Quinoline-3-carboxamide derivatives as potential cholesteryl ester transfer protein inhibitors

Article abstract of DOI:10.3390/molecules17055497

A series of novel quinoline-3-carboxamide derivatives 10-17 and 23-27 were designed and synthesized as cholesteryl ester transfer protein (CETP) inhibitors. All of them exhibited activity against CETP. Particularly, compounds 24 and 26 displayed the best activity against CETP with the same inhibitory rate of 80.1%.

Full text of DOI:10.3390/molecules17055497

Molecules 2012, 17, 5497-5507; doi:10.3390/molecules17055497
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Quinoline-3-carboxamide Derivatives as Potential Cholesteryl
Ester Transfer Protein Inhibitors
Wen-Yan Li 1, Xu-Qiong Xiong 1, Dong-Mei Zhao 1,*, Yu-Fang Shi 2, Zhi-Heng Yang 1, Chao Yu 1,
Pei-Wei Fan 1, Mao-Sheng Cheng 1 and Jing-Kang Shen 2,*
1
Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education,
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
2
Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai 201203, China
* Authors to whom correspondence should be addressed; E-Mails: dongmeiz-67@163.com (D.-M.Z.);
jkshen@mail.shcnc.ac.cn (J.-K.S.); Tel.: +86-024-2398-6413 (D.-M.Z.);
Fax: +86-024-2399-5043 (D.-M.Z.); Tel.: +86-021-5080-6600 (J.-K.S.);
Fax: +86-021-5080-7088 (J.-K.S.).
Received: 26 March 2012; in revised form: 14 April 2012 / Accepted: 20 April 2012 /
Published: 9 May 2012
Abstract: A series of novel quinoline-3-carboxamide derivatives 10–17 and 23–27 were
designed and synthesized as cholesteryl ester transfer protein (CETP) inhibitors. All of
them exhibited activity against CETP. Particularly, compounds 24 and 26 displayed the
best activity against CETP with the same inhibitory rate of 80.1%.
Keywords: CETP inhibitors; CETP; quinoline-3-carboxamide derivatives; synthesis;
high density lipoprotein cholesterol
1. Introduction
Coronary heart disease (CHD), a leading cause of death around the World [1], has an inverse
relationship with serum high density lipoprotein (HDL) cholesterol levels [2]. Raising of HDL
cholesterol levels provides a potential therapeutic benefit for CHD patients [3,4]. Cholesteryl ester
transfer protein (CETP) is a plasma glycoprotein which plays an important role in decreasing HDL-C
level and increasing LDL-C level [5]. Inhibition of CETP may be a new therapy for atherosclerosis [6–10].
The research on CETP inhibitors such as dalcetrapib, anacetrapib and evacetrapib (Figure 1) has
become a new hotspot for the treatment of CHD [11–13].

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Figure 1. Structures of current CETP inhibitors.
CF3
F3C
O
F
N N
N
N
N
F3C
N
O
N
O
O
NH
S
CF3
O
O
F3C
HO
Evacetrapib (Lily)
Dalcetrapib (Racho & Tobacoo)
Phase III clinical trial
Anacetrapib (Merck)
Phase III clinical trial
Phase II clinical trial
In our lab a series of 2,3-dihydro-4-tetrahydroquinolones were found to have potent CETP
inhibitory activity by virtual screening, including lead-like rule, clustering analysis, biological activity
spectra prediction, ADME/Tox prediction and synthetic feasibility prediction [14]. Compound 1, a best
effective CETP inhibitor among these derivatives, showed 30% inhibitory rate against CETP at 10 μ M
in a buffer assay. In this study, our primary objective was to optimize the potency of compound 1
against CETP and obtain more potent CETP inhibitors. Based on the scaffold hopping strategy,
2,3-dihydro-4-tetrahydroquinolone was changed to a quinoline ring while retaining the aryl group at
the 6 position (Figure 2). 6-Arylquinoline-3-carboxamide derivatives 10–17 were thus designed and
synthesized. The crystal structure of CETP reveals a long continuous tunnel (60 Å) with a very large
volume (2,560 Å3) [15], so in order to make the structures bind nicely with CETP in the bulky active
cavity, the phenyl ring substituent was replaced by larger and more flexible 6-benzyloxy and
7-methoxy groups to give the derivatives 23–27 which were also synthesized. All of target compounds
10–17, 23–27 were evaluated their CETP inhibitory activity by a radioisotope-based assay.
