Looking for new antiplasmodial quinazolines: DMAP-catalyzed synthesis of 4-benzyloxy- and 4-aryloxy-2-trichloromethylquinazolines and their in vitro evaluation toward Plasmodium falciparum

Article abstract of DOI:10.1016/j.ejmech.2016.04.059

A DMAP catalyzed synthesis of new 4-benzyloxy- and 4-aryloxy-2-trichloromethylquinazolines was studied, in a view to react 4-chloroquinazolines with poorly nucleophilic alcohols such as benzylic alcohols, via a simple and cheap S_NAr reaction ap

Full text of DOI:10.1016/j.ejmech.2016.04.059

European Journal of Medicinal Chemistry 119 (2016) 34e44
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Research paper
Looking for new antiplasmodial quinazolines: DMAP-catalyzed
synthesis of 4-benzyloxy- and 4-aryloxy-2-
trichloromethylquinazolines and their in vitro evaluation toward
Plasmodium falciparum
a
a
b
a
a
ꢀ
Armand Gellis , Nicolas Primas , Sebastien Hutter , Gilles Lanzada , Vincent Remusat ,
Pierre Verhaeghe c *, Patrice Vanelle a **, Nadine Azas b
Aix-Marseille Universite, CNRS, ICR UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculte de Pharmacie, 27 Boulevard Jean Moulin e CS30064,
,
,
a
ꢀ
ꢀ
13385 Marseille cedex 05, France
b
ꢀ
ꢀ
ꢀ
Aix-Marseille Universite, UMR MD 3, Infections Parasitaires, Transmission et Therapeutique, Faculte de Pharmacie, 27 Boulevard Jean Moulin e CS30064,
13385 Marseille cedex 05, France
c
ꢀ
ꢀ
Universite Paul Sabatier, Faculte des Sciences Pharmaceutiques ꢀ CNRS UPR 8241, Laboratoire de Chimie de Coordination, 205 Route de Narbonne, 31077
Toulouse cedex 04, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A DMAP catalyzed synthesis of new 4-benzyloxy- and 4-aryloxy-2-trichloromethylquinazolines was
studied, in a view to react 4-chloroquinazolines with poorly nucleophilic alcohols such as benzylic al-
cohols, via a simple and cheap SNAr reaction approach. A fast (1 h) general operating procedure, affording
good reaction yields, was achieved under microwave irradiation. Thus, a series of 35 molecules was
obtained and evaluated in vitro on the K1 multi-resistant Plasmodium falciparum strain, in parallel with a
cytotoxicity assessment on the human HepG2 cell line. 5 hit-molecules were identified, presenting both
Received 15 February 2016
Received in revised form
19 April 2016
Accepted 22 April 2016
Available online 28 April 2016
promising antiplasmodial activity (1.5 mM < IC50 < 2 mM) and low cytotoxicities (25 mM < CC50 < 45 mM).
Keywords:
Apart for 2 molecules, the global series displayed a satisfying solubility in the aqueous biological media.
Structure-activity relationships showed that the molecules presenting a benzyloxy moiety were less
cytotoxic than the ones bearing a phenoxy moiety at position 4 of the quinazoline ring. It also appeared
that the introduction of a heteroaryl moiety afforded inactive compounds. Finally, the most active and
selective molecules (Selectivity Index ¼ 22e27) were the ones presenting either an unsubstituted
benzyloxy group or a phenoxy group, this last bearing a p-bromo or an o-acetyl substituent.
© 2016 Elsevier Masson SAS. All rights reserved.
2-trichloromethylquinazoline
4-benzyloxyquinazoline
4-phenoxyquinazoline
DMAP-catalysis
SNAr reaction
Microwave-assisted chemistry
Plasmodium falciparum
Antiplasmodial activity
HepG2 cytotoxicity
SARs
1. Introduction
estimated deaths occurred in Africa, children under five repre-
senting a large majority of the victims.
Plasmodium falciparum is the protozoa responsible for cerebral
malaria, the leading cause of death among parasitic infections
worldwide. According to the 2015 World Malaria Report [1], 214
million people were infected by Plasmodium in 2014. It was also
estimated that 438.000 people died from this parasitic infection,
mainly because of the cerebral form of the disease. About 88% of the
Since the beginning of 2000, a very significant improvement of
the situation has been reached, thanks to the WHO intervention
and the involvement of several non-governmental organizations
(Bill and Melinda Gates Foundation, Roll Back Malaria, Medicines
for Malaria Venture …).
Nevertheless, the emergence of drug-resistant strains of the
parasite in Africa, South-East Asia and South America remains a
serious concern for the medical and scientific community, in a view
to keep on controlling the infection and to try to eradicate the
disease. For that purpose, the treatment of the patients infected by
P. falciparum is based on combination therapies including
* Corresponding author.
** Corresponding author.
E-mail addresses: pierre.verhaeghe@univ-tlse3.fr (P. Verhaeghe), patrice.
vanelle@univ-amu.fr (P. Vanelle).
http://dx.doi.org/10.1016/j.ejmech.2016.04.059
0223-5234/© 2016 Elsevier Masson SAS. All rights reserved.

A. Gellis et al. / European Journal of Medicinal Chemistry 119 (2016) 34e44
35
artemisinin derivatives, in order to cure the disease and avoid the
2. Results and discussion
selection of resistant strains and their spreading in the exposed
population, which would lead to a very worrying sanitary situation.
Concerning artemisinin derivatives, which are nowadays key-
molecules for the treatment of P. falciparum malaria, resistances
are emerging in Asia [2], and it has been demonstrated that they are
responsible for therapeutic failures in several infected patients [3].
Moreover, it has also recently been highlighted that the African
Anopheles gambiae mosquito could transmit such Asian resistant
parasites [4], indicating a major worldwide spreading risk. Thus,
research efforts have to be maintained so as to discover new
chemical entities presenting novel antiplasmodial mechanisms of
action, to use in combination therapies with the existing antima-
larial drugs, to guaranty their durable efficiency.
Considering all the scaffolds which were studied for their anti-
plasmodial potential, several bioactive molecules are based on a
quinazoline ring. For example, febrifugine is natural alkaloid
including a quinazolinone moiety which is extracted from the
Chinese herb Dichroa febrifuga, and which was employed by local
people as a medicine against fevers caused by malaria. Some syn-
thetic febrifugine derivatives were prepared and displayed good
in vitro and in vivo potential [5]. Many other quinazoline derivatives
were synthesized and evaluated toward P. falciparum, in particular,
quinazolines bearing, an amino group [6], an alkylamine moiety
[7,8] or an anilino substituent [9e11] at position 4 of the quinazo-
line ring.
In continuation with our research activity focusing on the syn-
thesis of new nitrogen-containing heterocycles with anti-infective
potential [12e14], our research group previously reported the
synthesis and in vitro study of numerous antiplasmodial molecules
based on a 2-trichloromethylquinazoline scaffold. Thus, several
series bearing an anilino [10], aryl [15], thiophenol [16], sulfon-
amide [17] or alkynyl moiety [18] at position 4 of the quinazoline
ring were prepared and revealed several hit-molecules which are
presented in Table 1. Among the antiplasmodial hit-molecules
which were identified, a 4-phenoxy-2-trichloromethylquinazoline
derivative was also discovered [19], presenting a 50% inhibitory
2.1. Synthesis
As aliphatic alcohols display poor nucleophilicity, reacting them
with chlorinated azaheterocycles, to provide the corresponding
SNAr products, is difficult and usually requires the preliminary in
situ formation of the corresponding alcoholate anion. Thus, in
quinazoline series, various operating procedures were reported in
the literature, using methylate sodium in methanol [20], sodium
hydride in dry DMF [21], sodium hydride in dry THF [22,23] or
sodium in dry THF [24]. These protocols, leading to the expected
products in moderate to good yields (32e84%), present several
disadvantages as they consist in 2 step-reactions (formation of the
anion followed by the SNAr), require the use of perfectly dry organic
solvents and involve highly reactive and flammable reagents.
Moreover, we tried to react 4-chloro-2-trichloromethylquinazoline
with benzyl alcohol, using the reaction conditions we previously
reported for the synthesis of 4-phenoxyquinazolines [19] (NaH,
DMSO, RT, 24 h) and obtained the expected product in a very low
11% yield (Table 2, entry 13).
