Synthesis and in vitro antitubercular activity of a series of quinoline derivatives

Article abstract of DOI:10.1016/j.bmc.2009.01.013

A series of 33 quinoline derivatives have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H₃₇Rv using the Alamar Blue susceptibility test and the activity expressed as the minimum inhibitory concentration (MIC) in μg/mL. Compounds 5e and 5f exhibited a significant activity at 6.25 and 3.12 μg/mL, respectively, when compared with first line drugs such as ethambutol and could be a good starting point to develop new lead compounds in the fight against multi-drug resistant tuberculosis.

Full text of DOI:10.1016/j.bmc.2009.01.013

Bioorganic & Medicinal Chemistry 17 (2009) 1474–1480
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and in vitro antitubercular activity of a series of quinoline derivatives
Marcus V. N. de Souza a, , Karla C. Pais a,b, Carlos R. Kaiser b, Mônica A. Peralta a,
*
Marcelle de L. Ferreira a,b, Maria C. S. Lourenço c
a FioCruz-Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos-Far Manguinhos, Rua Sizenando Nabuco, 100, Manguinhos, 21041-250 Rio de Janeiro, RJ, Brazil
b Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio de Janeiro, CP 68563, 21945-970 Rio de Janeiro, Brazil
c Instituto de Pesquisas Clínica Evandro Chagas, IPEC, Av. Brasil, 4365, Manguinhos, Rio de Janeiro, RJ, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 33 quinoline derivatives have been synthesized and evaluated for their in vitro antibacterial
Received 9 December 2008
Revised 8 January 2009
Accepted 9 January 2009
Available online 15 January 2009
activity against Mycobacterium tuberculosis H37Rv using the Alamar Blue susceptibility test and the activ-
ity expressed as the minimum inhibitory concentration (MIC) in
lg/mL. Compounds 5e and 5f exhibited a
significant activity at 6.25 and 3.12 g/mL, respectively, when compared with first line drugs such as eth-
l
ambutol and could be a good starting point to develop new lead compounds in the fight against multi-
drug resistant tuberculosis.
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Quinoline
Drugs
MDR-TB
Antitubercular activity
1. Introduction
the current first line drugs. Another serious problem, in the context
of MDR-TB, is the XDR-TB, abbreviation for extensively drug-resis-
The quinoline nucleus is an important class of heterocyclic com-
pounds found in many synthetic and natural products with a wide
range of pharmacological activities, such as antiviral1, anticancer2,
antibacterial3, antifungal4, antiobesity,5 and anti-inflammatory6,
which can be well illustrated by the large number of drugs in the
market containing this heterocyclic class. However, in spite of its
wide range of pharmacological activities, few studies have been
described against tuberculosis in comparison with others classes.
Nowadays, tuberculosis (TB), a contagious disease transmitted
through the air, and caused by the bacterium Mycobacterium tuber-
culosis, is an important world-wide public health problem, which
was declared a global health emergency in 1993 by the World
Health Organization (WHO). According to statistics, one-third of
the world’s population is currently infected with the TB bacillus,
each year, 8 million people world-wide develop active TB and
about 1.7 million people die.7 Currently, an important problem in
TB treatment is the development of multi-drug resistant tuberculo-
sis (MDR-TB), which can be defined as strains that are resistance to
at least isoniazid and rifampicin, important first line drugs used in
TB treatment. The spread of MDR-TB could cost between 100 and
1400 times the available treatment costs and further threatens to
make TB incurable. Exact data are hard to estimate, but at least
4% of all world-wide TB patients are resistant to at least one of
tant tuberculosis (TB), which are strains resistant to first and sec-
ond line anti-TB drugs. XDR-TB is commonly defined as strains
resistant to all the current first line drugs, as well as any fluoro-
quinolone and at least 1 of 3 injectable second line drugs (capreo-
mycin, kanamycin, or amikacin).8,9 A study made by CDC (US
Centers for Disease Control and Prevention) and WHO (World
Health Organization) in 17.690 isolates from 49 countries during
2000–2004 have demonstrated that 20% of the strains were
MDR-TB and 2% XDR-TB.10 Due to the high impact of MDR and re-
cently XDR in TB treatment, we urgently need new drugs and strat-
egies to treat this disease efficiently. In this context, the aim of this
article is to describe the synthesis and biological activity of a series
of quinoline derivatives.
The start point for the preparation of the quinoline derivatives
to be evaluated against TB were malaria drugs, such as quinine,
chloroquine, mefloquine, primaquine, and amodiaquine (Fig. 1),
which possessed moderate biological activity against TB, also being
evaluate by us using the Microplate Alamar Blue Assay (MABA).
Another reason for the searching of new leading compounds
based on quinoline derivatives is the diarylquinoline TMC207 (ex
R207910) (Fig. 2), which was developed at Johnson & Johnson
Pharmaceutical Research & Development. This compound pos-
sesses a new mechanism of action based on the interaction with
the enzyme adenosine triphosphate (ATP) synthase, which is the
energy source for the bacterium. Currently this drug is in phase 2
clinical trials and is very promising against MDR-TB.11
* Corresponding author.
E-mail address: marcos_souza@far.fiocruz.br (M.V.N. de Souza).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.01.013

M. V. N. de Souza et al. / Bioorg. Med. Chem. 17 (2009) 1474–1480
1475
H
some derivatives the chorine atom was replaced by hydrogen atom
at C(7) position, with the aim of establishing the importance of this
substituent for the biological activity of this compounds (Fig. 4).