Figure 2. Scaffold hopping from tetrahydroquinolone into quinoline analogues.

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2. Result and Discussion
2.1. Chemistry
The synthetic pathway to the 6-phenylquinoline-3-carboxamide derivatives is shown in Scheme 1.
Compound 3 was obtained in 65% yield by treatment of 3-bromobenzaldehyde 2 with violet
acid (H2SO4:HNO3 = 10:1, V/V). Suzuki coupling of aryl bromide 3 with phenylboronic acid or
4-methylphenylboronic acid gave compounds 4 or 5, which were reduced with zinc dust to provide
substituted o-amino benzaldehydes 6 or 7. 3-Quinolinecarboxylic acids 8 or 9 was prepared by
cyclization of 6 or 7 with ethyl acetoacetate and p-tolylsulfonic acid at 100 °C and then hydrolyzed
with 5% NaOH solution. Coupling of 8 or 9 with commercially available amines afforded the target
compounds 10–17.
Scheme 1. The synthesis of 6-phenylquinoline-3-carboxamide derivatives 10–17.
Reagents and conditions: (a) H2SO4, HNO3, −5 °C to r.t., 0.5 h, 65%; (b) PhB(OH)2 or
4-MePhB(OH)2, Pd(OAc)2, CH3COCH2COMe, K2CO3, EtOH, reflux, 1 h, 68%–72%; (c) Zn,
NH4Cl, EtOH, H2O, r.t., 2 h, 79%–84%; (d) CH3COCH2COOEt, p-TSA, 100 °C, 10 min; (e) 5%
NaOH, reflux, 2 h, 69%–81% (two steps); (f) R2NH2, HOBt, EDC·HCl, DIEA, DMF, r.t., 5 h,
22%–84%.
The preparation of the 6-benzyloxy-7-methoxyquinoline-3-carboxamide derivatives is shown in
Scheme 2. Alkylation of commercially available isovanillin (18) with benzyl bromide and potassium
carbonate at 90 °C in DMF produced compound 19, which was nitrated with nitric acid at 0 °C
to afford 20. The later steps were same as the synthesis of the 6-phenylquinoline-3-carboxamide
derivatives.

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Scheme 2. The synthesis of 6-benzyloxy-7-methoxyquinoline-3-carboxamide derivatives 23–27.
Reagents and conditions: (a) BnBr, K2CO3, DMF, 90 °C, 3 h, 91%; (b) HNO3, 0 °C to r.t., 2 h, 78%;
(c) Zn, NH4Cl, EtOH, H2O, r.t., 64%; (d) CH3COCH2COOEt, p-TSA, 100 °C, 10 min; (e) 5%
NaOH, reflux, 5 h, 76% (two steps); (f) R3NH2, HOBt, EDC·HCl, DIEA, DMF, r.t., 5 h, 27%–73%.
2.2. Biological Activity
In vitro inhibitory activity of all target compounds 10–17, 23–27 against CETP was evaluated by a
radioisotope-based assay. The inhibition (%) results are presented in Table 1. All the newly
synthesized derivatives exhibited considerable CETP inhibitory activity (inhibitory rates:
20.7%–80.1%). Particularly, p-tolyl amide 24 and t-butyl substituted amide 26 exhibited the best
inhibitory activity towards CETP, with the same inhibitory rate of 80.1%, which is approximately the
same activity of the positive control dalcetrapib. Substitution at 6 and 7 positions of the
quinoline-3-carboxamide scaffold was considered a determining factor in the activity. Indeed,
compounds 26, 24 and 23 with 6-benzyloxy-7-methoxy groups showed better activity than the
corresponding substituted 6-phenyl analogues 17, 14 and 11, respectively. We speculate that the bulky
6-benzyloxy-7-methoxy group packs nicely in the large hydrophobic cavity of CETP. In addition,
compounds 14 and 24 with a substituted aryl group on the 3-carboxamide nitrogen atom showed
higher potency than other corresponding alkyl analogues in the two chemical classes.
Table 1. CETP inhibitory rate of the target compounds (10–17, 23–27).
Compd.
Inhibition (%) a
30.0 ± 1.2
Compd.
