Design, synthesis and biological evaluation of 4-(Imidazolylmethyl)-2-aryl-quinoline derivatives as aromatase inhibitors and anti-breast cancer agents

Article abstract of DOI:10.2174/1570180812666150611185605

Some new quinoline derivatives were designed and synthesized to evaluate their biological activities as aromatase inhibitors and anti-breast cancer agents. Cytotoxicity of quinolines 8a-g against human breast cancer MCF-7 and T47D cell lines were evaluate

Full text of DOI:10.2174/1570180812666150611185605

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Letters in Drug Design & Discovery, 2016, 13, 89-97
89
Design, Synthesis and Biological Evaluation of 4-(Imidazolylmethyl)-2-
Aryl-Quinoline Derivatives as Aromatase Inhibitors and Anti-breast
Cancer Agents
Razieh Ghodsia, Ebrahim Azizib, Maria Grazia Ferlinc and Vincenzo Pezzid and Afshin Zarghie,*
b
aBiotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Depart-
c
ment of Toxicology, School of Pharmacy, Tehran University of Medical sciences, Tehran, Iran; De-
partment of Pharmaceutical Sciences, University of Padova, Padova, Italy; dDepartment of Pharmaco-
Biology, University of Calabria, Calabria, Italy; eDepartment of Pharmaceutical Chemistry, School of
Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Abstract: Some new quinoline derivatives were designed and synthesized to evaluate their biological
activities as aromatase inhibitors and anti-breast cancer agents. Cytotoxicity of quinolines 8a-g
against human breast cancer MCF-7 and T47D cell lines were evaluated. All the compounds 8a-g
were more cytotoxic against MCF-7 cells in comparison with those of T47D which express aromatase
mRNA less than MCF-7 cells. Their effects on Aromatase activity are also described. Our results
showed that compound 8b inhibits aromatase enzyme activity more than reference drug Letrozol.
Afshin Zarghi
Keywords: Aromatase activity, breast cancer, MCF-7, quinolines, T47D.ꢀ
O
E
1. INTRODUCTION
O
A
A
One of the most common cancers among women is breast
cancer which in most of women is estrogen-dependent be-
cause progress of breast tumor is dependent on high amounts
of serum estrogens, which cause proliferation in cancer cells.
In addition, after menopause, biologically active estrogens
are formed from inactive steroids in breast cancer tissues and
increase estrogenic activities in cancer cells [1, 2]. Several
enzymes are involved in production of estrogens in breast
cancer tissues, but aromatase is the key enzyme in this proc-
ess which promotes the aromatization of the A ring of an-
drogen precursors [3]. Aromatase is present in breast tissue,
and intratumoral aromatase is the source of local estrogen
production in breast cancer tissues. Accordingly, aromatase
inhibitors inhibit estrogen biosynthesis and are used for the
suppression of breast cancer. It is well established that aro-
matase inhibitors such as letrozole, and exemestane, are a
valid alternative to tamoxifen for the treatment of advanced
breast cancer [4, 5], and as a result, the interest to the synthe-
sis of potent inhibitors of aromatase has been increased [6-
10]. Structurally point of view aromatase inhibitors are di-
vided into two groups: steroidal and nonsteroidal com-
pounds. Steroidal inhibitors highlighted with a androstenedi-
one scaffold and different substituents at varying positions
on this scaffold [11]. Most of chemical modifications have
been made on the B ring of the steroidal scaffold. Substitu-
tion of bulky groups at the C-6 position of the B ring has
introduced several highly potent inhibitors of aromatase en-
zyme [12-17]. These compounds indicated the presence of a
C
B
C
B
O
D
O
D
OSO2NH2
compound A
Androstenedione
Lead compounds
N
N
B
C
R2
N
E
D
R1
X
X= F, OMe
R1=Me, H, Ph, R2=H
R1&R2= Ph, Cyclohexyl
Designed compounds
Fig. (1). Chemical structures of androstenedione and compound A
(lead compounds) and our designed scaffolds.
hydrophobic area near to the C6 position of the steroid scaf
fold [18]. A new class of steroidal AIs (6-(p-Sulpham-
oylphenyl)androstenedione) was reported by Numazawa
et al. [19]. One of the best inhibitors in the series, which
inhibits aromatase potently, is compound A (Fig. 1). The
chemical structure of nonsteroidal aromatase inhibitors con-
*Address correspondence to this author at the Department of Pharmaceuti-
cal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical
Sciences, Tehran, Iran; Tel: +98 21 8820096; Fax: +98 21 88665341;
E-mail: zarghi@sbmu.ac.ir
1875-628X/16 $58.00+.00
©2016 Bentham Science Publishers

90 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1
Ghodsi et al.
