Synthesis and study of new quinolineaminoethanols as anti-bacterial drugs

Article abstract of DOI:10.3390/ph12020091

The lack of antibiotics with a novel mode of action associated with the spread of drug resistant bacteria make the fight against infectious diseases particularly challenging. A quinoline core is found in several anti-infectious drugs, such as mefloquine and bedaquiline. Two main objectives were set in this work. Firstly, we evaluated the anti-mycobacterial properties of the previous quinolines 3, which have been identified as good candidates against ESKAPEE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and Escherichia coli) bacteria. Secondly, a new series 4 was designed and assessed against the same bacteria strains, taking the pair of enantiomers 3m/3n as the lead. More than twenty compounds 4 were prepared through a five-step asymmetric synthesis with good enantiomeric excesses (>90%). Interestingly, all compounds of series 3 were efficient on M. avium with MIC = 2–16 μg/mL, while series 4 was less active. Both series 3 and 4 were generally more active than mefloquine against the ESKAPEE bacteria. The quinolines 4 were either active against Gram-positive bacteria (MIC ≤ 4 μg/mL for 4c–4h and 4k/4l) or E. coli (MIC = 32–64 μg/mL for 4q–4v) according to the global lipophilicity of these compounds.

Full text of DOI:10.3390/ph12020091

pharmaceuticals
Article
Synthesis and Study of New Quinolineaminoethanols
as Anti-Bacterial Drugs
Pierre Laumaillé 1, Alexandra Dassonville-Klimpt 1,*, François Peltier 1,2, Catherine Mullié 1
,
Claire Andréjak 1,3, Sophie Da-Nascimento 1, Sandrine Castelain 1,2 and Pascal Sonnet 1,
*
1
AGIR, EA 4294, UFR of Pharmacy, Jules Verne University of Picardie, 80037 Amiens, France;
pierre.laumaille@etud.u-picardie.fr (P.L.); peltier.francois@chu-amiens.fr (F.P.);
catherine.mullie@u-picardie.fr (C.M.); andrejak.claire@chu-amiens.fr (C.A.);
sophie.da-nascimento@u-picardie.fr (S.D.-N.); sandrine.castelain@u-picardie.fr (S.C.)
Department of Bacteriology, Amiens University Hospital, 80054 Amiens, France
Respiratory and Intensive Care Unit, University Hospital Amiens, 80054 Amiens, France
2
3
*
Correspondence: alexandra.dassonville@u-picardie.fr (A.D.-K.); pascal.sonnet@u-picardie.fr (P.S.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 29 May 2019; Accepted: 14 June 2019; Published: 18 June 2019
Abstract: The lack of antibiotics with a novel mode of action associated with the spread of drug
resistant bacteria make the fight against infectious diseases particularly challenging. A quinoline core is
found in several anti-infectious drugs, such as mefloquine and bedaquiline. Two main objectives were
set in this work. Firstly, we evaluated the anti-mycobacterial properties of the previous quinolines 3,
which have been identified as good candidates against ESKAPEE (Enterococcus faecium, Staphylococcus
aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and
Escherichia coli) bacteria. Secondly, a new series
bacteria strains, taking the pair of enantiomers 3m
were prepared through a five-step asymmetric synthesis with good enantiomeric excesses (>90%).
Interestingly, all compounds of series were efficient on M. avium with MIC = 2–16 g/mL, while series
was less active. Both series and were generally more active than mefloquine against the ESKAPEE
bacteria. The quinolines were either active against Gram-positive bacteria (MIC g/mL for
4c 4h and 4k 4l) or E. coli (MIC = 32–64 g/mL for 4q 4v) according to the global lipophilicity of
these compounds.
4
was designed and assessed against the same
/
3n as the lead. More than twenty compounds
4
3
µ
4
3
4
4
≤
4 µ
–
/
µ
–
Keywords: Quinoline; tuberculosis; nosocomial infections; ESKAPEE bacteria; mycobacterium
1. Introduction
Infectious diseases are the second most prevalent cause of death in the world. Among them,
nosocomial infections and tuberculosis are particularly worrying. Approximatively 15% of all
hospitalized patients suffer from healthcare associated infections [1]. ESKAPEE bacteria (Enterococcus
faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa,
Enterobacter spp. and Escherichia coli) are the most common pathogens involved in nosocomial infections
and their antibiotic resistances make it difficult to implement effective treatments. Mycobacteria, such
as Mycobacterium tuberculosis, which is responsible for tuberculosis (TB), are also becoming resistant to
anti-TB drugs used for standard therapy. TB is one of the most common infectious diseases. In 2017,
10 million people developed TB infection and 1.6 million have died due to this disease. 400,000 cases of
multi-drug resistant (MDR) TB and 40,000 cases of extensively-drug resistant (XDR) TB were reported
in 2018 [
of four anti-mycobacterial drugs such as ethambutol, rifampin, isoniazid and pyrazinamide for two
months completed by the addition of rifampin and isoniazid across four additional months [ ]. The
2]. The treatment of uncomplicated TB is already difficult because it requires a combination
3
Pharmaceuticals 2019, 12, 91; doi:10.3390/ph12020091
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Pharmaceuticals 2019, 12, 91
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cure of MDR and XDR TB involves more drugs, more time (sometimes 24 months) and is much more
expensive [ ]. Non-Tuberculosis Mycobacteria (NTM) such as M. avium and M. abscessus are considered
as emerging pathogens and are also worrisome. In some countries, NTM pulmonary infections appear
to be more frequent than TB [ ]. The treatment of NTM pulmonary infections involves a combination
4
5
of at least two anti-mycobacterial drugs according to the severity of the disease and the tolerance to
the cure. For example, the treatment of a clarithromycin-sensitive M. avium complex lung infection
requires an association of ethambutol, rifampin and clarithromycin, which must be continued for at
least 12 months after culture conversion [6].
