Synthesis and in vitro cytotoxic evaluation of 7-chloro-4-anilino-quinoline amide derivatives

Article abstract of DOI:10.14233/ajchem.2013.14016

A series of new amide derivatives of 4-anilino-quinoline have been synthesized and evaluated in vitro cytotoxic activity against the human hepatocellular carcinoma (HepG2), human lung carcinoma (SK-LU-1) and human breast cancer (MCF-7). Compound 5g was found to be most potent cytotoxic activity against HepG2 and MCF-7 cell lines with IC50 values of 2.09 and 4.63 μg/mL, respectively. Compound 5e exhibited significant cytotoxic activity against three cell lines with IC50 values ranging from 5-10 μg/mL.

Full text of DOI:10.14233/ajchem.2013.14016

Asian Journal of Chemistry; Vol. 25, No. 8 (2013), 4453-4456
http://dx.doi.org/10.14233/ajchem.2013.14016
Synthesis and In Vitro Cytotoxic Evaluation of 7-Chloro-4-anilino-quinoline Amide Derivatives
*
BUI TRUNG HIEU, VU THU THUY, HOANG XUAN TIEN and TRAN KHAC VU
Department of Pharmaceutical Chemistry & Pesticides Technology, School of Chemical Engineering, Hanoi University of Science and Technology,
No 1 Dai Co Viet Street, Hai Ba Trung District, Hanoi, Vietnam
*Corresponding author: Tel: +844 3 8684963; E-mail: vutk-fct@mail.hut.edu.vn; vu.trankhac@hust.vn
(Received: 7 May 2012;
Accepted: 13 February 2013)
AJC-12987
A series of new amide derivatives of 4-anilino-quinoline have been synthesized and evaluated in vitro cytotoxic activity against the human
hepatocellular carcinoma (HepG2), human lung carcinoma (SK-LU-1) and human breast cancer (MCF-7). Compound 5g was found to be
most potent cytotoxic activity against HepG2 and MCF-7 cell lines with IC50 values of 2.09 and 4.63 µg/mL, respectively. Compound 5e
exhibited significant cytotoxic activity against three cell lines with IC50 values ranging from 5-10 µg/mL.
Key Words: Anticancer, Amide, Cell line, Cytotoxic, Quinoline.
In continuing program in the search for new candidates
as potential cytotoxic agents, we design the synthesis of two
new series of amides of 4-anilino-quinoline 4a-g, 5a-g and
report the results in this communication.
INTRODUCTION
The recent statistical data have revealed that cancer-
diseases characterized by uncontrolled cell growth, metastasis
and invasion are responsible for approximate 13 % of all
human deaths throughout the world1. Three most fatal cancers
are lung, liver and breast cancer. It is documented that in many
cellular processes, including cell proliferation, metabolism,
survival and apoptosis, there are involvements of protein
tyrosine kinase enzymes. The tumor growth and progression
are known to be driven by several protein tyrosine kinases,
which are activated in cancer cells2. The uncontrolled cell
growth is known to result from over expression, constitutive
activation or mutation caused by inappropriate or uncontrolled
activation of these kinases3.
EXPERIMENTAL
All chemicals and reaction solvents were purchased from
Merck and Aldrich. Melting points were determined in open
capillaries on Electrothermal IA 9200 Shimazu apparatus and
uncorrected. IR spectra were recorded on FT-IR IMPACT-410
1
using neat or KBr discs. H NMR spectra were recorded on
BrukerAVANCE 500 MHz spectrometer in CDCl3 and DMSO-
d6, chemical shifts (δ) are in ppm relative to TMS and coupling
constants (J) are expressed in hertz (Hz). Mass spectra were
recorded on FTICR MS Varian. Progress of the reaction was
monitored by thin-layer chromatography (TLC) using
precoated TLC sheets with Ultraviolet (UV) fluorescent silica
gel (Merck 60 F254) and spots were visualized by Dragendoff
reagent. Multiplicities are shown as the abbreviations: s
(singlet), brs (broad singlet), d (doublet), brd (broad doublet)
t (triplet), m (multiplet). Column chromatography was carried
out using silica gel 40-230 mesh. Solvents were commercially
available materials of reagent grade.
