Design, synthesis, X-ray crystallographic study and anticancer activity of novel 4-(7-chloro-1-methylquinolin-4-(1H)-ylideneamino)-phenyl-3-(dimethylamino)-prop-2-en-1-one

Article abstract of DOI:10.14233/ajchem.2014.18073

The disease of cancer has been ranked second after cardiovascular diseases and plant-derived molecules have played an important role for the treatment of cancer. On the account of the reported anticancer activity of quinolines containing the different bio

Full text of DOI:10.14233/ajchem.2014.18073

Asian Journal of Chemistry; Vol. 26, No. 24 (2014), 8497-8500
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.18073
Design, Synthesis, X-Ray Crystallographic Study and Anticancer Activity of Novel
4-(7-Chloro-1-methylquinolin-4-(1H)-ylideneamino)-phenyl-3-(dimethylamino)-prop-2-en-1-one
1,*
1
2
2
MOSTAFA M. GHORAB , MANSOUR S. ALSAID , HAZEM A. GHABBOUR and HOONG-KUN FUN
1Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Kingdom of Saudi Arabia
2Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
*Corresponding author: Fax: +966 1 4670560; Tel: +966 534292860; E-mail: mmsghorab@yahoo.com
Received: 23 May 2014;
Accepted: 1 October 2014;
Published online: 1 December 2014;
AJC-16389
The disease of cancer has been ranked second after cardiovascular diseases and plant-derived molecules have played an important role for
the treatment of cancer. On the account of the reported anticancer activity of quinolines containing the different biologically active
moieties, a novel 4-[7-chloro-1-methylquinolin-4-(1H)-ylideneamino]-phenyl-3-(dimethylamino)-prop-2-en-1-one (3) was synthesized
using 1-[4-(7-chloroquinolin-4-ylamino)phenyl]ethanone (2) as strategic starting material. Compound 3 was obtained in good yield via
reaction of 1-[4-(7-chloroquinolin-4-ylamino)phenyl]ethanone (2) with DMF-DMA in dry toluene. The structure of the newly synthesized
compound was confirmed on the basis of elemental analysis, IR, 1H NMR, 13C NMR spectra and X-ray crystallographic analysis. Cytotoxic
activity of the newly synthesized compound 3 was evaluated against human breast cancer cell line (MCF7). It was found that compound
3 is nearly as active as the reference drug (doxorubicin).
Keywords: Novel quinoline, X-Ray crystallographic study, Cytotoxic activity.
(CA). Cancer is a top killer of human beings. Thus there is a
INTRODUCTION
great urgency to develop highly efficacious and minimally
Cancer is a multifaceted disease that represents one of
toxic treatments for cancer.Although tremendous progress has
the leading causes of mortality in developed countries. World-
been achieved in the development of novel cancer treatments.
wide, one in eight deaths is due to cancer and it is the second
Most of the current cancer drugs usually exhibit high toxicity
most common cause of death in the US, exceeded only by
and are severely resisted by tumor cells in the clinic. This
heart disease1 Chemotherapy is the mainstay for cancer
dilemma is particularly true for DNA-damaging agents, the
mainstay of cancer treatment22. Quinolines were found to
treatment, the use of available chemotherapeutics is often
limited due to undesirable side effects. It is important to identify
possess several pharmacological properties, including anti-
cancer activity23-27. Also, a large number of structurally novel
new agents and new targets for the treatment of cancer.
Nitrogen heterocycles have received a great deal of attention
quinolines have ultimately been reported to show substantial
anticancer activity in vitro and in vivo28. Based on the above
in the literature due to their role as active pharmacophores of
historical significance. Among these heterocyclic systems,
information and as a continuation of a previous work on
anticancer agents29-36, we report the synthesis, X-ray crystallo-
especially those containing pyridine rings are associated with
diverse pharmacological properties such as anticancer2,3, anti-
graphic studies and anti-breast cancer activity of some novel
microbial4-6, anticonvulsant7, antiviral8 anti-HlV9, antifungal
quinoline derivative.
and antimycobacterial activities10. Recently considerable
attention has been devoted to the construction of new deri-
EXPERIMENTAL
vatives of quinoline on the account of their reported biological
activities11-18. From the literature survey, several methods have
The starting material 4,7-dichloroquinoline (1) was pur-
been described for the elaboration of substituted quinolines19-
chased from Sigma-Aldrich. Melting points were determined
21, which as a class have been reported to have anticancer and
on an electrothermal melting point apparatus (Stuart Scientific,
Stone) and were uncorrected. Precoated Silica gel plates (Kiesel
gel 0.25 mm, 60 F 254, Merck) were used for thin layer
chromatography (TLC). The developing solvent system was
antileukemic activity. Different mechanisms account for the
cytotoxic effect of this class of compounds, the most prominent
mechanism was the inhibition of carbonic anhydrase isozymes