N
E
N
N
N
B
C
C
B
N
N
D
D
E
O
E
R
R
A
C
B
O
D
OSO2NH2
compound A
N
E
N
N
N
B
C
C
B
N
D
N
R
E
R
Fig. (2). Lead compound (A), described BCDE- and BCE-ring mimetic aromatase inhibitors.
sist of two parts. One part is the azole part having nitrogen
atom which bind to the heme iron atom of aromatase. The
second part is usually the bulky aryl part that is hydrophobic
and acts the same as the steroid ring of the substrate [20]. In
the recent study, several new quinoline derivatives have been
designed and synthesized as nonstroidal aromatase inhibi-
tors, these compounds posses imidazole ring for interacting
with the heme iron atom of aromatase and B, C, D and E
rings in an orientation in which B, C and D rings mimic
rings B, C and D of the andrestondione substrate and com-
pound A and E ring mimics E ring of compound A respec-
tively. E ring in our compounds might occupy the hydropho-
bic area near to the C6 position of the steroid scaffold of
andrestondione substrate in the aromatase active site (Fig. 2).
The anti-breast cancer activity of the quinoline derivatives
8a-g was evaluated by MTT assay [21] against MCF-7 and
T47D cell lines which both are two estrogen-positive breast
cancer cell lines and since the amount of aromatase enzyme
in MCF-7 cells is more than T47D cells [22] we compared
the cytotoxic effect of our compounds (designed as aro-
matase inhibitors) against these two cell lines.
triple quadrupole mass spectrometer (LCMS) with an elec-
trospray ionization (ESI) interface was used to obtain the
mass spectra. Microanalyses, determined for C and H, were
within 0.4% of theoretical values.
2.2. Chemistry
General Procedure for Preparation of 2-(4-(substituted)
phenyl)-7, 8-substituted –quinoline-4-carboxylic Acid
(Doebner Reaction)
A solution of 4-(substituted) benzaldehyde (9.45 mmol)
and pyruvic acid (1.26 g, 14.3 mmol) in ethanol (5 ml) was
heated for 15 min then appropriate amine (9.45 mmol) was
added to the solution and refluxed overnight. Then, the mix-
ture was cooled and the obtained precipitate was filtered and
washed by ethanol, benzene and hexane and recrystallized in
methanol (yields: 11-31%).
2-(4-Methoxyphenyl)-8-phenylquinoline-4-carboxylic Acid
(4a)
º
Yield: 13%; yellow crystalline powder; mp=227-228 C;
2. MATERIALS AND METHODS
2.1. Materials
IR (KBr): ν (cm-1), 3543-2409(OH), 1700 (C=O); LCMS
+
(ESI): 356.9 (M+1) 100; Anal. Calcd. for C23H17NO3: C,
77.73; H, 4.82; N, 3.94. Found: C, 77.89; H, 4.99; N, 4.19.
All chemicals and solvents were prepared from Aldrich
Chemical and Merck AG. A Thomas–Hoover capillary appa-
ratus was used to determine the melting points. Infrared
spectra were acquired by a Perkin Elmer Model 1420 spec-
trometer. A Bruker FT-500 MHz instrument (Brucker Bio-
sciences, USA) was used to acquire 1HNMR spectra. TMS as
internal standard and chloroform-D were used as internal
standard and solvent, respectively. An 6410 Agilent LCMS
2-(4-Fluorophenyl)-8-phenylquinoline-4-carboxylic Acid
(4b)
º
Yield: 11%; yellow crystalline powder; mp=217-218 C;
IR (KBr): ν (cm-1), 3194-2355(OH), 1695 (C=O); LCMS
(ESI): 344.7 (M+1)+100; Anal. Calcd. for C23H14NO2F: C,
77.74; H, 3.97; N, 3.94. Found: C, 77.98; H, 4.12; N, 4.21.

Design, Synthesis and Biological Evaluation
Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1 91
2-(4-Methoxyphenyl)benzo[h]quinoline-4-carboxylic Acid
(4c)
General Procedure for the Preparation of 2-(4-substituted-
phenyl)-7,8-substituted-quinoline -4-yl)methanol
Yield: 23%; yellow crystalline powder; mp: 279-280 ºC;
LiAlH4 (0.45 g, 12 mmol) was suspended in dry THF (20
ml) under a nitrogen atmosphere. Under vigorous stirring, a
solution of appropriate acid (5.67 mmol) in dry THF was
added dropwise to avoid producing a lot of gas bubbles. Af-
ter stirring for 2 h at room temperature, then NaOH solution
(10%) was added to the resulting mixture till no more gas
bubbles were produced. The solid was filtered off and
washed with chloroform. The filtrate was dried over Na2SO4
and the solvent was evaporated to yield yellow oil which was
crystallized from ether/hexane (25:75 v/v), (yield: 25-77 %).
1
IR (KBr): ν (cm-1) 3198-2726 (OH), 1712 (C=O), HNMR
(DMSO-D6): δ (ppm) 3.83 (s, 3H, OCH3 ), 7.11 (d, 2H, 4-
methoxy phenyl H3 & H5, J=8.85 Hz), 7.75-7.78 (m, 2H,
benzoquinoline H8 &H9), 7.96 (d, 1H, benzoquinoline H7,
J=9.2 HZ), 8.01 (d, 1H, benzoquinoline H6, J= 9.05), 8.37
(d, 2H, 4-methoxyphenyl H2 & H6 , J=8.85 Hz), 8.45-8.47
(m,2H, benzoquinoline H3 & H10), 9.33 (d, 1H, benzoquino-
line H5, J=9.31 Hz), 13.98 (s, 1H, COOH); LCMS (ESI):
330.4 (M+1)+100; Anal. Calcd. for C21H15NO3: C, 76.58; H,
4.59; N, 4.25. Found: C, 76.78; H, 4.44; N, 4.18.