Inhibition (%) a
35.2 ± 0.7
10
11
12
13
14
15
16
17
23
24
25
26
27
34.2 ± 0.7
41.8 ± 1.5
31.5 ± 1.1
71.7 ± 2.2
52.5 ± 2.1
36.7 ± 1.9
51.5 ± 2.6
80.1 ± 1.3
29.8 ± 2.5
80.1 ± 0.8
20.7 ± 2.3
82.5 ± 2.0
Dalcetrapib b
a
Values represent the percent inhibition of CETP at 10 µM of the test compounds
and are the average of three independent experiments; b The positive control.

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3. Experimental
3.1. General
All melting points were obtained on a Büchi Melting Point B-540 apparatus (Büchi Labortechnik,
Flawil, Switzerland) and were uncorrected. Mass spectra (MS) were taken in ESI mode on Agilent
1100 LC-MS (Agilent, Palo Alto, CA, USA). Nuclear magnetic resonance spectroscopy was
performed using Bruker ARX-300, 300 MHz spectrometers (Bruker Bioscience, Billerica, MA, USA)
with TMS as an internal standard. IR spectra (KBr disks) were recorded with a Bruker IFS-55
instrument (Bruker). All the materials were obtained from commercially available sources and used
without further purification, unless otherwise specified. Yields were not optimized. Compound 21 was
synthesized according to the literature [16,17].
5-Bromo-2-nitrobenzaldehyde (3). Compound 2 (27.1 g, 0.15 mol) was slowly added dropwise to
violet acid (150 mL, H2SO4:HNO3 = 10:1, V/V) cooled to −5 °C and then stirred at room temperature
for 0.5 h. The reaction mixture was poured into ice water to give a white precipitate which was filtered
off and purified by recrystallization from 5:1 petroleum ether/ethyl acetate to give the desired product
3 (21.7 g, 65%) as a off-white solid; m.p. 60.5–61.9 °C. 1H-NMR (CDCl3) δ: 7.89 (1H, dd, J1 = 8.7 Hz,
J2 = 2.1 Hz), 8.03 (1H, d, J = 8.7 Hz), 8.06 (1H, d, J = 2.1 H), 10.41 (1H, s).
4-Nitrobiphenyl-3-benzaldehyde (4). To a solution of 3 (22.7 g, 0.1 mol) in alcohol (150 mL) and
K2CO3 (1 M) (150 mL) was added phenylboronic acid (16.8 g, 0.14 mol) and then Pd(AcO)2 (0.10 g,
0.4 mmol) and acetylacetone (0.3 mL, 1.2 mmol). The mixture was refluxed for 1 h and cooled to
room temperature. The solution was concentrated and quenched with water, then extracted with ethyl
acetate. The organic layer was washed with water and brine, and then dried over Na2SO4. Solvent was
removed under reduced pressure and the resulting residue was purified by column chromatography
(25% EtOAc/petroleum ether, silica) to provide the title compound (16.3 g, 72% yield) as a yellow
1
solid; m.p. 71.0–73.4 °C. H-NMR (CDCl3) δ: 7.49 (2H, t, J = 6.3 Hz), 7.50 (1H, t, J = 6.3 Hz), 7.66
(2H, d, J = 8.1 Hz ), 7.93 (1H, d, J = 8.4 Hz), 8.1 (1H, d, J = 2.1 Hz), 8.22 (1H, d, J = 8.4 Hz), 10.51 (1H, s).
4'-Methyl-4-nitrobiphenyl-3-benzaldehyde (5). 5 was obtained as a yellow solid (67.7% yield) from
1
compound 3 as described for 4; m.p. 54.2–58.4 °C. H-NMR (CDCl3) δ: 2.43 (3H, s), 7.32 (2H, d,
J = 8.1 Hz), 7.56 (2H, d, J = 8.1 Hz), 7.92 (1H, d, J = 8.4 Hz), 8.1 (1H, d, J = 2.1 Hz), 8.20 (1H, d,
J = 8.4 Hz), 10.52 (1H, s).
4-Aminobiphenyl-3-benzaldehyde (6). To a solution of 4 (5.0 g, 22 mmol) in water (100 mL) and
alcohol (33 mL) was added ammonium chloride (7.1 g, 132 mmol) and then zinc dust (17.2 g, 264
mmol). The mixture was stirred at room temperature for 2 h and filtered. The filtrate was concentrated
and quenched with water, then extracted with ethyl acetate. The organic layer was washed with water
and brine and then dried over Na2SO4. Solvent was removed under reduced pressure and obtained 6
(3.4 g, 79% yield) as a yellow solid used directly to the next step without any purification; m.p.