8498 Ghorab et al.
Asian J. Chem.
chloroform/methanol (10: 3) and the spot were detected by
ultraviolet light. Infrared spectra (KBr disc) were recorded on
FT-IR spectrophotometer (Perkin Elmer) at the Research
Center, College of Pharmacy, King Saud University, Saudi
Arabia. 1H NMR spectra were scanned in dimethylsulfoxide
(DMSO-d6) on a NMR spectrophotometer (Bruker AXS Inc.)
operating at 500 MHz for 1H and 125.76 MHz for 13C at the
aforementioned Research Center. Chemical shifts are expre-
ssed in δ values (ppm) relative to tetramethylsilane (TMS) as
an internal standard. Exchangeable protons were confirmed
by addition of drop of D2O. Elemental analyses were done on
a model 2400 CHNSO analyzer (Perkin Elmer). The X-ray
measurement of compound 3 was performed using Bruker
SMART APEXII CCD diffractometer37,38. Crystallographic
data of compound 3 has been deposited with the Cambridge
Crystallographic Data Center (supplementary publication
numbers CCDC-923085). Copy of the data may be obtained
free of charge from the Director, CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK (deposit@ccdc.cam.ac.uk).
X-Ray crystallography: Single crystal suitable for X-
ray diffraction was mounted on glass fibres. The diffraction
data were collected on Bruker APEX-II CCD area-detector
diffract-tometer with CuKα radiation (λ = 1.54178 Å) at a
temperature of 296(2) K. The data for this compound was
processed with SAINT and corrected for absorption using
multi-scan39. The structures were solved by direct methods
using the program SHELXTL9740 and refined by full-matrix
least squares technique on F2 using anisotropic displacement
parameters using SHELXTL40 program.All geometrical calcu-
lations were carried out using the program PLATON41. Mole-
cular graphics were drawn using SHELXTL40 and PLATON41
program. All the hydrogen atoms were fixed at calculated
positions with a common isotropic displacement parameters
set to 1.2 (1.5 for methyl groups) times the equivalent isotropic
U values of the parent carbon atoms. A rotating group model
was applied to the methyl groups. The crystallographic data
are given in Table-1. Hydrogen bonding interactions are shown
in Table-2. The selected bond lengths and bond angles are
listed in Table-3. The scheme of the synthesis of the compound
is shown in Scheme-I.
11.49; found: C, 68.66; H, 5.22; N, 11.74. Crystals suitable
for X-ray diffraction was obtained after a week on slow evapo-
ration of the solution43.
in vitro Cytotoxic activity: The human tumor breast
cancer cell line (MCF7) was obtained from the National Cancer
Institute, Cairo, Egypt. The cytotoxic activity of the synthesized
compound was measured by the Sulfo-Rhodamine-B stain
(SRB) assay as reported by Skehan et al.44. Cells were plated
in 96-multiwell plate (104 cells per well) for 24 h before treat-
ment with the compounds to allow attachment of cell to the
wall of the plate. Tested compounds were dissolved in DMSO
and diluted with saline. Different concentrations of the
compounds under test (5, 12.5, 25 and 40 µmol L-1) were added
to the cell monolayer. Triplicate wells were prepared for each
individual dose. Monolayer cells were incubated with the
compounds for 48 h at 37 °C and in atmosphere of 5 % CO2.
After 48 h, cells were fixed, washed and stained for 0.5 h.
