Synthesis and cytotoxic evaluation of 7-chloro-4-phenoxyquinolines with formyl, oxime and thiosemicarbazone scaffolds

Article abstract of DOI:10.1007/s00044-016-1688-6

New 7-chloro-4-phenoxyquinoline derivatives bearing formyl, oxime and thiosemicarbazone functional groups were easily prepared using 4,7-dichloroquinoline and functionalized phenols as inexpensive and commercially available starting materials. Their chemi

Full text of DOI:10.1007/s00044-016-1688-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1688-6
ORIGINAL RESEARCH
Synthesis and cytotoxic evaluation of 7-chloro-4-phenoxyquinolines with
formyl, oxime and thiosemicarbazone scaffolds
Vladimir V. Kouznetsov1 Felipe Sojo2,3 Fernando A. Rojas-Ruiz1,4
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Diego R. Merchan-Arenas4 Francisco Arvelo2,3
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Received: 19 February 2016 / Accepted: 8 July 2016
© Springer Science+Business Media New York 2016
Abstract New 7-chloro-4-phenoxyquinoline derivatives
bearing formyl, oxime and thiosemicarbazone functional
groups were easily prepared using 4,7-dichloroquinoline
and functionalized phenols as inexpensive and commer-
cially available starting materials. Their chemical structures
were confirmed by use of infrared and 1H, 13C nuclear
magnetic resonance experiments. All the synthesized com-
pounds were evaluated for their cytotoxicity against the cell
lines MCF-7, SKBR-3, PC3, HeLa and human dermis
fibroblast as non-tumor cells, in vitro using the 3-
(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
(MTT) for assay. The quinoline derivatives 3a and 3d
resulted as promising models for antitumor drugs, display-
ing good cytotoxic activity against four human cancer cell
lines (9.18 µM < IC50 < 50.75 µM). The phenoxyquinoline
3d stands out by its low unspecific cytotoxicity and high
selectivity on tumor lines SKBR-3, HeLa and PC3 cells.
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Keywords 7-Chloro-4-phenoxyquinoline Lipinski’s rule
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OSIRIS software In vitro antitumor and cytotoxic analysis
Introduction
New leads with anticancer potential are needed urgently since
anticancer drugs used in clinics are commonly highly toxic
and non-selective molecules. In addition, the resistance inci-
dence for some chemotherapeutic agents has become
remarkable in recent decades. In this sense, the design of more
selective and safer anticancer agents stands out as an actual
and vital task. Quinolines and their derivatives have shown to
display a wide spectrum of biological activities. Quinoline
nucleus is generally present in a large number of synthetic and
natural molecules with relevant parasites growth inhibition
properties. Moreover, different examples have revealed their
potent anticancer activity (Afzal et al., 2015; Arafa et al.,
2013; Zhao et al., 2005). Currently, quinoline derivatives are
available as antimalarial (chloroquine, mefloquine, amodia-
quinine, primaquine, etc.), antibacterial (ciprofloxacin, spar-
foxacin, gatifloxacin, etc.) or anticancer drugs (camptothecin,
irinotecan, topotecan, etc.). Hydroxyquinoline scaffolds also
play an important role in anticancer drug development, as
their derivatives have shown excellent results through differ-
ent mechanism of action such as growth inhibitors by cell
cycle arrest, apoptosis and inhibition of angiogenesis or
cell migration disruption. Lenvatinib (A) and cabozantinib (B)
are anticancer drugs based on the C-4 substituted aryl
oxyquinoline skeleton while experimental anticancer drug
Electronic supplementary material The online version of this article
(doi:10.1007/s00044-016-1688-6) contains supplementary material,
which is available to authorized users.
* Vladimir V. Kouznetsov
kouznet@uis.edu.co
vkuznechnik@gmail.com
Francisco Arvelo
franarvelo@yahoo.com
1
Laboratorio de Química Orgánica y Biomolecular, Universidad
Industrial de Santander, Parque Tecnologico Guatiguara, Km 2 vía
refugio, Piedecuesta, A.A 681011, Colombia
2
Centro de Biociencias Fundación Instituto de Estudios Avanzados-
IDEA, Caracas, , Venezuela
3
Laboratorio de Cultivo de Tejidos y Biología de Tumores,
Instituto de Biología Experimental, Universidad Central de
Venezuela, código postal 1041, Caracas, Venezuela
4
Grupo de Investigación e Innovación en Básicas, Universidad
Manuela Beltrán, Calle de los Estudiantes 10-20 Ciudadela Real
de Minas, Código Postal, Bucaramanga 680005, Colombia

Med Chem Res
Fig. 1 Anticancer drugs with the aryl oxyquinoline moiety
dofequidar (MS-209, C; Katayama et al., 2009) is a
5-alkoxyquinoline derivative (Fig.1).
against the organism based on the topological descriptors
were explored for to potential risk assessment, employing
the Osiris software (Osiris).
On the other hand, it is important to recall the fact that the
pharmacological properties of synthetic drugs depend mark-
edly on the structures of the pharmacophores incorporated into
them. Thiosemicarbazones and oximes are structural moieties
present in a wide variety of compounds with numerous bio-
logical activities including, antiviral (Banerjee et al., 2011),
antitumor (Berényi et al., 2013; Arora et al., 2014), antifungal
(Al-Amiery et al., 2012), among others. Hence, the synthesis
of new series of bioactive compounds containing thiosemi-
carbazone and hydroxyquinoline fragments results promising.
In fact, heterocyclic oximes and thiosemicarbazones, including
quinoline derivatives, are polyfunctional substrates, widely
used in the development of methods for the synthesis of bio-
logically active compounds. These kinds of molecules could
be prominent medicinal agents (Waghamale and Piste, 2013;
Saad et al., 2011; Kaur et al., 2007; Chen et al., 2011). Based
on these facts, increased attention is now given to the chem-
istry of quinoline derivatives, specially to the quinoline-2(8)-
carboxaldehydethiosemicarbazones and 4-phenoxy-6,7-dis-
ubstituted quinoline (thio)semicarbazones, which have shown
in vitro topoisomerase II action (Bisceglie et al., 2015) and
c-Met kinase inhibition on a single-digital nanomolar level
(Qi et al., 2013), respectively.