Among the available alternative strategies, palladium cross-
coupling reactions could have been considered. Nevertheless,
because of the expensive costs of both palladium catalysts and li-
gands, in order to set up a cheap and simple operating procedure,
we decided to study the one pot SNAr reaction between 4-chloro-2-
trichloromethylquinazoline 1 and benzyl alcohol. To facilitate the
SNAr reaction between 1 and poorly nucleophilic species like
amino-substituted heterocycles, our group recently reported a
synthetic procedure using N-N-dimethylaminopyridine (DMAP) as
an efficient catalyst, involving the formation of a highly reactive
quinazoline intermediate which we isolated and characterized by
X-ray diffraction [25]. Then, benefiting from our experience in the
use of microwave irradiation for introducing substituents at posi-
tion 4 of the quinazoline ring [26], and considering that a successful
microwave-assisted SNAr reaction between a 4-chloroquinazoline
derivative and ethylene glycol had been reported [27], we
focused on a SNAr reaction protocol combining a DMAP catalysis
with microwave irradiation. For that purpose, we first prepared
substrate 1 (Fig. 1), from commercial 2-methylquinazolin-4(3H)-
one, according to a previously reported microwave synthesis using
PCl5 in POCl3 [28].
concentration (IC50) of 1.1
mM and a 50% cytotoxicity concentration
(CC50) of 50 M (Table 1), reaching an encouraging selectivity index
m
of 45, in comparison with chloroquine and doxycycline. Then,
searching for novel analogs presenting an oxygen-containing sub-
stituent at position 4 of the quinazoline ring, we present herein the
synthesis work which was conducted for reacting 4-chloro-2-
trichloromethylquinazoline with poorly nucleophilic benzylic al-
cohols, to afford the target molecules in a fast, simple and cheap
way, using the SNAr reaction. The in vitro biological evaluation and
the SARs will then be presented and discussed.
Then, the DMAP-catalyzed SNAr reaction between 1 and benzyl
alcohol was studied (Fig. 2) by varying the solvent nature, the
amount of catalyst, the amount of benzyl alcohol, the reaction
temperature, the microwave irradiation mode and the reaction
time. The experimental results are presented in Table 2.
When using 0.1 equiv. DMAP in the presence of toluene, the
Table 1
In vitro antiplasmodial profiles of the previously identified hit-molecules in 2-trichloromethylquinazoline series.
Antiplasmodial activity
P. falciparum W2 or K1 IC50
Cytotoxicity
2.5
0.4
16
40
1.1
50
45
0.9
(mM)
>125
50
>25
>28
HepG2 CC50
Selectivity index
(CC50/IC50
(mM)
)
Reference molecules: Chloroquine (IC50 K1 P. falciparum ¼ 0.6
m
M, CC50 HepG2 ¼ 30
m
M, SI ¼ 50); Doxycycline (IC50 K1 P. falciparum ¼ 6
mM, CC50 HepG2 ¼ 20
m
M, SI ¼ 3.3).

36
A. Gellis et al. / European Journal of Medicinal Chemistry 119 (2016) 34e44
Table 2
Studied parameters for the DMAP-catalyzed reaction of 1 with benzyl alcohol.
Entry
DMAP (equiv.)
Reaction conditionsa
Alcohol equiv.
Solvent
Yield (%)
1
2
3
4
5
6
7
8
0.1
0.1
0.1
0.1
0.2
0.3
0.4
0.3
0.3
0.3
0.4
0.4
e
1 h, 130 ꢁC/monomode MW
1 h, 150 ꢁC/monomode MW
1 h, 150 ꢁC/monomode MW
1 h, 80 ꢁC/monomode MW
1 h, 130 ꢁC/monomode MW
0.5 h, 130 ꢁC/monomode MW
1 h, 130 ꢁC/monomode MW
1 h, 130 ꢁC/monomode MW
1 h, 130 ꢁC/monomode MW
2 h, 110 ꢁC/monomode MW
0.5 h, 150 ꢁC/monomode MW
2 h, 800 W, 110 ꢁC/multimode MW
NaH 95% (2 equiv.), RT, 24 h [19]
2
2
2
2
2
2
2
1.2
2
2
2
2
1
toluene
DMSO
DMF
23
5b
3b
THF
Tracesc
42
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMSO
27
51
53
9
53
10
11
12
13
39b
18b
27
11
The values in bold indicate best results.
a
The monomode microwave oven used was a Biotage Initiator. The multimode microwave oven used was a Milestone SynthLab Station.
Formation of resins.
Detected by LC/MS.
b
c
(molecules 2e19). As presented in Table 3, the reaction yields varied
from moderate (35%) to excellent (97%). In addition, the same
protocol was applied to the synthesis of a series of 13 derivatives
bearing a phenoxy moiety at position 4 of the quinazoline ring
(molecules 20e32). These molecules were obtained in 38e99%
yields. Finally, 4 more derivatives were prepared, bearing a heter-
oaryloxy moiety at position 4 of the quinazoline ring (molecules
33e36), in 55e98% yields. Thus, this DMAP-catalyzed operating
procedure appeared as generally applicable to aliphatic alcohols,
phenols and hydroxyheteroaryl reagents.
Fig. 1. Microwave-assisted synthesis of substrate
methylquinazolin-4(3H)-one.
1
from commercial 2-
Among the 35 synthesized molecules, 2 were previously re-
ported. Thus, compound 2 was mentioned in a 2001 publication
[29] but no experimental data is available. Concerning quinazoline
27, it is to note that it had previously been synthesized, according to
another protocol [19], in 25% yield. As shown in Fig. 4, from the
same substrate, the presently described DMAP protocol led to the
formation of product 27 in 98% yield and only 1 h, indicating its
high efficiency for preparing most of 4-phenoxyquinazolines (apart
for molecules 23 and 26).
Fig. 2. Studied reaction: preparation of 4-benzyloxy-2-trichloromethylquinazoline 2
from substrate 1.
reaction yield reached 23%, higher than with DMSO, DMF, or THF.
Then, by increasing the amount of DMAP to 0.2 equiv., the reaction
yield was improved to 42%. Finally, via a 1 h monomode microwave
irradiation at 130 ꢁC, the use of 0.3 equiv. of DMAP, allowed a
decrease in the amount of alcohol (1.2 equiv.) needed and a 53%
reaction yield was reached. From that point, decreasing reaction
temperature, reaction time, or using a multimode microwave
irradiation did not provide satisfying reaction yields.
2.2. Biological evaluation
All synthesized molecules were then evaluated in vitro on the
multi-resistant K1 P. falciparum strain, by determining their 50%
inhibitory concentration (IC50), and compared with 2 antimalarial
drug-compounds: chloroquine and doxycycline. In parallel, these
molecules were assessed in vitro on the HepG2 human hepatocyte
For comparison purposes, the same reaction was carried out
without DMAP and then conducted with other tertiary amine de-
rivatives (DBU, DABCO and TEA). Indeed, DMAP was the only ter-
tiary amine which allowed the reaction to proceed.
According to this general procedure, summarized in Fig. 3, the
SNAr reaction of 1 with aliphatic alcohols (mainly benzyl alcohols)
was then extended to the synthesis of a series of 18 derivatives
cell line, by determining their 50% cytotoxic concentrations (CC50
)
and comparing them to the one of doxorubicin, used as a cytotoxic
reference drug-compound, in order to calculate their respective
Selectivity Index (SI ¼ CC50/IC50). The results are presented in
Table 3 and highlight 5 hit-molecules (2, 6, 16, 20, 26), presenting
both IC50 values < 2
mM and CC50 values > 25 mM, reaching selec-
tivity indexes ranging between 17 and 27.
Fig. 3. Optimal conditions for preparing derivatives belonging to the 4-benzyloxy-2-trichloromethylquinazoline series from substrate 1.

A. Gellis et al. / European Journal of Medicinal Chemistry 119 (2016) 34e44
37
Table 3
Reaction yields, in vitro antiplasmodial and in vitro cytotoxicity evaluations of all synthesized quinazolines.
Molecule
2
R-
Yield (%)
53
HepG2 CC50
43.8
(
mM)
PfK1 IC50
(
mM)
SIe
2.0
21.9
3
4
5
6
72
65
97
96
50.9
90.3
33.4
34.9
4.0
>10d
2.5
12.7
<9
13.4
19.4
1.8
7
8
91
87
29.9
2.2
2.3
13.6
>10c
>4.3
9
83
81
27.8
33.3
2.8
9.9
10
>10d
<3.3
11
12
64
35
118.4
39.9
3.9
3.3
30.6
12.1
13
14
15
68
69
84
25.1
30.2
24.6
3.5
4.2
2.4
7.2
7.2
10.2
16
17
18
41
85
45
25.7
28.7
1.5
3.1
2.6
17.1
9.3
31.25
12.0
19
68
62.5
3.8
16.4
20
21
99
45
1.8
25
99
36.7
2.3
16.0
(continued on next page)

38
A. Gellis et al. / European Journal of Medicinal Chemistry 119 (2016) 34e44
Table 3 (continued )
Molecule
R-
Yield (%)
99
HepG2 CC50
26.2
(
mM)
PfK1 IC50
(
mM)
SIe
22
1.9
13.8
23
24
38
95
>8c
1.6
2.3
>5
49.5
21.5
25
99
1.0
1.7
0.6
26
27
47
40.0
1.5
26.7
98
0.5
1.9
0.3
28
29
78
94
75.0
43.7
10.0
4.4
7.5
9.9
30
79
57.0
>10d
<5.7
31
32
92
89
5.3
0.9
1.2
5.9
22.1
18.4
33
34
67
98
62.7
4.9
>10d
>10d
<6.3
<0.5
35
36
67
55
30.3
59.0
>10d
>10d
<3.0
<5.9
Doxorubicinea
Chloroquineb
Doxycyclineb
0.2
30.0
20.0
e
e
0.6
6.0
50
3.3
In bold: hit-compounds (IC50 ꢂ 2
m
M, CC50 ꢃ 25
m
M and SI ꢃ 17).
a
Doxorubicine was used as a cytotoxic reference-drug.
b
c
Chloroquinine and doxycycline were used as antimalarial reference-drugs.
