, CH2); 13C NMR (DMSO-d6, 101 MHz),
δ ppm, 161.50, 158.67, 145.73, 142.23, 140.81 (Ar–C),
d6, 101 MHz),
δ ppm, 162.18 (O=C–NH), 149.05
(N=C–NH), 147.07, 143.67, 142.92, 139.72, 128.91,
125.04, 122.51, 121.00, 117.73 (Ar–C), 116.32–123.95 (q,
J = 255 Hz, OCF3), 104.49, 46.12 (Ar–CH2–NH); ESI-MS
m/z: calcd for C16H14N4O2F3 [M + H]+ 351.1063, found
351.1066.

Medicinal Chemistry Research
2-amino-6-((pyridin-4-ylmethyl)amino)quinazolin-4(3H)-
one (4c) Yield: 65%, mp: 241.0–242.2 °C; IR (νmax, cm
−1): 3314, 3145 (NH), 2906, 2830 (C–H), 1647 (C=O),
1617 (C=C aromatic), 1561, 1531 (C=N); 1H NMR
(DMSO-d6, 400 MHz), δ ppm, 10.91 (1H, s, NH), 8.48
(2H, d, J = 5.7 Hz, Ar–H), 7.35 (2H, d, J = 5.8 Hz, Ar–H),
7.02 (2H, s, Ar–H), 6.86 (1H, s, Ar–H), 6.38 (1H, t, J =
6.1 Hz, NH), 6.05 (2H, s, NH2), 4.33 (2H, d, J = 6.0 Hz,
CH2); 13C NMR (DMSO-d6, 101 MHz), δ ppm, 162.36
(O=C–NH), 150.33 (N=C–NH), 149.56, 143.53, 124.97,
122.63, 122.26, 121.60, 117.69, 104.64 (Ar–C), 45.83 (Ar–
CH2–NH); ESI-MS m/z: calcd for C14H14N5O [M + H]+
268.1193, found 268.1201.
MTT cytotoxicity assay
The cytotoxicity activities of compounds 3a–l, 4a–c,
and 5a–c were evaluated against HCT-15, MDA-MB-231,
and SKOV-3 (colorectal, breast and ovarian cancer,
respectively) using the standard MTT assay in vitro with
Gefitinib and PD153035 as positive controls. The cell lines
were acquired from American Type Culture Collection
(ATCC).
The cell were maintained in RPMI-1640 medium
(Invitrogen, 31800022) supplement with heat inactivated
10% fetal bovine serum (FBS) (Byproducts, SFB
500MX) in a humidified atmosphere of 5% CO2, 95%
air at 37 °C.
Each cell line was seeded overnight onto 96-well plate
with RPMI-1640 medium, 10% FBS at a density of 8 × 103
cells per well. Thereafter, the tested compounds were added
at 50 µM for the first screening and (50–0.78 µM) for IC50
determination. Cell viability was determined after 24 h by
addition of an MTT solution (15 µL of 5 mg/mL MTT in
PBS) and incubation at 37 °C for 2 h. In each of the wells,
the supernatant was carefully removed and 100 µL of
DMSO were added to dissolve the formazan crystals formed
by the cellular reduction of MTT. The absorbance at 570 nm
was measured with a microplate reader (Epoch Microplate
Spectrophotometer, Biotek). The results were expressed as
the IC50 (μM) which is the concentration of the compounds
inducing a 50% inhibition of cell growth of the cells treated
when compared to the growth of control cells. Each
experiment was performed four times at least three inde-
pendent experiments.
N6-(pyridin-3-ylmethyl)quinazoline-2,4,6-triamine
(5a)
Yield: 70%, mp: 230.3–233.6 °C; IR (νmax, cm−1): 3459,
3331, 3089, 1417 (NH), 1666, 1629 (C=C aromatic), 1543,
1
(C=N); H NMR (DMSO-d6, 400 MHz), δ ppm, 8.64 (1H,
d, J = 1.7 Hz, Ar–H), 8.43 (1H, dd, J = 4.8, 1.6 Hz, Ar–H),
7.80 (1H, dt, J = 7.8, 1.9 Hz, Ar–H), 7.34 (1H, ddd, J = 7.8,
4.8, 0.7 Hz, Ar–H), 7.04 (2H, s, Ar–H), 6.97 (1H, s, Ar–H),
6.95 (2H, s, NH2), 6.02 (1H, t, J = 6.3 Hz, NH), 5.51 (2H, s,
NH2), 4.32 (2H, d, J = 6.2 Hz, CH2); 13C NMR (DMSO-d6,
101 MHz), δ ppm, 161.41, 158.44, 149.23, 147.94, 145.32,
142.36, 135.49, 135.35, 125.18, 123.43, 123.37, 110.69,
100.61 (Ar–C), 44.48 (Ar–CH2–NH); ESI-MS m/z: calcd
for C14H15N6 [M + H]+ 267.1353, found 267.1361.