H
N
HO
H3CO
2. Results and discussion
2.1. Chemistry
N
Quinine
a
MIC = 100 µg/ mL
The synthetic routes for the preparation of 7-chloroquinoline
C(4)-functionalized derivatives (1 to 6a–j) are summarized in
Scheme 1. From 4,7-dichloroquinoline, the derivatives (1), (5a–f),
and (6a–j) were obtained by chorine substitution at C(4) position
for appropriate amines, diamines, or aminoalcohols in good yields
(51–96%). Afterwards, the terminal hydroxyl of derivative (1) was
replaced by a cyano or chorine substituent, leading to the com-
pounds (2) and (4) in 94% and 35% (2 steps) yields, respectively. Be-
sides that, the compounds (3a–f) were prepared from derivative
(2) by chorine substitution in the aliphatic portion for an azide
group or other amines or aminoalcohols in 46–95% yields.
All these compounds were identified by spectral data. In gen-
eral, the 1H NMR spectrum showed the five quinoline protons at
8.20–6.44 ppm and the aliphatic protons at 3.90–1.02 ppm. The
13C NMR spectrum showed the nine quinoline carbons signals at
the region of 153.3–90.5 ppm and the aliphatic carbons signals at
64.5–11.0 ppm.
Moreover, the derivatives (7a–c) were prepared from com-
pounds (1), (2), (6b), and (6f) by catalytic hydrogenation that pro-
motes the C–Cl bond cleavage leading to the desired substances
(7a–d) in 81–98% yields (Scheme 2). These derivatives also were
identified by spectral data. In general, when we compare the 1H
NMR spectrums of derivatives (7a–c) with their corresponding pre-
cursors, there is a different proton signal at 7.93–7.98 ppm as a
double doublet that confirms the chloro substitution for a hydro-
gen atom.
CH3
CH3
HO
N
N
CH3
H
HN
N
CF3
Cl
CF3
a
N
Chloroquine
Resistent
Mefloquine
CH3
MIC = 25 µg/ mL
N
CH3
OH
OCH3
HN
N
HN
NH2
Cl
N
CH3
Primaquine
Amodiaquine
a
a
MIC = 100 µg/ mL
MIC = 50 µg/ mL
Figure 1. Malaria drugs. aMIC (minimal inhibition concentration) was defined as
the lowest drug concentration, which prevented a color change from blue to pink.
Ph
OH
N(CH3)2
Br
Furthermore, two chloro derivatives (8a and 8b) were synthe-
sized from the hydroxyl derivatives 6g and 6j (Scheme 3), with
the aim of establishing the importance of these groups (OH and
Cl) for the biological activity of quinoline derivatives. These deriv-
atives also were identified by spectral data. In general, when we
compare the 13C NMR spectrums of derivatives (8a–b) with their
corresponding precursors, we observe that the HO-CH2 signal
moved from 60.9–64.3 to 43.4–47.0 ppm for the Cl-CH2 signal that
confirms this molecular modification.
OCH3
N
Figure 2. Diarylquinoline TMC207.
The design concept of quinoline derivatives attempts to intro-
duce the ethambutol pharmacophore, a first line TB drug, into
the core structure of the starting material 4,7-dichloroquinoline,
in the expectation to improve its activity, possible by the incorpo-
ration of a different mode of action through a different target
(Fig. 3).
2.2. Antimycobacterial activity
The antimycobacterial activities of all synthesized compounds
were assessed against M. tuberculosis ATTC 27294 using the Micro-
plate Alamar Blue Assay (MABA)12,13 (Tables 1–4). This methodol-
ogy is nontoxic, uses a thermally stable reagent and shows
good correlation with proportional and BACTEC radiometric
methods.14,15
Based on this design concept, we proposed the synthesis of 7-
chloroquinoline C(4)-functionalized derivatives. Furthermore, in
Cl
HO
Firstly, for the 7-chloro-4-amino-quinolines (1–4) series, we
can observe that the most active derivative was (2)
(MIC = 12.5 lg/mL), which has a chorine atom in a terminal posi-
tion. The antimycobacterial activity decreases when this atom is
replaced by other groups, such as azide (N3) or other amines that
indicates the relevance of chorine atom for the biological activity
in this series of compounds (Table 1).
For the 7-chloro-4-diamino-quinolines derivatives (5a–f), the
addition of carbon atoms in the alkyl chain leads to improved bio-
logical activity, which can be demonstrated by MIC variation that
H
N
CH3
N
H3C
H
Cl
N
OH
Ethambutol
Molecular
Hybridization
4,7-Dichloroquinoline
R
HN
n
n = 1, 2, 3, 4, etc.
R = H, NH2, OH, Halogen, N3, etc.
changes from 25
to 3.12 g/mL (5f, n = 10). Furthermore, it is important to remark
that clogP values could be contributing to increase the antituber-
lg/mL (5d, n = 6) to 6.25 lg/mL (5e, n = 8) and
Cl
N
l
Figure 3. Design concept of quinoline derivatives.

1476
M. V. N. de Souza et al. / Bioorg. Med. Chem. 17 (2009) 1474–1480
R
R
Cl
HN
HN
R´
N
R´
Cl
N
Cl
N
N
Cl
N
4,7-dichloroquinoline
(7a-b)
(1), (2), (3a-f), (4)
(6a-j)
(7c-d)
R'= N3 , NH2 , amines or aminoalcohols
R= Cl, N3 , CN or amines
HN
NH
2
n
Cl
N
(5a-f)
n= 2, 3, 4, 6, 8 and 10
Figure 4. Retrosynthetic analysis of quinoline derivatives.