CC50 could not be determined because of a lack of solubility of the tested molecule in the culture medium.
d
e
IC50 was not reached at the highest tested concentration (10
mM).
Selectivity index (SI) was calculated according to the formula: SI ¼ CC50/IC50
.
2.3. Structure-activity relationships
appeared slightly cytotoxic (CC50 ¼ 4.9
mM), because of the pres-
ence of two bromine atoms.
Apart compounds 8 and 23, all tested molecules presented
satisfying solubilities in the biological media as the determination
of their in vitro activities was not hindered by any precipitation. In
the benzyloxy series, no cytotoxicity was identified whereas, in the
phenoxy series, compounds 25, 27 and 31, presenting a substituent
at the meta position of the benzene ring, displayed low CC50 values
Concerning antiplasmodial activity, the molecules belonging to
the heteroaryloxy series were not active. In the benzyloxy series,
compounds 2, 6 and 16 appeared as hit-molecules with IC50 values
ranging from 1.5 to 2 mM and selectivity indexes being around 20, in
comparison with the values noted for reference drugs. Compound
2, bearing a benzyloxy group at position 4 of the quinazoline ring,
was found more active and selective than its phenyloxy analog
(0.5e5.3
mM). In the heteroaryloxy series, compound 34 also

A. Gellis et al. / European Journal of Medicinal Chemistry 119 (2016) 34e44
39
Fig. 4. Comparison of synthetic routes A and B [19] for the synthesis of compound 27.
(IC50 ¼ 3,1
m
M/SI ¼ 16) [19]. In most cases (apart for nitrated
quinazoline ring. Structure-activity relationships showed that the
derivatives presenting a benzyloxy, a p-bromophenoxy or an o-
acetylphenoxy moiety were the most active and selective ones. The
molecule 6), the substitution of the benzene ring of the benzyloxy
group was globally deleterious toward antiplasmodial activity,
nevertheless, considering compound 16, it can be noted that the
introduction of a substituent on the benzylic carbon, for example
via a nitrile function, is compatible with maintaining biological
activity.
global
series
was
prepared
from
4-chloro-2-
trichloromethylquinazoline via a DMAP catalyzed SNAr reaction
with benzylic alcohols, phenols or hydroxyheterocycles, under
microwave irradiation. This operating procedure appears as an
efficient, simple, fast and cheap operating protocol for introducing
a large diversity of alkoxy, phenoxy or heteroaryloxy substituents at
position 4 of 4-chloroquinazolines, substrates of wide pharma-
ceutical interest.
In the phenoxy series, compounds 20 and 26 were identified as
hit-molecules, displaying IC50 values of 1.8 and 1.5 mM and selec-
tivity indexes above 25. When comparing para-brominated mole-
cule 20 to its chlorinated analog (Table 1), in accordance with the
SAR conclusions that we previously reported [19], it can be
concluded that the substitution of the benzene ring by a chlorine or
bromine atom is favorable toward the antiplasmodial activity if
located at the para position of the benzene ring, chlorine remaining
slightly more favorable. Indeed, we also identified that the intro-
duction of an acetyl substituent at the ortho position of the benzene
ring (compound 26) allowed antiplasmodial activity. This selective
activity is decreased when changing the substitution position or
when changing the acetyl group into a formyl analog (compound
28). To validate the key role play67ed by the 2-
trichloromethylquinazoline scaffold of hit-molecule 26, its deha-
logenated analog 37 was prepared in two steps (Fig. 5).
As presented in Fig. 6, the antiplasmodial activity of compound
26 depends from the presence of a trichloromethyl group at posi-
tion 2 of the quinazoline ring, in accordance with the results that
we previously reported. Thus, compounds 2 (in the original ben-
zyloxy series) and 26 (first active o-substituted phenoxy derivative)
appear as novel hit-molecules and extend the available SAR data in
the 2-trichloromethylquinazoline series.
4. Experimental
4.1. Chemistry
4.1.1. General
€
Melting points were determined on a Kofler melting point
apparatus and are uncorrected. Elemental analyses were carried
ꢀ
^
out at the Spectropole, Faculte des Sciences de Saint-Jerome
(Marseille) with a Thermo Finnigan EA1112 analyzer and a Brucker
Nonius diffractometer. NMR spectra were recorded on a Bruker ARX
ꢀ
200 spectrometer at the Faculte de Pharmacie of Marseille
(200 MHz 1H NMR: reference CHCl3
d
¼ 7.26, and 50 MHz 13C:
reference CHCl3
d
¼ 76.9). The following adsorbent was used for
column chromatography: silica gel 60 (Merck, particle size
0.063e0.200 mm, 70e230 mesh ASTM). TLC was performed on
5 cm ꢄ 10 cm aluminum plates coated with silica gel 60F-254
(Merck) in an appropriate eluent. Visualization was performed with
ultraviolet light (234 nm). Purity of synthesized compounds was
ꢀ
checked by LC/MS analyses, which were realized at the Faculte de
3. Conclusion
Pharmacie of Marseille with a Thermo Scientific Accela High Speed
LC System® coupled using a single quadrupole mass spectrometer
Thermo MSQ Plus®. The RP-HPLC column is a Thermo Hypersil
Gold® 50 ꢄ 2.1 mm (C18 bounded), with particles of a diameter of
Five antiplasmodial hit-molecules were identified from an
in vitro screening of 35 new 2-trichloromethylquinazoline de-
rivatives bearing an oxygen-containing moiety at position 4 of the
1.9 mm. The volume of sample injected on the column is 1
mL.
Fig. 5. Two step synthesis of molecule 37.

40
A. Gellis et al. / European Journal of Medicinal Chemistry 119 (2016) 34e44
Fig. 6. Comparison of the in vitro antiplasmodial activities of molecules 26 and 37.
Chromatographic analysis, total duration of 8 min, is on the
gradient of the following solvents: t ¼ 0 min, methanol/water
50:50; 0 < t < 4 min, linear increase in the proportion of water to a
methanol/water ratio of 95:5; 4 < t < 6 min, methanol/water 95:5;
6 < t < 7 min, linear decrease in the proportion of water to return to
a methanol/water ratio of 50:50; 6 < t < 7 min, methanol/water
50:50. The water used was buffered with ammonium acetate 5 mM.
The flow rate of the mobile phase was 0.3 mL/min. The retention
times (tR) of the molecules analyzed are indicated in min. The mi-
crowave reactions were performed using multimode reactors:
ETHOS Synth Lab station and MicroSYNTH® Lab terminal 1024
(Ethos start, Milestone Inc.); or monomode reactors: Biotage Initi-
ator® classic in sealed vials.
5.68 min, m/z [M þ H]þ 367.11/368.98/371.30. MW: 367.66 g/mol.
Anal. Calcd for C17H13Cl3N2O: C, 55.54; H, 3.56; N, 7.62. Found: C,
55.39; H, 3.53; N, 7.51.
4.1.6. 4-(4-Methoxybenzyloxy)-2-(trichloromethyl)quinazoline (4)
Yield 65%. Pale beige powder. Mp 86 ꢁC, (isopropanol). 1H NMR
(200 MHz, CDCl3)
7.90 (t, J ¼ 8 Hz, 1H),7.67e7.54 (m, 3H), 6.94e6.90 (d, J ¼ 8 Hz, 2H),
5.68 (s, 2H), 3.82 (s, 3H). 13C NMR (50 MHz, CDCl3)
d
¼ 8.21 (d, J ¼ 8 Hz, 1H), 8.06 (d, J ¼ 8 Hz, 1H),
d
¼ 167.6, 159.9,
150.4, 134.4, 131.0, 128.7, 128.6, 127.7, 126.9, 123.7, 115.6, 114.1, 114.0,
97.2, 69.4, 55.3. LC-MS (ESIþ) tR 5.33 min, m/z [M þ H]þ 382.94/
384.77/386.88. MW: 383.66 g/mol. Anal. Calcd for C17H13Cl3N2O2:
C, 53.22; H, 3.42; N, 7.30. Found: C, 53.13; H, 3.39; N, 7.51.
2-Methylquinazolin-4(3H)-one was purchased from Sigma
Aldrich.
4.1.7. 4-(4-Chlorobenzyloxy)-2-(trichloromethyl)quinazoline (5)
Yield 97%. Beige powder. Mp 95 ꢁC, (isopropanol). 1H NMR
4.1.2. 4-Chloro-2-trichloromethylquinazoline (1)
(200 MHz, CDCl3)
d
¼ 8.22 (d, J ¼ 8 Hz, 1H), 8.08 (d, J ¼ 8 Hz, 1H),
4-Chloro-2-trichloromethylquinazoline
described in the literature [28]. Yield 82%. White solid. Mp 127 ꢁC
(lit. 127 ꢁC).6 1H NMR (CDCl3, 200 MHz)
1 was prepared as
7.90 (dd, J ¼ 2 Hz; 7 Hz, 1H), 7.69e7.61 (m, 1H), 7.57e7.53 (d,
J ¼ 8 Hz, 2H), 7.39e7.34 (d, J ¼ 8 Hz, 2H), 5.69 (s, 2H). 13C NMR
d
¼ 7.82e7.90 (m, 1H),
(50 MHz, CDCl3)
d
¼ 167.4, 160.0, 150.4, 134.5, 134.1, 130.5, 128.8,
8.03e8.12 (m, 1H), 8.20e8.24 (m, 1H), 8.33e8.38 (m, 1H).