with 0.4 % (m/v) SRB dissolved in 1 % acetic acid. Unbounded
dye was removed by four washes with 1 % acetic acid and
attached stain was recovered with tris-EDTA buffer. Colour
intensity was measured in an ELISA reader (sunostick medical
technology, SPR-960B, U.K.). Negative control was added by
using the cell lines with the solvent without drug. The relation
between surviving fraction and drug concentration was plotted
to get the survival curve of each tumor cell line after the
specified time. The concentration required for 50 % inhibition
of cell viability (IC50) was calculated and compared with
the reference drug doxorubicin and the results are given in
Table-3.
RESULTS AND DISCUSSION
The present work was to design, synthesis, X-ray crysta-
llographic study and antibreast cancer activity of novel 4-(7-
chloro-1-methylquinolin-4-(1H)-ylide-neamino)-phenyl)-3-
(dimethylamino)-prop-2-en-1-one (3) (Scheme-I). Interaction
of 4-(7-chloro-1-methylquinolin-4-(1H)-ylideneamino)-
phenyl-ethanone (2)42 with dimethylformamide-dimethylacetal
in dry toluene yielded the corresponding 4-(7-chloro-1-methyl-
quinolin-4-(1H)-ylideneamino)-phenyl)-3-(dimethyl)-prop-2-
en-one (3) in good yield. The structure of compound 3 was
Synthesis of 1-(4-(7-chloroquinolin-4-ylamino)phenyl)-
ethanone (2): This compound was synthesized according the
reported method42.
proved on the basis of elemental analysis, IR, 1H NMR, 13
C
NMR and x-ray analysis. The IR spectrum of 3 showed bands
at 3100 cm-1 (CH aromatic), 2966, 2856 cm-1 (CH aliphatic),
1696 cm-1 (C=O), 776 cm-1 (C-Cl). Also, 1H NMR spectrum
in (DMSO-d6) indicated the presence of a singlet at 2.4 ppm
which could be assigned to N(CH3)2 groups, 2.9 ppm due to
N-CH3 group, 5.4, 6.5 two duplets for CH=CH groups of
quinoline ring and 6.1, 7.4 two duplets for CO-CH=CH group.
13C NMR spectrum of 3 in (DMSO-d6) exhibited signals at
36.3, 44.5(2), 91.5, 114.6, 115.3, 116.9, 121.4(2), 131.7,
132.8(2), 133.0, 135.9, 136.6, 141.4, 146.2, 152.5, 161.4,
166.4, 191.3.
Crystal structure description of compound (3): Slow
evaporation of the pure compound 3 from ethanol yielded its
single crystal. Single crystal of suitable size was selected for
X-ray diffraction analysis. Data was collected on a Bruker
APEX-II CCD area diffractometer equipped with graphite
monochromatic CuKα radiation (λ = 1.54178 Å) at 296 K.
Synthesis of 4-(7-chloro-1-methylquinolin-4(1H)-ylide-
neamino)phenyl-3-(dimethylamino)-prop-2-en-1-one (3): A
mixture of 1-(4-(7-chloroquinolin-4-ylamino)-phenyl)-
ethanone (2) (2.97 g, 0.01 mol) and dimethylformamide-dimethyl-
acetal (1.19 g, 0.01 mol) in dry toluene (30 mL) was refluxed
for 10 h. The reaction mixture was cooled and the obtained
solid was recrystallized from ethanol to give 3. Yield 89 %;
m.p. 268.1 °C; IR (KBr, νmax, cm-1): 3100 (CH arom.), 2966,
2856 (CH aliph.), 1696 (C=O), 1618 (C=N), 776 (C-Cl). 1H
NMR spectrum in ( DMSO-d6): 2.4 [s, 3H, N(CH3)2] 2.9 [s,
3H, N-CH3], 5.4, 6.5[2d, 2H, CH=CH quinoline, J = 7.1, 7.3
Hz], 6.1, 7.4 [2d, 2H, CH=CH, J = 7.5, 7.4 Hz], 6.9-7.6
[m, 3H, Ar-H]. 13C NMR spectrum of 3 in ( DMSO-d6 ): 36.3,
44.5(2), 91.5, 114.6, 115.3, 116.9, 121.4(2), 131.7, 132.8(2),
133.0, 135.9, 136.6, 141.4, 146.2, 152.5, 161.4, 166.4,191.3.
Anal. Calcd for C21H20N3OCl (365.86): C, 68.94; H, 5.51; N,