So, it is evident that ESKAPEE bacteria and mycobacteria are a major problem for public health due
to their resistances to the antibiotics. Unfortunately, since 1970 few antibiotics with new mechanisms of
action have been marketed. They are either active against Gram-positive bacteria or mycobacteria but
not against gram-negative bacteria. Consequently, there is a dire need to design new drugs efficient
against a larger panel of bacteria and able to fight resistant strains.
The quinoline core is found in anti-infectious drugs such as mefloquine (MQ 1a/1b, Figure 1) or
bedaquiline (BQ, compound 2a, Figure 1) [
as an anti-TB compound to treat MDR M. tuberculosis [
7
–
13]. BQ
2
is a diarylquinoline which was recently marketed
], while MQ is an aminoquinolinemethanol
7
1
used as antimalarial drug [10]. These two drugs, which possess two asymmetric centers, are used
either as a racemic mixture ((R,S)-MQ 1a + (S,R)-MQ 1b) or as enantiopure form ((R,S)-BQ 2a). Despite
their structural similarity, these two quinolines possess two different antimicrobial spectra. BQ 2a
is only active against mycobacteria [
Plasmodium falciparum in the nanomolar range and Gram-positive bacteria and mycobacteria in the
micromolar range (Figure 1) [ 15 17]. (R,S)-BQ 2a targets very specific mycobacteria, including M.
7,14] in the nanomolar range, while MQ 1a/1b is active against
9
, –
tuberculosis and M. avium [14], due to its great affinity to the mycobacteria F0F1-ATP synthase [18]. This
one was reported to be about 630-fold more active than its enantiomer 2b against M. tuberculosis [19].
The mechanism of action in MQ
no study has clearly highlighted the main antiplasmodial and/or antibacterial MQ-target [
1
is much less clear. Despite its use as an antimalarial since the 1970s,
20 22].
9
, –
However, some biochemical evidence has associated the antibacterial properties of MQ to its interaction
with the F0F1-ATP synthase [21]. Even if MQ 1a/1b is used as racemic mixture, studies suggest this is
the best activity of the enantiomer (+)-(S,R)-MQ compared to its optical antipode against P. falciparum
and M. tuberculosis in vitro and M. avium in vivo [16,17,23]. However, this difference in activity is not
observed against bacteria such as S. aureus, Enterococcus faecalis or Streptococcus pneumonia [9,21].
Figure 1. Mefloquine 1 and bedaquiline 2 enantiomers and their biological activities.
During previous work on the development of new enantiopure MQ-based antimalarial drugs, we
identified a series of compounds
3a 3l displayed activities on the nanomolar range against P. falciparum 3D7 and W2 strains whatever
the length of the aliphatic side chain while the enantiomers 3m and 3n were inactive on these strains
3 containing an aliphatic side chain (Figure 2) [22]. These MQ analogs
–
(half maximal inhibitory concentration, IC50 > 400 nM) [22]. Interestingly, for 3a
were always more active than their (R)-counterpart by a factor of two to 15.
–3l, (S)-enantiomers

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Figure 2. Previous series of quinoline-based antimicrobial drugs 3a–3n.
Thereafter, the antibacterial potential of all these compounds was assessed on Gram-positive
strains (S. aureus and E. faecalis) and Gram-negative strains (E. coli and P. aeruginosa) (Table 1) [24].
The MQ analogs
bacteria. However, some of them (3c
(MIC) lower than 32 g/mL on E. coli. For this series, the side chain length has an influence on
the antibacterial activity in connection with the lipophilicity determined here by the clogP value.
Compounds displaying a clogP value ranging from 4.95 (3e 3f) to 5.70 (3i 3j) were more active against
Gram-positive bacteria. The best activity against Gram-negative bacteria was observed for compounds
with a clogP value lower than 4.60 corresponding to C4 (3a 3b) and C5 (3c 3d) alkyl side chain length or
a 4-hydroxyphenylethyl group (3m 3n). This latter pair of enantiomers was the more effective on E. coli
g/mL) while remaining active on Gram-positive bacteria (MIC = 8 g/mL).
3
were often more active against Gram-positive bacteria compared to Gram-negative
,
3f, 3m and 3n) showed a minimum inhibitory concentration
µ
/
/
/
/
/
(MIC = 8 (3m) and 16 (3n
)
µ
µ
Table 1. Antibacterial activities of compounds 3a–3n.
MIC (µg/mL) a
clogP b
Compound
S. aureus
CIP 103.429
E. faecalis
CIP 103.214
E. coli
DSM 1103
P. aeruginosa
DSM 1117
3a (3b)
3c (3d)
3e (3f)
3g (3h)
3i (3j)
16 (16)
16 (16)
4 (4)
1 (2)
1 (1)
16 (16)
16 (16)
4 (4)
1 (2)
1 (1)
32 (64)
16 (32)
>128 (>128)
>128 (>128)
>128 (>128)
>128 (>128)
>128 (>128)
>128 (>128)
>128 (>128)
>128
4.30
4.59
4.95
5.31
5.70
6.01
4.46
NDc
ND
>128 (16)
>128 (>128)
>128 (>128)
>128 (>128)
8 (16)
3k (3l)
16 (>128)
8 (8)
16 (>128)
8 (8)
3m (3n)
mefloquine
ciprofloxacin
16
0.25
32
0.25
64
0.0625
0.125
a
b
c
Minimum inhibitory concentration. logP calculated with Qikprop, a Schrödinger software. Not determined.