Quinoline, a heterocyclic aromatic compound, is consi-
dered to be an important scaffold and prevalent in variety of
pharmacologically active synthetic compounds as well as in
naturally occurring products4. Studies have shown that quino-
line derivatives possess a wide range of biological activities,
including antimalarial5, antibacterial6, antitumor7,8, anticancer9,
antidepressant activities10. Recent continued researches about
cytotoxic activities of quinoline derivatives have resulted in a
lot of encouraging results11.
General procedure for the synthesis of 2 and 3:A mix-
ture of 4,7-dichloroquinoline (1 g, 5.05 mmol) and 3 and
4-aminobenzoic acid (0.691 g, 5.05 mmol) in MeOH
(25 mL) was refluxed for 6 h. The solvent was evaporated
under vacuum and solid mass was obtained. The solid was
recrystallized by methanol to obtain compound 2 and 3 as
yellow solids.
Among different structural classes of tyrosine kinase
inhibitions, 4-anilino-quinazoline and its bio-isosteric, 4-anilino-
quinolines have been reported to be the most promising mole-
cules, which were selective inhibition to epidermal cell growth
factor receptor (EGFR)12. Some recently synthesized anilino-
quinoline derivatives exhibited potent inhibitory activity against
MCF-7 cell line13.

4454 Hieu et al.
Asian J. Chem.
4-(7-Chloro-quinolin-4-yl)-benzoic acid (2): m.p. ≥
1
300 ºC. H NMR (DMSO-d6, 500 MHz): δ 11,16 (br, 1H),
815. 1H NMR (CDCl3, 500 MHz): δ 8.56 (d, J = 5.5Hz, 1H),
8.05-8.02 (m, 2H), 7.44 (dd, J = 2 Hz, 9 Hz, 1H), 7.40 (d, J =
8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 5.5 Hz, 1H),
3.82-3.5 (brs, 4H), 2.50-2.45 (br, 4H), 2.04 (br, 2H, CH2), 1.12
(t, J = 7 Hz, 3H, CH3). 13C NMR (CDCl3, 125 MHz): δ 169.8,
151.7, 149.7, 147.2, 141.5, 135.5, 131.3, 128.8, 128.7, 126.3,
121.9, 121.6, 118.6, 103.3, 52.3 (3C), 11.9. ESI-MS m/z 395
[M + H]+.
8.86 (d, J = 9 Hz, 1H), 8.61 (d, J = 7 Hz, 1H), 8.17 (d, J =
2Hz, 1H), 8.11 (d, J = 8.5 Hz, 2H), 9.90 (dd, J = 2Hz, 9Hz,
1H), 7.63 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 6.5 Hz, 1H). 13C
NMR (DMSO-d6, 125 MHz): δ 166.5, 153.8, 144.2, 141.4,
139.8, 138.2, 128.8, 127.4, 126.1, 124.2, 119.7, 117.8, 101.2.
4-(7-Chloro-quinolin-3-yl)-benzoic acid (3): m.p. ≥
300 ºC. 1H NMR (DMSO-d6, 500 MHz): δ 11.4 (br, 1H, NH),
8.95 (d, J = 9 Hz, 1H), 8.55 (d, J = 7 Hz, 1H), 8.21 (d, J = 2
Hz, 1H), 8.01 (s, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.87 (dd, J = 2
Hz, 9 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.69 (t, J = 7.5 Hz,
1H), 6.86 (d, J = 7Hz, 1H). 13C NMR (DMSO-d6, 125 MHz):
δ 166.5, 154.7, 143.6, 139.2, 138.3, 137.5, 132.5, 130.3, 129.5,
128.0, 127.4, 126.3, 125.8, 119.3, 116.2, 100.4.