Vol. 26, No. 24 (2014)
Design, Synthesis, X-Ray Crystallographic Study andAnticancerActivity of Novel Quinoline Derivatives 8499
O
The crystal structure of the title compound 3 contains one
O
molecule in the asymmetric unit. The labeled displacement
ellipsoid plot of this molecule is shown in Fig. 1. The hydrogen-
Cl
bonding interactions are listed in Table-2. Fig. 2 depicts the
HN
NH2
packing of the molecules in the crystal structure.
EtOH/24h, reflux
Cl
N
TABLE-2
Cl
N
HYDROGEN-BOND GEOMETRY (Å, °)
( 1 )
(2)
D-H···A
D-H
H···A
D···A
D-H···A
PhMe/reflux
C5-H5A···N2
C14-H14A···O1
C18-H18A···O1
C21-H21A···O1i
C21-H21C···O1ii
0.9300
0.9300
0.9300
0.9600
0.9600
2.5100
2.4100
2.3600
2.4400
2.5300
2.820 (3)
2.735 (3)
2.744 (3)
3.381 (2)
3.335 (3)
100.00
100.00
104.00
166.00
142.00
DMF-DMA
h
10
O
N
Symmetry codes: (i) -x, -y, -z + 1; (ii) x + 1/2, -y + 1/2, z + 1/2
N
Cl
N
(3)
Seheme-I: Formation of novel quinoline derivative 3
Fig. 1. ORTEP diagram of the title compound 3 drawn at 40 % ellipsoids
Cell refinement and data reduction were done by Bruker
SAINT; program used to solve structure and refine structure
is SHELXTL. The final refinement was performed by full-
matrix least-squares techniques with anisotropic thermal data
for non-hydrogen atoms on F2. All the hydrogen atoms were
placed in calculated positions and constrained to ride on their
parent atoms. Multi-scan absorption correction was applied
by use of SADABS software. The crystallographic data and
refinement information are summarized in Table-1.
for non-hydrogen atoms
TABLE-1
CRYSTALLOGRAPHIC DATA OF COMPOUND 3
Empirical formula
Formula weight
Temperature (K)
Crystal system
Space group
CuKα radiation, λ
a (Å)
b (Å)
c (Å)
α (º)
β (º)
C21H20N3OCl
365.85
296
Monoclinic
C2/c
1.54178 Å
24.6582 (6)
10.1905 (2)
18.6459 (5)
90.0
128.311 (3)
90.0
3676.38 (15)
4
1536
3.6-69.1
1.95
Fig. 2. Crystal packing of compound 3 showing the intermolecular
hydrogen bonds
in vitro Antibreast cancer activity: The corresponding
4-(7-chloro-1-methylquinolin-4-(1H)-ylideneamino)phenyl-3-
(dimethylamino)-prop-2-en-1-one (3) was evaluated for their
in vitro cytotoxic activity against human breast cancer cell
line (MCF7). Doxorubicin which is one of the most effective
anticancer agents was used as the reference drug in this study.
The relationship between surviving fraction and drug concen-
tration was plotted to obtain the survival curve of breast cancer
cell line (MCF7). The response parameter calculated was the
IC50 value, which corresponds to the concentration required
for 50 % inhibition of cell viability. Table-3 shows the in vitro
cytotoxic activity of the tested compound compared to the
reference drug. It was found that, in the negative control,
solvent has no effect on the cells as the surviving fraction is
1.00, from this results it was found that the corresponding 4-
(7-chloro-1-methylquinolin-4-(1H)-ylideneamino)phenyl-3-
(dimethylamino)-prop-2-en-1-one (3) with (IC50 = 74.3 µM)
is nearly as active as the positive control (doxorubicin) with
(IC50 = 71.8 µM).
γ (º)
V (Å3)
Z
F(000)
θ Range for data collection (°)
µ (mm-1)
Density (calc.) (g/cm3)
Crystal shape and color
Crystal size (mm3)
h/k/l
1.322
Block, brown
0.25 × 0.24 × 0.11
-30,27/-12,12/-18,22
19443
3447 [Rint = 0.061]
2878
Measured reflections
Independent reflections
Reflections with I > 2σ(I)
Goodness-of-fit on F2
R[F2 > 2 σ(F2)]
wR(F2)
1.05
0.040
0.0.113
0.18
∆ρmax (e Å-3)
∆ρmin (e Å-3)
-0.25

8500 Ghorab et al.
Asian J. Chem.
TABLE-3
in vitro CYTOTOXIC ACTIVITY OF SOME NEWLY SYNTHESIZED
COMPOUND 3 AGAINST HUMAN BREAST CANCER CELL LINE (MCF7)
Compound concentration (µmol L-1)
Compound no.
Control
IC50 µM
5
12.5
25
40
Surviving fraction (mean SE)a
DOX
3
1.00
1.00
0.721 0.020
0.913 0.01
0.546 0.020
0.511 0.02
0.461 0.010
0.334 0.01
0.494 0.030
0.617 0.03
71.8
74.3
an = 3
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The novel synthesized 4-(7-chloro-1-methylquinolin-4-
(1H)-ylideneamino)phenyl-3-(dimethylamino)-prop-2-en-1-
one (3) has been spectroscopically characterized by FT-IR,
1H, 13C NMR and single crystal X-ray diffraction study. The
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The authors would like to extend their sincere appreciation
to the Deanship of Scientific Research at King Saud University
for funding of this research through the Research Group Project
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