CN
HN
d, e
Cl
N
(4)
OH
R
Cl
c
HN
HN
HN
a
b
Cl
Cl
N
Cl
N
Cl
N
(1)
(2)
(3a-h)
a: R= N3
e: R=NH i-Pr
f: R= NHBu
b: R= NH(CH2)2OH
c: R= NHMe
HN
NH2
n
g: R=NHcyclohexyl
h: R= NHBn
Cl
N
d: R= NHPr
4,7-dichloroquinoline
f
a: n = 2 d: n = 6
b: n = 3 e: n = 8
c: n = 4 f: n = 10
Cl
N
(5a-f)
R´
g
f: R´= NHBu
g: R´= NHPrOH
a: R´= N3
b: R´= NH2
c: R´= NHMe
d: R´= NHPr
e: R´= NH i-Pr
h: R´= (R)-NHCH(CH2CH3)CH2OH
i: R´= (S)-NHCH(CH2CH3)CH2OH
j: R´= (R,S)-NHCH(CH2CH3)CH2OH
Cl
N
(6a-j)
Scheme 1. Reagents and conditions: (a) 1-ethanolamine, Et3N, 120 °C, 2 h, 94%; (b) SOCl2, DMF, 24 h, 94%; (c) Compound 3a: NaN3; DMF; 4 h; 46%; Compounds 3b–f:
corresponding amine, Et3N; 1–24 h, 80–120 °C, 72–95%; (d) TsCl, Py, 50 °C, 4 h; (e) KCN, DMF, 100 °C, 1 h, 35% in two steps; (f) corresponding diamine, 80–135 °C, 4 h, 51–
94%; (g) Compound 6a: NaN3, DMF, 100 °C, 3 h, 70%; Compound 6b: phenol, NH3(g), 170 °C, 2 h, 82%; Compounds 6c–j: corresponding amine or aminoalcohol, Et3N, 60–
120 °C, 2–24 h, 66–96%.
NHR
NHR
NHROH
NHRCl
a
a
Cl
N
N
(7a): R= CH2CH2OH
(7b): R= CH2CH2 Cl
(7c): R= H
Cl
N
Cl
N
(1): R= CH2CH2OH
(2): R= CH2CH2Cl
(6b): R= H
(8a): R= Pr
(8b): R= (R,S)CH(Et)CH2
(6g): R= Pr
(6j): R= (R,S)CH(Et)CH2
(7c): R= Bu
(6f): R= Bu
Scheme 3. Reagents and conditions: SOCl2, DMF, rt, 2–24 h, 91–95%.
Scheme 2. Reagents and conditions: H2 Pd–C, EtOH, rt, 1–3 h, 81–98%.
cular activity, because of that, the most active derivative (5f) shows
the highest clogP value (5.55), indicating that lipophilicity is an
important parameter to the biological activity in this series
(Table 2).

M. V. N. de Souza et al. / Bioorg. Med. Chem. 17 (2009) 1474–1480
1477
Table 1
Table 4
The in vitro activity of compounds (1–4) against M. tuberculosis H37Rv strain (ATCC
27294, susceptible both to rifampin and isoniazid) and clogP measurements
The in vitro activity of compounds (8a–b) against M. tuberculosis H37Rv strain (ATCC
27294, susceptible both to rifampin and isoniazid) and clogP measurements
R
NHRCl
HN
N
Cl
Cl
N
Compound
R
MIC (lg/mL)
clogPa
Compound
R
MIC (
l
g/mL)
clogPa
8a
8b
Pr
50.0
50.0
3.62
4.06
(R,S)CH(Et)CH2
1
2
OH
Cl
N3
>100.0b
12.5
50.0
>100.0
>100.0
100.0
>100.0
>100.0
100.0
50.0
1.95
3.18
2.70
1.54
2.07
3.14
2.95
3.67
4.13
4.08
2.06
a
Calculated on ACD/ChemSketch v.11.0 (Freeware).
3a
3b
3c
3d
3e
3f
3g
3h
4
NHCH2CH2OH
NHMe
NHPr
NHi-Pr
NHBu
NHCyclohexyl
NHBn
CN
Table 5
The in vitro activity of compounds (7a–c) against M. tuberculosis H37Rv strain (ATCC
27294, susceptible both to rifampin and isoniazid) and clogP measurements
NHR
>100.0
a
Calculated on ACD/ChemSketch v.11.0 (Freeware).
MIC > 100.0 lg/mL indicates that the strain is resistant to tested substance.
b
N
Table 2
(7a-d)
The in vitro activity of compounds (5a–f) against M. tuberculosis H37Rv strain (ATCC
27294, susceptible both to rifampin and isoniazid) and clogP measurements
Compound
R
MIC (lg/mL)
clogPa
7a
7b
7c
7d
CH2CH2OH
CH2CH2Cl
H
Bu
>100.0b
>100.0
>100.0
50.0
1.67
2.90
2.08
4.04
HN
NH2
n
a
Calculated on ACD/ChemSketch v.11.0 (Freeware).
MIC > 100.0 lg/mL indicates that the strain is resistant to tested substance.
b
N
Cl
Compound
n
MIC (lg/mL)
clogPa
5a
5b
5c
5d
5e
5f
2
3
4
6
8
10
>100.0b
>100.0
>100.0
25.0
6.25
3.12
1.84
2.17
2.56
3.43
4.49
5.55
biological activity of quinoline derivatives (6c–f) increases (>100 to
12.5 g/mL) due to the enlargement of the alkyl chain. It is also
important to be mentioned that the presence of a hydroxyl group
in the structure of compounds (6g–j) could be responsible for the
decrease of biological activity (Table 3). This hypothesis could be
l
confirmed when the compounds (6g) and (6j) (100 lg/mL) were
converted into their respective derivatives (8a) and (8b) (50 lg/
a
Calculated on ACD/ChemSketch v.11.0 (Freeware).
MIC > 100.0 lg/mL indicates that the strain is resistant to tested substance.
b
mL) (Table 4).