[4-(7-Chloro-quinolin-4-ylamino)-phenyl]-(4-methyl-
piperazin-1-yl)-methanone (4e): m.p. 224-2250C. IR (KBr,
νmax, cm-1): 3200, 1658, 1544, 1455, 1329, 1217, 1098, 866.
1H NMR (CDCl3, 500 MHz): δ 8.56 (d, J = 5 Hz, 1H), 8.06 (d,
J = 9 Hz, 1H), 8.02 (d, J = 2 Hz, 1H), 7.44 (dd, J = 2 Hz, 9Hz,
1H), 7.39 (d, J = 8 Hz, 2H), 7.24 (d, J = 8 Hz, 2H), 7.03 (d,
J = 5 Hz, 1H), 3.80-3.48 (br, 4H, 2CH2), 2.47 (brs, 4H, 2CH2),
2.34 (s, 3H, CH3). 13C NMR (CDCl3, 125 MHz): δ 169.9, 151.7,
149.7, 147.2, 141.5, 135.5, 131.1, 128.8, 128.7, 126.2, 122.1,
121.6, 118.6, 103.2, 55.6, 46.0, 39.7. ESI-MS m/z 381 [M +
H]+.
General procedure for the synthesis of amide deriva-
tives: 4a-g and 5a-g: A mixture of 2 or 3 (1 mmol) in CH2Cl2
(15 mL) and amines (1 mmol), EDC (1 mmol), DMAP (0.3
mmol) were stirred at room temperature for 24 h. The reaction
mixture was then extracted with water. The organic phase was
separated and dried on anhydrous Na2SO4. The solvent was
evaporated to obtain residues which after recrystallization in
methanol or column chromatography on silica gel using proper
solvent mixtures as eluting systems to give target compounds.
[4-(7-Chloro-quinolin-4-ylamino)-phenyl]-(4-phenyl-
piperazine-1-yl)-methanone (4a): m.p. 226-227 ºC. IR (KBr,
νmax, cm-1): 3429, 3062, 2971, 2899, 1651, 1566, 1457, 1346,
1269, 1120, 871. 1H NMR (CDCl3, 500 MHz): δ 8.58 (d, J =
5.5 Hz, 1H), 8.04-8.02 (m, 2H), 7.44 (m, 3H), 7.31-7.25 (m,
4H), 7.06 (d, J = 5Hz, 1H), 6.96-6.91 (m, 3H), 3.85 (brs, 4H),
3.23 (br, 4H). 13C NMR (CDCl3, 125 MHz): δ 169.9, 151.8,
150.9, 149.8, 146.9, 141.7, 135.5, 130.9, 129.3, 128.9, 128.8,
126.3, 121.9, 121.4, 120.8, 118.6, 116.8, 103.5. 57.7, 49.4.
ESI-MS m/z 443 [M + H]+.
[4-(7-Chloro-quinolin-4-ylamino)-phenyl]-pyrrolidin-
1-yl-methanone (4f): m.p. 288-289 ºC. IR (KBr, νmax, cm-1):
3229, 2833, 1665, 1500, 1444, 1366, 1200, 1081, 827, 775.
1H NMR (CDCl3 + DMSO-d6, 500 MHz): δ 8.63 (s, 1H), 8.55
(d, J = 5 Hz, 1H), 8.29 (d, J = 9 Hz, 1H), 7.95 (d, J = 2 Hz,
1H), 7.58 (d, J = 8 Hz, 2H), 7.43 (dd, J = 2 Hz, 9 Hz, 1H),
7.38 (d, J = 8 Hz, 2H), 7.11 (d, J = 5 Hz, 1H), 3.64 (brs, 2H),
3.64 (m, 2H), 3.54 (m, 2H), 1.99 (m, 2H), 1.92 (m, 2H). 13C
NMR (CDCl3, + DMSO-d6, 125 MHz): δ 168.5, 151.3, 149.4,
147.1, 141.8, 134.4, 131.5, 128.2, 127.8, 124.9, 123.2, 120.4,
118.5, 102.7, 49.1, 23.8. ESI-MS m/z 352 [M + H]+.