In light of these encouraging results, we are particularly interested in establishing novel
structure-antimicrobial activity relationships in the promising quinoline-based series 3. The 3m/3n pair
displaying the broader antimicrobial spectrum of this series possesses a phenyl grafted to the alkyl side
chain. It allows us to make structural changes to determine new structure-activity relationships. Here,
the chosen optimization strategy consists of exploring the hydrophobic (
π
-constant) and the electronic
of quinoline-based
space ( ) around the phenyl by modifying the R2 group to form a novel series
σ
4
drugs (Figure 3). The substituents (R2) were selected on the base of the Craig Plot tool to ensure that all
possible combinations of pi (π) and sigma (σ) were studied [25].

Pharmaceuticals 2019, 12, 91
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Figure 3. Novel series of quinoline-based drugs 4.
We present herein not only the antimycobacterial activity of the previously synthetized
quinolineaminoethanols , but also the synthesis, antibacterial activities of the new enantiopure
quinoline-based drugs , and analogs of the compounds 3m 3n. We will compare the antibacterial
activities of these two series and in relation to the nature of their quinoline substituents and their
3
4
/
3
4
stereochemistry to establish structure–activity relationships.
2. Results and Discussion
2.1. Chemical Synthesis
The synthesis of compounds
(Scheme 1). We have previously described the first four steps that allowed us to obtain the key
intermediate 26]. First, the 4-hydroxyquinoline was reacted with POBr3 to create , which was
4 was carried out from the 4-hydroxyquinoline 5 in a five-step
9
[
5
6
coupled with the sodium vinyl trifluoroborate through a Suzuki reaction to give the 4-vinylquinoline
in 94% yield. Then, an asymmetric Sharpless dihydroxylation was carried out using either AD-mix-
7
α
to give the diol
condensation with retention of the configuration allowed us to obtain the two enantiomers of the
key epoxyde depending of the diol used. Finally, (R)- or (S)- was reacted with the commercially
available amines 10 to give the corresponding compound . Only the amines 10a (R2 = COOMe) and
8 as the S enantiomer or AD-mix-β to obtain 8 as the R enantiomer. A three-step
9
9
9
4
10b (R2 = CONH2) allowed us to obtain the two pairs of enantiomers, and 4k/4l and 4q/4r, respectively
were synthesized in one step (see experimental Section 3.2.1.).
Scheme 1. Synthetic pathway of compounds 4.
Hence, twenty-two compounds
4 were obtained, in five steps with a global yield ranging from 14
to 47% (Table 2). The enantiomeric purity was quantified using chiral HPLC (High Performance Liquid
Chromatography) where possible and the optical rotation was measured for each couple of enantiomers
(Table 2). All 1H and 13C NMR spectra of compounds 4a
–4u are provided in Supplementary Materials
(Figures S1–S22).

Pharmaceuticals 2019, 12, 91
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Table 2. Yields, enantiomeric excesses and optical rotation of compounds 4.
c
c
N◦
4a
4b
4c
4d
4e
4f
4g
4h
4i
R2
AC a
R
S
R
S
R
S
R
S
Yield (%)
αDT
N◦
4l
R2
AC a
Yield (%)
αDT
ee b
99
94
94
97.5
95
96
97
94
ee b
73
63
37
79
80
87
68
84
78
61
−52.9
+53.0
−52.9
+64.7
−61.3
+64.6
−56.7
+53.4
−32.6
+44.6
H
COOMe
S
53
94
+55.4
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
R
S
R
S
R
S
R
S
R
S
86
84
72
68
39
26
76
77
89
89
99
90
−63.6
+45.1
−26.1
+43.6
−37.7
+44.1
−40.0
+43.0
−40.9
+53.4
Me
OMe
Cl
CN
ND d
ND
ND
ND
ND
ND
ND
ND
COOH
CONH2
SO2NH2
NH2
R
S
98
94
NO2
4j
4k
COOMe
R
77
99
−67.9
a
b
Absolute configuration.
Enantiomeric excess in % determined by HPLC, see conditions to experimental
Section 3.2.2. Optical rotation, see concentration, solvent and T to experimental Section 3.2.2. Not determined.
c
d
2.2. Biological Activity
MQ and compounds
4 were tested in vitro against S. aureus CIP 103.429 and E. faecalis CIP 103.214
(CIP: Collection de l’Institut Pasteur, Paris, France) as Gram-positive bacteria and E. coli DSM 1103
and P. aeruginosa DSM 1117 as Gram-negative bacteria (Deutsche Sammlung für Mikroorganismen,
Braunschweig, Germany). The anti-mycobacterial activity of compounds 3 and 4 was also assessed
through assays on M. avium ATCC 700,898 (American Type Culture Collection) and compared with
those of MQ and its enantiomers 1a and 1b. The MIC determinations were carried out using the broth
microdilution technique as advised by the Clinical and Laboratory Standards Institute (CLSI) with
drug concentrations ranging from 0.0625 to 128
µg/mL [27] for the anti-bacterial screening and from 2
to 64 g/mL for the anti-mycobacterial evaluation [28]. M. avium susceptibility test was realized in
µ
cation-adjusted Mueller–Hinton broth (CAMHB) supplemented with Oleic Albumin Dextrose Catalase
(OADC). Furthermore, as anti-TB drugs such as clarithromycin can be influenced by the growth medium,
MiddleBrook 7H9 (MB 7H9) supplemented with 5% OADC was used in parallel. Ciprofloxacin was
used as control for Gram-negative and Gram-positive bacteria while clarithromycin was employed
for experiments with mycobacteria. In this latter assay, rifampin, ethambutol, ciprofloxacin and
bedaquiline 2a were added as indicators.