Another important information about the structure–activity
relationship of the 4-chloroquinoline derivatives is that the chorine
atom at position C-7 in the quinoline nucleus is essential for the
anti-TB activity. This fact can be demonstrated by the substitution
of the chloro atom by hydrogen in the compounds (1) (MIC >
Table 3
The in vitro activity of compounds (6a–j) against M. tuberculosis H37Rv strain (ATCC
27294, susceptible both to rifampin and isoniazid) and clogP measurements
R'
100.0
lg/mL), (2) (MIC > 100.0
lg/mL), (6a) (MIC > 100.0 lg/mL),
and (6f) (MIC = 12.5
lg/mL), which was responsible for decrease
of the antitubercular activity of compounds (7d) (MIC = 50.0 lg/
mL) (Table 5).
N
Cl
Compound
R0
MIC (
l
g/mL)
clogPa
3. Experimental
6a
6b
6c
6d
6e
6f
6g
6h
6i
N3
NH2
>100.0b
>100.0
100.0
50.0
50.0
12.5
>100.0
>100.0
>100.0
>100.0
3.21
2.38
2.72
3.78
3.60
4.31
1.70
2.82
2.82
2.82
3.1. General procedures
NHMe
NHPr
NHi-Pr
NHBu
NHPrOH
NH(R)CH(Et)CH2OH
NH(S)CH(Et)CH2OH
NH(R,S)CH(Et)CH2OH
Melting points were determined on a Buchi apparatus and are
uncorrected. Infrared spectra were recorded on a Thermo Nicolet
Nexus 670 spectrometer as potassium bromide pellets and fre-
quencies are expressed in cmꢀ1. Mass spectra (CG/MS) were
recorded on a Agilent Technologies 6890/5972A mass spectrome-
ter. NMR spectra were recorded on a Bruker Avance 500 spectrom-
eter operating at 500 MHz (1H) and 125 MHz (13C) or 400 MHz (1H)
and 100 MHz (13C), in deuterated methanol or dimethylsulfoxide.
Chemical shifts are reported in ppm (d) relative to tetramethylsil-
ane. Proton and carbon spectra were typically obtained at room
6j
a
Calculated on ACD/ChemSketch v.11.0 (Freeware).
MIC > 100.0 lg/mL indicates that the strain is resistant to tested substance.
b
In the series of compounds (6a–j), the size of the alkyl chain is
also a critical factor for increased anti-TB activity. For example, the

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M. V. N. de Souza et al. / Bioorg. Med. Chem. 17 (2009) 1474–1480
temperature. For TLC, plates coated with silica gel were run in ethyl
acetate and spots were developed in Ultraviolet.
3.1.3.2.5. N-Butyl-N0-(7-chloroquinolin-4-yl)ethane-1,2-diamine
(3f). Yield: 93%, mp: 187–190 °C.
NMR-1H (500 MHz, MeOD) d: 8.41 (1H; d; J = 5.5 Hz; H2); 8.18
(1H; d; J = 9.0 Hz; H5); 7.78 (1H; d; J = 1.5 Hz; H8); 7.44 (1H; dd;
J = 9.0 and 1.5 Hz; H6); 6.64 (1H; d; J = 5.5 Hz; H3); 3.69 (2H; t;
3.1.1. Synthesis of 2-[(7-chloroquinolin-4-yl)amino]ethanol (1)
A mixture of 4,7-dichloroquinoline (2.0 g, 10.1 mmol), ethanol-
amine (12.1 mL, 20.2 mmol), and Et3N (21.0 mL, 15 mmol) was
stirred under nitrogen at 120 °C for 2 h. After cooling to room tem-
perature, ice was added and the resulting mixture stored in the
refrigerator for 1 h. The precipitate was filtered and the residue
washed with cold water (2 ꢁ 5 mL) and then with cold ethyl ether
(2 ꢁ 5 mL). Yield: 94%, mp: 220–222 °C (213–215 °C).16
0
0
0
0
J = 6.5 Hz; H1 or H2 ); 3.23 (2H; t; J = 6.5 Hz; H1 or H2 ); 2.95–
00
00
2.90 (2H; m; H1 ); 1.68–1.62 (2H; m; H2 ); 1.45–1.39 (2H; m;
H3 ); 0.97 (3H; q; J = 7.5 Hz; H4 ) ppm; NMR-13C (125 MHz, MeOD)
152.7; 152.3; 149.3; 136.8; 127.4; 126.5; 124.8; 118.9; 100.0;
00
0
d:
47.6; 41.5; 40.6; 30.6; 21.2; 14.20 ppm.
IR mmax (cmꢀ1; KBr pellets): 3257 (N–H); 1579 (C@C).
MS/ESI: m/z [MꢀH]+: 278.2.
3.1.2. Synthesis of 7-chloro-N-(2-chloroethyl)quinolin-4-amine
(2)
3.1.3.2.6. N-(7-Chloroquinolin-4-yl)-N0-cyclohexylethane-1.2-dia-
mine (3g). Yield: 82%, mp: 151–152 °C (151 °C).20
3.1.3.2.7. N-Benzyl-N0-(7-chloroquinolin-4-yl)ethane-1.2-diamine
(3h). Yield: 75%, mp: 141–143 °C.