128.7, 123.6, 115.5, 97.1, 68.7. LC-MS (ESIþ) tR 5.59 min, m/z
[M þ H]þ 386.61/388.96/390.91. MW: 388.08 g/mol. Anal. Calcd for
C9H4Cl4N2, MW: 282.18 g/mol.
C16H10Cl4N2O: C, 49.52; H, 2.60; N, 7.22. Found: C, 49.70; H, 2.58; N,
7.14.
4.1.3. General procedure for the preparation of compounds 2 to 34
A mixture of 4-chloro-2-trichloromethylquinazoline 1 (0.2 g,
0.71 mmol), DMAP (26 mg, 0.21 mmol, 0.3 equiv) and adequate
alcohol derivative (0.85 mmol, 1.2 equiv) in toluene (3 mL) was
introduced in miniaturized sealed reactor (5 mL). The reaction
mixture was irradiated in a monomode microwave oven, for 1 h at
130 ꢁC. After removal of the toluene under reduced pressure, the
residue was purified by silica gel column chromatography and
recrystallized from appropriate solvent.
4.1.8. 4-(4-Nitrobenzyloxy)-2-(trichloromethyl)quinazoline (6)
Yield 96%. Yellow powder. Mp 199 ꢁC, (isopropanol). 1H NMR
(200 MHz, CDCl3)
8.04e7.98 (m, 1H), 7.85e7.74 (m, 3H), 5.88 (s, 2H). 13C NMR
(50 MHz, CDCl3)
129.1, 129.0, 123.9, 123.4, 115.3, 97.0, 68.0. LC-MS (ESIþ) tR 5.06 min,
m/z [M þ H]þ 397.93/399.91/402.06. MW: 398.63 g/mol. Anal. Calcd
for C16H10Cl3N3O3: C, 48.21; H, 2.53; N, 10.54. Found: C, 48.33; H,
2.55; N, 10.41.
d
¼ 8.34e8.30 (m, 3H), 8.18e8.15 (m, 1H),
d
¼ 167.1, 159.8, 150.5, 147.9, 142.8, 134.8, 129.3,
4.1.4. 4-(Benzyloxy)-2-(trichloromethyl)quinazoline (2)
Yield 53%. Beige powder. Mp 115 ꢁC, (isopropanol). 1H NMR
(200 MHz, CDCl3)
1H), 7.88 (dd, J ¼ 1 Hz; 5 Hz, 1H), 7.66e7.58 (m, 3H), 7.45e7.37 (m,
3H), 5.74 (s, 2H). 13C NMR (50 MHz, CDCl3)
135.6,134.4,129.0,128.7,128.6,123.7,115.5, 97.3, 69.4. LC-MS (ESIþ)
tR 5.38 min, m/z [M þ H]þ 351.79/354.40/355.98. MW: 353.63 g/
mol. Anal. Calcd for C16H11Cl3N2O: C, 54.34; H, 3.14; N, 7.92. Found:
C, 54.45; H, 3.11; N, 7.98.
d
¼ 8.23 (dd, J ¼ 1 Hz; 8 Hz, 1H), 8.07 (d, J ¼ 8 Hz,
4.1.9. 4-(3-Nitrobenzyloxy)-2-(trichloromethyl)quinazoline (7)
Yield 91%. Yellow powder. Mp 147 ꢁC, (isopropanol). 1H NMR
d
¼ 167.7, 160.1, 150.4,
(200 MHz, CDCl3)
7.88e7.81 (m, 3H), 7.69e7.54 (m, 2H), 5.95 (s, 2H). 13C NMR
(50 MHz, CDCl3)
d
¼ 8.27e8.24 (m, 1H), 8.19e8.14 (m, 2H),
d
¼ 167.1, 159.7, 150.3, 148.0, 134.9, 133.5, 131.7,
130.1, 129.3, 128.9, 128.8, 124.9, 123.2, 115.1, 97.2, 67.8. LC-MS (ESIþ)
tR 4.95 min, m/z [M þ H]þ 397.94/399.89/401.96. MW: 398.63 g/
mol. Anal. Calcd for C16H10Cl3N3O3: C, 48.21; H, 2.53; N, 10.54.
Found: C, 48.03; H, 2.56; N, 10.66.
4.1.5. 4-(4-Methylbenzyloxy)-2-(trichloromethyl)quinazoline (3)
Yield 72%. Pale beige powder. Mp 130 ꢁC, (isopropanol). 1H NMR
(200 MHz, CDCl3)
d
¼ 8.23 (d, J ¼ 8 Hz, 1H), 8.07 (d, J ¼ 8 Hz, 1H),
4.1.10. 4-(2-Nitrobenzyloxy)-2-(trichloromethyl)quinazoline (8)
7.90 (t, J ¼ 8 Hz, 1H), 7.67e7.53 (m, 1H), 7.53e7.49 (d, J ¼ 8 Hz, 3H),
Yield 87%. Yellow powder. Mp 141 ꢁC, (isopropanol). 1H NMR
7.23e7.19 (d, J ¼ 8 Hz, 1H), 5.70 (s, 2H), 2.37 (s, 3H). 13C NMR
(200 MHz, CDCl3)
d
¼ 8.28e8.23 (m, 1H), 8.14e8.07 (m, 2H), 7.94
(50 MHz, CDCl3)
d
¼ 167.6, 160.1, 150.4, 138.5, 134.4, 132.6, 129.2,
(dd, J ¼ 2 Hz; 7 Hz, 1H), 7.82e7.48 (m, 4H), 6.13 (s, 2H). 13C NMR
129.3, 128.7, 128.6, 123.7, 115.6, 97.6, 69.5, 27.3. LC-MS (ESIþ) tR
(50 MHz, CDCl3)
d
¼ 167.0, 159.9, 150.5, 148.2, 134.7, 133.6, 131.7,

A. Gellis et al. / European Journal of Medicinal Chemistry 119 (2016) 34e44
41
130.3,129.2,129.0,128.9,125.1,123.5,115.3, 96.9, 66.1. LC-MS (ESIþ)
4.1.16. 4-(1-(2,4-Dichlorophenyl)ethoxy)-2-(trichloromethyl)
quinazoline (14)
Yield 69%. Brown powder. Mp 123 ꢁC, (isopropanol). 1H NMR
(200 MHz, CDCl3)
¼ 8.31 (d, J ¼ 8 Hz, 1H), 8.07 (d, J ¼ 8 Hz, 1H),
tR 4.82 min, m/z [M þ H]þ 397.91/400.02/401.86. MW: 398.63 g/
mol. Anal. Calcd for C16H10Cl3N3O3: C, 48.21; H, 2.53; N, 10.54.
Found: C, 48.31; H, 2.50; N, 10.39.
d
7.96e7.87 (m, 1H), 7.69 (t, J ¼ 7 Hz, 1H), 7.49e7.39 (m, 2H), 7.20 (dd,
J ¼ 2 Hz; 8 Hz, 1H), 6.78 (q, J ¼ 7 Hz, 1H), 1.81 (d, J ¼ 7 Hz, 3H) . 13
C
4.1.11. 2-(Trichloromethyl)-4-(4-(trifluoromethyl)benzyloxy)
quinazoline (9)
NMR (50 MHz, CDCl3)
d
¼ 165.3, 159.2, 150.8, 135.3, 131.6, 130.8
129.4, 129.3, 129.0, 128.6, 123.4, 115.4, 96.9, 72.7, 21.0. LC-MS (ESIþ)
tR 6.02 min, m/z [M þ H]þ 434.74/436.86/438.81. MW: 436.55 g/
mol. Anal. Calcd for C17H11Cl5N2O: C, 46.77; H, 2.54; N, 6.42. Found:
C, 46.41; H, 2.52; N, 6.51.