[4-(7-Chloro-quinolin-4-ylamino)-phenyl]-(2-methyl-
piperidin-1-yl)-methanone (4g): m.p. 222-223 ºC. IR (KBr,
νmax, cm-1): 3425, 2888, 2777, 1646, 1519, 1454, 1326, 1203,
1054, 906, 816, 740. 1H NMR (CDCl3, 500 MHz): δ 8.53 (d,
J = 5.5 Hz, 1H), 8.18 (d, J = 9 Hz, 1H), 8.00 (d, J = 2 Hz, 1H),
7.83 (br, 1H), 7.41 (dd, J = 2.5 Hz, 9 Hz, 9 Hz, 1H), 7.29 (d,
J = 9 Hz, 2H), 7.18 (d, J = 9 Hz, 2H), 6.98 (d, J = 5.5 Hz, 1H),
3.06 (br, 1H), 2.12 (br, 1H), 1.74-1.69 (br, 5 H), 1.59 (br, 1H),
1.51(br, 1H), 1.29 (d, J = 6.5 Hz, 3H). 13C NMR (CDCl3, 125
MHz): δ 170.2, 151.8, 149.8, 147.6, 141.1, 135.3, 132.3, 128.7,
127.9, 125.9, 122.4, 122.1, 118.6, 102.8, 46.7, 44.6, 30.4, 26.1,
18.9, 16.2. ESI-MS m/z 380 [M + H]+.
[4-(7-Chloro-quinolin-4-ylamino)-phenyl]-(4-methyl-
piperidin-1-yl)-methanone (4b): m.p. 233-234 ºC. IR (KBr,
νmax, cm-1): 3422, 2978, 2879, 1644, 1577, 1464, 1345, 1256,
1157, 1111, 874. 1H NMR (CDCl3, 500 MHz): δ 8.51 (d, J =
5 Hz, 1H), 8.20 (d, J = 9.5 Hz, 2H), 7.97 (d, J = 2Hz, 1H),
7.36 (dd, J = 2Hz, 9Hz, 1H), 7,29 (d, J = 8.5 Hz, 2H), 7.18 (d,
J = 8.5 Hz, 2H), 6.97 (d, J = 5 Hz, 1H), 4.69 (brs, 1H), 3.83
(brs, 1H), 2.86-2.65 (br, 2H), 1.77-1.67 (br, 3H), 1.25 (br, 2H),
0.99 (d, J = 6.5 Hz, 3H). 13C NMR (CDCl3, 125 MHz): δ 170.1,
151.6, 149.7, 147.7, 141.5, 135.2, 131.5, 128.4, 128.2, 125.8,
122.7, 121.8, 118.7, 102.7, 44.5, 31.1, 27.6, 21.6. ESI-MS
m/z 380 [M + H]+.
[3-(7-Chloro-quinolin-4-ylamino)-phenyl]-(4-phenyl-
piperazin-1-yl)-methanone (5a): m.p. 223-224 ºC. IR (KBr,
νmax, cm-1): 3439, 2971, 2899, 1659, 1457, 1306, 1269, 1120,
871. 1H NMR (CDCl3 + DMSO-d6, 500 MHz): δ 8.55 (d, J =
5.5 Hz, 1H), 8.30 (s, 1H), 8.20 (d, J = 9 Hz, 1H), 7.98 (d, J =
2 Hz, 1H), 7.46-7.40 (m, 4H), 7.28 (t, J = 7.5 Hz, 2H), 7.18-
7.16 (m, 1H), 7.05 (d, J = 5 Hz, 1H), 6.94-6.89 (m, 3H), 3.93
(br, 2H), 3.65 (br, 2H), 3.25 (br, 4H). 13C NMR (CDCl3, 125
MHz): δ 169.5, 151.6, 150.6, 149.7, 147.5, 140.8, 136.8, 134.9,
129.4, 128.9, 128.3, 125.4, 122.9, 121.9, 120.4, 120.3, 118.6,
116.5, 113.6, 102.7, 57.6, 49.4. ESI-MS m/z 443 [M + H]+.