A mixture of (1) (0.5 g, 2.2 mmol), thionyl chloride (33 mL,
45 mmol), and DMF (0.3 mL, 0.22 mmol) was stirred under nitro-
gen at room temperature for 24 h. After that, the resulting mixture
was neutralized with a saturated aqueous solution of sodium
bicarbonate and extracted with ethyl acetate. The combined organ-
ic phases were dried over anhydrous sodium sulfate and concen-
trated under reduced pressure to lead the compound (2) without
further purification. Yield: 94%, mp: 153–154 °C (155 °C).17
NMR-1H (500 MHz, MeOD) d: 8.32 (1H; d; J = 6.0 Hz; H2); 8.06
(1H; d; J = 9.0 Hz; H5); 7.76 (1H; d; J = 2.0 Hz; H8); 7.38 (1H; dd;
00
00
J = 9.0 and 2.0 Hz; H6); 7.32–7.35 (5H; m; H1 –H5 ); 6.50 (1H; d;
0
0
0
J = 6.0Hz; H3); 3.81 (2H; s; H3 ); 3.49 (2H; t; J = 7.5Hz; H1 or H2 );
2.93 (2H; t; J = 7.5 Hz; H1 or H2 ) ppm; NMR-13C (125 MHz, MeOD)
152.8; 152.5; 149.7; 140.6; 136.5; 129.7; 128.4; 127.7; 126.2;
0
0
d:
124.4; 118.9; 99.9; 54.4; 47.8; 43.4 ppm.
IR mmax (cmꢀ1; KBr pellets): 3217 (N–H); 1579 (C@C).
MS/ESI: m/z [MꢀH]+: 312.3.
3.1.3. General procedures for preparing 7-chloroquinolineami-
nes derivatives (3a–h)
3.1.3.1. N-(2-Azidoethyl)-7-chloroquinolin-4-amine (3a).
A
mixture of (2) (0.5 g, 2.2 mmol), sodium azide (8.5 g, 13.2 mmol),
and DMF (2 mL) was stirred under nitrogen at 100 °C for 4 h. After
that, sodium azide was filtered and DMF was removed under re-
duced pressure. Then, the crude product was extracted with water
(15 mL) and chloroform (3 ꢁ 20 mL) and the combined organic
phases were dried over anhydrous sodium sulfate and concen-
trated under reduced pressure. The residue was purified by chro-
matography column (hexane/ethyl acetate 7:3), to lead the
desired product (3a). Yield: 70%, mp: 145–147 °C.
3.1.4. Synthesis of 3-[(7-chloroquinolin-4-yl)amino]
propanenitrile (4)
A mixture of (1) (0.5 g, 2.2 mmol), 4-toluenesulfonyl chloride
(6.3 g, 3.3 mmol), and pyridine 10 mL was stirred under nitrogen
at 50 °C for 4 h to obtain 2-[(7-chloroquinolin-4-yl)amino]ethyl-
4-methylbenzenesulfonate. The resulting mixture was extracted
with chloroform and the combined organic phases were dried over
anhydrous sodium sulfate and concentrated under reduced pres-
sure. Then, a mixture of the compound prepared previously
(4.0 g, 1.0 mmol) and potassium cyanide (4.3 g, 6 mmol) in 4 mL
N,N-dimethylformamide, was stirred under nitrogen at 100 °C for
1 h. The resulting mixture was extracted with chloroform
(2 ꢁ 50 mL) and the combined organic phases were dried over
anhydrous sodium sulfate and concentrated under reduced pres-
sure. The residue was purified by chromatography column (chloro-
form), to lead to the desired product (4). Yield: 35% (two steps),
mp: 178–180 °C (174–175 °C).21
NMR-1H (500 MHz, Acetone) d: 8.49 (1H; d; J = 5.0 Hz; H2); 8.17
(1H; d; J = 9.0 Hz; H5); 7.85 (1H; d; J = 2.0 Hz; H8); 7.40 (1H; dd;
J = 2.5 and 9.0 Hz; H6); 6.89 (1H; s; NH); 6.64 (1H; d; J = 5.5 Hz;
H3); 3.71 (2H; t; J = 5.5 Hz; H1 or H2); 3.67 (2H; t; J = 5.5 Hz; H1
or H2) ppm; NMR-13C (125 MHz, Acetone) d: 153.0; 150.4; 150.6;
134.9; 129.2; 125.4; 123.9; 118.6; 99.9; 50.2; 43.1 ppm.
IR m
max (cmꢀ1; KBr pellets): 3225 (N–H); 2131 (N3); 1578 (C@C).
MS/ESI: m/z [MꢀH]+: 246.1.
3.1.3.2. Compounds (3b–h). The conditions employed for the
preparation these compounds were those described above in the
procedure of Section 3.1.1. However, 44.0 mmol of appropriated
amine and 2.2 mmol (0.5 g) of (2) were used as starting materials.
3.1.3.2.1. 2-({2-[(7-Chloroquinolin-4-yl)amino]ethyl}amino]etha-
nol (3b). Yield: 80%, mp: 235–236 °C (239–241 °C).18
3.1.5. General procedures for the synthesis of 7-chloroquino-
line diamines derivatives (5a–f)
A mixture of 4,7-dichloroquinoline (2.0 g, 10.1 mmol) and the
appropriate diaminoalkane (20.2 mmol) was slowly heated to
80 °C and maintained at that temperature for 1 h without stirring
and subsequently at 135 °C for 3 h with stirring to drive the reac-
tion to completion. Ice was added to the reaction mixture and it
was stored in the refrigerator for 1 h. The precipitate was filtered,
washed with cold water (10 mL) and ethyl ether (2 ꢁ 10 mL),
obtaining the pure derivatives (5a–c). The compounds (5d–f) were
purified by chromatography column (chloroform/methanol 10%
with 1% Et3N).
3.1.3.2.2. N-(7-Chloroquinolin-4-yl)-N0-methylethane-1.2-diamine
(3c). Yield: 95%, mp: 110–111 °C (110–111.5 °C).19
3.1.3.2.3. N-(7-Chloroquinolin-4-yl)-N0-propylethane-1.2-diamine
(3d). Yield: 91%, mp: 91–93 °C.