(2-(4-Methoxyphenyl)-8-phenylquinolin-4-yl)methanol (7a)
2-(4-Fluorophenyl)benzo[h]quinoline-4-carboxylic
(4d)
Acid
º
Yield: 59%; yellow crystalline powder; mp=101-103 C;
IR (KBr): ν (cm-1), 3700-3056(OH); LCMS (ESI): 342.4
(M+1)+100; Anal. Calcd. for C23H19NO2: C, 80.91; H, 5.61;
N, 4.10. Found: C, 81.12; H, 5.88; N, 4.17.
Yield: 22%; pale yellow crystalline powder; mp: 303-304
ºC; IR (KBr): ν (cm-1) 3074-2893 (OH), 1696 (C=O),
1HNMR (DMSO-D6): δ (ppm) 7.39 (t, 2H, 4-fluorophenyl
H2 & H6, J=8.81 Hz), 7.76-7.81 (m, 2H, benzoquinoline H8
&H9), 8.00-8.04 (m, 2H, benzoquinoline H6 & H7), 8.47-8.50
(m, 3H, 4-fluorophenyl H3 & H5 & benzoquinoline H10), 8.52
(s, 1H, benzoquinoline H3), 9.35 (m, 1H, benzoquinoline
H5), 14.01 (s, 1H, COOH); LCMS (ESI): 318.3 (M+1)+100;
Anal. Calcd. for C20H12NO2F: C, 75.70; H, 3.81; N, 4.41.
Found: C, 76.01; H, 4.05; N, 4.28.
(2-(4-Fluorophenyl)-8-phenylquinolin-4-yl)methanol (7b)
º
Yield: 74%; yellow crystalline powder; mp=121-123 C;
IR (KBr): ν (cm-1), 3711-2623(OH); LCMS (ESI): 330.9
(M+1)+100; Anal. Calcd. for C22H16NOF: C, 80.22; H, 4.90;
N, 4.25. Found: C, 80.33; H, 4.77; N, 4.05.
(2-(4-Methoxyphenyl)benzo[h]quinolin-4-yl)methanol (7c)
º
2-(4-Fluorophenyl)-7,8,9,10-tetrahydrobenzo[h]quinoline-
4-carboxylic Acid (4e)
Yield: 41%; yellow crystalline powder; mp=111-113 C;
IR (KBr): ν (cm-1), 3688-2678(OH); LCMS (ESI): 316.9
(M+1)+100; Anal. Calcd. for C21H17NO2: C, 79.98; H, 5.43;
N, 4.44. Found: C, 79.85; H, 5.20; N, 4.54.
º
Yield: 31%; yellow crystalline powder; mp=256-257 C;
IR (KBr): ν (cm-1), 3543-2361 (OH), 1698 (C=O); LCMS
(ESI): 322.7 (M+1)+100; Anal. Calcd. for C20H16NO2F: C,
74.75; H, 5.01; N, 4.36. Found: C, 74.98; H, 5.23; N, 4.27.
(2-(4-Fluorophenyl)benzo[h]quinolin-4-yl)methanol (7d)
º
Yield: 41%; yellow crystalline powder; mp=139-141 C;
IR (KBr): ν (cm-1), 3583-2656(OH); LCMS (ESI): 304.8
(M+1)+100; Anal. Calcd. for C20H14NOF: C, 79.19; H, 4.65;
N, 4.62. Found: C, 79.32; H, 4.82; N, 4.45.
Preparation of 2-(4-(substituted)phenyl)-quinoline-4-car-
boxylic Acid (Pfitzinger Reaction)
Isatin (0.37 g, 2.5 mmol) was added in 10 ml ethanol and
heated, then (7.5 mmol) of 33% potassium hydroxide was
added to the isatin solution and heated for 15 min then 1-4-
(substituted)phenyl ethanone (0.5 g, 2.5 mmol) was added
and refluxed for 48h, then ethanol was evaporated and the
obtained precipitate was acidified with acetic acid 10% and
was filtered and washed with acetic acid 10%, ethanol and
hexane, (yield:76-90 %).
(2-(4-Fluorophenyl)-7,8,9,10-tetrahydrobenzo[h]quinolin-
4-yl)methanol (7e)
º
Yield: 75%; cream crystalline powder; mp=91-93 C; IR
(KBr): ν (cm-1), 3678-3057 (OH); LCMS (ESI):308.9
(M+1)+100; Anal. Calcd. for C20H18NOF: C, 80.22; H, 4.90;
N, 4.25. Found: C, 80.33; H, 4.77; N, 4.05.