Taking into account the above stated, in the present study
we have synthesized new 7-chloro-4-phenoxyquinolines
possessing formyl, oximes and thiosemicarbazones scaf-
folds. Incorporation of these pharmacophores into 4-
phenoxyquinoline nucleus would enhance anticancer prop-
erties of these molecules. Their potential human tumor cell
growth inhibitory effect on MCF-7 (breast carcinoma, no
overexpresses the HER2/c-erb-2 gene), SKBR-3 (breast
carcinoma, overexpresses the HER2/c-erb-2 gene), PC3
(prostate carcinoma), HeLa (cervical epithelial carcinoma)
cancer cell lines and for non-tumor cells (primary culture of
human dermis fibroblast—control cells) was tested. All the
prepared molecules have been subjected to absorption,
distribution, metabolism and excretion (ADME) molecular
properties prediction by Molinspiration online calculation
software and MolSoft program, to determine their bioa-
vailability following the Lipinski’s “rule of five” (Lipinski
et al., 1997). Additionally, their potential adverse effects
Material and methods
Chemistry
The melting points (uncorrected) were determined on a
Fisher-Johns melting point apparatus. The infrared (IR)
spectra were recorded using a Infralum FT-02 spectro-
photometer in KBr. 1H and 13C nuclear magnetic resonance
(NMR) spectra were recorded on Bruker AM-400 or AC-
300 spectrometers. Chemical shifts are reported in ppm (δ)
1
relative to the solvent peak (CDCl3, 7.24 ppm for H and
77.23 ppm for 13C; or dimethyl sulfoxide (DMSO)-d6, 2.5
1
ppm for H and 39.51 ppm for 13C). Signals are designated
as follows: s, singlet; d, doublet; dd, doublet of doublets; m,
multiplet. A Hewlett Packard 5890a series II Gas Chro-
matograph interfaced to an HP 5972 Mass Selective
Detector with an Hewlett Packard (HP) Mass Spectrometry
(MS) Chemstation Data system was used for MS identifi-
cation at 70 eV using a 60 m capillary column coated with
HP-5 (5 %-phenyl-poly(dimethyl-siloxane)). Elemental
analyses were performed on a Perkin Elmer 2400 Series II
analyzer and were within 0.4 of theoretical values. The
reaction progress was monitored using thin layer chroma-
tography (TLC) on a silufol UV254 TLC aluminum sheet.
Synthesis of polyfunctionalized quinolines 3a–d of the
series I tested in this work were easily carried out using
diverse aldehydes 2a–d and 4,7-dichloroquinoline 1 as
starting materials following our published procedure
(Bueno et al., 2012). Briefly, 0.50 g (2.5 mmol) of 4,7-
dichloroquinoline 1, 0.37 g (3.01 mmol) of benzaldehydes
2a–d and 1.0 g (7.60 mmol) of K2CO3 were dissolved in 3
mL of Dimethylformamide (DMF). The resulting mixture
was subjected to reflux under vigorous stirring for 8 h,
according to TLC monitoring. The reaction mass was
diluted with water and extracted with dichloromethane (2 ×
30 mL). Finally, the organic phases were dehydrated using
Na2SO4, and concentrated under vacuum. Compounds 3a–d

Med Chem Res
were purified by columm chromatography using petroleum
ether and ethyl acetate combinations as eluting solvents.
119.4 (C-4a), 111.6 (C-2′), 104.1 (C-3), 56.1 (OCH3); GC-
MS: tR = 25.8 min.; MS (EI), m/z (%):315 [(M+2), 32], 313
(M+• 98), 282 (32), 176 (100), 162 (35), 151 (34), 135 (48);
Anal. Calcd for C17H12ClNO3: C, 65.08; H, 3.86; N, 4.46.
Found: C, 65.28; H, 3.67; N, 4.64.
4-((7-Chloroquinolin-4-yl)oxy)benzaldehyde (3a)
White solid, 80 %, mp 130–135 °C; IR (KBr) νmax 1698,
1
1604 cm−1; H NMR (400 MHz, CDCl3): δ = 10.03 (1H, s,
3-((7-Chloroquinolin-4-yl)oxy)-4-methoxybenzaldehyde
–CHO), 8.76 (1H, d, J = 5.1 Hz, 2-H), 8.22 (1H, d, J = 8.9
Hz, 5-H) 8.12 (1H, d, J = 1.9 Hz, 8-H), 7.98–8.02 (2H, dd,
J = 8.6, 1.9 Hz, 3′-H, 5′-H), 7.52–7.55 (1H, dd, J = 8.9, 2.0
Hz, 6-H), 7.30–7.34 (2H, dd, J = 8.5, 2.2 Hz, 2′-H, 6′-H),
6.71 (1H, d, J = 5.1 Hz, 3-H); 13C NMR (100 MHz, CDCl3):
δ = 187.9 (–CHO), 161.5 (C-4′), 156.2 (C-4), 152.2 (C-2),
150.3 (C-8a), 136.5 (C-7), 136.2 (C-1′), 131.9 (C-2′, C-5′),
129.6 (C-8), 128.3 (C-6), 128.3 (C-4a), 127.7 (C-3), 126.4
(C-5), 119.5 (C-3′, C-5′); Gas Chromatography-Mass
Spectrometry (GC-MS): tR = 24.0 min.; MS (Electron
Impact (EI)), m/z (%):285 [(M+2), 30], 283 (M+•, 99), 219
(33), 121(100), 99 (49); Anal. Calcd for C16H10ClNO2: C,
67.74; H, 3.55; N, 4.94. Found: C, 67.41; H, 3.31; N, 4.85.