124.5–125.8 °C. 1H-NMR (CDCl3) δ: 6.19 (2H, s), 6.77 (1H, d, J = 8.5 Hz), 7.33 (2H, t, J = 7.3 Hz),
7.45 (2H, t, J = 7.3 Hz), 7.56 (1H, d, J = 7.1 Hz), 7.61 (1H, dd, J1 = 2.2 Hz, J2 = 8.5 Hz), 7.74 (1H, d,
J = 2.2 Hz), 9.98 (1H,s). MS m/z: 198.1 [M+H]+.

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4'-Methyl-4-aminobiphenyl-3-benzaldehyde (7). Compound 7 was obtained from compound 5 as a
yellow solid (84.8% yield) as described for 6 and used directly to the next step without any purification;
m.p. 148.2–149.4 °C. MS m/z: 212.1 [M+H]+.
6-Phenyl-2-methylquinoline-3-carboxylic acid (8). Compound 6 (3.4 g, 17 mmol) was mixed with
acetoacetic ester (2.3 g, 17 mmol) and p-tolylsulfonic acid (2.9 g, 17 mmol). The mixture was heated to
100 °C for 10 min and cooled to room temperature. Next 10% NaOH (20 mL) was added and stirred
for 30 min to give a yellow precipitate. The precipitate was isolated by filtration and washed with
water to give 8 as a yellow solid. Without any purification, the solid was dissolved in 5% NaOH
(100 mL). The solution was refluxed for 2 h and cooled to room temperature. The reaction mixture’s
pH value was adjusted to 2 with 6 N hydrochloric acid giving a greyish white precipitate. The
precipitate was filtered and washed with water to pH 7. The filter cake was dried to give 8 (3.1 g, 69%
yield for two steps) as a greyish white solid; m.p. 187.8–188.9 °C. 1H-NMR (DMSO-d6) δ: 2.96 (3H, s),
7.46 (1H, t, J = 7.1 Hz), 7.55 (2H, t, J = 7.2 Hz), 7.85 (2H, d, J = 7.4 Hz), 8.30–8.19 (2H, m), 8.53 (1H, d,
J = 8.8 Hz), 9.08 (1H, s), 11.20 (1H, s). MS m/z: 262.1 [M−H]−.
2-Methyl-6-(p-tolyl)quinoline-3-carboxylic acid (9). Compound 9 was obtained from compound 7 as a
1
greyish white solid (80.9% yield) as described for 8; m.p. 201.8–203.4 °C. H-NMR (CDCl3) δ: 2.45
(3H, s), 2.96 (3H, s), 7.30 (2H, d, J = 8.0 Hz), 7.46 (2H, d, J = 7.9 Hz), 8.28–8.17 (2H, m), 8.49 (1H, d,
J = 8.8 Hz), 9.01 (1H, s), 11.1 (1H, s).
3'-O-Benzylisovanillin (19). Compound 19 was obtained as a white solid (92% yield) according to the
literature [17]; m.p. 50.1–52.9 °C. 1H-NMR (CDCl3) δ: 3.96 (3H, s), 5.22 (2H, s), 7.01 (1H, d, J = 8.1 Hz),
7.25–7.49 (7H, m), 9.80 (1H, s).
5-Benzyloxy-4-methoxy-2-nitrobenzaldehyde (20). Compound 20 was obtained as a white solid (78%
1
yield) according to the literature [16]; m.p. 131.8–133.0 °C. H-NMR (CDCl3) δ: 4.01 (3H, s), 5.25
(2H, s), 7.44 (6H, m), 7.63 (1H, s), 10.42 (1H, s).
5-Benzyloxy-4-methoxy-2-aminobenzaldehyde (21). Compound 21 was obtained from compound 20 as
a yellow solid (64% yield) as described for 6 and used directly to the next step without any purification;
m.p. 180–184 °C. MS m/z: 258.1 [M+H]+.
6-Benzyloxy-7-methoxy-2-methylquinoline-3-carboxylic acid (22). Compound 22 was obtained from
1
compound 21 as a greyish white solid (76% yield) as described for 8; m.p. 274.2–278.4 °C. H-NMR
(DMSO-d6) 2.82 (3H, s), 4.02 (3H, s), 5.27 (2H, s), 7.37–7.70 (7 H, m), 8.66 (1H, s).