As for the first series
than Gram-negative bacteria (Table 3 vs. Table 1). A better activity was often observed on S. aureus
compared to E. faecalis, especially for the pairs of enantiomers 4i 4j and 4m 4n carrying the more
electron-withdrawing groups ( p = 0.778 (R2 = NO2) and 0.660 (R2 = CN)). The additional four
efficiency pairs of enantiomers 4c 4d 4e/4f 4g/4h and 4k/4l on this strain (MIC g/mL) were
among the more lipophilic with a clogP values between 4.37 (4k 4l) and 5.75 (4g 4h). These were less
active than the referenced ciprofloxacin but more active than MQ by four to 16-fold depending on the
3, the quinolines 4 were generally more active against Gram-positive bacteria
/
/
σ
/
,
,
≤
4 µ
/
/
substituent. The same trend was found on E. faecalis even if 4e
MIC (MIC = 8 µg/mL).
/4f and 4k displayed a slightly superior

Pharmaceuticals 2019, 12, 91
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Table 3. Antibacterial activities and physicochemical constant of compounds
4 vs. 3m, 3n and
mefloquine (MQ).
MIC (µg/mL) b
Physicochemical Constant
N◦
AC a
P.
R2
S. aureus
CIP103.429
E. faecalis
CIP 103214
E. coli
DSM 1103
c
clogP g
π f
aeruginosa
DSM 1117
σ
p
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
8
8
2
2
4
4
1
1
64
64
4
4
8
8
8
4
2
8
8
2
2
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
64
64
64
64
32
64
8
16
64
>128
>128
>128
>128
32
H
Me
0
0
5.23
5.47
5.12
5.75
4.49
4.37
4.52
2.33
3.58
2.90
4.12
4.46
–0.170
−0.268
0.227
0.56
OMe
Cl
−0.02
0.71
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
0.125
128
128
8
0.778d
0.619e
0.660
NO2
−0.28
−0.01
−0.57
−0.28
−1.49
−1.82
−1.23
−0.67
COOMe
CN
4
>128
>128
64
64
32
32
32
16
8
16
8
8
32
0.25
8
64
64
32
16
16
16
8
8
8
8
16
0.25
COOH
CONH2
SO2NH2
NH2
0.257
0.627
4s
4t
4u
4v
3m
3n
0.621
−0.660
−0.357
OH
mefloquine
ciprofloxacin
0.0625
a
b
c
d
Absolute configuration. Minimum inhibitory concentration. Hammett’s para substituent constant [29].
[30].
e
f
Hammett’s para substituent constant—substituent constant for reactions of phenols and anilines. Hydrophobic
g
substituent value—values from benzene series used—[31]. logP calculated with Qikprop, a Schrödinger software.
As expected, the most hydrophilic compounds 4o
were less active against Gram-positive strains (MIC between 8 and 64
activity than others compounds of this series, except 4o–4p with a COOH group, against E. coli (MIC
–
4v (R2 = COOH, CONH2, SO2NH2, NH2),
µg/mL) but showed a better
between 32 and 64
µ
g/mL). These three pairs of enantiomers 4q–4v displayed an activity similar or
g/mL) than MQ (MIC = 64 g/mL) against E. coli but lower than the lead pair of
g/mL). For all quinolines , no significant difference in anti-bacterial
activities was observed between the enantiomers.
Among the quinolines of this series , the more active on E. coli 4q
NH2) were also more effective against M. avium with an MIC equal to 64
the pair of enantiomers 3m/3n (R2 = OH) were the most efficient on this mycobacterium with an
MIC nearer to those of ethambutol and rifampin. However, the compounds 3a 3l with aliphatic side
chains were generally more active than the compounds with MIC 32 g/mL and often equal to
2 or 4 g/mL, especially in the CAMHB. For this series , the anti-mycobacterial activity seems less
dependent to the side chain length and to the clogP values (4.30–6.01) compared to the antibacterial
activity (Table 4 vs. Table 1). The quinolines were often less active than the reference clarithromycin
better (MIC = 8–64
µ
µ
enantiomers 3m/3n (MIC = 8–16
µ
4
4
–
4v (R2 = CONH2, SO2NH2,
g/mL. Not surprisingly,
µ
-
4
≤
µ
µ
3
3
in CAMHB medium but as active in MB 7H9 medium, as active as MQ and more active than the three
anti-TB drugs; ethambutol, rifampin, and ciprofloxacin. A slight difference of activity between the two
enantiomers can be observed especially for the pair 3g/3h in the MB 7H9 culture medium.

Pharmaceuticals 2019, 12, 91
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Table 4. Activity against M. avium for compounds of series 3 and 4.
MIC (µg/mL) b
Compound
clogP e
M. avium
M. avium
ATCC 700898
in MB 7H9 d
ATCC 700898
in CAMBH c
N◦
R2
H
ACa
4a
4b
R
S
>64
>64
>64
>64
5.23
5.47
5.12
5.75
4.49
4.37
4.52
2.33
3.58
2.90
4.12
4.46
4c
4d
R
S
>64
>64
>64
>64
Me
OMe
Cl
4e
4f
R
S
>64
>64
>64
>64
4g
4h
R
S
>64
>64
>64
>64
4i
4j
R
S
>64
>64
>64
>64
NO2
4k
4l
R
S
>64
>64
>64
>64
COOMe
CN
4m
4n
R
S
>64
>64
>64
>64
4o
4p
R
S
>64
>64
>64
>64
COOH
CONH2
SO2NH2
NH2
4q
4r
R
S
64
64
64
64
4s
4t
R
S
64
64
64
64
4u
4v
R
S
64
64
64
64
3m
3n
R
S
32
32
32
32
OH
R1
ACa
3a
3b
R
S
4
8
16
32
-CH2CH3
4.30
4.59
4.95
5.31
5.70
6.01
3c
3d
R
S
4
8
16
8
-(CH2)2CH3
-(CH2)3CH3
-(CH2)4CH3
-(CH2)5CH3
-(CH2)6CH3
8–16 f
8–16 f
8–16 f
8–16 f
3e
3f
R
S
3g
3h
R
S
8
4
16
4
3i
3j
R
S
ND g
4
ND
4
8–16 f
2
8–16 f
8
3k
3l
R
S

Pharmaceuticals 2019, 12, 91
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Table 4. Cont.