(3d)
White solid, 73 %, mp 70–73 °C; IR (KBr) νmax 1696, 1604
cm−1; 1H NMR (400 MHz, CDCl3): δ = 9.92 (1H, s,
–CHO), 8.64 (1H, d, J = 5.2 Hz, 2-H), 8.34 (1H, d, J = 8.9
Hz, 5-H), 8.09 (1H, d, J = 2.0 Hz, 8-H), 7.88–7.85 (1H, dd,
J = 8.4, 2.0 Hz, 4′-H), 7.76 (1H, d, J = 2.0, 6′-H), 7.56–7.53
(1H, dd, J = 8.9, 2.0 Hz, 3′-H), 7.20 (1H, d, J = 8.5 Hz,
6-H), 6.39 (1H, d, J = 5.2, 3-H), 3.86 (3H, s, OCH3); 13C
NMR (100 MHz, CDCl3): δ = 189.7 (–CHO), 161.2 (C-4),
156.7 (C-2), 152.1 (C-3′), 150.2 (C-4′), 142.8 (C-8a), 136.2
(C-7), 130.5 (C-1′), 130.2 (C-5), 128.1 (C-8), 127.2 (C-6′),
123.4 (C-6), 123.2 (C-5′), 119.4 (C-4a), 112.8 (C-2′), 103.4
(C-3), 56.2 (OCH3); GC-MS: tR = 26.4 min.; MS (EI), m/z
(%):315 [(M+2), 30], 313 (M+•, 100), 282 (35), 176 (98),
162 (36), 151 (34), 135 (50); Anal. Calcd for C17H12ClNO3:
C, 65.08; H, 3.86; N, 4.46. Found: 65.24; H, 3.63; N, 4.61
2-((7-Chloroquinolin-4-yl)oxy)benzaldehyde (3b)
White solid, 65 %, mp 80–83 °C; IR (KBr) νmax 1698, 1599
cm−1; 1H NMR (400 MHz, CDCl3): δ = 10.02 (1H, s,
–CHO), 8.62 (1H, d, J = 6.7 Hz, 2-H), 8.07 (1H, d, J = 8.5
Hz, 5-H), 8.03–7.96 (1H, ddd, J = 8.7, 7.4, 1.9 Hz, 4′-H),
8.01 (1H, d, J = 1.6, Hz, 8-H), 7.50–7.48 (1H, dd, J = 8.5,
1.9 Hz, 6-H), 7.46–7.41 (1H, ddd, J = 7.8, 1.9 Hz, 6′-H),
7.34–7.32 (1H, dd, J = 8.7, 7.8,1.9 Hz, 5′-H), 7.20–7.07
(1H, dd, J = 8.7, 1.9 Hz, 3′-H), 6.57 (1H, d, J = 6.7 Hz,
3-H); 13C NMR (100 MHz, CDCl3): δ = 188.8 (–CHO),
164.2 (C-4), 160.0 (C-2′) 151.4 (C-2), 150.2 (C-8a), 132.8
(C-7), 131.3 (C-4′), 129.1 (C-6′), 127.4 (C-1′), 127.2 (C-8),
126.7 (C-5), 126.4 (C-6), 122.0 (C-5′), 119.1 (C-3′), 118.9
(4a), 101.9 (C-3); GC-MS: tR = 26.0 min.; MS (EI), m/z
(%):285 [(M+2), 33], 283 (M+•, 99), 219 (45), 121(99), 99
(35); Anal. Calcd for C16H10ClNO2: C, 67.74; H, 3.55; N,
4.94. Found: C, 67.40; H, 3.32; N, 4.90.
Synthesis of (7-chloroquinolin-4-yl)oxy)benzaldehyde
oximes (4a–d); General experimental procedure
A mixture of benzaldehydes 3a–d (14.13 mmol), hydro-
xylamine hydrochloride (17 mmol) and sodium carbonate
(17 mmol) was homogenized in a mortar and added to a
flask (25 mL). The mixture was irradiated in a domestic
microwave oven set at medium-low power for a period of 5
min monitored by TLC. Then, 15 mL of distilled water was
added to the reaction mixture, precipitating and filtering the
formed oximes 4a–d. The crude products were washed with
water (2 × 10 mL) and dried under vacuum. Finally, the
pure product was obtained by column chromatography
using mixtures of petroleum ether-ethyl acetate as mobile
phase.
4-((7-Chloroquinolin-4-yl)oxy)-3-methoxybenzaldehyde
(3c)
4-((7-Chloroquinolin-4-yl)oxy)benzaldehydeoxime (4a)
White solid, 65 %, mp 140–143 °C; IR (KBr) νmax 1690,
White solid, 99 %, mp 170–173 °C; IR (KBr) νmax 3217,
1583 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 10.02
(1H, s, HC=N), 8.74 (1H, d, J = 5.2 Hz, 2-H), 8.32 (1H, d,
J = 8.9 Hz, 5-H), 8.22 (1H, s, N–OH), 8.10 (1H, d, J = 1.9
Hz, 8-H), 7.75 (2H, d, J = 8.6 Hz, 2′-H, 6′-H), 7.69 (1H, dd,
J = 8.8, 2.0 Hz, 6-H), 7.35 (2H, d, J = 8.6 Hz, 3′-H,5′-H),
6.71 (1H, d, J = 5.1 Hz, 3-H); 13C NMR (100 MHz, DMSO-
d6): δ = 187.9 (–C=N–OH), 161.5 (C-4′), 156.2 (C-4),
152.2 (C-2), 150.3 (C-8a), (C-7), 136.2 (C-1′), 131.9 (C-2′,
C-5′), 129.6 (C-8), 128.3 (C-6), 128.3 (C-4a), 127.7 (C-3),
1
1590 cm−1; H NMR (400 MHz, CDCl3): δ = 10.02 (1H, s,
–CHO), 8.70 (1H, d, J = 5.2 Hz, 2-H), 8.32 (1H, d, J = 8.9
Hz, 5-H), 8.10 (1H, d, J = 1.9 Hz, 8-H), 7.61 (1H, d, J =
1.6 Hz, 2′-H), 7.58–7.53 (2H, t, J = 9.1 Hz, 2.0 Hz, 5′-H, 6′-
H), 7.35 (1H, d, J = 8.0 Hz, 6-H), 6.45 (1H, d, J = 5.2 Hz,
3-H), 3.85 (3H, s, OCH3); 13C NMR (100 MHz, CDCl3): δ
= 190.7 (–CHO), 160.8 (C-4), 152.3 (C-2), 152.2 (C-3′),
150.3 (C-4′), 147.6 (C-8a), 136.2 (C-7), 135.1(C-1′), 128.1
(C-5), 127.2 (C-8), 125.2 (C-6′), 123.4 (C-6), 122.8 (C-5′),

Med Chem Res
126.4 (C-5), 119.5 (C-3′, C-5′); gas chromatography mass
spectrometry (GC-MS): tR = 27.5 min.; MS (EI), m/z (%):
298 (M+•, nd), 282 (30), 280 [(M+•-H2O), 100], 245 (60),
162 (50), 99 (45); Anal. Calcd for C16H11ClN2O2: C, 64.33;
H, 3.71; N, 9.38. Found: C, 64.13; H, 3.90; N, 9.19.