Yield 83%. Pale yellow powder. Mp 130 ꢁC, (isopropanol). 1H
NMR (200 MHz, CDCl3)
8.04e7.98 (m, 1H), 7.97e7.89 (m, 1H), 7.75e7.64 (m, 4H), 5.79 (s,
2H). 13C NMR (50 MHz, CDCl3)
d
¼ 8.27e8.23 (m, 1H), 8.18e8.12 (m, 1H),
d
¼ 167.3, 160.0, 150.4, 139.6, 134.7,
129.0, 128.9, 126.7, 125.6, 125.5, 123.5, 121.3, 115.4, 97.1, 68.5. LC-MS
(ESIþ) tR 5.52 min, m/z [M þ H]þ 420.88/422.92/424.93. MW:
421.63 g/mol. Anal. Calcd for C17H10Cl3F3N2O: C, 48.43; H, 2.39; N,
6.64. Found: C, 48.59; H, 2.41; N, 6.58.
4.1.17. 4-(1-Phenylprop-2-ynyloxy)-2-(trichloromethyl)quinazoline
(15)
Yield 84%. Pale yellow powder. Mp 120 ꢁC, (isopropanol). 1H
NMR (200 MHz, CDCl3)
d
¼ 8.28e8.24 (m, 1H), 8.07 (d, J ¼ 8 Hz, 1H),
7.95e7.87 (m, 1H), 7.82e7.77 (m, 2H), 7.69e7.61 (m, 1H), 7.47e7.39
(m, 3H), 7.26e7.24 (m, 1H), 2.75 (d, J ¼ 2 Hz, 1H) . 13C NMR (50 MHz,
4.1.12. 4-(4-Isopropylbenzyloxy)-2-(trichloromethyl)quinazoline
(10)
CDCl3)
d
¼ 166.3, 159.7, 150.6, 136.3, 134.7 129.4, 128.8, 128.7, 128.4,
Yield 81%. Pale beige powder. Mp 121 ꢁC, (isopropanol). 1H NMR
123.8, 115.4, 97.0, 80.1, 76.4, 68.6. LC-MS (ESIþ) tR 5.20 min, m/z
[M þ H]þ 377.11/379.05/381.08. MW: 377.65 g/mol. Anal. Calcd for
(200 MHz, CDCl3)
d
¼ 8.23 (d, J ¼ 8 Hz, 1H), 8.07 (d, J ¼ 8 Hz, 1H),
C18H11Cl3N2O: C, 57.25; H, 2.94; N, 7.42. Found: C, 57.61; H, 2.95; N,
7.93e7.85 (m, 1H), 7.67e7.53 (m, 3H), 7.28 (d, J ¼ 8 Hz, 2H), 5.72 (s,
2H), 2.94 (sept, J ¼ 7 Hz, 1H), 1.27 (d, J ¼ 7 Hz, 6H). 13C NMR
7.35.
(50 MHz, CDCl3)
d
¼ 167.6, 160.2, 150.4, 149.5, 134.4, 133.0, 129.3,
4.1.18. 2-Phenyl-2-(2-(trichloromethyl)quinazolin-4-yloxy)
acetonitrile (16)
128.7, 128.6, 126.7, 123.8, 115.6, 97.3, 68.5, 34.0, 24.0. LC-MS (ESIþ)
tR 5.73 min, m/z [M þ H]þ 395.10/396.96/399.02. MW: 395.71 g/
mol. Anal. Calcd for C19H17Cl3N2O: C, 57.67; H, 4.33; N, 7.08. Found:
C, 57.76; H, 4.35; N, 7.21.
Yield 41%. Pale yellow powder. Mp 141 ꢁC, (isopropanol). 1H
NMR (200 MHz, CDCl3)
7.99 (td, J ¼ 2 Hz; 8 Hz, 1H), 7.80e7.68 (m, 3H), 7.54e7.49 (m, 3H),
7.14 (s, 1H) . 13C NMR (50 MHz, CDCl3)
d
¼ 8.36e8.21 (m, 1H), 8.14 (d, J ¼ 8 Hz, 1H),
d
¼ 166.3, 159.7, 150.6, 136.3,
4.1.13. 4-(3,4-Dimethoxybenzyloxy)-2-(trichloromethyl)
quinazoline (11)
134.7 129.4, 128.8, 128.7, 128.4, 123.8, 116.0, 114.7, 96.5, 65.9. LC-MS
(ESIþ) tR 4.73 min, m/z [M þ H]þ 377.99/380.01/381.99. MW:
378.64 g/mol. Anal. Calcd for C17H10Cl3N3O: C, 53.93; H, 2.66; N,
11.10. Found: C, 53.89; H, 2.70; N, 11.12.
Yield 64%. Beige powder. Mp 127 ꢁC, (isopropanol). 1H NMR
(200 MHz, CDCl3)
d
¼ 8.22 (d, J ¼ 8 Hz, 1H), 8.06 (d, J ¼ 8 Hz, 1H),
7.90 (t, J ¼ 8 Hz, 1H), 7.63 (t, J ¼ 8 Hz, 1H), 7.20e7.16 (m, 2H), 6.89 (d,
J ¼ 8 Hz, 1H), 5.68 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H) . 13C NMR
4.1.19. 4-((6-Nitrobenzo[d][1,3]dioxol-5-yl)methoxy)-2-
(trichloromethyl) quinazoline (17)
(50 MHz, CDCl3)
d
¼ 167.6, 160.1, 150.4, 149.4, 149.0, 134.4, 129.0,
Yield 85%. Pale yellow powder. Mp 181 ꢁC, (isopropanol). 1H
128.7, 128.6, 128.1, 126.8, 123.7, 122.2, 115.6, 112.6, 111.0, 97.3, 69.7,
56.0, 55.9. LC-MS (ESIþ) tR 4.95 min, m/z [M þ H]þ 413.00/414.75/
416.93. MW: 413.68 g/mol. Anal. Calcd for C18H15Cl3N2O3: C, 52.26;
H, 3.65; N, 6.77. Found: C, 52.09; H, 3.64; N, 6.72.
NMR (200 MHz, CDCl3)
1H), 7.98e7.92 (m, 1H), 7.74e7.65 (m, 2H), 7.27e7.24 (m, 1H), 6.13
(s, 2H), 6.08 (s, 2H). 13C NMR (50 MHz, CDCl3)
d
¼ 8.25 (d, J ¼ 8 Hz, 1H), 8.10 (d, J ¼ 8 Hz,
d
¼ 167.1, 159.9, 152.2,
150.5, 147.8, 142.3, 134.8 129.0, 128.9, 123.5, 115.3, 109.1, 106.0,
103.2, 96.9, 66.2. LC-MS (ESIþ) tR 5.00 min, m/z [M þ H]þ 441.87/
443.97/445.95. MW: 442.64 g/mol. Anal. Calcd for C17H10Cl3N3O5:
C, 46.13; H, 2.28; N, 9.49. Found: C, 45.91; H, 2.27; N, 9.57.
4.1.14. 4-(1-Phenylethoxy)-2-(trichloromethyl)quinazoline (12)
Yield 35%. Beige powder. Mp 141 ꢁC, (isopropanol). 1H NMR
(200 MHz, CDCl3)
d
¼ 8.28 (dd, J ¼ 1 Hz; 8 Hz, 1H), 8.05 (d, J ¼ 8 Hz,
1H), 7.89 (t, J ¼ 8 Hz, 1H), 7.70e7.56 (m, 3H), 7.41e7.29 (m, 3H), 6.58
4.1.20. (E)-4-(3-(4-Nitrophenyl)allyloxy)-2-(trichloromethyl)
quinazoline (18)
(q, J ¼ 7 Hz, 1H), 1.84 (d, J ¼ 7 Hz, 3H). 13C NMR (50 MHz, CDCl3)
d
¼ 167.1, 160.1, 150.4, 141.2, 135.5, 134.3, 129.2, 129.0, 128.8, 128.5,
Yield 45%. Yellow powder. Mp 140 ꢁC, (isopropanol). 1H NMR
128.1, 126.9, 126.8, 123.7, 115.7, 97.2, 76.0, 22.1. LC-MS (ESIþ) tR
5.83 min, m/z [M þ H]þ 366.97/368.97/371.04. MW: 367.66 g/mol.
Anal. Calcd for C17H13Cl3N2O: C, 55.54; H, 3.56; N, 7.62. Found: C,
55.59; H, 3.59; N, 7.71.
(200 MHz, CDCl3)
d
¼ 8.29 (m, 4H), 7.98e7.89 (m,1H), 7.73e7.65 (m,
1H), 7.58e7.24 (m, 2H), 6.98 (d, J ¼ 16 Hz, 1H), 6.80e6.66 (m, 1H),
5.41 (dd, J ¼ 1 Hz; 6 Hz, 2H). 13C NMR (50 MHz, CDCl3)
d
¼ 167.3,
160.0,150.4,147.4,142.6,134.6,133.0,131.9,129.6,129.1,128.9,128.8
127.6, 127.3, 124.1 123.8, 123.5, 115.4, 96.3, 67.7. LC-MS (ESIþ) tR
5.34 min, m/z [M þ H]þ 423.94/425.92/427.96. MW: 424.67 g/mol.
Anal. Calcd for C18H12Cl3N3O3: C, 50.91; H, 2.85; N, 9.89. Found: C,
51.08; H, 2.86; N, 9.75.