NMR-1H (400 MHz, MeOD) d: 8.40 (1H; d; J = 5.5 Hz; H2); 8.17
(1H; d; J = 9.0 Hz; H5); 7.79 (1H; d; J = 5.5 Hz; H8); 7.44 (1H; dd;
J = 5.5 and 9.0 Hz; H6); 6.64 (1H; d; J = 5.5 Hz; H3); 3.68 (2H; t;
0
0
0
0
J = 6.5 Hz; H1 or H2 ); 3.20 (2H; t; J = 6.5 Hz; H1 or H2 ); 2.90–
3.1.5.1. N-(7-Chloroquinolin-4-yl)ethane-1,2-diamine (5a). Yield:
94%, mp: 137–139 °C (145–147 °C).22
00
00
2.86 (2H; m; H1 ); 1.73–1.64 (2H; m; H2 ); 1.00 (3H; t; J = 8.0 Hz;
00
H3 ) ppm; NMR-13C (100 MHz, MeOD) d: 152.8; 152.3; 149.3;
136.9; 127.5 126.6; 124.8; 119.0; 100.1; 51.7; 47.8; 41.7; 22.2;
11.7 ppm.
3.1.5.2. N-(7-Chloroquinolin-4-yl)propane-1,3-diamine (5b). Yield:
90%, mp: 96–98 °C (96–98 °C).23
IR mmax (cmꢀ1; KBr pellets): 3293 (N–H); 1582 (C@C).
MS/ESI: m/z [MꢀH]+: 262.4.
3.1.3.2.4. N-(7-Chloroquinolin-4-yl)-N0-isopropylethane-1,2-diamine
(3e). Yield: 90%, mp: 129–130 °C (129–130 °C).20
3.1.5.3. N-(7-Chloroquinolin-4-yl)butane-1,4-diamine (5c). Yield:
75%, mp: 122–124 °C (122–124 °C).23

M. V. N. de Souza et al. / Bioorg. Med. Chem. 17 (2009) 1474–1480
1479
3.1.5.4. N-(7-Chloroquinolin-4-yl)hexane-1,6-diamine (5d). Yield:
3.1.6.3.7. (2S)-2-[(7-Chloroquinolin-4-yl)amino]butan-1-ol
55%, mp: 133–134 °C (133–134 °C).24
(6i). Yield: 80%, mp: 196–198 °C.
NMR-1H (400 MHz, MeOD) d: 8.33 (1H; d; J = 5.5 Hz; H2); 8.17
(1H; d; J = 9.2 Hz; H5); 7.77 (1H; d; J = 2.0 Hz; H8); 7.38 (1H; dd;
3.1.5.5. N-(7-Chloroquinolin-4-yl)octane-1,8-diamine (5e). Yield:
51%, mp: 131–133 °C.
0
J = 2.0 and 9.0 Hz; H6); 6.59 (1H; d; J = 5.5 Hz; H3); 3.71 (3H; m; H1
NMR-1H (500 MHz, MeOD) d: 8.33 (1H; d; J = 5.5 Hz; H2); 8.09
(1H; d; J = 9.0 Hz; H8); 7.76 (1H; d; J = 2.0 Hz; H5); 7.37 (1H; dd;
J = 2.0 and 9.0 Hz; H6); 6.48 (1H; d; J = 6.0 Hz; H3); 3.31 (2H; t;
0
0
0
and H2 ); 1.81–1.88 (1H; m; H3 ); 1.66–1.73 (1H; m; H3 ); 1.02 (3H;
t; J = 7.5 Hz; H4 ) ppm; NMR-13C (100 MHz, MeOD) d: 153.9; 152.4;
0
149.9; 136.4; 127.6; 126.0; 124.4; 118.9; 100.1; 64.3; 57.5; 25.2;
11.0 ppm.
0
0
0
0
H1 or H8 ); 2.65 (2H; t; J = 7.0 Hz; H1 or H8 ); 1.73 (2H; m;
IRm
max (cmꢀ1; KBr pellets): 3260 (N–H); 1579 (C@C); 1066 (C–O).
0
0
0
0
0
J = 7.0 Hz; H2 ); 1.46 (10H; m; J = 7.0 Hz; H3 ; H4 ; H5 ; H6 ; and
0
H7 ); NMR-13C (125 MHz, MeOD) d: 152.9; 152.5; 149.8; 136.4;
MS/ESI: m/z [MꢀH]+: 249.3
127.7; 126.0; 124.4; 118.9; 99.7; 44.1; 42.3; 33.0; 30.6; 30.6;
29.5; 28.3; 28.0 ppm.
3.1.6.3.8. 2-[(7-Chloroquinolin-4-yl)amino]butan-1-ol (6j). Yield:
84%, mp: 196–198 °C.
IR mmax (cmꢀ1; KBr pellets): 3323 (N–H); 1581 (C@C).
MS/ESI: m/z [MꢀH]+: 306.4.
NMR-1H(400 MHz,MeOD)d:8.33(1H;d;J = 5.6 Hz;H2);8.18(1H;
d; J = 8.8 Hz; H5); 7.77 (1H; d; J = 2.0 Hz; H8); 7.38 (1H; dd; J = 2.0 and
0
0
8.8 Hz; H6); 6.59 (1H; d; J = 5.6 Hz; H3); 3.71 (3H; m; H1 and H2 );
3.1.5.6. N-(7-Chloroquinolin-4-yl)decane-1,10-diamine (5f). Yield:
60%, mp: 90–92 °C.
0
0
1.82–1.88 (1H; m; H3 ); 1.66–1.73 (1H; m; H3 ); 1.02 (3H; t;
J = 7.2 Hz; H4 ) ppm; NMR-13C (100 MHz, MeOD) d: 153.0; 152.4;
0
NMR-1H (500 MHz, MeOD) d: 8.32 (1H; d; J = 5.7 Hz; H2); 8.12
(1H; d; J = 9.0 Hz; H8); 7.76 (1H; d; J = 2.1 Hz; H5); 7.39 (1H; dd;
J = 2.1 and 9.0 Hz; H6); 6.49 (1H; d; J = 5.7 Hz; H3); 3.35 (2H; t;
149.9; 136.5; 127.6; 126.1; 124.5; 118.9; 100.1; 64.3; 57.6; 25.2;
11.1 ppm.