(1H, d, J = 8.7 Hz, 5′-H), 6.51 (1H, d, J = 5.2 Hz, 3-H),
3.75 (3H, s, OCH3); 13C NMR (100 MHz, DMSO-d6): δ =
190.7 (–C=N–OH), 160.8 (C-4), 152.3(C-2), 152.2(C-3′),
150.3(C-4′), 147.6(C-8a), 136.2(C-7), 135.1(C-8), 128.1(C-
1′), 127.2 (C-5), 125.2 (C-6′), 123.4 (C-6), 122.8 (C-5′),
119.4 (C-4a), 111.6 (C-2′), 104.1 (C-3), 56.1 (OCH3); GC-
MS: tR = 30.0 min.; MS (EI), m/z (%): 328 (M+•, nd), 312
(30), 310 [(M+•-H2O), 100], 279 (40), 176 (90), 99 (45);
Anal. Calcd for C17H13ClN2O3: C, 62.11; H, 3.99; N, 8.52.
Found: C, 62.31; H, 3.79; N, 8.73.
2-((7-Chloroquinolin-4-yl)oxy)benzaldehydeoxime (4b)
White solid, 99 %, mp 158–160 °C; IR (KBr) νmax 3248,
1588 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 10.02
(1H, s, HC=N), 8.74 (1H, d, J = 5.2 Hz, 2-H), 8.32 (1H, d,
J = 8.9 Hz, 5-H), 8.22 (1H, s, N–OH), 8.10 (1H, d, J = 1.9
Hz, 8-H), 7.75 (2H, d, J = 8.6 Hz, 2′,6′-H), 7.69 (1H, dd, J
= 8.8, 2.0 Hz, 6-H), 7.35 (2H, d, J = 8.6 Hz, 3′,5′-H), 6.71
(1H, d, J = 5.1 Hz, 3-H); 13C NMR (100 MHz, DMSO-d6):
δ = 188.8 (–C=N–OH), 164.2 (C-4), 160.0 (C-2′) 151.4 (C-
2), 150.2 (C-8a), 132.8 (C-7), 131.3 (C-4′), 129.1 (C-6′),
127.4 (C-1′), 127.2 (C-8), 126.7 (5 C), 126.4 (C-6), 122.0
(C-5′), 119.1 (C-3′), 118.9 (4a), 101.9 (C-3); GC-MS: tR =
27.5 min.; MS (EI), m/z (%): 298 (M+•, nd), 282 (30), 280
[(M+•-H2O), 100], 245 (50), 162 (60), 99 (45); Anal. Calcd
for C16H11ClN2O2: C, 64.33; H, 3.71; N, 9.38. Found: C,
64.53; H, 3.51; N, 9.20.
Synthesis of (7-Chloroquinolin-4-yl)oxy)benzylidene)
hydrazine-1-carbothioamides (5a–d); General experimental
procedure
A mixture of 0.2 g of benzaldehydes 3a–d (14.13 mmol)
and thiosemicarbazide 0.08 g (17 mmol) in 5 mL of ethanol
was subjected to heating (60 °C) in a 25 mL flask until
complete dissolution. Subsequently, some drops of the
glacial acetic acid were added to the resulting solution. The
precipitate formed was kept under stirring and heating for 1
h (TLC). Finally, the reaction mixture was cooled to room
temperature and the formed solid was filtered and washed
with cold ethanol to yield the products 5a–d.
4-((7-Chloroquinolin-4-yl)oxy)-3-methoxybenzaldehyde
oxime (4c)
2-(4-((7-Chloroquinolin-4-yl)oxy)benzylidene)hydrazine-1-
carbothioamide (5a)
White solid, 99 %, mp 180–183 °C; IR (KBr) νmax 3250,
1580 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 10.02
(1H, s, HC=N), 8.68 (1H, d, J = 5.2 Hz, 2-H), 8.35 (1H, d,
J = 8.9 Hz, 5-H), 8.21 (1H, s, N–OH), 8.09 (1H, d, J = 2.0
Hz, 8-H), 7.69 (1H, dd, J = 8.9, 2.1 Hz, 6-H), 7.49 (1H, d, J
= 1.6 Hz, 2′-H), 7.36 (1H, d, J = 8.1 Hz, 5′-H), 7.31 (1H,
dd, J = 8.2, 1.6 Hz, 6′-H), 6.51 (1H, d, J = 5.2 Hz, 3-H),
3.74 (3H, s, OCH3); 13C NMR (100 MHz, DMSO-d6): δ =
189.7 (-C=N–OH), 161.2 (C-4), 156.7 (C-2), 152.1 (C-3′),
150.2 (C-4′), 142.8 (C-8a), 136.2 (C-7), 130.5 (C-1′), 130.2
(C-5), 128.1 (C-8), 127.2 (C-6′), 123.4 (C-6), 123.2 (C-5′),
119.4 (C-4a), 112.8 (C-2′), 103.4 (C-3), 56.2 (OCH3); GC-
MS: tR = 29.3 min.; MS (EI), m/z (%):328 (M+•, nd), 312
(30), 310 [(M+•-H2O), 100], 279 (40), 176 (80), 99 (35);
Anal. Calcd for C17H13ClN2O3: C, 62.11; H, 3.99; N, 8.52.
Found: C, 62.31; H, 3.79; N, 8.71.