4.1.15. 4-(1-(4-Chlorophenyl)ethoxy)-2-(trichloromethyl)
quinazoline (13)
Yield 68%. Brown powder. Mp 86 ꢁC, (isopropanol). 1H NMR
(200 MHz, CDCl3)
d
¼ 8.22 (d, J ¼ 8 Hz, 1H), 8.05 (d, J ¼ 8 Hz, 1H),
7.90 (dd, J ¼ 1 Hz; 7 Hz, 1H), 7.66 (td, J ¼ 1 Hz; 7 Hz, 1H), 7.52 (d,
J ¼ 8 Hz, 2H), 7.32 (d, J ¼ 8 Hz, 2H), 6.53 (q, J ¼ 7 Hz, 1H), 1.82 (d,
4.1.21. 4-(3-(Benzyloxy)benzyloxy)-2-(trichloromethyl)quinazoline
(19)
J ¼ 7 Hz, 3H). 13C NMR (50 MHz, CDCl3)
d
¼ 166.9,160.0,150.4,139.7,
Yield 68%. Yellow powder. Mp 96 ꢁC, (isopropanol). 1H NMR
134.4, 133.9 128.8, 128.7, 128.3, 123.5, 115.6, 97.1, 75.2, 22.0. LC-MS
(ESIþ) tR 5.83 min, m/z [M þ H]þ 400.96/402.81/404.83. MW:
402.10 g/mol. Anal. Calcd for C17H12Cl4N2O: C, 50.78; H, 3.01; N,
6.97. Found: C, 50.48; H, 3.03; N, 6.90.
(200 MHz, CDCl3)
d
¼ 8.23 (dd, J ¼ 1 Hz; 8 Hz, 1H), 8.10 (d, J ¼ 8 Hz,
1H), 7.91 (td, J ¼ 1 Hz; 8 Hz, 1H), 7.69e7.61 (m, 1H), 7.47e7.18 (m,
8H), 5.72 (s, 1H), 5.72 (s, 2H), 5.10 (s, 2H). 13C NMR (50 MHz, CDCl3)
d
¼ 167.6, 160.1, 159.0, 150.4, 137.2, 136.9, 134.5, 130.0, 129.7, 128.9,

42
A. Gellis et al. / European Journal of Medicinal Chemistry 119 (2016) 34e44
128.8, 128.6, 128.0, 127.5, 123.7, 121.4, 115.5, 115.3, 115.0, 97.2, 70.1,
69.3. LC-MS (ESIþ) tR 5.87 min, m/z [M þ H]þ 458.74/460.72/462.84.
MW: 459.75 g/mol. Anal. Calcd for C23H17Cl3N2O2: C, 60.09; H, 3.73;
N, 6.09. Found: C, 59.87; H, 3.70; N, 5.98.
7.34. Found: C, 53.21; H, 2.90; N, 7.42.
4.1.28. 1-(2-(2-(Trichloromethyl)quinazolin-4-yloxy)phenyl)
ethanone (26)
Yield 47%. White powder. Mp 147 ꢁC, (isopropanol). 1H NMR
4.1.22. 4-(4-Bromophenoxy)-2-(trichloromethyl)quinazoline (20)
(200 MHz, CDCl3)
8.05e7.89 (m, 2H), 7.83e7.75 (m, 1H), 7.68e7.59 (m, 1H), 7.46e7.33
(m, 2H), 2.50 (s, 3H). 13C NMR (50 MHz, CDCl3)
159.9, 151.2, 150.6, 135.1, 133.6, 131.3, 130.4, 129.4, 129.0, 126.3,
123.7, 115.2, 96.8, 29.7. LC-MS (ESIþ) tR 4.16 min, m/z [M þ H]þ
381.03/383.03/384.99. MW: 381.64 g/mol. Anal. Calcd for
d
¼ 8.46 (d, J ¼ 8 Hz, 1H), 8.12 (d, J ¼ 8 Hz, 1H),
Yield 99%. White powder. Mp 179 ꢁC, (isopropanol). 1H NMR
(200 MHz, CDCl3)
d
¼ 8.42e8.38 (m, 1H), 8.16 (d, J ¼ 8 Hz, 1H), 8.02
d
¼ 197.4, 167.5,
(td, J ¼ 1 Hz; 8 Hz, 1H), 7.81e7.73 (m, 1H), 7.59 (d, J ¼ 8 Hz, 2H), 7.30
(d, J ¼ 8 Hz, 2H). 13C NMR (50 MHz, CDCl3)
d
¼ 166.9, 160.1, 151.4,
151.3, 134.9,132.5,129.2,129.1, 123.5,123.3,118.9,115.3, 96.7. LC-MS
(ESIþ) tR 5.38 min, m/z [M þ H]þ 418.26/420.82/422.93. MW:
418.5 g/mol. Anal. Calcd for C15H8BrCl3N2O: C, 43.05; H, 1.93; N,
6.69. Found: C, 43.25; H, 1.95; N, 6.58.
C17H11Cl3N2O2: C, 53.50; H, 2.91; N, 7.34. Found: C, 53.27; H, 2.93; N,
7.29.
4.1.29. 4-(3-Methoxyphenoxy)-2-trichloromethylquinazoline (27)
4.1.23. 4-(3-Bromophenoxy)-2-(trichloromethyl)quinazoline (21)
Yield 98%. White powder. Mp 101 ꢁC (Lit. 101 ꢁC [19]), (iso-
Yield 99%. White powder. Mp 114 ꢁC, (isopropanol). 1H NMR
propanol). 1H NMR (200 MHz, CDCl3)
d
¼ 8.39e8.43 (m, 1H),
(200 MHz, CDCl3)
J ¼ 1 Hz; 8 Hz, 1H), 7.81e7.73 (m, 1H), 7.63e7.62 (m, 1H), 7.48e7.30
(m, 3H). 13C NMR (50 MHz, CDCl3)
d
¼ 8.41e8.37 (m, 1H), 8.18e8.14 (m, 1H), 8.01 (td,
8.13e8.17 (m, 1H), 7.95e8.03 (m, 1H), 7.72e7.80 (m, 1H), 7.32e7.40
(m,1H), 6.96e7.05 (m, 2H), 6.83e6.89 (m,1H), 3.83 (s, 3H). 13C NMR
d
¼ 166.8, 160.0, 152.5, 151.2,
(50 MHz, CDCl3)
d
¼ 167.4, 160.4, 160.1, 153.1, 151.0, 134.8, 129.7,
135.1,130.5,129.3,129.1,125.1,123.6,122.3,120.4,115.2, 96.6. LC-MS
(ESIþ) tR 5.43 min, m/z [M þ H]þ 418.18/420.78/422.82. MW:
418.5 g/mol. Anal. Calcd for C15H8BrCl3N2O: C, 43.05; H, 1.93; N,
6.69. Found: C, 42.91; H, 1.92; N, 6.76.
129.1, 128.9, 123.7, 115.4, 113.5, 112.0, 107.2, 96.8, 55.5 LC-MS (ESIþ)
tR 5.10 min, m/z [M þ H]þ 369.01/371.15/373.09. MW: 369.63 g/mol.
Anal. Calcd for C16H11Cl3N2O2: C, 51.99; H, 3.00; N, 7.58. Found: C,
52.16; H, 3.07; N, 7.67.
4.1.24. 4-(2-Bromophenoxy)-2-(trichloromethyl)quinazoline (22)
4.1.30. 2-(2-(Trichloromethyl)quinazolin-4-yloxy)benzaldehyde
(28)
Yield 99%. White powder. Mp 138 ꢁC, (isopropanol). 1H NMR
(200 MHz, CDCl3)
(td, J ¼ 1 Hz; 8 Hz, 1H), 7.84e7.67 (m, 2H), 7.49e7.39 (m, 2H),
7.28e7.17 (m, 1H). 13C NMR (50 MHz, CDCl3)
d
¼ 8.51e8.47 (m, 1H), 8.17 (d, J ¼ 8 Hz, 1H), 8.02
Yield 78%. White powder. Mp 111 ꢁC, (isopropanol). 1H NMR
(200 MHz, CDCl3)
(d, J ¼ 8 Hz, 1H), 8.06e7.98 (m, 2H), 7.87e7.69 (m, 2H), 7.52e7.45
(m, 2H). 13C NMR (50 MHz, CDCl3)
d
¼ 10.19 (s, 1H), 8.47 (dd, J ¼ 1 Hz; 8 Hz, 1H), 8.17
d
¼ 166.7, 159.9, 151.1,
149.4, 135.0, 133.4, 129.2, 128.9, 128.4, 127.4, 123.8, 123.7, 116.2,
114.9, 96.5. LC-MS (ESIþ) tR 5.05 min, m/z [M þ H]þ 418.07/420.73/
422.87. MW: 418.5 g/mol. Anal. Calcd for C15H8BrCl3N2O: C, 43.05;
H, 1.93; N, 6.69. Found: C, 42.89; H, 1.91; N, 6.81.
d
¼ 188.4, 167.5, 163.1, 153.3,
151.2, 146.7,135.5,130.1, 129.5,129.1,126.7, 123.6,123.3,120.9,114.9,
96.5. LC-MS (ESIþ) tR 4.20 min, m/z [M þ H]þ 367.03/369.02/371.03.
MW: 367.61 g/mol. Anal. Calcd for C16H9Cl3N2O2: C, 52.28; H, 2.47;
N, 7.62. Found: C, 52.59; H, 2.45; N, 7.68.