MIC (µg/mL) b
Compound
clogP e
M. avium
ATCC 700898
in CAMBH c
M. avium
ATCC 700898
in MB 7H9 d
mefloquine racemic
4
4
4
16
16
8
mefloquine 1a
mefloquine 1b
R,S
S,R
ND
bedaquiline 2a
≤0.063
≤0.063
32–64
4–8
ND
ND
ND
ND
ND
rifampin
clarithromycin
ethambutol
64
1
8–16
8
8
ciprofloxacin
4–8
a
c
b
Absolute configuration. Minimum inhibitory concentration. The experiments were carried out in duplicate.
d
culture medium = cation-adjusted Mueller-Hinton Broth (CAMHB) + 5% OADC(pH = 7.3). culture medium =
e
f
MiddleBrook 7H9 + 5% OADC (pH = 6.8). logP calculated with Qikprop, a Schrödinger software. Different
values were obtained in experiment 1 and 2. Not determined.
g
Thanks to these results, it is possible to establish new structure-activity relationships about the
two series of quinoline-based drugs 3 and 4 (Table 5). For the quinolines 4 and 3m/3n carrying a phenyl
group, the compounds with a clogP value above four were the more active against Gram-positive
bacteria. Although we do not know the mechanism of action of this quinoline series, this better
activity against Gram-positive bacteria perhaps could be due to a better intracellular internalization.
None of the quinolines (series
3
and
4) were active against P. aeruginosa but some of them showed
a moderate activity on E. coli. The compounds with a clogP value below 4 (4q
–
4t) were the less
efficient against Gram-positive strains but were active against E. coli and M. avium, except if the
compound was a carboxylic acid (4o–4p). The introduction of a more polar substituent of the phenyl
core may allow a better translocation through the outer membrane of the Gram-negative bacteria. For
clogP value ranging from four to five, the best activities against E. coli and M. avium were observed
for the compounds carrying hydrophilic substituents (-
effect (- ) around the phenyl group (3m 3n 4u 4v). For the quinoline-based drugs with an aliphatic
side chain (3a 3l), all the compounds were active against M. avium whatever the side chain length
(MIC ≤ 16 µg/mL in CAMHB).
π) and preferably with an electron-donor
σ
/
,
/
–
Table 5. Structure-antimicrobial activity relationships for compounds 3 and 4.
clogP < 4.6
n = 2–3
4.6 < clogP < 6
n = 4–6
clogP > 6
n = 7
active against E. coli
(MIC = 16–64 µg/mL).
activity is increased against Gram-positive
3l is the lead compound
against M. avium
bacteria (MIC = 1–4 µg/mL).
(MIC = 2 µg/mL).
All compounds were active against M. avium whatever the clogP value
clogP < 4
4 < clogP < 5
clogP > 5
−σ and −π (R = NH2, OH):
activity is increased against E. coli (MIC =
8–64 µg/mL) and M. avium (MIC =32–64
R = COOH, CONH2, SO2NH2
R = H, Me, OMe, Cl
µ
g/mL) and retained against Gram-positive
activity is decreased against
Gram-positive bacteria (MIC =
16–64 µg/mL) and weak on E. coli
and M. avium (MIC = 64 µg/mL).
activity is increased
against Gram-positive
bacteria
bacteria (MIC = 8–16 µg/mL).
+σ and +π (R = NO2):
(MIC = 1–8 µg/mL).
activity is weak against Gram-positive
bacteria and no activity against E. coli.

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3. Materials and Methods
3.1. Generalities
All reagents and solvents were obtained from commercial suppliers and were used without further
purification. Anhydrous solvents were dried with the solvent drier, Pure Solv-Innovative Technology
PS-MD-5. Some reactions were carried out with a Discover SP microwave reactor (commercialized
by CEM). Column chromatography was performed over silica gel Kielselgel 60 (40–60 µm). Routine
monitoring of reactions was carried out using Merck Silica Gel 60 F254 plates thin layer chromatography
(TLC) and visualized under UV light (254 nm). Nuclear magnetic resonance (NMR) spectra were
recorded using Bruker 400-cryosonde NMR instrument (1H NMR at 400 MHz and 13C NMR at
101 MHz). Chemical shifts were expressed in parts per million (ppm) downfield from tetramethylsilane
and were referenced to the deuterated solvent. 1H NMR and 13C NMR data were reported in the
order of chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qt = quintuplet,
m = multiplet), integration, coupling constants in Hertz (Hz). LC-HRMS analyses were performed on
an ACQUITY UPLC H-Class system (Waters-Micromass, Manchester, UK) coupled with a SYNAPT
G2-Si Q-TOF hybrid quadrupole time-of-flight instrument (Waters-Micromass, Manchester, UK),
equipped with an electrospray (ESI) ionization source (Z-spray). Enantiomeric excesses were measured
with Schimadzu LC-20AD equipped with a Chiralpak column (IA, IB, IC, ID or IG). Specific rotations
were measured on a Jasco P1010 polarimeter, with 1 dm length cuvette and a continuous wave lamp at
sodium D-line (589 nm). Concentrations were expressed in g/100 mL and measures were realized in
dichloromethane at 23 or 26 ◦C. High-resolution mass spectra were obtained from a Micromass-Waters
Q–TOF Ultima spectrometer, in electrospray ionization mode (positive or negative). Infrared spectra
were recorded with a Jasco FT/IR-4200 and were reported using the frequency of absorption (cm−1).
Gas Chromatography–Mass Spectrometry (GCMS) was carried out on a Schimadzu GCMS-QP2010S
equipped with a SLB-5 ms column. Melting points were determined with a Stuart SMP3 device.