[3-(7-Chloro-quinolin-4-ylamino)-phenyl]-(4-methyl-
piperidin-1-yl)-methanone (5b): m.p. 147-149 ºC. IR (KBr,
νmax, cm-1): 3431, 2979, 2890, 1654, 1457, 1336, 1269, 1120.
1H NMR (CDCl3, 500 MHz): δ 8.53 (d, J = 5 Hz, 1H), 8.02-
8.00 (m, 2H), 7.43 (dd, J = 2 Hz, 9 Hz, 2H), 7.35 (t, J = 8 Hz,
1H), 7.29 (d, J = 2 Hz, 1H), 7.22 (s, 1H), 7.10 (d, J = 7 Hz,
[4-(7-Chloro-quinolin-4-ylamino)-phenyl]-piperidin-1-
yl-methanone (4c): m.p. 247-248 ºC. IR (KBr, νmax, cm-1):
3404, 3060, 1665, 1560, 1444, 1375, 1311, 1260, 1118, 875.
1H NMR (CDCl3, 500 MHz): δ 8.52 (d, J = 5 Hz, 1H), 8.15 (d,
J = 9Hz, 1H), 8.0 (d, J = 1.5 Hz, 1H), 7.40 (dd, J = 2Hz, 9Hz,
1H), 7.33 (d, J = 8.5Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 6.99 (d,
J = 5Hz, 1H), 3.74-3.47 (m, 4H), 1.71-1.59 (m, 6H). 13C NMR
(CDCl3, 125 MHz): δ 170.0, 151.6, 149.7, 141.3, 135.4, 131.8,
128.6, 128.4, 126.0, 125.9, 122.3, 121.8, 118.6, 102.9, 46.9,
25.9, 24.6. ESI-MS m/z 366 [M+H]+.
[4-(7-Chloro-quinolin-4-ylamino)-phenyl]-(4-ethyl-
piperazin-1-yl)-methanone (4d): m.p. 232-234 ºC. IR (KBr,
νmax, cm-1): 3201, 2886, 1665, 1561, 1455, 1362, 1295, 1097,

Vol. 25, No. 8 (2013)
Synthesis and In Vitro Cytotoxic Evaluation of 7-Chloro-4-anilino-quinoline Amide Derivatives 4455
1H), 6.95 (d, J = 5 Hz, 1H), 4.67 (brd, J = 10Hz, 1H), 3.77
(brd, J = 11.5 Hz, 1H), 3.02 (brs, 1H), 2.77 (brs, 1H), 1.77 (br,
1H), 1.69-1.62 (m, 2H), 1.27-1.22 (m, 1H), 1.11 (s, 1H), 0.98
(d, J = 6.5 Hz, 3H). 13C NMR (CDCl3, 125 MHz): δ 169.6,
151.8, 149.8, 147.5, 140.3, 137.9, 135.4, 129.6, 128.8, 126.1,
123.1, 122.4, 122.0, 120.7, 118.5, 102.8, 48.2, 34.7, 31.1, 21.6.
ESI-MS m/z 380 [M + H]+.
Hz, 3H). 13C NMR (CDCl3, 125 MHz): δ 169.9, 151.7, 149.8,
147.7, 140.4, 138.2, 135.3, 129.6, 128.6, 125.9, 122.9, 122.4,
121.8, 120.4, 118.5, 102.6, 46.6, 44.4, 30.3, 26.0, 25.2, 16.1.
ESI-MS m/z 380 [M + H]+.
RESULTS AND DISCUSSION
The synthetic route for the preparation of novel amide
derivatives of quinoline 4a-f, 5a-f is described in Scheme-I.