4.1.25. 4-(2-(Trichloromethyl)quinazolin-4-yloxy)benzonitrile (23)
Yield 38%. White powder. Mp 194 ꢁC, (isopropanol). 1H NMR
4.1.31. 4-(Perfluorophenoxy)-2-(trichloromethyl)quinazoline (29)
(200 MHz, CDCl3)
d
¼ 8.41 (d, J ¼ 8 Hz, 1H), 8.19 (d, J ¼ 8 Hz, 1H),
Yield 94%. White powder. Mp 139 ꢁC, (isopropanol). 1H NMR
8.07e8.00 (m,1H), 7.84e7.78 (m, 3H), 7.57 (d, J ¼ 8 Hz, 2H). 13C NMR
(200 MHz, CDCl3)
d
¼ 8.43 (dd, J ¼ 1 Hz; 8 Hz, 1H), 8.22 (d, J ¼ 8 Hz,
(50 MHz, CDCl3)
d
¼ 166.4, 159.7, 155.4, 151.3, 135.4, 133.8, 129.6,
1H), 8.07 (td, J ¼ 1 Hz; 8 Hz, 1H), 7.88e7.80 (m, 1H). 13C NMR
129.2, 123.5, 122.7, 118.3, 115.0, 109.9, 96.5. LC-MS (ESIþ) tR
4.46 min, m/z [M þ H]þ 364.10/365.99/367.99. MW: 364.61 g/mol.
Anal. Calcd for C16H8Cl3N3O: C, 52.71; H, 2.21; N, 11.52. Found: C,
52.71; H, 2.21; N, 11.52.
(50 MHz, CDCl3)
d
¼ 165.4, 159.5, 151.4, 135.7, 129.9, 129.2, 123.4,
114.0, 96.0. LC-MS (ESIþ) tR 5.49 min, m/z [M þ H]þ 428.71/430.78/
432.67. MW: 429.56 g/mol. Anal. Calcd for C15H4Cl3F5N2O: C, 41.94;
H, 0.94; N, 6.52. Found: C, 42.12; H, 0.97; N, 6.42.
4.1.26. 1-(4-((2-(Trichloromethyl)quinazolin-4-yl)oxy)phenyl)
ethanone (24)
4.1.32. 3-Methoxy-5-nitro-4-(2-(trichloromethyl)quinazolin-4-
yloxy)benzaldehyde (30)
Yield 95%. White powder. Mp 149 ꢁC, (isopropanol). 1H NMR
Yield 79%. Yellow powder. Mp 171 ꢁC, (isopropanol). 1H NMR
(200 MHz, CDCl3)
d
¼ 8.41 (d, J ¼ 8 Hz, 1H), 8.18e7.97 (m, 4H), 7.78
(200 MHz, CDCl3)
d
¼ 10.28 (s, 1H), 8.49e8.46 (m, 2H), 8.24e8.05
(t, J ¼ 8 Hz,1H), 7.52 (d, J ¼ 8 Hz, 2H), 2.65 (s, 3H). 13C NMR (50 MHz,
(m, 3H), 7.86 (t, J ¼ 6 Hz, 1H), 3.86 (s, 3H). 13C NMR (50 MHz, CDCl3)
CDCl3)
d
¼ 196.9, 166.7, 159.9, 155.8, 151.2, 135.2, 134.7, 130.0, 129.4,
d
¼ 186.2, 166.6, 159.6, 152.8, 151.4, 148.0, 146.5, 135.6, 135.1, 129.8,
129.1, 123.6, 121.6, 115.2, 96.6, 26.7. LC-MS (ESIþ) tR 4.48 min, m/z
129.6, 129.3, 123.5, 115.6, 114.3, 111.5, 96.2, 56.9. LC-MS (ESIþ) tR
4.01 min, m/z [M þ H]þ 441.87/443.71/445.72. MW: 442.64 g/mol.
Anal. Calcd for C17H10Cl3N3O5: C, 46.13; H, 2.28; N, 9.49. Found: C,
45.95; H, 2.30; N, 9.55.
[M þ H]þ 381.07/383.07/385.02. MW: 381.64 g/mol. Anal. Calcd for
C
17H11Cl3N2O2: C, 53.50; H, 2.91; N, 7.34. Found: C, 53.71; H, 2.89; N,
7.41.
4.1.27. 1-(3-(2-(Trichloromethyl)quinazolin-4-yloxy)phenyl)
ethanone (25)
4.1.33. 4-(4-Chloro-3-methylphenoxy)-2-(trichloromethyl)
quinazoline (31)
Yield 99%. White powder. Mp 106 ꢁC, (isopropanol). 1H NMR
Yield 92%. White powder. Mp 98 ꢁC, (isopropanol). 1H NMR
(200 MHz, CDCl3)
1H), 8.05e7.89 (m, 3H), 7.83e7.75 (m, 1H), 7.67e7.54 (m, 2H), 2.64
(s, 3H). 13C NMR (50 MHz, CDCl3)
135.1, 129.7, 129.3, 129.0, 126.3, 125.8, 123.6, 121.5, 115.2, 96.7, 26.8.
LC-MS (ESIþ) tR 4.47 min, m/z [M þ H]þ 381.07/383.05/384.98. MW:
381.64 g/mol. Anal. Calcd for C17H11Cl3N2O2: C, 53.50; H, 2.91; N,
d
¼ 8.43 (dd, J ¼ 1 Hz; 8 Hz, 1H), 8.17 (d, J ¼ 8 Hz,
(200 MHz, CDCl3)
d
¼ 8.37 (dd, J ¼ 1 Hz; 8 Hz, 1H), 8.16e8.12 (m,
1H), 8.02e7.94 (m, 1H), 7.79e7.70 (m, 1H), 7.41 (d, J ¼ 8 Hz, 1H),
d
¼ 197.1, 167.0, 159.9, 151.1, 138.5,
7.31e7.30 (m, 1H), 7.20 (dd, J ¼ 1 Hz; 8 Hz, 1H), 2.41 (s, 3H). 13C NMR
(50 MHz, CDCl3)
d
¼ 166.9, 159.9, 151.0, 150.4, 137.3, 134.9, 131.1,
129.6, 129.1, 128.9, 123.7, 123.5, 120.1, 115.2, 96.7, 20.3. MW:
388.08 g/mol. HRMS (ESI): m/z [MþNa]þ calcd for [C16H10 Cl4N2O]þ:

A. Gellis et al. / European Journal of Medicinal Chemistry 119 (2016) 34e44
43
408.94395; found: 408.94429.
this intermediate product, leading to molecule 37 in 45% yield, as a
beige powder. Mp 118 ꢁC, (isopropanol). 1H NMR (200 MHz, CDCl3)
4.1.34. 4-[(2,4-Dichlorophenyl)oxy]-2-(trichloromethyl)quinazoline
(32)
d
¼ 8.33 (d, J ¼ 8 Hz, 1H), 7.95e7.83 (m, 3H), 7.65e7.56 (m, 2H),
7.42e7.25 (m, 2H), 2.59 (s, 3H), 2.47 (s, 3H). 13C NMR (50 MHz,
CDCl3)
Yield 89%. White powder. Mp 110 ꢁC, (isopropanol). 1H NMR
d
¼ 197.9, 166.3, 163.7, 152.0, 150.9, 134.3, 133.3, 132.0, 130.1,
(200 MHz, CDCl3)
8.06e7.98 (m, 1H), 7.84e7.75 (m, 1H), 7.54e7.33 (m, 3H). 13C NMR
(50 MHz, CDCl3)
d
¼ 8.43e8.48 (m, 1H), 8.18 (d, J ¼ 8 Hz, 1H),
127.1, 127.0, 126.0, 123.8, 123.4, 114.3, 30.1, 26.2. LC-MS (ESIþ) tR
4.60 min, m/z [M þ H]þ 279.19. MW: 278.31 g/mol. Anal. Calcd for
d
¼ 166.5, 159.8, 151.2, 147.0, 135.2, 131.9, 130.2,
C17H14N2O2: C, 73.37; H, 5.07; N, 10.07. Found: C, 73.82; H, 5.11; N,
129.4, 129.0, 128.0, 127.9, 124.6, 123.6, 114.8, 96.4. LC-MS (ESIþ) tR
4.60 min, m/z [M þ H]þ 408.05/410.09/411.98. MW: 408.49 g/mol.
Anal. Calcd for C15H7Cl5N2O: C, 44.10; H, 1.73; N, 6.86. Found: C,
44.50; H, 1.71; N, 6.97.
9.93.