White solid, 90 %, mp 190–193 °C; IR (KBr) νmax 3176,
3070–3065, 1573, 1265 cm−1; 1H NMR (400 MHz, DMSO-
d6): δ = 11.51 (1H, s, HC=N), 8.73 (1H, d, J = 4.6 Hz, 2-
H), 8.26–8.22 (2H, m, N–H, 5-H), 8.13–8.06 (3H, m, 8-H,
NH2), 7.97 (2H, d, J = 7.9 Hz, 3′-H, 5′-H), 7.66 (1H, d, J =
8.2 Hz, 6-H), 7.32 (2H, d, J = 7.9 Hz, 2′-H, 6′-H), 6.69 (1H,
d, J = 4.6 Hz, 3-H); 13C NMR (100 MHz, DMSO-d6): δ =
178.5 (–C=N), 109.8 (–C=S), 159.0 (C-4′), 157.5 (C-4),
153.5 (C-2), 148.4 (C-8a), 146.8 (C-7), 135.7 (C-1′), 130.2
(C-2′,C-5′), 129.6 (C-8), 128.9 (C-6), 128.7 (C-4a), 123.2
(C-3), 121.4 (C-3′,C-5′), 115.9 (C-5); Anal. Calcd for
C17H13ClN4OS: C, 57.22; H, 3.67; N, 15.70. Found: C,
57.42; H, 3.82; N, 15.51.
2-(2-((7-Chloroquinolin-4-yl)oxy)benzylidene)hydrazine-1-
carbothioamide (5b)
3-((7-Chloroquinolin-4-yl)oxy)-4-methoxybenzaldehyde
oxime (4d)
White solid, 80 %, mp 180–183 °C; IR (KBr) νmax 3175,
3071–3065, 1573, 1264 cm−1; 1H NMR (400 MHz, DMSO-
d6): δ = 11.53 (1H, s, HC=N), 8.74 (1H, d, J = 4.6 Hz,
2-H), 8.26–8.22 (2H, m, N–H, 5-H), 8.14–8.08 (3H, m, 8-
H, NH2), 7.99 (2H, d, J = 7.9 Hz, 3′-H,5′-H), 7.70 (1H, d, J
= 8.2 Hz, 6-H), 7.29 (2H, d, J = 7.9 Hz, 2′-H,6′-H), 7.06
(1H, d, J = 4.6 Hz, 3-H); 13C NMR (100 MHz, DMSO-d6):
δ = 178.5 (–C=N), 109.8 (–C=S), 158.9 (C-4), 159.0
White solid, 99 %, mp 190–192 °C; IR (KBr) νmax 3216,
1581 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 10.02
(1H, s, HC=N), 8.69 (1H, d, J = 5.2 Hz, 2-H), 8.36 (1H, d,
J = 8.9 Hz, 5-H), 8.13 (1H, s, N–OH), 8.09 (1H, d, J = 1.9
Hz, 8-H), 7.69 (1H, dd, J = 8.9, 2.0 Hz, 6-H), 7.59 (1H, dd,
J = 8.7, 1.7 Hz, 6′-H), 7.53 (1H, d, J = 1.7 Hz, 2′-H), 7.32

Med Chem Res
(C-2′), 153.5 (C-2), 148.4 (C-8a), 146.0 (C-7), 135.7 (C-4′),
135.1 (C-6′), 131.7 (C-1′), 128.7 (C-8), 128.9 (C-5), 124.7
(C-6), 123.9 (C-5′), 123.2 (C-3′), 115.9 (C-4a). Anal. Calcd
for C17H13ClN4OS: C, 57.22; H, 3.67; N, 15.70. Found: C,
57.42; H, 3.80; N, 15.54.
MCF-7 (breast carcinoma, no overexpresses the HER2/c-
erb-2 gene), SKBR-3 (breast carcinoma, overexpresses the
HER2/c-erb-2 gene) and primary culture of normal human
dermis fibroblast used as control cells were grown in Dul-
becco's Modified Eagle Medium (Invitrogen). Cells were
grown in a humidified incubator with 5 % CO2 and 95 % air
at 37 °C until they reach the exponential growth phase. For
treatments exponentially growing cells were collected,
counted, re-suspended in fresh culture medium and incu-
bated in 96-sterile-well plates.
2-(4-((7-Chloroquinolin-4-yl)oxy)-3-methoxybenzylidene)
hydrazine-1-carbothioamide (5c)
Gray solid, 77 %, mp 155–158 °C; IR (KBr) νmax 3177,
3071–3065, 1573, 1264 cm−1; 1H NMR (400 MHz, DMSO-
d6): δ = 11.40 (1H, s, HC=N), 8.70 (1H, d, J = 5.0 Hz, 2-
H), 8.38 (1H, d, J = 9.0 Hz, 5-H), 8.13–8.08 (2H, m, 8-H,
N–H ), 8.08–8.02 (3H, m, 6′-H, NH2), 7.71 (1H, dd, J =
9.0, 1.4 Hz, 6-H), 7.63 (1H, dd, J = 9.0, 1.5 Hz, 2′-H), 7.29
(1H, d, J = 9.0 Hz, 3′-H), 6.50 (1H, d, J = 5.0 Hz, 3-H),
3.74 (3H, s, OCH3); 13C NMR (100 MHz, DMSO-d6): δ =
178.5 (–C=N), 157.1 (–C=S), 153.5 (C-4), 151.7 (C-2),
148.4 (C-3′), 146.8 (C-4′), 146.5 (C-8a), 135.7 (C-7), 134.2
(C-1′), 130.8 (C-5), 128.7 (C-8), 126.1 (C-6′), 123.2 (C-6),
121.3 (C-5′), 115.9 (C-4a), 111.9 (C-2′), 109.8 (C-3), 56.1
(OCH3); Anal. Calcd for C18H15ClN4O2S: C, 55.89; H,
3.91; N, 14.48. Found: C, 55.67; H, 3.13; N, 14.29.
Cytotoxic activity
Cell viability was assessed using the 3-(4,5-dimethylthiazol-
2-yl)-2,5-diphenyltetrazolium bromide (MTT) for assay,
which is based on the ability of viable cells to metabolically
reduce a yellow tetrazolium salt (MTT; Sigma) to a purple
formazan product. This reaction takes place when mito-
chondrial reductases are active (Mosmann, 1983). Cells
were grown in 96-well plates (5×103 cells/well) for 24 h.