At first, 4,7-dichloroquinoline (1) was reacted with 3 and
4-aminobenzoic acid in methanol under reflux for 6 h. The
precipitated solids resulting from reaction mixture were
filtered, dried and recrystallized from methanol to yield the
intermediate compounds 2 and 3 in good yields as yellow
solids.
[3-(7-Chloro-quinolin-4-ylamino)-phenyl]-(piperidin-
1-yl)-methanone (5c): m.p. 127-129 ºC. IR (KBr, νmax, cm-1):
1
3339, 2989, 2890, 1656, 1457, 1306, 1266, 1120. H NMR
(CDCl3, 500 MHz): δ 8.48 (d, J = 5.5 Hz, 1H), 8.08 (d, J = 8.5
Hz, 1H), 7.98 (d, J = 2Hz, 1H), 7.83 (brs, 1H), 7.37(dd, J = 2
Hz, 9 Hz, 1H), 7.32-7.28 (m, 2H), 7.20 (s, 1H), 7.07 (d, J = 7
Hz, 1H), 6.92 (d, J = 5Hz, 1H), 3.70 (brs, 2H), 3.38 (brs, 2H),
2.31 (brs, 2H), 1.68 (brs, 2H), 1.53 (brs, 2H). 13C NMR (CDCl3,
125 MHz): δ 169.8, 151.7, 149.8, 147.6, 140.4, 137.7, 135.3,
129.6, 128.6, 125.9, 123.1, 122.3, 122.2, 120.7, 118.5, 102.6,
48.8, 26.5, 24.5. ESI-MS m/z 366 [M + H]+.
O
OH
HN
Cl
[3-(7-Chloro-quinolin-4-ylamino)-phenyl]-(4-ethyl-
piperazin-1-yl)-methanone (5d): IR (KBr, neat, νmax, cm-1):
1
3369, 2988, 2891, 1651, 1457, 1326, 1266, 1122. H NMR
Cl
N
i
2. 4'-subst
Cl
N
(CDCl3, 500 MHz): δ 8.53 (d, J = 5.5 Hz, 1H), 8.08 (d, J = 8.5
Hz, 1H), 8.0 (d, J = 2Hz, 1H), 7.83 (brs, 1H), 7.37 (dd, J = 2
Hz, 9 Hz, 1H), 7.32-7.28 (m, 2H), 7.18 (s, 1H), 7.07 (d, J = 7
Hz, 1H), 6.92 (d, J = 5Hz, 1H), 3.80-3.5 (brs, 4H), 2.50-2.45
(br, 4H), 2.14 (br, 2H, CH2), 1.17 (t, J = 7 Hz, 3H, CH3). 13C
NMR (CDCl3, 125 MHz): δ 169.8, 151.5, 149.7, 147.3, 140.4,
137.8, 135.3, 129.6, 128.6, 126.0, 123.1, 122.3, 122.2, 120.5,
118.6, 102.6, 52.2 (3C), 12.1. ESI-MS m/z 395 [M + H]+.
[3-(7-Chloro-quinolin-4-ylamino)-phenyl]-(4-methyl-
piperazin-1-yl)-methanone (5e): IR (KBr, neat, νmax, cm-1):
3427, 2998, 1665, 1437, 1313, 1266, 1122. 1H NMR (CDCl3,
500 MHz): δ 8.55 (d, J = 5 Hz, 1H), 8.02 (d, J = 9 Hz, 1H),
7.99 (d, J = 2 Hz, 1H), 7.43 (dd, J = 2 Hz, 9 Hz, 1H), 7.37 (d,
J = 8 Hz, 2H), 7.22 (d, J = 8 Hz, 2H), 7.10 (d, J = 5 Hz, 1H),
3.78-3.40 (br, 4H, 2CH2), 2.44 (brs, 4H, 2CH2), 2.31 (s, 3H,
CH3). 13C NMR (CDCl3, 125 MHz): δ 169.8, 151.9, 149.7,
147.6, 140.3, 138.5, 135.3, 129.4, 128.5, 125.8, 123.6, 122.5,
122.3, 121.3, 118.5, 102.4, 55.8, 46.2, 39.8. ESI-MS m/z 381
[M + H]+.