3.2. General Procedure for the Synthesis of Quinoline-3-carboxamide Derivatives 10–17, 23–27
To a solution of 8, 9, 22 (1 mmol) in dry DMF (10 mL) was added 1-hydroxybenzotrizole (HOBt)
(1.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl, 1.5 mmol). The
mixture was stirred at room temperature for 2 h, and then the corresponding amine (2.0 mmol) and
DIEA (2.0 eq) were added. The reaction mixture was stirred at room temperature for 5 h, poured into

Molecules 2012, 17
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ice water. The precipitate was filtered, washed with water, and then recrystallized with ethyl acetate or
purified by column chromatography (silica gel) to give 10–17, 23–27.
N-Decyl-2-methyl-6-phenylquinoline-3-carboxamide (10). White solid, 84% yield, m.p.
1
109.1–109.5 °C. H-NMR (DMSO-d6) δ: 0.85 (3H, t), 1.25–1.32 (14H, m), 1.55 (2H, t), 2.68 (3H, s),
3.28 (2H, t), 7.42 (1H, t, J = 7.3 Hz), 7.53 (2H, t, J = 7.2 Hz), 7.81 (2H, d, J = 7.5 Hz), 8.02 (1H, d,
J = 8.8 Hz), 8.10 (1H, dd, J1 = 8.8 Hz, J2 = 2.0 Hz), 8.29 (1H, d, J = 1.8 Hz), 8.33 (1H, s), 8.58 (1H, s).
13C-NMR (DMSO-d6) δ: 13.9, 22.1, 23.3, 26.4, 28.7, 29.0, 31.3, 125.3, 125.8, 127.0, 128.6, 129.1,
129.3, 131.4, 134.6, 137.7, 139.2, 146.3, 155.8, 167.7. HR-MS m/z: 403.2838 (calcd for C27H35N2O
[M+H]+: 403.2744). IR (KBr) cm−1: 3230, 3055, 2917, 2851, 1634, 1600, 1578, 837, 755, 699.
N-Benzyl-2-methyl-6-phenylquinoline-3-carboxamide (11). White solid, 52% yield, m.p.
1
168.9–171.1 °C. H-NMR(DMSO-d6): 2.70 (3H, s), 4.53 (2H, d, J = 5.8 Hz), 7.26–7.30 (1H, m),
7.35–7.45 (5H, m), 7.54 (2H, t, J = 7.3 Hz), 7.82 (1H, d, J = 7.4 Hz), 8.03 (1H, d, J = 8.7 Hz), 8.11
(1H, dd, J1 = 8.7 Hz, J2 = 1.9 Hz), 8.33 (1H, d, J = 1.7 Hz), 8.43 (1H, s), 9.17 (1H, t, J = 5.9 Hz).
13C-NMR (DMSO-d6) δ: 23.4, 42.6, 125.4, 125.8, 126.9, 127.0, 127.3, 127.9, 128.4, 128.6, 129.1,
129.4, 130.9, 134.8, 137.8, 139.1, 139.2, 146.4, 155.9, 167.8. HR-MS m/z: 353.1658 (calcd for
C24H21N2O [M+H]+: 353.1648). IR (KBr) cm−1: 3241, 3066, 1629, 1598, 1573, 1023, 838, 755, 699.
N-Cyclopropyl-2-methyl-6-phenylquinoline-3-carboxamide (12). White solid, 22% yield, m.p.
1
186.7–187.1 °C. H-NMR(DMSO-d6) δ: 0.51–0.64 (2H, m), 0.69–0.75 (2H, m), 2.68 (3H, s),
2.87–2.93 (1H, m), 7.42 (1H, t, J = 7.4 Hz), 7.53 (2H, t, J = 9.1 Hz), 7.81 (2H, d, J = 7.4 Hz), 8.01 (1H,
d, J = 8.7 Hz), 8.10 (1H, dd, J1 = 8.8 Hz, J2 = 1.9 Hz), 8.28 (1H, d, J = 1.7 Hz), 8.33 (1H, s), 8.65 (1H, s).
13C-NMR (DMSO-d6) δ: 5.7, 22.8, 23.3, 125.3, 125.7, 127.0, 127.8, 128.6, 129.1, 129.4, 131.0, 134.7,
137.8, 139.2, 146.3, 155.9, 168.9. HR-MS m/z: 303.1564 (calcd for C20H19N2O [M+H]+: 303.1492). IR
(KBr) cm−1: 3290, 3034, 1643, 1594, 1579, 1529, 696.