N6-(pyridin-4-ylmethyl)quinazoline-2,4,6-triamine
(5b)
Yield: 70%, mp: 249.5–250.2 °C; IR (νmax, cm−1): 3408,
3334, 3074 (NH), 2847, 2803 (C–H), 1639 (C=C aro-
matic), 1565, 1516 (C=N); 1H NMR (DMSO-d6,
400 MHz), δ ppm, 8.45–8.52 (2H, m, Ar–H), 7.37–7.41
(2H, m, Ar–H), 7.06 (2H, d, J = 1.4 Hz, Ar–H), 6.93 (2H, s,
NH2), 6.90–6.92 (1H, m, Ar–H), 6.11 (1H, t, J = 6.5 Hz,
Conclusions
NH), 5.53 (2H, s, NH2), 4.35 (2H, d, J = 6.4 Hz, NH2); 13
C
In order to develop new bioactive heterocyclic compounds,
synthesis and screening of biological activity was per-
formed using the MTT assay of quinazoline-2,4,6-triamine
derivatives and 2,6-diaminoquinazolin-4(3H)-one. Cell
viability assay data (50 µM at 24 h) revealed that among the
eighteen compounds studied, quinazoline-2,4,6-triamine
derivatives (3a–l) showed inhibition of cell growth greater
than 50% compared to quinazolinone (4a–c) and pyridine
derivatives (5a–c) against three cell lines (HCT-15, SKOV-
3, and MDA-MB-231). Determination of the IC50 showed
that the compounds 3e–f exhibited high activity patterns
against the three cell lines compared to the two controls
(Gefitinib and PD153035). Compounds 3e–f are character-
ized by having a trifluoromethoxy substituent in the ben-
zene ring. Owing to significant results obtained, chemical
studies are being conducted to improve the citotoxic activity
of quinazoline-2,4,6-triamine diversified the pattern of tri-
fluoromethoxy substitution.
NMR (DMSO-d6, 101 MHz), δ ppm, 161.4, 158.49, 149.52,
149.37, 145.41, 142.27, 125.29, 123.22, 122.64, 110.73,
100.59 (Ar–C), 45.74 (Ar–CH2–NH); ESI-MS m/z: calcd
for C14H15N6 [M + H]+ 267.1353, found 267.1358.
4-(((2,4-diaminoquinazolin-6-yl)amino)methyl)-6-(hydroxy-
methyl)-2-methylpyridin-3-ol (5c) Yield: 60%, mp >350 °
C; IR (νmax, cm−1): 3336, 3197 (NH), 1649, 1623 (C=C
aromatic), 1562, 1535 (C=N); 1H NMR (DMSO-d6,
300 MHz), δ ppm, 7.85 (1H, s, Ar–H), 7.23 (1H, s, Ar–H),
7.02 (4Hs, Ar–H, NH2), 5.57 (2H, s, NH2), 4.53 (2H, s,
CH2), 4.31 (2H, s, CH2), 2.35 (3H, s, CH3); 13C NMR
(DMSO-d6, 75 MHz), δ ppm, 161.69, 158.68, 151.45,
146.49, 145.71, 142.70, 138.30, 134.17, 130.75, 124.92,
123.98, 110.69, 102.37 (Ar–C), 59.06 (Ar–CH2–OH),
19.95 (Ar–CH3); ESI-MS m/z: calcd for C16H19N6O2 [M +
H]+ 327.1564, found 327.1565.

Medicinal Chemistry Research
Acknowledgements This study was sponsored by grants from
UNAM-DGAPA-PAPIIT IN218117 and CONACYT-CB220664. We
are grateful to Rosa Isela del Villar, Nayeli López and Marisela
Gutiérrez from Facultad de Química, USAI, UNAM for the determi-
nation of IR and NMR spectra. Also, we thank to Geiser Cuéllar-
Rivera, from Department of Chemistry of the CINVESTAV, for the
analytical support in the mass spectrometry; Adriana-Guadalupe
Pérez-Ruiz for assisting with the counseling of biological tests; Abi-
mael Mondragón-Peralta for assisting with the biological evaluation;
José Fausto Rivero-Cruz for his technical assistance.
effects. Curr Drug Metab 10:470–481. https://doi.org/10.2174/
138920009788897975
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Compliance with ethical standards
Massagué J, Obenauf AC (2016) Metastatic colonization by circulat-
ing tumour cells. Nature 529:298–306. https://doi.org/10.1038/na
ture17038
Conflict of interest The authors declare that they have no conflict of
interest.
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Navarro A, Aguilar-Suárez R, Montero-Cortes MD, Nogueda-
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