IR m
max (cmꢀ1; KBr pellets): 3280 (N–H); 1582 (C@C); 1070 (C–O).
0
0
0
0
J = 7.3 Hz; H1 or H10 ); 2.87 (2H; t; J = 7.6 Hz; H1 or H10 ); 1.73 (2H;
MS/ESI: m/z [MꢀH]+: 249.3.
0
0
0
m; J = 7.2 Hz; H2 ); 1.61 (2H; m; J = 7.0 Hz; H9 ); 1.43 (2H; m; H3 );
1.33 (10H; m; H4 ; H5 ; H6 ; H7 ; and H8 ); NMR-13C (125 MHz, MeOD)
153.1; 152.1; 149.4; 136.5; 127.4; 126.1; 124.5; 118.8; 99.7; 44.1;
0
0
0
0
0
3.1.7. General procedures for the synthesis of quinolineamines
derivatives (7a–d)
d:
41.0; 30.7; 30.5; 30.5; 30.3; 29.4; 29.0; 28.3; 27.6 ppm.
IR mmax (cmꢀ1; KBr pellets): 3363 (N–H); 1581 (C@C).
MS/ESI: m/z [MꢀH]+: 334.6.
To a solution of (1), (2), (6b), and (6f) (1.5 mmol) in EtOH
(10 mL) catalytic amounts of 10% Pd–C (10 wt% of the substrate,
0.02 mmol) were added, and the mixture was treated with H2 for
3 h. The catalyst was filtered off and washed with EtOH
(2 ꢁ 20 mL), and the filtrate was concentrated to lead the pure
products (7a–d).
3.1.6. General procedures for preparing 7-chloroquinolineamines
derivatives (6a–j)
3.1.6.1. 4-Azido-7-chloroquinoline (6a). The conditions em-
ployed for the preparation of this compound were those described
above in general procedure of Section 3.1.3.1. Yield: 82%, mp: 110–
112 °C (118 °C).25
3.1.7.1. 2-(Quinolin-4-ylamino)ethanol (7a). Yield: 98%, mp:
158–160 °C (153–154 °C).28
3.1.7.2. N-(2-Chloroethyl)quinolin-4-amine (7b). Yield: 88%,
mp: 85–87 °C.
3.1.6.2. 7-Chloro-4-aminoquinoline (6b)17
148 °C (147–148 °C).
. Yield: 92%, mp: 147–
NMR-1H(500 MHz, MeOD) d: 8.44 (2H;d;J = 7.5;H2 andH8);7.98
(1H;ddd;J = 8.5, 7.5, and1.0 Hz;H7); 7.94(1H;d; J = 8.5; 1.0 Hz;H5);
7.74 (1H; ddd; J = 8.5, 7.5, and 1.0 Hz; H6); 6.99 (1H; d; J = 7.0 Hz;
3.1.6.3. Compounds (6c–i). The conditions employed for the
preparation of these compounds were those described above in
the procedure of Section 3.1.1. However, the reaction time was
modified to 4 h (derivatives 6c and 6e), 6 h (derivatives 6d and
6f), or 24 h (derivatives 6g–h). In the case of derivatives (6c–f),
the bath temperature also was modified to 80 °C.
3.1.6.3.1. 7-Chloro-N-methylquinolin-4-amine (6c). Yield: 90%,
mp: 166 °C (247–248 °C).26
0
0
0
H3); 4.01 (2H; t; J = 6.0 Hz; H1 or H2 ); 3.94 (2H; t; J = 6.0 Hz; H1 or
0
H2 ) ppm; NMR-13C (125 MHz, MeOD) d: 158.1; 143.4; 139.4;
135.1; 128.4; 123.9; 121.2; 118.4; 99.5; 46.2; 42.7 ppm.
IR mmax (cmꢀ1; KBr pellets): 3272 (N–H); 1572 (C@C);
MS/ESI: m/z [MꢀH]+: 269.2.
3.1.7.3. Quinolin-4-amine (7c). Yield: 93%, mp: 153–154 °C.29
3.1.6.3.2. 7-chloro-N-propylquinolin-4-amine (6d). Yield: 73%,
mp: 123–125 °C.26
3.1.7.4. N-Butylquinolin-4-amine (7d). Yield: 92%, mp: 123–
125 °C (130–132 °C).30
3.1.6.3.3. 7-Chloro-N-isopropylquinolin-4-amine (6e). Yield:
66%, mp: 158–159 °C.
3.1.6.3.4. 7-Chloro-N-butyl-quinolin-4-amine (6f). Yield: 83%,
3.1.8. General procedures for the synthesis of derivatives (8a–b)
The conditionsemployed for the preparation of these compounds
were those described above in the procedure of Section 3.1.2.
mp: 128–130 °C (130–132 °C).26
3.1.6.3.5. 3-[(7-Chloroquinolin-4-yl)amino]propan-1-ol (6g). Yield:
96%, mp: 130–133 °C.27
3.1.8.1. 7-Chloro-N-(3-chloropropyl)quinolin-4-amine (8a). Yield:
96%, mp: 130–133 °C.31
3.1.6.3.6. (2R)-2-[(7-Chloroquinolin-4-yl)amino]butan-1-ol
(6h). Yield: 82%, mp: 196–198 °C.