2-(4-Methoxyphenyl)quinoline-4-carboxylic Acid (4f)
(2-(4-Methoxyphenyl)quinolin-4-yl)methanol (7f)
º
º
Yield: 76%; yellow crystalline powder; mp=206-207 C;
Yield: 25%; yellow crystalline powder; mp=110-112 C;
IR (KBr): ν (cm-1), 3585-3085 (OH), 1696 (C=O); LCMS
(ESI): 280.7 (M+1)+100; Anal. Calcd. for C17H13NO3: C,
73.11; H, 4.69; N, 5.01. Found: C, 72.98; H, 4.32; N, 4.85.
IR (KBr): ν (cm-1), 3588-2570(OH); LCMS (ESI): 266.8
(M+1)+100; Anal. Calcd. for C17H15NO2: C, 78.15; H, 5.90;
N, 4.56. Found: C, 78.26; H, 5.77; N, 4.72.
(2-(4-Fluorophenyl)quinolin-4-yl)methanol (7g)
2-(4-Fluorophenyl)quinoline-4-carboxylic Acid (4g)
º
º
Yield: 39%; yellow crystalline powder; mp=180-182 C;
Yield: 90%; yellow crystalline powder; mp=223-224 C;
IR (KBr): ν (cm-1), 3554-2331(OH), LCMS (ESI): 254.7
(M+1)+100; Anal. Calcd. for C16H12NOF: C, 75.88; H, 4.78;
N, 5.53. Found: C, 75.69; H, 4.55; N, 5.81.
IR (KBr): ν (cm-1), 3485-2945 (OH), 1720 (C=O); LCMS
(ESI): 268.6 (M+1)+100; Anal. Calcd. for C16H10NO2F: C,
71.91; H, 3.77; N, 5.24. Found: C, 71.87; H, 4.01; N, 5.31.

92 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1
Ghodsi et al.
General Procedure for Preparation of 4-((1H-imidazol-1-
yl)methyl)-2-(4-substituted-phenyl)-7,8-substituted-quino-
line
(ESI): 366.8 (M+1)+100; Anal. Calcd. for C24H19N3O: C,
82.49; H, 5.48; N, 12.02. Found: C, 82.69; H, 5.67; N, 11.81.
4-((1H-Imidazol-1-yl)methyl)-2-(4-fluorophenyl)benzo[h]-
quinoline (8d)
To a solution of the appropriate alcohol (1.59 mmol) in
15 ml NMP (N-methyl-2-pyrrolidone), CDI (carbonyl 1, 1-
diimidazole) (1.29 g, 7.9 mmol) was added. Then the solu-
tion was refluxed for 20 hours at 170 ºC. Then it is cooled to
room temperature, and water (50 ml) was added and ex-
tracted with ethyl acetate. The obtained organic phases was
washed with brine and water, dried over Na2SO4, and evapo-
rated. Then, the obtained product was purified by flash
chromatography on silica gel (dichloromethane/methanol,
90:10 v/v), (yield: 13-62%).
Yield: 17%; pale cream crystalline powder; mp=181-
183ºC; 1HNMR (CDCl3): δ (ppm) 5.73 (s, 2H, CH2), 7.05 (s,
1H, imidazole H5), 7.23-7.25 (m, 3H, 4-flourophenyl H2 &
H6 & imidazole H2), 7.37 (s, 1H, imidazole H4), 7.74-7.83
(m, 4H,benzoquinoline H3,H6,H8 &H9), 7.90 (d, 1H, benzo-
quinoline H7, J=9.01 Hz), 7.96 (d, 1H, benzoquinoline H10,
J=7.58Hz), 8.23 (m, 2H, 4-flourophenyl H3&H5), 9.51 (d,
1H, quinoline H5); LCMS (ESI): 354.9 (M+1)+100; Anal.
Calcd. for C23H16N3F: C, 78.17; H, 4.56; N, 11.89. Found: C,
78.41; H, 4.27; N, 11.80.
4-((1H-Imidazol-1-yl)methyl)-2-(4-methoxyphenyl)-8-phen-
ylquinoline (8a)
4-((1H-imidazol-1-yl)methyl)-2-(4-fluorophenyl)-7,8,9,10-
tetrahydrobenzo [h] quinoline (8e)
Yield: 23%; pale yellow crystalline powder; mp= 145-
1
146 ºC; HNMR (CDCl3): δ (ppm) 3.87 (s, 3H, OMe), 5.71
(s, 2H, CH2), 6.96 (d, 2H, 4-methoxyphenyl H3 & H5, J=8.68
Hz),7.05 (s, 1H, imidazole H5), 7.25 (s, 1H, imidazole H2),
7.32 (s, 1H, imidazole H4), 7.47 (t, 1H, phenyl H4 , J=7.11
Hz), 7.55 (t, 2H, phenyl H3&H5, J=7.63 Hz), 7.64 (t, 1H,
quinoline H6, J=7.74 Hz), 7.73 (s, 1H, quinoline H3), 7.82-
7.84 (m, 3H, phenyl H2 & H6 & quinoline H5), 7.88 (d, 1H,
quinoline H7, J=8.28 Hz), 7.99 (d, 2H, 4-methoxyphenyl H2
& H6 , J=8.68 Hz); LCMS (ESI): 392.4 (M+1)+100; Anal.