3. 3'-subst
1
O
NR1R2
HN
N
ii
a. R1 = R2 = 1-Phenylpiperazine
b. R1 = R2 = 4-Methylpiperidine
c. R1 = R2 = Piperidine
Cl
4a-g: 4'-subst
5a-g: 3'-subst
d. R1 = R2 = 1-Ethylpiperazine
e. R1 = R2 = 1-Methylpiperazine
f. R1 = R2 = Pyrrolidine
g. R1 = R2 = 2-Methylpiperidine
Scheme-I:Reagents and condition: (i) aminobenzoic acids, MeOH, reflux,
6 h. (ii) amines, CH2Cl2, EDC, DMAP, rt, 24 h
These compounds were then reacted with secondary
amines in dichloromethane at room temperature for 24 h in
the presence of EDC and DMAP as catalysts to furnish the
target compounds 4a-g and 5a-g in moderate to good yields.
Compound 4a and 5a were obtained by recrystallization in
methanol after a work-up with water and dichloromethane.
Compounds 4b-e, 5b,c were purified by column chromato-
graphy on silica gel using dichloromethane:methanol (96:4)
as an eluting system. Other compounds after a work-up with
water and dichloromethane were purified by column chroma-
tography on silica gel using dichloromethane:methanol:Et3N
(98:2:0.2) as an eluting system. The structure of compounds
[3-(7-Chloro-quinolin-4-ylamino)-phenyl]-(pyrrolidin-
1-yl)-methanone (5f): m.p. 188-189 ºC. IR (KBr, νmax, cm-1):
3421, 2990, 1666, 1439, 1311, 1266, 1122. 1H NMR (CDCl3,
500 MHz): δ 8.49 (d, J = 5 Hz, 1H), 8.12 (d, J = 9 Hz, 1H),
7.99 (d, J = 2 Hz, 1H), 7.84 (s, 1H), 7.39 (dd, J = 2 Hz, 9 Hz,
1H), 7.35-7.32 (m, 3H), 7.21-7.19 (m, 2H), 6.90 (d, J = 5 Hz,
1H), 3.62 (t, J = 7.0 Hz, 2H), 3.43 (t, J = 6.5 Hz, 2H), 1.98-
1.94 (m, 2H), 1.91(m, 2H). 13C NMR (CDCl3, 125 MHz): δ
169.2, 151.7, 149.7, 147.7, 140.3, 138.5, 135.3, 129.4, 128.6,
125.9, 123.6, 122.6, 122.4, 121.3, 118.5, 102.6, 46.3, 24.4.
ESI-MS m/z 352 [M + H]+.
was confirmed by the H NMR, 13C NMR, IR and MS. For
1
structural elucidation, the compound 5a was an example. The
presence of more five prontons of the phenyl ring and eight
[3-(7-Chloro-quinolin-4-ylamino)-phenyl]-(2-methyl-
piperidin-1-yl)-methanone (5g): m.p. 139-140 ºC. IR (KBr,
1
1
νmax, cm-1): 3431, 2998, 1656, 1433, 1314, 1266, 1121. H
protons of piperazine group was observed in the H NMR
spectra. In the 13C NMR spectra, four more carbons of phenyl
ring were also observed. In addition, the carbon peak of amide
carbon was observed at 169.5 ppm in the 13C NMR and a strong
peak of amide and broad peak of NH at 1659 and 3439 cm-1 in
the IR spectra supports the structure of 5a.