NMR-1H (500 MHz, MeOD) d: 8.33 (1H; d; J = 5.5 Hz; H2); 8.20
(1H; d; J = 9.2 Hz; H5); 7.77 (1H; d; J = 2.4 Hz; H8); 7.40 (1H; dd;
J = 9.2 and 2.4 Hz; H6); 6.60 (1H; d; J = 5.5 Hz; H3); 3.68–3.72
3.1.8.2. 7-Chloro-N-[1-(chloromethyl)propyl]quinolin-4-amine
(8b). Yield: 95%, mp: 120–121 °C.
0
0
0
NMR-1H (400 MHz, MeOD) d: 8.37 (1H; d; J = 5.6 Hz; H2); 8.21
(1H; d; J = 8.8 Hz; H8); 7.80 (1H; d; J = 2.5 Hz; H5); 7.42 (1H; dd;
J = 8.8 and 2.5 Hz; H6); 6.60 (1H; d; J = 5.6 Hz; H3); 3.97–3.90 (1H;
(3H; m; H1 and H2 ); 1.80–1.87 (1H; m; H3 ); 1.66–1.72 (1H; m;
H3 ); 1.02 (3H; t; J = 7.2 Hz; H4 ) ppm; NMR-13C (100 MHz, MeOD)
d: 152.2; 152.2; 149.7; 136.7; 127.5; 126.1; 124.6; 118.9; 100.2;
64.4; 57.7; 25.2; 11.1 ppm.
0
0
0
0
0
m; H2 ); 3.79–3.72 (2H; m; H1 ); 1.98–1.73 (2H; m; H3 ); 1.77 (1H;
m; H3 ); 1.03 (3H; t; J = 7.2 Hz; H4 ) ppm; NMR-13C (100 MHz, MeOD)
152.5; 151.4; 149.9; 136.5; 127.8; 126.2; 124.4; 118.8; 100.2;
56.8; 47.0; 26.2; 10.9 ppm.
IR mmax (cmꢀ1; KBr pellets): 3280 (N–H); 1582 (C@C); 1070
(C–O).
0
0
d:
MS/ESI: m/z [MꢀH]+: 249.3.

1480
M. V. N. de Souza et al. / Bioorg. Med. Chem. 17 (2009) 1474–1480
3. Kaminsky, D.; Meltzer, R. I. J. Med. Chem. 1968, 11, 160.
IR mmax (cmꢀ1; KBr pellets): 3324 (N–H); 1601 (C@C);
4. Musiol, R.; Jampilek, J.; Buchta, V.; Silva, L.; Niedbala, H.; Podeszwa, B.; Palka,
A.; Majerz-Maniecka, K.; Oleksyn, B.; Polanski, J. Bioorg. Med. Chem. 2006, 14,
3592.
MS/ESI: m/z [MꢀH]+: 207.2.
5. Warshakoon, N. C.; Sheville, J.; Bhatt, R. T.; Ji, W.; Mendez-Andino, J. L.; Meyers,
K. M.; Kim, N.; Wos, J. A.; Mitchell, C.; Paris, J. L.; Pinney, B. B.; Reizes, O.; Hu, X.
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3.1.9. General procedures for biological tests
Briefly, 200 lL of sterile deionized water was added to all outer-
perimeter wells of sterile 96 well plates (falcon, 3072: Becton
Dickinson, Lincoln Park, NJ) to minimize evaporation of the medium
in the test wells during incubation. The 96 plates received 100 lL of
the Middlebrook 7H9 broth (Difco Laboratories, Detroit, MI, USA)
and a serial dilution of the compounds 1–8b was made directly
on the plate. The final drug concentrations tested were 0.01–
10.0
lL/mL. Plates were covered, sealed with parafilm and incu-
bated at 37 °C for 5 days. After this time, 25
lL of a freshly prepared
12. Canetti, J.; Rist, E.; Grosset, R. Pneumology 1963, 27, 217.
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Microbiol. 2004, 42, 2247.
1:1 mixture of Alamar Blue (Accumed International, Westlake,
Ohio) reagent and 10% tween 80 was added to the plate and incu-
bated for 24 h. A blue color in the well was interpreted as no bacte-
rial growth, and a pink color was scored as growth. The MIC
(minimal inhibition concentration) was defined as the lowest drug
concentration, which prevented a color change from blue to pink.
16. Chiyanzu, I.; Clarkson, C.; Smith, P. J.; Lehman, J.; Gut, J.; Rosenyhal, P. J.;
Chibale, K. Bioorg. Med. Chem. 2005, 13, 3249.
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Am. Chem. Soc. 1948, 7, 4063.
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4. Conclusions
Amongst the 33 synthesized compounds, the derivatives 2, 3a,
3d, 3g, 3h, 5d–f, 6c–f, 7b, 8a, and 8b exhibited activity between
3.12 and 100.0 lg/mL. The antimycobacterial activities of the quin-
oline derivatives described here suggest that they may be selec-
tively targeted to M. tuberculosis growth. These compounds are
not cytotoxic to host cells at the concentrations effective in inhib-
iting M. tuberculosis infection. Compounds 5e and 5f exhibited a
significant activity at 6.25 and 3.12 lg/mL, respectively, when
24. Nelson, P. H.; Unger, S. H. Eur. Pat. Appl. 1986, 39 pp.
25. Hollywood, F.; Khan, Z. U.; Scriven, E. F. V.; Smalley, R. K.; Suschitzky, H.;
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Labelled Compd. Radiopharm. 1978, 15, 681.
compared with first line drugs such ethambutol and could be con-
sidered a good starting point to develop new lead compounds in
the fight against multi-drug resistant tuberculosis.
27. Burgess, S. J.; Selzer, A.; Kelly, J. X.; Smilkstein, M. J.; Riscoe, M. K.; Peyton, D. H.
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References and notes
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