Calcd. for C26H21N3O: C, 79.77; H, 5.41; N, 10.73. Found:
C, 78.98; H, 5.17; N, 10.81.
Yield: 15%; yellow crystalline powder; mp=150-151ºC;
1HNMR (CDCl3): δ (ppm) 1.94-2.06 (m, 4H, (CH2)8 &
(CH2)9), 2.97 (m, 2H, (CH2)7), 3.47 (m, 2H, (CH2)10), 5.65
(s, 2H, CH2), 7.0 (s, 1H, imidazole H5), 7.16-7.21 (m, 3H, 4-
flourophenyl H3& H5 & imidazole H4), 7.2 (s, 1H, imidazole
H2), 7.26 (s, 1H, imidazole H4), 7.32 (d, 1H, quinoline H6,
J=8.51 Hz), 7.64 (d, 1H, quinoline H5, J=8.53 Hz), 7.74 (s,
1H, quinoline H3), 8.14 (m, 2H, 4-fluorophenyl H2 & H6);
LCMS (ESI):358.5 (M+1)+100; Anal. Calcd. for C23H20N3F:
C, 77.29; H, 5.64; N, 11.76. Found: C, 77.46; H, 5.87; N,
11.99.
4-((1H-Imidazol-1-yl)methyl)-2-(4-fluorophenyl)-8-phenyl-
quinoline (8b)
4-((1H-Imidazol-1-yl)methyl)-2-(4-methoxyphenyl)quino-
line (8f)
Yield: 21%; cream crystalline powder; mp= 157-158ºC;
1HNMR (CDCl3): δ (ppm) 5.74 (s, 2H, CH2), 7.07 (s, 1H,
imidazole H5), 7.12 (t, 2H, 4-fluorophenyl H3 &H5 , J=8.62
Hz), 7.27 (s, 1H, imidazole H2), 7.32 (s, 1H, imidazole H4),
7.48 (t, 1H, phenyl H4 , J=7.35 Hz), 7.55 (t, 2H, phenyl H3 &
H5, J=7.54 Hz), 7.68 (t, 1H, quinoline H6, J= 7.79Hz), 7.76
(s, 1H, quinoline H3), 7.81 (d, 2H, phenyl H2 &H6, J=7.46
Hz), 7.86 (d, 1H, quinoline H5 , J=6.94 Hz), 7.92 (d, 1H,
quinoline H7, J=8.26 Hz), 8.02 (t, 2H, 4-fluorophenyl H2
&H6 , J=7.04 Hz); LCMS (ESI): 380.9 (M+1)+100; Anal.
Calcd. for C25H18N3F: C, 79.14; H, 4.78; N, 11.07. Found: C,
79.38; H, 4.92; N, 11.22.
Yield: 21%; cream crystalline powder; mp=155-156ºC;
1HNMR (CDCl3): δ (ppm) 3.89 (s, 3H, OMe), 5.67 (s, 2H,
CH2), 7.02-7.04 (m, 3H, 4-methoxyphenyl H3 & H5& imida-
zole H5), 7.24 (s, 1H, imidazole H2), 7.25 (s, 1H, imidazole
H4), 7.58 (t, 1H, quinoline H6, J=8.08 Hz), 7.70 (s, 1H, qui-
noline H3), 7.78 (t, 1H, quinoline H7, J=8.22 Hz), 7.88 (d,
1H, quinoline H5, J=8.34 Hz), 8.04 (d, 2H, 4-methoxyphenyl
H2 &H6, J=8.82 Hz), 8.22 (d, 1H, quinoline H8); LCMS
(ESI): 316.8 (M+1)+100; Anal. Calcd. for C20H17N3O: C,
76.17; H, 5.43; N, 13.32. Found: C, 76.39; H, 5.79; N, 13.52.
4-((1H-Imidazol-1-yl)methyl)-2-(4-fluorophenyl)quinoline
(8g)
4-((1H-Imidazol-1-yl)methyl)-2-(4-methoxyphenyl)benzo-
[h]quinoline (8c)
Yield: 13%; pale yellow crystalline powder; mp= 148-
150 ºC; 1HNMR (CDCl3): δ (ppm) 5.70 (s, 2H, CH2), 7.02 (s,
1H, imidazole H5), 7.19 (t, 2H, 4-fluorophenyl H3 & H5,
J=11.59 Hz), 7.23-7.24 (d, 2H, imidazole H2 & H4), 7.62 (t,
1H, quinoline H6, J=8.07 Hz), 7.71 (s, 1H, quinoline H3),
7.81 (t, 1H, quinoline H7), 7.91 (d, 1H, quinoline H5), 8.04-
8.08 (m, 2H, 4-fluorophenyl H2 & H6), 8.24 (d, 1H, quinoline
H8); LCMS (ESI): 304.9 (M+1)+100; Anal. Calcd. for
C19H14N3F: C, 75.23; H, 4.56; N, 13.85. Found: C, 75.39; H,
4.71; N, 13.89.