4.2. Biology
4.2.1. In vitro antiplasmodial evaluation
4.1.35. 2-Methyl-3-(2-(trichloromethyl)quinazolin-4-yloxy)-4H-
pyran-4-one (33)
In this study, a K1 culture-adapted P. falciparum strain resistant
to chloroquine, pyrimethamine and proguanil was used in an
in vitro culture. Maintenance in continuous culture was done as
described previously by Trager and Jensen [30]. Cultures were
maintained in fresh Aþ human erythrocytes at 2.5% hematocrit in
complete medium (RPMI 1640 with 25 mM HEPES, 25 mM NaHCO3,
10% of Aþ human serum) at 37 ꢁC under reduced O2 atmosphere
(gas mixture 10% O2, 6% CO2, and 84% N2). Parasitaemia was
maintained daily between 1% and 6%. The P. falciparum drug sus-
ceptibility test was carried out by comparing quantities of DNA in
treated and control cultures of parasite in human erythrocytes ac-
cording to a SYBR Green I fluorescence-based method [31] using a
96-well fluorescence plate reader. Compounds, previously dis-
solved in DMSO (final concentration less than 0.5% v/v) were
Yield 67%. Beige powder. Mp 202 ꢁC, (isopropanol). 1H NMR
(200 MHz, CDCl3)
1H), 7.99 (td, J ¼ 1 Hz; 8 Hz,1H), 7.82e7.72 (m, 2H), 6.49 (d, J ¼ 4 Hz,
1H), 2.36 (s, 3H). 13C NMR (50 MHz, CDCl3)
d
¼ 8.41 (dd, J ¼ 1 Hz; 8 Hz, 1H), 8.15 (d, J ¼ 8 Hz,
d
¼ 171.9, 165.9, 159.8,
154.4, 151.3, 135.4, 135.1, 129.2, 128.9, 126.8, 123.8, 117.0, 113.0, 96.5,
15.2. LC-MS (ESIþ) tR 3.29 min, m/z [M þ H]þ 370.97/372.99/375.00.
MW: 371.60 g/mol. Anal. Calcd for C15H9Cl3N2O3: C, 48.48; H, 2.44;
N, 7.54. Found: C, 48.38; H, 2.41; N, 7.62.
4.1.36. 4-(5,7-Dibromoquinolin-8-yloxy)-2-(trichloromethyl)
quinazoline (34)
Yield 98%. Brown powder. Mp 186 ꢁC, (isopropanol). 1H NMR
(200 MHz, CDCl3)
d
¼ 8.77e8.55 (m, 3H), 8.21e8.12 (m, 2H), 8.04 (t,
incubated in a total assay volume of 200 mL of synchronized culture
J ¼ 8 Hz, 1H), 7.83 (t, J ¼ 6 Hz, 1H), 7.56e7.53 (m, 1H). 13C NMR
suspension (2% hematocrit and 0.4% parasitaemia) for 72 h in a
humidified atmosphere (14% O2 and 6% CO2) at 37 ꢁC, in 96-well flat
bottom plates. Duplicate assays were performed for each sample.
(50 MHz, CDCl3)
d
¼ 167.13, 159.6, 151.4, 151.3, 146.5, 142.2, 136.2,
135.1, 133.3, 129.3, 128.9, 127.8, 124.1, 122.8, 119.5, 116.9, 114.8, 96.4.
LC-MS (ESIþ) tR 5.37 min, m/z [M þ H]þ 546.08/547.52/549.54. MW:
548.44 g/mol. Anal. Calcd for C18H8Br2N3O: C, 39.42; H,1.47; N, 7.66.
Found: C, 39.49; H, 1.50; N, 7.51.
After incubation, 125
washed twice with 125
transferred to 96-well flat bottom nonsterile black plates (Greiner
Bio-one) already containing 15 L of the SYBR Green I lysis buffer
mL supernatant was discarded and cells were
m
L 1ꢄ PBS. 15 L re-suspended cells were
m
m
4.1.37. 4-(Quinolin-2-yloxy)-2-(trichloromethyl)quinazoline (35)
(2ꢄ SYBR Green I, 20 mM Tris base pH 7.5, 20 mM EDTA, 0.008% w/v
saponin, 0.08% w/v Triton X-100). Negative control, treated by
solvents (DMSO or H2O) and positive controls (chloroquine and
doxycycline) were added to each set of experiments. Plates were
incubated for 15 min at 37 ꢁC and then read on a TECAN Infinite F-
200 spectrophotometer with excitation and emission wavelengths
at 485 and 535 nm, respectively. The concentrations of compounds
required to induce a 50% decrease of parasite growth (IC50 K1) were
calculated from three independent experiments.
Yield 67%. Yellow powder. Mp 163 ꢁC, (isopropanol). 1H NMR
(200 MHz, CDCl3)
d
¼ 8.52 (d, J ¼ 8 Hz, 1H), 8.34 (d, J ¼ 8 Hz, 1H),
8.18 (d, J ¼ 8 Hz,1H), 8.07e7.72 (m, 5H), 7.64e7.49 (m, 2H). 13C NMR
(50 MHz, CDCl3)
d
¼ 166.9, 159.8, 157.4, 151.3, 146.3, 140.1, 135.3,
130.5, 129.4, 129.0, 128.4, 127.3, 126.8, 124.0, 115.7, 115.2, 96.5. LC-
MS (ESIþ) tR 4.60 min, m/z [M þ H]þ 389.95/391.95/394.06. MW:
390.65 g/mol. Anal. Calcd for C18H10Cl3N3O: C, 55.34; H, 2.58; N,
10.76. Found: C, 55.13; H, 2.56; N, 10.91.
4.1.38. 4-(2-(Trichloromethyl)quinazolin-4-yloxy)-2H-chromen-2-
one (36)
4.2.2. In vitro cytotoxicity evaluation
HepG2 cell line was maintained at 37 ꢁC, 6% CO2, with 90% hu-
Yield 55%. Yellow powder. Mp 237 ꢁC, (isopropanol). 1H NMR
midity in RPMI supplemented with 10% fœtal bovine serum, 1%
glutamine (200 mM) and penicillin (100 U/mL)/streptomycin
(100 g/mL) (complete RPMI medium). The evaluation of the tested
L-
(200 MHz, CDCl3)
8.10 (t, J ¼ 8 Hz, 1H), 7.92e7.80 (m, 2H), 7.68e7.60 (m, 1H),
7.47e7.30 (m, 2H), 6.96 (s, 1H). 13C NMR (50 MHz, CDCl3)
d
¼ 8.45 (d, J ¼ 8 Hz, 1H), 8.26 (d, J ¼ 8 Hz, 1H),
m
d
¼ 165.3,
molecules cytotoxicity on the HepG2 (hepatocarcinoma cell line
purchased from ATCC, ref HB-8065) cell line was performed ac-
cording to the method of Mosmann [32] with slight modifications.
161.6, 159.7, 153.7, 151.7 135.9, 133.0, 130.1, 129.6, 124.4, 123.1, 122.9,
117.3, 115.5, 115.1, 104.3, 96.1. LC-MS (ESIþ) tR 4.60 min, m/z
[M þ H]þ 406.93/408.93/411.18. MW: 407.63 g/mol. Anal. Calcd for
Briefly, 5.103 cells in 100
m
L of complete medium were inoculated
into each well of 96-well plates and incubated at 37 ꢁC in a hu-
midified 6% CO2. After 24 h incubation, 100 L of medium with
C
18H9Cl3N2O3: C, 53.04; H, 2.23; N, 6.87. Found: C, 52.86; H, 2.24; N,
6.92.
m
various product concentrations dissolved in DMSO (final concen-
tration less than 0.5% v/v) were added and the plates were incu-
bated for 72 h at 37 ꢁC. Triplicate assays were performed for each
sample. Each plate-well was then microscope-examined for
detecting possible precipitate formation before the medium was
4.1.39. Preparation of 1-(2-(2-methylquinazolin-4-yloxy)phenyl)
ethanone (37)
Molecule 37 was prepared in two steps from commercial 2-
methylquinazolin-4(3H)-one. This last was first chlorinated at po-
sition 4, by using POCl3, according to a previously microwave-
assisted reported procedure [25], leading to 4-chloro-2-
methylquinazoline in 73% yield. Then, the general DMAP-
catalyzed operating procedure described in x 3.1.3. was applied to
aspirated from the wells. 100
mL of MTT (3-(4,5-dimethyl-2-
thiazolyl)-2,5-diphenyl-2H-tetrazolium
bromide) solution
(0.5 mg/mL in medium without FCS) were then added to each well.
Cells were incubated for 2 h at 37 ꢁC. After this time, the MTT

44
A. Gellis et al. / European Journal of Medicinal Chemistry 119 (2016) 34e44
approach to the new potentially bioactive pyrimidinones, Heterocycles 55
solution was removed and DMSO (100
mL) was added to dissolve
(2001) 535e544.
the resulting blue formazan crystals. Plates were shaken vigorously
(700 rpm) for 10 min. The absorbance was measured at 570 nm
with 630 nm as reference wavelength using a BIO-TEK ELx808
Absorbance Microplate Reader. DMSO was used as blank and
doxorubicin (purchased from Sigma Aldrich) as positive control.
Cell viability was calculated as percentage of control (cells incu-
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)
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Acknowledgment
ꢁ
[17] N. Primas, P. Verhaeghe, A. Cohen, C. Kieffer, A. Dumetre, S. Hutter, S. Rault,
This work was supported by the Centre National de la Recherche
P. Rathelot, N. Azas, P. Vanelle, A new synthetic Route to original sulfonamide
derivatives in 2-Trichloromethylquinazoline series: a structure-activity rela-
tionship study of antiplasmodial activity, Molecules 17 (2012) 8105e8117.
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ꢀ
Scientifique and by Aix-Marseille Universite.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2016.04.059.
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