N-(2-Phenylethyl)-2-methyl-6-(p-tolyl)quinoline-3-carboxamide (13). Yellow solid, 64% yield, m.p.
174.5–175.6 °C. 1H-NMR (DMSO-d6) δ: 2.37 (3H, s), 2.59 (3H, s), 2.89 (2H, t, J = 7.1 Hz), 3.55 (2H,
t, J = 6.5 Hz), 7.22–7.35 (7H, m), 7.72 (2H, d, J = 7.8 Hz), 7.99 (1H, d, J = 8.7 Hz), 8.07 (1H, d,
13
J = 8.7 Hz), 8.22 (1H, s), 8.26 (1H, s), 8.68 (1H, s). C-NMR (DMSO-d6) δ: 20.7, 23.2, 34.9, 40.5,
124.8, 125.8, 126.1, 126.8, 128.3, 128.5, 128.7, 129.2, 129.7, 131.2, 134.5, 136.3, 137.3, 137.7, 139.3,
146.2, 155.7, 167.4. HR-MS m/z: 381.1971 (calcd for C26H25N2O [M+H]+: 381.1961). IR (KBr) cm−1:
3237, 3063, 3028, 2936, 1631, 1599, 1574, 1491, 811, 748, 700.
N-(4-methoxyphenyl)-2-methyl-6-(p-tolyl) quinoline-3-carboxamide (14). Yellow solid, 84 % yield,
1
m.p. 221.0–221.8 °C. H-NMR (DMSO-d6) δ: 2.37 (3H, s), 2.74 (3H, s), 3.76 (3H, s), 6.96 (2H, d,
J = 8.9 Hz), 7.34 (2H, d, J = 8.0 Hz), 7.67–7.74 (4H, m), 8.04 (1H, d, J = 8.7 Hz), 8.12 (1H, dd,
J1 = 8.8 Hz, J2 = 1.7 Hz), 8.31 (1H, d, J = 1.3 Hz), 8.51 (1H, s), 10.49 (1H, s). 13C-NMR (DMSO-d6) δ:
20.7, 23.4, 55.2, 113.9, 121.2, 124.9, 125.8, 126.8, 128.5, 129.5, 129.7, 131.1, 132.2, 135.1, 136.2,
137.3, 137.8, 146.3, 155.6, 166.0. HR-MS m/z: 383.1842 (calcd for C25H23N2O2 [M+H]+: 383.1754).
IR (KBr) cm−1: 3247, 3029, 1648, 1595, 1525,1512, 1245, 813.

Molecules 2012, 17
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N-Benzyl-2-methyl-6-(p-tolyl)quinoline-3-carboxamide (15). Yellow solid, 31 % yield, m.p.
1
181.8–182.4 °C. H-NMR( DMSO-d6) δ: 2.31 (3H, s), 2.69 (3H, s), 4.53 (2H, d), 7.46–7.24 (7H, m),
7.73 (2H, d, J = 7.9 Hz ), 8.01 (1H, d, J = 8.7 Hz), 8.08 (1H, d, J = 9.1 Hz), 8.29 (1H, s), 8.41 (1H, s),
13
9.15 (1H, m). C-NMR (DMSO-d6) δ: 20.7, 23.4, 42.6, 124.9, 125.8, 126.8, 126.9, 127.3, 128.4,
128.5, 129.3, 129.7, 130.9, 134.8, 136.3, 137.3, 137.7, 139.2, 146.3, 155.7, 167.9. HR-MS m/z:
367.1892 (calcd for C25H23N2O [M+H]+: 367.1805). IR (KBr) cm−1: 3273, 2919, 1631, 1594, 1540, 808.
N-Cyclopropyl-2-methyl-6-(p-tolyl) quinoline-3-carboxamide (16). White solid, 43% yield, m.p.