Yield: 62%; pale yellow crystalline powder; mp=168-
170ºC; 1HNMR (CDCl3): δ (ppm) 3.93 (s,3H, OMe), 5.68 (s,
2H, CH2), 7.02 (s, 1H, imidazole H5), 7.07 (d, 2H, 4-
methoxyphenyl H3 & H5, J=8.76 Hz), 7.23(s, 1H, imidazole
H2), 7.36 (s, 1H, imidazole H4), 7.70 (s, 1H, benzoquinoline
H3), 7.73-7.77 (m, 2H,benzoquinoline H6&H8), 7.84 (t, 1H,
benoquinoline H9, J=7.01 Hz), 7.94 (d, 1H,benzoquinoline
H10, J=7.72Hz), 8.20 (d, 2H, 4-methoxyphenyl H2 & H6,
J=8.76 Hz), 9.53 (d, 1H, quinoline H5, J=8.04 Hz); LCMS

Design, Synthesis and Biological Evaluation
Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1 93
2.3. Molecular Modeling Studies
incubated at 37 ºC in 5% Co2 incubator for 48h and 72h.
Then 25 µL of MTT solution (4mg Ml-1) was added to each
well and further incubated at 37 ºC for 3h. At the end of in-
cubation, formazan crystals were dissolved in 100 µL of
DMSO and plates were read in a plate reader (TECAN, Aus-
tria) at 540 nm. This experiment was performed in triplicate
determination each time.
Molecular modeling (Docking studies) was done using
AUTODOCK software Version 3.0.5. The crystal structure
of aromatase bound to natural substrate androstenedione
(PDB id 3EQM) was obtained from the RCSB Protein Data
Bank and was used as a docking target for our compounds.
At first, the natural substrate androstenedione was removed,
then the hydrogen atoms, salvation parameters and Kollman
atom charges were added using AutoDockTools. The ligands
were constructed using the Builder module and were energy
minimized till to reaching a convergence of 0.01 kcal/mol Å.
The energy minimized ligands were superimposed on an-
drostenedione in the PDB file (3EQM) after which andros-
tenedione was deleted. These docked structures were very
similar to the minimized structures obtained initially. The
intermolecular energy of the ligand–enzyme assembly de-
termines the best docked structures [23, 24].
3. RESULTS AND DISCUSSION
3.1. Chemistry
A one-step Doebner reaction was used to prepare the 2-
(4-(substituted)phenyl)-7,8-substituted-quinoline-4-carboxy-
lic acid derivatives 4a–e. As illustrated in Scheme (1), an
appropriate amine 1, 4-(substituted) benzaldehyde 2, and
pyruvic acid 3 were heated in ethanol to provide 4-carboxy
quinolines 4a–e (11–31%). However, the well known
Doebner-type synthesis of quinolines did not yield the ex-
pected 2-(4-(substituted)phenyl)-quinoline-4-carboxylic acid
derivatives. Therefore, the desired quinoline derivatives 4f-g
were prepared using Pfitzinger reaction [25]. Accordingly, 4-
(substituted)acetophenone 5 was reacted with isatin 6 in al-
kaline ethanol to provide 4f-g (76-90%). The low yield of
doebner reaction in comparison with pfitzinger reaction may
be attributed to formation of side products in multicompo-
nent doebner reaction, which we observed in the TLC of our
compounds. The synthesis of alcohol derivatives 7a-g was
carried out by reduction of the carboxylic acid derivatives
4a-g in the presence of lithium aluminum hydride in dry
THF (25-77%) [26]. The percentage yield of reduction reac-
tion of some of our carboxylic acid derivatives was low be-
cause they were not very soluble in THF and so the reaction
did not proceed completely. The obtained alcohols 7a–g
were subjected to a reaction with N,N-carbonyldiimidazole
(CDI) to give the target imidazole substituted compounds
8a-g (13-62%) [27, 28]. All of these target compounds 8a-g
were purified by flash chromatography and the polarity of
some impurities was very close to most of our compounds,
which led to obtain less percentage yield of pure target com-
pounds.
2.4. Evaluation of Inhibition of Aromatase Activity in
H295R Cell Line
The ability of quinoline derivatives 8a-g to inhibit aro-
matase activity in H295R cell lines was measured by the
titrated water release assay using 0.5 M [1 -3H(N)]-androst-
4-ene-3,17-dione (25.3 Ci/mmol; DuPont NEN, Boston,
MA, USA) as substrate. At first, H295R cells were seeded at
2.5×104 cells/well on 24-well plates and after 24 h com-
pounds (0,1, 1, 10 µM) or Letrozole (5 M) were added to the
culture medium. After additional 24 h the treatment medium
was replaced with the assay medium containing 30 pmol
[1-3H]androstenedione . After 2-h incubation at 37 °C, 200 L
of incubation media was mixed with 200 L of 3%
trichloroacetic acid and the mixture was vortexed vigorously.
With every tested compound, two separated experiments,
each one in triplicate,were performed.