3.2. Synthesis
The synthetic route to prepare 9 has already been described by our research group [26].
3.2.1. Synthesis of amines 10
Methyl 4-(2-aminoethyl)benzoate 10a
4-(2-aminoethyl)benzoic acid hydrochloride (250 mg, 1 eq) was solved in MeOH (5 mL). SOCl2 (310 mg,
2.1 eq) was added slowly at 0 ◦C and the mixture was stirred at 65 ◦C over 10 h. The crude product was
evaporated to dryness then solved in dichloromethane (DCM) and evaporated again. This procedure
was repeated three times. An aqueous NaOH solution (1M) was added, and the mixture was extracted
three times with DCM. Then, the saturated NaCl solution was added and the mixture was extracted
three times with DCM. The combined organic layers were dried over Na2SO4 and concentrated in
vacuo to give 214 mg of yellow oil (97% yield).
1183, 1108, 764, 632 cm−1; 1H NMR (400 MHz, Chloroform-d)
3.91 (s, 3H), 3.00 (t, 3J = 6.8 Hz, 2H), 2.81 (t, 3J = 6.8 Hz, 2H). 13C NMR (101 MHz, Chloroform-d)
ν
max: 3280, 2947, 2850, 1717, 1628, 1542, 1436, 1279,
7.97 (d, 3J = 8.5 Hz, 2H), 7.29 (m, 2H),
168.0,
δ
δ
145.4, 129. 8, 128.9, 128.2, 52.0, 43.3, 40.2. HRMS (ESI, m/z): calculated for [M + Na] C10H13NO2Na,
202.0844, found 202.0840.
4-(2-aminoethyl)benzamide 10b
4-(2-aminoethyl)benzonitrile hydrochloride (500 mg, 1 eq) was solved in a mixture of EtOH/H2O
(10 mL, 8:2 v/v) then KOH (1.63 g, 5 eq) was added. The solution was heated at 80 ◦C for 2 h. Water
was added (5 mL), then a solution of Na2CO3 (10−2 M) until it reached pH=10. The solution was
evaporated to dryness. The product was purified by chromatography on silica gel (DCM/5% NH3 in
MeOH 6:4) to give 240 mg (53% yield) of orange/brown paste. m.p. 175 ◦C;
νmax: 3352, 3237, 3125, 3055,

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1661, 1559, 1383, 1054, 621 cm−1; 1H NMR (400 MHz, Methanol-d4)
δ
7.89 (d, 3J = 8.3 Hz, 2H), 7.41(d, 3J
= 8.3 Hz, 2H), 3.23 (m, 2H), 3.09 (m, 2H). 13C NMR (101 MHz, Methanol-d4)
δ 177.1, 140.9, 132.5, 128.6,
127.9, 40.1, 33.0. HRMS (ESI, m/z): calculated for [M + H] C9H13N2O, 165.1028, found 165.1028.
3.2.2. Synthesis of Compounds 4
General Procedure
(R) or (S)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline
9 (50 mg, 1 eq) was solved in ethanol (1mL),
then the corresponding amine (3 eq) was added. The mixture was heated with a microwave oven at
130 ◦C and 150W for 30 min. The crude product was purified by chromatography on silica gel.
(R)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(phenethylamino)ethan-1-ol (4a)
(R)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline was reacted with 2-phenylethan-1-amine (0.062 mL,
3 eq) according to the general procedure. The crude product was purified by chromatography on
silica gel (DCM/5% NH3 in MeOH: 99/1) to give 51 mg (73% yield) of white solid. m.p. 160 ◦C;
ν
:
max
3280, 2983, 2705, 2589, 2168, 1991, 1607, 1315, 1103, 1024, 866, 769, 703, 664 cm−1
;
[α]2D6
= 52.9 (c 0.1,
−
DCM); ee = 99% (column Chiralpak IB, heptane/iPrOH 97:3, 1 mL/min, tR(R) = 15.7 min, tR(S) = 21.1
min); HRMS (ESI, m/z): calculated for [M + H] C21H19N2OF6, 429.1402, found 429.1398; 1H NMR (400
MHz, Chloroform-d) δ
8.18 (d, 3J = 8.9 Hz, 1H), 8.16 (d, 3J = 8.9 Hz, 1H), 8.09 (s, 1H), 7.71 (t, 3J = 8.0
Hz, 1H), 7.36–7.14 (m, 6H), 5.44 (dd, 3J = 8.8 Hz, 3J = 3.6 Hz, 1H), 3.17 (dd, 2J = 12.5 Hz, 3J = 3.7 Hz,
1H), 3.09–2.86 (m, 2H), 2.86–2.76 (m, 2H), 2.71 (dd, 2J = 12.5 Hz, 3J = 8.9 Hz, 1H). 13C NMR (101 MHz,
Chloroform-d)
δ
151.3, 143.7, 139.3, 128.7 (3JC-F = 4.1 Hz), 127.0, 126.9, 126.5, 114.5, 67.3, 55.4, 50.5, 36.5.
(S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(phenethylamino)ethan-1-ol (4b)
(S)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline was reacted with 2-phenylethan-1-amine (0.062 mL,
3 eq) according to the general procedure. The crude product was purified by chromatography on silica
gel (DCM/5% NH3 in MeOH: 99/1) to give 44 mg (63% yield) of white solid. [α]2D6 = +53.0 (c 0.1, DCM);
ee = 94% (column Chiralpak IB, heptane/iPrOH: 97/3, 1 mL/min, tR(R) = 15.8 min, tR(S) = 19.6 min);
HRMS (ESI, m/z): calculated for [M + H] C21H19N2OF6, 429.1402, found 429.1399. NMR, IR spectra
and mp were the same as 4a.