1
220.0–220.9 °C. H-NMR (DMSO-d6) δ: 0.58 (2H, s), 0.73 (2H, s), 2.37 (3H, s), 2.67 (3H, s), 2.88
(1H, s), 7.34 (2H, d, J = 5.6 Hz), 7.71 (2H, d, J = 5.4 Hz), 8.01 (1H, s), 8.06 (1H, s), 8.24 (1H, s) 8.30
13
(1H, s), 8.62 (1H, s). C-NMR (DMSO-d6) δ: 20.7, 23.3, 23.5, 32.2, 40.0, 50.8, 124.8, 125.9, 126.8,
128.5, 129.1, 129.7, 131.4, 134.5, 136.3, 137.2, 137.6, 146.2, 155.7, 167.3. HR-MS m/z: 317.1633
(calcd for C21H21N2O [M+H]+: 317.1648). IR (KBr) cm−1: 3279, 2962, 2869, 1632, 1542, 806.
N-(tert-Butyl)-2-methyl-6-(p-tolyl)quinoline-3-carboxamide (17). White solid, 24% yield, m.p.
181.7–183.6 °C. 1H-NMR (CDCl3) δ: 1.47 (9H, s), 2.36 (3H, s), 2.78 (3H, s), 7.23 (2H, d, J = 8.0 Hz),
13
7.51 (2H, d, J = 8.1 Hz), 7.89 (2H, d, J = 9.4 Hz), 8.01 (1H, d, J = 9.3 Hz), 8.08 (1H, s). C-NMR
(DMSO-d6) δ: 20.7, 23.1, 28.5, 50.9, 124.8, 125.9, 126.7, 128.5, 128.9, 129.7, 132.3, 134.1, 136.3,
137.2, 137.5, 146.1, 155.5, 167.7. HR-MS m/z: 333.2041 (calcd for C22H25N2O [M+H]+: 333.1961). IR
(KBr) cm−1: 3252, 2967, 1647, 1600, 1548, 929, 813, 802.
6-(Benzyloxy)-7-methoxy-2-methyl-N-(benzyl)quinoline-3-carboxamide (23). White solid, 33% yield,
m.p. 214.6–215.3 °C. 1H-NMR (DMSO-d6) δ: 2.60 (3H, s), 3.91 (3H, s), 4.46 (2H, d, J = 5.7 Hz), 5.19
(2H, s), 7.25 (1H, s), 7.33–7.41 (8H, m), 7.46–7.49 (3H, m), 8.12 (1H, s), 9.00 (1H, d, J = 7.1 Hz).
13C-NMR (DMSO-d6) δ: 23.2, 42.5, 55.7, 69.9, 107.1, 107.2, 120.6, 126.8, 127.2, 128.0, 128.3, 128.5,
133.1, 136.5, 139.4, 144.3, 148.2, 153.0, 153.2, 168.2. HR-MS m/z: 413.1870 (calcd for C26H25N2O3
[M+H]+: 413.1860). IR (KBr) cm−1: 3283, 3029, 2964, 2935, 1634, 1540, 748, 703.
6-(Benzyloxy)-7-methoxy-2-methyl-N-(4-methylphenyl)quinoline-3-carboxamide (24). White solid,
44% yield, m.p. 202.1–202.8 °C. 1H-NMR (DMSO-d6) δ: 2.28 (3H, s), 2.93 (3H, s), 4.02 (3H, s), 5.28
13
(2H, s), 7.16–7.81 (11H, m), 8.93 (1H, s), 10.78 (1H, s). C-NMR (DMSO-d6) δ: 23.4, 55.2, 113.9,
121.2, 125.4, 125.7, 127.0, 127.9, 128.7, 129.1, 129.6, 131.1, 132.2, 135.1, 137.9, 139.2, 146.4, 155.6,
155.8, 166.0. HR-MS m/z: 413.1869 (calcd for C26H25N2O3 [M+H]+: 413.1860). IR (KBr) cm−1: 3261,
3033, 2927, 1648, 1522, 752.
6-Benzyloxy-7-methoxy-2-methyl-N-(2-(thiophen-2-yl)ethyl)quinoline-3-carboxamide (25). White solid,
27% yield, m.p. 178.8–179.5 °C. 1H-NMR (DMSO-d6) δ: 2.58 (3H, s), 3.09 (2H, t), 3.48–3.57 (2H, q),
3.93 (3H, s), 5.22 (2H, s), 6.93–7.01 (2H, m), 7.33–7.46 (6H, m), 7.48–7.55 (2H, m), 8.05 (1H, s),
13
8.63 (1H, s). C-NMR (DMSO-d6) δ: 23.1, 29.2, 40.7, 55.7, 69.9, 107.1, 107.2, 120.5, 124.1, 125.3,
126.9, 128.0, 128.1, 128.4, 128.5, 132.9, 136.5, 141.5, 144.2, 148.2, 152.9, 153.2, 168.2. HR-MS m/z:
433.1681 (calcd for C25H25O3N2S [M+H]+: 433.1580). IR (KBr) cm−1: 3311, 3081, 2966, 2924, 2863,
1636, 1536.