2.5. Cytotoxicity Assay
2.5.1. Cell line and Culture Conditions
The human breast cancer T47D and MCF-7 cell lines
were obtained from Pasteur Institute Cell Bank of IRAN
(Tehran, IRAN). Cells were maintained in RPMI-1640
(Gibco, UK) culture medium after adding 10% fetal bovine
serum (Gibco, UK) and 100 U Ml-1 of penicillin and 100 ng
Ml-1 of streptomycin (Gibco, UK) at 37 C in 5% CO2 incuba-
tor. All reagent and chemicals used in this experiment were
of cell culture or molecular biology grade, purchased from
different international sources.
3.2. Biological Evaluation
The ability of the quinoline derivatives 8a-g to inhibit
aromatase enzyme activity was determined in subconfluent
H295R cells by the tritiated water release assay using [1-
3H(N)]-androst-4-ene-3,17-dione and Letrozol (potent aro-
matase inhibitor) at 5 μM concentration was used as positive
control according to the previously reported method [29, 30].
Unexpectedly, most of the compounds were not able to in-
hibit aromatase enzyme activity at concentration ≤ 10μM (in
comparison with 5 μM Letrozole). However, the compounds
8a, 8b and 8c in this series display inhibition of aromatase
enzyme activity at concentration ≤ 10μM and 8b inhibited
the enzyme activity strongly and was more potent than
the reference drug letrozole. Unexpectedly, some of the
compounds 8f, 8g and 8c in low concentration increased the
activity of aromatase. This paradoxical result might be
because of the activation of phosphorylative pathways which
2.5.2. General Procedure
The MTT (3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyl
tetrazolium bromide) based assay was performed by seeding
5000 cells (T47D and MCF-7) per 180 µL RPMI complete
culture medium in each well of 96-well culture plates. The
day after seeding, culture medium was changed with me-
dium containing standard anti-tumor drug Doxorubicin as
well as different concentrations of newly synthesized com-
pounds and RPMI control (no drug). Cells were then

94 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1
Ghodsi et al.
O
COOH
N
O
H
a
OH
R2
NH2
X
R2
R1
O
R1
X
1
3
2
4a; R1 = Ph, R2 = H, X = OMe
4b; R1 = Ph, R2 = H, X= F
4c; R1&R2 = Ph, X = OMe
4d; R1&R2 = Ph, X = F
4e; R1&R2 = Cyclohexyl, X = F
O
O
COOH
b
O
N
X
H
N
5
6
X
4f; X= OMe
4g; X= F
COOH
CH2OH
c
R2
N
R2
N
R1
R1
X
X
4a-4g
7a; R1 = Ph, R2 = H, X = OMe
7b; R1 = Ph, R2 = H, X= F
7c; R1&R2 = Ph, X = OMe
7d; R1&R2 = Ph, X = F
7e; R1&R2 = Cyclohexyl, X = F
7f; R1=R2 = H, X= OMe
7g; R1= R2 = H, X= F
N
N
CH2OH
N
d
R2
R2
N
R1
R1
X
X
7a-g
8a; R1 = Ph, R2 = H, X = OMe
8b; R1 = Ph, R2 = H, X= F
8c; R1&R2 = Ph, X = OMe
8d; R1&R2 = Ph, X = F
8e; R1&R2 = Cyclohexyl, X = F
8f; R1=R2 = H, X= OMe
8g; R1= R2 = H, X= F
Scheme (1). Reagents and conditions: (a) ethanol, reflux, 1-5 h; (b) ethanol/KOH, reflux, 48h; (c) LiAlH4/THF, 2h; (d) CDI/NMP, 170°C,
20h.

Design, Synthesis and Biological Evaluation
Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1 95
Fig. (4). Docking 4-((1H-imidazol-1-yl) methyl)-2-(4- methoxy-
phenyl benzo[h] quinoline (8b) in the active site of the aromatase.
Fig. (3). Inhibition of aromatase activity in H295R cells for deriva-
tives 8a-c. Results were expressed as percentage of inhibition in
comparison to the control (untreated cells or basal value 100) (bs).
Bars (*) and (**) indicate statistically significant inhibition of the
activity in comparison with the control. Letrozol (aromatase spe-
cific inhibitor) at 5 μM concentration was used as positive control.
sure inhibits 50% proliferation of MCF-7 cells and 8d and 8f
were the least potent compounds. The most potent com-
pounds against T47D cells were 8e and 8a, which exhibited
20.1%, 6.9% of survival (after 2 days exposure) respectively
(IC50 ≤ 10μM). In addition, their cytotoxic effects were time-
dependent. Our results also showed that 8c, 8b and 8g after 2
days exposure inhibited about 70% proliferation of T47D
cells, and their cytotoxic effects were time-dependent, and
can activate the enzyme and as a consequence increase its
activity [30-32]. (See the data of enzyme activity assay in
Fig. 3). These results indicated that some of the lipophilic
compounds, such as 8a, 8b and 8c, apparently penetrate cells
and inhibit aromatase activity. The significant inhibition of
aromatase activity by compound 8b may be related to better
interaction with amino acids present in the active site of aro-
matase. Compounds 8f and 8g which are not possessing any
lypophilic substituent in their 8-position did not inhibit the
aromatase activity and inserting a phenyl group in 8-position
of quinolines (8a and 8b) help them to inhibit the aromatase
activity. It showed that hydrophobicity of the quinolines in 8
position enhanced aromatase inhibition and it may be due to
their potential binding to interaction with aliphatic and
hydrophobic amino acids in the active site of aromatase.