(R)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-((4-methylphenethyl)amino)ethan-1-ol (4c)
(R)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline was reacted with 2-(p-tolyl)ethan-1-amine
(0.071 mL, 3 eq) according to the general procedure. The crude product was purified by chromatography
on silica gel (DCM/5% NH3 in MeOH: 99/1) to give 26 mg (37% yield) of white solid. m.p. 153 ◦C;
ν
max: 2950, 2925, 2840, 1600, 1516, 1462, 1305, 1107, 1038, 887, 835, 809, 766 cm−1
;
[α]2D3
= −52.9 (c 0.1,
DCM); ee = 94% (column Chiralpak IB, heptane/iPrOH: 97/3, 0.5 mL/min, tR(R) = 35.5 min, tR(S) = 43.3
min); HRMS (ESI, m/z): calculated for [M + H] C22H21N2OF6, 443.1558, found 443.1558; 1H NMR (400
MHz, Chloroform-d) δ
8.21 (d, 3J = 8.0 Hz, 1H), 8.18 (d, 3J = 8.0 Hz, 1H), 8.12 (s, 1H), 7.73 (t, 3J = 7.9
Hz, 1H), 7.12 (q, 3J = 8.0 Hz, 4H), 5.47 (dd, 3J = 8.9 Hz, 3J = 3.6 Hz, 1H), 3.20 (dd, 2J = 12.5 Hz, 3J = 3.8
Hz, 1H), 3.04 (m, 1H), 2.94 (m, 1H), 2.82 (td, 3J = 6.7 Hz, 2J = 2.3 Hz, 2H), 2.73 (dd, 2J = 12.6, 3J = 8.8 Hz,
1H), 2.35 (s, 3H). 13C NMR (101 MHz, Chloroform-d)
δ
148.4 (2JC-F = 35.4 Hz), 136.1, 136.1, 128.7 (3JC-F
= 5.5 Hz), 128.4, 127.0, 126.9, 123.5 (1JC-F = 276.7 Hz), 121.3 (1JC-F = 276.7 Hz), 114.5 (3JC-F = 2.0 Hz),
67.4, 55.4, 50.6, 35.9, 21.0.
(S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-((4-methylphenethyl)amino)ethan-1-ol (4d)
(S)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline was reacted with 2-(p-tolyl)ethan-1-amine
(0.071 mL, 3 eq) according to the general procedure. The crude product was purified by chromatography
on silica gel (DCM/5% NH3 in MeOH: 99/1) to give 56 mg (79% yield) of white solid. [α]2D3 = +64.7 (c
0.1, DCM); ee = 97.5% (column Chiralpak IB, heptane/iPrOH: 97/3, 0.5 mL/min, tR(R) = 37.2 min, tR(S)

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= 41.2 min); HRMS (ESI, m/z): calculated for [M + H] C22H21N2OF6, 443.1558, found 443.1564. NMR,
IR spectra and mp were the same as 4c.
(R)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-((4-methoxyphenethyl)amino)ethan-1-ol (4e)
(R)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline was reacted with 2-(4 methoxyphenyl)ethan-1-
amine (0.072 mL, 3 eq) according to general the procedure. The crude product was purified by
chromatography on silica gel (DCM/5% NH3 in MeOH: 99/1) to give 56 mg (80% yield) of white solid.
m.p. 154 ◦C; max: 2957, 2938, 2841, 1607, 1512, 1453, 1306, 1247, 1104, 1035, 889, 815, 772 cm−1
ν ; =
[α]2D3
−
61.3 (c 0.1, DCM); ee = 95% (column Chiralpak IB, heptane/iPrOH: 95/5, 0.5 mL/min, tR(R) = 41.1 min,
tR(S) = 49.8 min); HRMS (ESI, m/z): calculated for [M + H] C22H21N2O2F6, 459.1507, found 459.1512;
1H NMR (400 MHz, Chloroform-d) 8.21 (d, 3J = 8.0 Hz, 1H), 8.18 (d, 3J = 7.2 Hz, 1H), 8.12 (s, 1H), 7.73
δ
(t, 3J = 8.0 Hz, 1H), 7.13 (m, 3J = 6.4 Hz, 2H), 6.88 (d, 3J = 8.8 Hz, 2H), 5.47 (dd, 3J = 8.8 Hz, 3J = 3.7 Hz,
1H), 3.82 (s, 3H), 3.19 (dd, 2J = 12.5 Hz, 3J = 3.8 Hz, 1H), 3.02 (m, 1H), 2.93 (m, 1H), 2.80 (td, 3J = 6.7 Hz,
2J = 2.6 Hz, 2H), 2.74 (dd, 2J = 12.5, 3J = 8.7 Hz, 1H). 13C NMR (101 MHz, Chloroform-d)
δ 158.3, 129.4,
128.6 (3JC-F = 5.1 Hz), 127.0, 126.9, 121.2 (1JC-F = 274.2 Hz), 113.5 (1JC-F = 274.2 Hz), 114.5, 114.1, 67.3,
55.4, 55.3, 50.6, 35.5.
(S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-((4-methoxyphenethyl)amino)ethan-1-ol (4f)
(S)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline was reacted with 2-(4 methoxyphenyl)ethan-1-
amine (0.072 mL, 3 eq) according to the general procedure. The crude product was purified by
chromatography on silica gel (DCM/5% NH3 in MeOH: 99/1) to give 64 mg (87% yield) of white solid.