NMR (CDCl3, 500 MHz): δ 8.48 (d, J = 5 Hz, 1H), 8.08 (d,
J = 9 Hz, 1H), 7.99 (d, J = 2 Hz, 1H), 7.79 (br, 1H), 7.40 (dd,
J = 2 Hz, 8.5 Hz, 1H), 7.23-7.28 (m, 2H), 7.16 (m, 1H), 7.05-
7.03 (m, 1H), 6.92 (d, J = 5 Hz, 1H), 3.01 (br, 1H), 2.23 (brs,
2H), 1.76-1.60 (br, 4H), 1.55-1.38 (m, 2H), 1.24 (d, J = 6.5

4456 Hieu et al.
Asian J. Chem.
TABLE-1
IN VITRO CYTOTOXIC ACTIVITY DATA FOR COMPOUNDS: 4a-g AND 5a-g
IC50 (µg/mL)
No
Compounds
Substituents (R)
HepG2
>128
72.33
76.86
86.61
>128
>128
>128
>128
>128
19.29
21.46
6.72
SK-LU-1
>128
97.96
>128
89.93
>128
>128
>128
>128
>128
66.17
55.11
5.35
MCF-7
>128
40.61
98.41
98.68
>128
>128
>128
>128
>128
47.99
48.55
9.50
1
2
1-Phenylpiperazine
4-Methylpiperidine
Piperidine
4a
4b
3
4c
4
1-Ethylpiperazine
1-Methylpiperazine
Pyrrolidine
4d
5
4e
6
4f
7
2-Methylpiperidine
1-Phenylpiperazine
4-Methylpiperidine
Piperidine
4g
8
5a
9
5b
10
11
12
13
14
15
5c
1-Ethylpiperazine
1-Methylpiperazine
Pyrrolidine
5d
5e
5f
>128
2.09
>128
>128
0.78
>128
4.63
2-Methylpiperidine
–
5g
Ellipticine
0.99
0.82
Note: The reference substance, ellipticine, exhibited cytotoxic activity against HepG2 (ATCC-HB-8065), SK-LU-1 (ATCC-HTB-57) and MCF-7
(ATCC-HTB-22) cells with IC50 values of 0.99, 0.78 and 0.82 µg/mL, respectively. The values shown for these compounds are the average of three
determinations.
The bio-assay of the synthesized compounds 4a-g and
5a-g was carried out at the Institute of Chemistry, Vietnam
Academy of Science and Technology.
ACKNOWLEDGEMENTS
The authors thank Vietnam's National Foundation for
Science and Technology Development (NAFOSTED) for
financial support and the Institute of Chemistry, Vietnam
Academy for Science and Technology for bioassay.
Though compounds 4a and 4e were synthesized and tested
for antimalarial and antifilarial activity14, in this communication,
two series of 4a-g and 5a-g were evaluated for in vitro cytotoxic
activity against three human cancer cell lines (HepG2, SK-
LU-1 and MCF-7) according to a described protocol15. The
results are shown in Table-1. The initial structure-activity
observations revealed that seven derivatives: 4a, 4e-g, 5a-b
and 5f exhibited no cytotoxic activity against all three cell
lines and none of the other derivatives can compare with the
reference drug, ellipticine in terms of IC50 values. Some
derivatives 4c-d showed weak activity against three cell lines
tested. Some other derivatives showed quite noteworthy cyto-
toxicity. For example, 5c and 5d exhibited IC50 values of less
than 22 µg/mL against HepG2 cell line. Compound 5d was
more active than 4d with moderate cytotoxicity against HepG2
cell line at IC50 value of 21.46 µg/mL while 4d possessing the
same ethylpiperazine group exhibited weak cytotoxic activity
against three cell lines. Among the synthesized compounds,
compound 5e exhibited significant cytotoxic activity against
three cell lines with the IC50 values of 6.72, 5.35 and 9.50 µg/mL,
respectively. Especially, compound 5g showed most potent
cytotoxic activity against HepG2 and MCF-7 cell lines with
IC50 values of 2.09 and 4.63 µg/mL, respectively, but showed
no activity against SK-LU-1 cell line. Unexpectedly, compound
4g, which possessed the same 2-methylpiperidine group, was
inactive against three cell lines tested.
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Conclusion
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