Cultures were carried out at 37 °C in a humidified atmo-
sphere with 5 % CO2. cells were incubated with the syn-
thetics products or chemotherapeutic drugs in 100 μL of
complete culture medium containing 0, 1, 5, 10, 25, 100 µg/
mL concentrations of each compounds for 72 h. After
incubation, the medium was removed and the cells were
treated with 100 μL 0.4 mg/mL MTT for 3 h at 37 °C.
Subsequently, 100 μL DMSO was added to the mixture.
The solubilized formazan product was quantified with the
help of a microtiter plate reader TECAN-sunrise at 570 nm.
Adriamycin was used as a positive control in the assay. In
all cases, the compounds were dissolved in DMSO, at the
final concentration in the culture medium was lower than 1
%, a concentration that had neither cytotoxic effect nor
caused any interference with the colorimetric detection
method.
2-(3-((7-Chloroquinolin-4-yl)oxy)-4-methoxybenzylidene)
hydrazine-1-carbothioamide (5d)
Yellow solid, 76 %, mp 145–148 °C; IR (KBr) νmax 3178,
1
3070–3065, 1573, 1265 cm−1; H NMR (400 MHz, DMSO-
d6): δ = 11.54 (1H, s, HC=N), 8.68 (1H, d, J = 5.2 Hz,
2-H), 8.34 (1H, d, J = 9.0 Hz, 5-H), 8.32 (1H, s, N–H), 8.20
(2H, s, NH2), 8.09 (1H, d, J = 4.5 Hz, 8-H), 7.78 (1H, s,
2′-H), 7.68 (1H, d, J = 9.0 Hz, 6-H), 7.40 (1H, d, J = 8.1 Hz,
6′-H), 7.34 (1H, d, J = 8.1 Hz, 5′-H), 6.50 (1H, d, J = 5.2 Hz,
3-H), 3.78 (3H, s, OCH3); 13C NMR (100 MHz, DMSO-d6):
δ = 178.5 (–C=N), 159.0 (–C=S), 153.5 (C-4), 151.7 (C-2),
148.4 (C-3′), 146.8 (C-4′), 146.5(C-8a), 135.7(C-7), 134.2
(C-1′), 128.9 (C-5), 128.7 (C-8), 128.6(C-6′), 123.2 (C-6),
122.5 (C-5′), 115.9 (C-4a), 111.7 (C-2′), 109.8(C-3), 56.1
(OCH3); Anal. Calcd for C18H15ClN4O2S: C, 55.89; H, 3.91;
N, 14.48. Found: C, 55.01; H, 3.73; N, 14.28.
Selectivity index (SI) and statistical analysis
The SI was calculated as the IC50 (control cells)/IC50
(tumoral cell line) ratio. A SI > 1 indicates that the cyto-
toxicity on tumoral cells surpassed that on healthy non-
tumoral cells (Nugroho et al., 2013). All experiments were
performed at least three times. The results are expressed as
mean SD. Anova test were performed. Only post hoc
Dunnet test P < 0.01 was considered to be statistically
significant. The dose–response curves were plotted with the
OriginPro ver.8.0 programs, and 50 % growth inhibitory
concentrations (IC50) of synthetics products or chemother-
apeutic drugs were determined by a non-linear regression of
individual experiments calculated through computation with
GraphPad prism v.5.02 software program (Intuitive Soft-
ware for Science, San Diego, CA, USA).
Biological activity
Reagents and compounds
Human tumor cell lines and culture media: The cells were
kindly donated by Dr Marie France Poupon, Curie Institute,
Paris- France. PC3 (prostate carcinoma), HeLa (cervical
epithelial carcinoma) were grown in RPMI 1640 medium
(Invitrogen) supplemented with 10 % heat inactivated fetal
bovine serum, 1 % of L-glutamine, 1 % streptomicyn, 100
units/mL penicillin (all obtained from Sigma Aldrich USA).

Med Chem Res
Results and discussion
Chemistry
Computational analysis: study of bioavailability
parameters
It is well known that a considerable number of new syn-
thetic compounds with significant activity failed during
human clinical trials due to ADME and toxicity problems
(Hou et al., 2006). One of the preliminary steps in high-
throughput screening process for drug research is to use in
silico drug-likeness evaluation of desired molecules to be
prepared, giving information about its bioavailability.
Taking into consideration these facts, the Molinspiration
Cheminformatics software (Lipinski et al., 1997) was used
in this study. Therefore, all synthesized molecules were
subjected to the Lipinski’s Rule of Five analysis, associated
to drug-like physicochemical parameters (molecular weight,
lipophilicity (Log P), hydrogen bond acceptor and donor
properties, polar surface area and rotatable bonds), which
can predict oral bioavailability and membrane permeability
of the synthetic molecules. Thus, according to these criteria,
all the quinoline derivatives studied in the current research
displayed good bioavailability properties as no violation to
The 4-((7-chloroquinolin-4-yl)oxy)benzaldehyde molecules
3a–d were easily obtained from inexpensive and commer-
cially available 4,7-dichloroquinoline 1 and functionalized
phenols
2
(p-hydroxybenzaldehyde 2a, o-hydro-
xybenzaldehyde 2b, vanillin 2c and iso-vanillin 2d) through
a nucleophilic reaction in the presence of K2CO3 in DMF
(Scheme1).
Then, prepared quinolin-4-oxybenzaldehydes 3 were
subjected to addition-elimination reactions with hydro-
xyamine and thiosemicarbazine to generate a small series of
7-chloro-4-phenoxyquinolines possessing oxime and thio-
semicarbazone scaffolds 4 and 5, respectively. All com-
pounds were prepared in good to excellent yields, and
obtained as stable crystalline substances with well-defined
melting points. Their structures were easily assigned by IR
1
and MS (Table 1), and confirmed by H and 13C NMR
experiments.