Molecules 2012, 17
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6-Benzyloxy-7-methoxy-2-methyl-N-(tert-butyl)quinoline-3-carboxamide (26). White solid, 35% yield,
1
m.p. 136.8–138.1 °C. H-NMR (DMSO-d6) δ: 1.39 (9H, s). 2.59 (3H, s), 3.93 (3H, s), 5.20 (2H, s),
13
7.33–7.52 (7H, m), 7.99 (1H, s), 8.06 (1H, s). C-NMR (DMSO-d6) δ: 22.8, 28.5, 50.8, 55.7, 69.7,
107.1, 120.6, 128.0, 128.5, 132.6, 136.5, 143.9, 148.0, 152.7, 152.9, 168.1. HR-MS m/z: 379.2025
(calcd for C23H27N2O3 [M+H]+: 379.2016). IR (KBr) cm−1: 3227, 3029, 2965, 1666, 1604, 1503, 748.
6-Benzyloxy-7-methoxy-2-methyl-N-(n-pentyl)quinoline-3-carboxamide (27). Yellow solid, 73% yield,
m.p. 168.0–168.5 °C. 1H-NMR (DMSO-d6) δ: 0.89 (3H, t, J = 6.6 Hz), 1.33–1.34 (4H, m), 1.51–1.56
(2H, m), 2.61 (3H, s), 3.24–3.33 (2H, m), 3.93 (3H, s), 5.21 (2H, s), 7.35–7.53 (7H, s), 8.05 (1H, s),
8.45 (1H, t, J = 5.3 Hz). 13C-NMR (DMSO-d6) δ: 13.9, 21.8, 23.0, 28.6, 28.7, 55.7, 69.9, 107.1, 107.2,
120.6, 128.0, 128.5, 128.8, 132.8, 136.5, 144.1, 148.1, 152.9, 153.1, 168.1. HR-MS m/z: 393.2183
(calcd for C24H29N2O3 [M+H]+: 393.2173). IR (KBr) cm−1: 3283, 2929, 2857, 1634, 1500.
3.3. CETP Inhibition Assay
CETP activity was determined by detecting the exchange of radioactive cholesteryl ester between
labelled HDL and unlabelled LDL [18]. Briefly, fresh rabbit serum containing CETP was incubated in
TSE buffer (50 mM Tris, 50 mM NaCl, 2 mM EDTA and 1% bovine serum albumin) containing
10 μmol/L test compounds dissolved in dimethyl sulfoxide [final concentration of both rabbit serum
and dimethyl sulfoxide in incubation mixture was 0.5% in 300 μL volume] for 4 h at 37 °C. Then
incubated for another 16 h at 37 °C with 0.5 μL [3H]cholesteryl ester-labeled HDL and 5 μL unlabelled
LDL in 600 μL volume. LDL was precipitated with dextran sulfate (final concentration: 0.027%) and
MgCl2 (final concentration: 27 mM) for 30 min. Centrifuged at 5,000 g and 4 °C for 30 min to get the
supernatant, and its radioactivity was measured in a liquid scintillation counter (Wallac 1410,
Pharmacia, Uppsala, Sweden). The CETP activity was determined by the decrease in radioactivity
versus that of a blank without serum.
4. Conclusions
In conclusion, a series of novel quinoline-3-carboxamide derivatives 10–17 and 23–27 were
synthesized and their CETP inhibitory activity evaluated. Generally, compounds substituted with
6-benzyloxy-7-methoxy groups possessed more potent CETP inhibitory activity. Compounds 24 and
26 exhibited promising inhibitory activity of CETP (80.1%) compared with the lead compound 1
(30%). As a novel CETP inhibitor scaffold, further structural modifications of the quinoline-3-carboxamide
moiety are progressing in our lab.
Acknowledgments
The authors thank Yi-Ping Wang of the Shanghai Insititute of Materia Medica, Chinses Academy of
Science for the activity assays.

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Sample Availability: Samples of the compounds 10–17, 23–27 are available from the authors.
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).