However, the disparity in inhibition of aromatase activity
achieved in the cell culture by the similar analogs, suggests
that other factors, such as intracellular transport by the
culture system may be involved. The cytotoxicity of qui-
nolines 8a-g against human breast cancer MCF-7 and T47D
cells by MTT assay after 2 and 3 days of exposure was also
evaluated. After some initial evaluations, concentrations of
10 and 25 μM of quinolines were used for the evaluation of
cytotoxicity of these compounds in comparison with
doxorubicin at concentration of 250 nM against MCF-7 cells
and concentrations of 25 and 50 μM of quinolines were used
for the evaluation of cytotoxicity of these compounds in
comparison with doxorubicin at concentration of 100 nM
against T47D cells. Results for each compound as the per-
centage of growth of the treated cells in comparison to un-
treated cells are shown in Table 1. The most active com-
pounds against MCF-7 cells were 8e and 8a, which exhibited
18.2%, 25.8% of survival (after 2 days exposure) respec-
tively (IC50 ≤ 5μM) and their cytotoxic effects were time-
dependent, the IC50 of 8c and 8b was 10 μM and their cyto-
toxic effects were not time-dependent, 8g after 3 days expo-
8d and 8f were the least potent compounds with IC50
=
25μM. The calculated IC50 values of all tested compounds
after two days exposure showed that the order of the cytotox-
icity against MCF-7 cells was 8e > 8a > 8c = 8b > 8g = 8d >
8f and in T47D cells was 8a > 8e > 8c = 8b = 8g > 8d = 8f.
These data showed that the increase of lipophilic properties
of substituents on the C-7 and C-8 quinoline ring increased
their cytotoxicity on MCF-7 and T47D cells. This may be
due to their ability to penetrate the cell membrane or their
ability to inhibit or suppress some factors and enzymes such
as aromatase. In some other studies [33, 34] it is also con-
cluded that the higher cytotoxic activity of non-polar com-
pounds could be attributed to their higher lipophilicity lead-
ing to better permeability to lipophilic cell membranes.
These quinolines 8a-g were more cytotoxic against MCF-
7 cells in comparison with those of T47D. MCF7 and T47D
cells are both ER-positive but MCF7 cells express higher
levels of aromatase mRNA than T47D cells [16], so this may
be due to their ability to inhibit aromatase or decrease aro-
matase activity. Furthermore, compound 8b that decreased
the aromatase activity more than the others was not the most
potent antiprolifrative agent, suggesting other effects in addi-
tion to inhibition of aromatase activity.
3.3. Molecular Modeling Studies
The binding interactions of 8b within the aromatase bind-
ing site were investigated. The most stable enzyme–ligand
complex of 4-((1H-imidazol-1-yl)methyl)-2-(4-methoxyph-
enyl)benzo[h]quinoline (8b) within the aromatase binding
site (Fig. 4) shows that imidazole moiety is well oriented
towards the heme iron of aromatase and its nitrogen can co-
ordinate with the Fe3+ of the heme. In addition, our docking

96 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1
Table 1. In vitro Cytotoxicity of Quinolines 8a-g.
Ghodsi et al.
N
N
R2
N
R1
R3
Survival a (%)
(10µM )
Survival b(%)
IC50(µM)
MCF-7
IC50(µM)
T47D
Compound
R1
R2
R3
(25µM)
48h 72h
48h 72h
8e
cyclohexyl
F
OMe
OMe
F
<5
<5
18.2
25.8
57
2
<10
<10
ND
ND
ND
25
20.1
6.9
0.7
0.7
8a
Ph
H
3.8
8c
Phenyl
Phenyl
10
40.7
48.7
47.2
61.7
65.6
31.7
33.3
31.2
33.6
49.2
47.8
53.2
11.1
20.3
22
8b
Ph
H
H
H
10
53
8g
F
ND
ND
ND
0.25
61
8d
8f
F
63.3
84.8
50.2
36.8
32.7
27.1
H
-
H
-
OMe
25
Doxorubicin
-
0.1
aPercent survival of MCF-7 cells following exposure to 10µM concentration of compounds was determined after 48h and 72h exposure using MTT assay.
bPercent survival of T47D cells following exposure to 25µM concentration of compounds was determined after 48h and 72h exposure using MTT assay.
CND: Not determined.
studies showed that F-atom at para position of phenyl ring
attached at 2-position of quinoline ring was positioned at 2.5
Å from the hydroxyl group of Ser478 and can form hydrogen
binding interactions with this amino acid and the phenyl ring
at 8-position of quinoline is close to hydrophobic side chain
of Phe134 and Met374 and Leu477. Quinoline ring was sur-
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Received: March 03, 2015
Revised: May 30, 2015
Accepted: June 11, 2015