Scheme 1 Synthesis of tested 7-chloro-4-phenoxyquinoline derivatives

Med Chem Res
Table 1 Physicochemical
properties of prepared 4-
phenoxyquinoline derivatives
3–5
Compounds
Formula
Yield (%)
Mp (°C)
MW (g/mol)
MS (M+●, m/z)
3a
3b
3c
3d
4a
4b
4c
4d
5a
5b
5c
5d
C16H10NClO2
85
65
65
73
99
99
99
99
90
80
77
76
130–133
80–83
283.5
283.5
313.5
313.5
298.7
298.7
328.8
328.8
356.8
356.8
386.9
386.9
283
283
313
313
280a
280a
310a
310a
nd
C
C
C
C
16H10NClO2
17H12NClO3
17H12NClO3
16H11ClN2O2
140–143
70–73
170–173
158–160
180–183
190–192
190–193
180–183
155–158
145–148
C16H11ClN2O2
C17H13ClN2O3
C17H13ClN2O3
C17H13ClN4OS
C
17H13ClN4OS
C18H15ClN4O2S
18H15ClN4O2S
nd
nd
C
nd
nd not detected
a
ion corresponds to H2O elimination
Table 2 Molecular properties
related to bioavailability of new
4-aryloxyquinoline derivatives
3–5
Compounds Type MW (g/ % Absorption Log P TPSA HA HD ROTB Lipinski’s rule Drug-
mol)
violation
score
3a
3b
3c
I
283.7
283.7
313.7
313.7
298.7
298.7
328.8
328.8
356.8
356.8
386.9
386.9
543.5
95.48
95.48
92.29
92.29
89.09
89.09
86.94
86.94
83.97
83.97
80.79
80.79
37.90
4.37
4.37
4.16
4.16
4.98
4.98
4.79
4.79
4.50
4.50
4.31
4.31
0.48
39.18
39.18
48.43
48.43
57.72
57.72
63.95
63.95
72.54
72.54
81.77
81.77
3
3
4
4
4
4
5
5
5
5
6
6
0
0
0
0
1
1
1
1
3
3
3
3
7
3
3
4
4
3
3
4
4
5
5
6
6
5
0
0
0
0
0
0
0
0
0
0
0
0
1
0.10
0.14
0.10
0.12
0.45
0.46
0.44
0.43
0.46
0.47
0.47
0.47
7.19
I
I
3d
4a
4b
4c
I
II
II
II
II
III
III
III
III
–
4d
5a
5b
5c
5d
Adr.
206.1 12
Percentage of absorption is calculated by % Absorption = 109−(0.345 × TPSA)
Drug-score was calculated by OSIRIS program
TPSA, topological polar surface area, Log P logarithm of partition coefficient of the molecule in an octanol/
water system calculated by Molinspiration online tool, HA hydrogen bond acceptors, HD hydrogen bond
donors, ROTB number of rotatable bonds, Adr.adriamycin
this rules was observed (Table 2). However, it should be
noted that the values of calculated partition coefficient (Log
P) are above the lipophilicity optimum interval (0 < Log P
< 3). This means that all synthetized quinoline molecules
have a low water solubility character (Log P > 4.31-4.98)
that could compromise the absorption properties of these
compounds (Kerns and Di, 2008).
Bearing this in mind, we addressed to study different
molecular descriptors as the topological polar surface area
(TPSA = 39.18–81.77; ROTB ≤ 10) and the absorption
percentage (% Abs).This study confirmed the potential
intestinal absorption, bioavailability and hematoencephalic
barrier permeation of our compounds according to Veber’s
rules (TPSA < 140 A2; Veber et al., 2002). The same way a
good plasmatic membrane permeability as their % Abs
ranged between 80.78 and 95.48 %, even higher than the
adriamycin, could be expected (Zhao et al., 2002). In
summary, this in silico study pointed the quinoline deriva-
tives synthesized in our work as potential models for new
antitumor agents development.

Med Chem Res
Cytotoxic activity
and 5d (series III) exhibited also significant cytotoxic
activity against PC3 and HeLa tumor cells (Table 3).Among
this series, the compound 5d showed the best inhibitory
action with a IC50 equal to 11.58 µM.
According with the structure–activity relationship ana-
lysis, the inclusion of an oxime functional group (series II)
decreases the potential inhibitory action against these car-
cinoma lines. Nevertheless, although the best result was
acquired with the carbonyl group original from vainillin, the
thiosemicarbazone functional group insertion allows to
reach good results in more cell’s variability. In con-
sequence, compound 5d has been active against more
cancer cells lines.
Regarding the cytotoxicity on human dermis fibroblast,
in general the phenoxyquinolines are not toxic for normal
human cells, however a low activity was detected for the-
phenoxyquinoline 3d (IC50 328.34 µM). The phenox-
yquinoline 5d was the most toxic compound showing IC50
61.28 µM.
Comparison of cytotoxicity and nonspecific cytotoxicity
of the tested compounds is presented in Table 4. According
to this results, quinoline compound 3d presented a high
selectivity for the four tumor cell lines MCF-7, SKBR-3,
PC3 and HeLa evaluated for the cells control, while the
compounds 3c and 5b were more specific for tumor lines
PC3, displaying high selectivity (SI > 7.7). At that time, the
quinoline derivative 3a tested for all tumor lines showed a
moderate selectivity (SI ≤ 7.7), as well as derivatives 3c in
MCF-7 and HeLa, and 5d for HeLa.
In this study, 12 substituted phenoxyquinolines 3–5 of the
series I–III were tested in four cancer cell lines, as well as a
normal cell line. MCF-7, SKBR-3, PC3, HeLa were used to
study their potential human tumor cell growth inhibitory
effect. As control cells, primary culture of human dermis
fibroblast (non-tumor cells) was employed to discern an
unspecific cytotoxicity of prepared phenoxyquinolines.
Reference anticancer drug was adriamycin and the cytotoxic
activity was evaluated using MTT assay. Biological results
are shown in Table 3. The analysis of the quinoline deri-
vatives of each series (I, II and III) and the cytotoxic
activities revealed some structure–activity relationships.
First, some quinoline derivatives 3 with formyl function
(series I) and quinolines 5 possessing thiosemicarbazone
scaffold (series III) were active against all four cancer cell
lines (comp. 3a, 3d, 5d), while quinoline molecules 4
bearing oxime function (series II) resulted practically
inactive against all cancer cell lines studied (comp. 4a, 4b,
4c and 4d). Within the series I, phenoxyquinoline 3a has
more pronounced cytotoxic effect on breast carcinoma cells
with IC50 18.47 µM, whereas phenoxyquinoline 3d dis-
played considerable cytotoxic activity against cervical epi-
thelial carcinoma cells (IC50 9.18 µM) close to adriamycin
toxic effect (IC50 3.62 µM). Despite the cytotoxic activity of
our compounds are lower than the adriamycin drug, we
found a new potential lead in cervix cancer research, 3d,
IC50 < 10 µM. On the other hand, the 3a and 3d compounds
presented also midcytotoxic activity against PC3 cells,
22.14 and 21.29 µM, respectively. Phenoxyquinolines 5c
The remaining compounds have low SI values (SI < 5.5)
with respect to control cells. Several studies have shown
Table 3 Biological activity of the 7-chloro-4-phenoxyquinolines 3–5
Compounds
Type
Cytotoxicity IC50 (µM)
Unspecific cytotoxicity IC50 (µM)
MCF-7
SKBR-3
PC3
HeLa
Human dermis fibroblast
3a
3b
3c
I
18.47 1.05
NA
31.62 1.02
NA
22.14 1.16
NA
25.17 1.00
84.35 1.02
41.22 3.12
9.18 1.07
NA
123.05 1.01
275.50 1.26
318.78 1.02
328.34 1.39
334.78 1.01
NT
I
I
54.89 1.01
50.75 1.04
NA
NA
21.29 1.14
23.11 1.18
NA
3d
4a
4b
4c
I
29.01 1.04
NA
II
II
NT
NT
NT
NT
II
NA
NA
NA
NA
NA
4d
5a
5b
5c
II
NA
NA
NA
NA
NA
III
NA
NA
50.76 1.04
31.89 1.00
15.17 1.13
18.01 1.06
3.62 0.12
89.85 1.02
94.09 1.02
16.39 1.04
11.58 1.80
2.45 0.37
280.27 1.02
280.27 1.01
258.46 1.03
61.28 1.00
III
NA
NA
III
NA
NA
5d
Adr.
III
52.16 1.01
1.66 0.08
17.70 1.00
2.36 0.4
0.74 0.05
Marked in bold parameters indicated a pronounced anticancer activity
Adr. adriamycin, NA not active (IC50 > 100 µM), NT not tested

Med Chem Res
Table 4 Selectivity index of the prepared 7-chloro-4-phenoxyquinolines 3–5
Compounds Type Selective index, SIa
In silico toxic effects
MCF-7 SKBR-3 PC3 HeLa Mutagenic (M)
Tumorigenic (T)
Irritant (I)
Reproductive (R)
3a
3b
3c
3d
4a
4c
4d
5a
5b
5c
5d
Adr.
a
I
6.7
—
3.9
—
5.6
2.0
4.9
3.3
high-risk
high-risk
high-risk
high-risk
non-risk associated high-risk
non-risk associated high-risk
non-risk associated high-risk
non-risk associated high-risk
non-risk associated
non-risk associated
non-risk associated
non-risk associated
I
I
5.8
6.5
—
—
15.0 7.7
I
11.3
—
14.2 35.7
II
II
II
III
III
III
III
—
—
non-risk associated non-risk associated non-risk associated non-risk associated
non-risk associated non-risk associated non-risk associated non-risk associated
non-risk associated non-risk associated non-risk associated non-risk associated
non-risk associated non-risk associated non-risk associated non-risk associated
non-risk associated non-risk associated non-risk associated non-risk associated
non-risk associated non-risk associated non-risk associated non-risk associated
non-risk associated non-risk associated non-risk associated non-risk associated
non-risk associated non-risk associated non-risk associated non-risk associated
—
—
—
—
—
—
—
—
—
—
5.5
8.8
3.1
3.0
—
—
—
—
17.0 15.8
1.2
3.3
3.5
1.5
3.4
1.0
5.3
0.7
Marked in bold parameters indicated a pronounced selectivity
that adriamicyn have harmful effects on health and can lead
to the development of primary and secondary drug resis-
tance in tumor cells, thereby limiting the clinical success of
cancer chemotherapy (Sánchez et al., 2009). Our results
showed that the majority of the phenoxyquinolines obtained
have a significant selectivity for tumor cells.
On the other hand, the information acquired from the
topological analysis of the tested compounds, allowed us to
afford substantial information about their potential toxic
effects such as mutagenic (M), tumorigenic (T), irritant (I)
and reproductive (R; Table 3). Only phenoxyquinolines
with formyl function (3a–d, series I) showed a high-risk
profile as tumorigenic and irritant agents.
In an attempt to corelate the bioassay results and the
bioavailability expressed through the calculated partition
coefficient (CLog P), we can concluded that: (1) all mole-
cules have log P values lower than five according to
Lipinsky’s rule, but these values do not entry in the optimal
interval; (2) reference drug (adriamycin) has much more
marked lipophilic character than the tested arylox-
yquinolines and (3)within the group of active molecules
there are not much differences between their lipophilicity.
derivatives 3a and 3d stand out as interesting models for
antitumor drugs, displaying good cytotoxic activity against
four human cancer cells lines. Compounds 3c, 3d have been
more selective than other prepared phenoxyquinolines,
while 5d have low selective indexes for all tumor cells. The
phenoxyquinoline 3d stands out by their low unspecific
cytotoxicity and highly exceptional selectivity for HeLa
cells. These results are important data for the design
and synthesis of new 7-chloro-7-phenoxyquinoline-based
molecules, which could be a good lead for the development
of new anticancer agents.
Acknowledgment Financial support from Patrimonio Autónomo
Fondo Nacional de Financiamiento para la Ciencia, la Tecnología y la
Innovación, Francisco José de Caldas, contract RC-0346-2013, is
gratefully acknowledged. DRMA thanks COLCIENCIAS for the
doctoral fellowship.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interests.
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