[α]2D3 = +64.6 (c 0.1, DCM); ee = 96% (column Chiralpak IB, heptane/iPrOH: 95/5, 0.5 mL/min, tR(R) =
45.2 min, tR(S) = 48.1 min); HRMS (ESI, m/z): calculated for [M + H] C22H21N2O2F6, 459.1507, found
459.1518. NMR, IR spectra and mp were the same as 4e.
(R)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-((4-chlorophenethyl)amino)ethan-1-ol (4g)
(R)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline was reacted with 2-(4-chlorophenyl)ethan-1- amine
(0.072 mL, 3 eq) according to the general procedure. The crude product was purified by chromatography
on silica gel (DCM/5% NH3 in MeOH: 99/1) to give 51 mg (68% yield) of white solid. m.p. 162 ◦C;
ν
max: 2945, 2922, 2853, 1601, 1520, 1455, 1309, 1109, 1039, 891, 819, 764, 703 cm−1
;
[α]2D3
= −56.7 (c 0.1,
DCM); ee = 97% (column Chiralpak IA, heptane/iPrOH: 9/1, 1mL/min, tR(R) = 9.9 min, tR(S) = 28.2
min); HRMS (ESI, m/z): calculated for [M + H] C21H18N2O2F6Cl, 463.1012, found 463.1019; 1H NMR
(400 MHz, Chloroform-d) δ
8.21 (d, 3J = 8.5 Hz, 1H), 8.19 (d, 3J = 7.2 Hz, 1H), 8.12 (s, 1H), 7.74 (t, 3J =
8.0 Hz, 1H), 7.31 (m, 3J = 8.4 Hz, 2H), 7.16 (d, 3J = 8.4 Hz, 2H), 5.47 (dd, 3J = 8.8 Hz, 3J = 3.6 Hz, 1H),
3.20 (dd, 2J = 12.5 Hz, 3J = 3.7 Hz, 1H), 3.07–2.91 (m, 2H), 2.89–2.80 (m, 2H), 2.74 (dd, 2J = 12.5 Hz, 3J =
8.9 Hz, 2H). 13C NMR (101 MHz, Chloroform-d)
δ 151.2, 143.7, 137.7, 132.3, 130.0, 128.8, 127.0, 126.8,
126.6, 114.5, 67.4, 55.4, 50.4, 35.9.
(S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-((4-chlorophenethyl)amino)ethan-1-ol (4h)
(S)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline was reacted with 2-(4-chlorophenyl)ethan-1- amine
(0.072 mL, 3 eq) according to the general procedure. The crude product was purified by chromatography
on silica gel (DCM/5% NH3 in MeOH: 99/1) to give 63 mg (84% yield) of white solid. [α]2D3 = +53.4 (c
0.1, DCM); ee = 94% (column Chiralpak IA, heptane/iPrOH 9:1, 1mL/min, tR(R) = 10.3 min, tR(S) = 27.6
min); HRMS (ESI, m/z): calculated for [M + H] C21H18N2O2F6Cl, 463.1012, found 463.1029. NMR, IR
spectra and mp were the same as 4g.
(R)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-((4-nitrophenethyl)amino)ethan-1-ol (4i)
2-(4-nitrophenyl)ethan-1-amine hydrochloride (100 mg, 3 eq) was quenched by NaOH 1M then
extracted with ethyl acetate. The combined organic layers were dried and the resulting solid was

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reacted with (R)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline (50 mg, 1 eq) according to the general
procedure. The crude product was purified by chromatography on silica gel (DCM then DCM/5% NH3
in MeOH: 99/1) to give 60 mg (78% yield) of white solid. m.p. 180 ◦C;
ν
max: 3279, 2921, 2854, 2018,
32.6 (c 0.1, DCM); ee = 98% (column Chiralpak
IA, heptane/iPrOH 9:1, 1 mL/min, tR(R) = 21.0 min, tR(S) = 53.3 min); HRMS (ESI, m/z): calculated for
1602, 1518, 1308, 1108, 930, 849, 772, 702 cm−1
;
[α]2D6
=
−
[M + H] C21H18N3O3F6, 474.1252, found 474.1260; 1H NMR (400 MHz, DMSO-d6) 8.63 (d, 3J = 8.8
δ
Hz, 1H), 8.35 (d, 3J = 7.2 Hz, 1H), 8.10 (s, 1H), 8.06 (d, 3J = 8.8 Hz, 2H), 7.91 (t, 3J = 8.0 Hz, 1H), 7.39 (d,
3J = 8.4 Hz, 2H), 6.00 (d, 3J = 4.3 Hz, 1H), 5.58 (m, 1H), 2.94 (dd, 3J = 12.4, 3J = 4.3 Hz, 1H), 2.90–2.75
(m, 5H).13C NMR (101 MHz, DMSO-d6)
δ
155.6, 149.5, 147.7 (2JC-F = 34.4 Hz), 146.2, 143.1, 130.3, 130.1
(3JC-F = 6.1 Hz), 129.8, 128.1, 123.6, 121.7 (1JC-F = 275.7 Hz), 115.3, 68.6, 56.6, 50.3, 36.0.
(S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-((4-nitrophenethyl)amino)ethan-1-ol (4j)
2-(4-nitrophenyl)ethan-1-amine hydrochloride (100 mg, 3 eq) was quenched by NaOH 1M then
extracted with ethyl acetate. The combined organic layers were dried and the resulting solid was
reacted with (S)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline (50 mg, 1 eq) according to the general
procedure. The crude product was purified by chromatography on silica gel (DCM then DCM/5%
NH3 in MeOH: 99/1) to give 60 mg (78% yield) of white solid. [α]2D6 = +44.6 (c 0.1, DCM); ee = 94%
(column Chiralpak IA, heptane/iPrOH: 9/1, 1 mL/min, tR(R) = 24.7 min, tR(S) = 57.7 min); HRMS (ESI,
m/z): calculated for [M + H] C21H18N3O3F6, 474.1252, found 474.1251. NMR, IR spectra and mp were
the same as 4i.
Methyl (R)-4-(2-((2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-hydroxyethyl)amino)ethyl)benzoate (4k
)
(R)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline was reacted with methyl 4-(2-aminoethyl)benzoate
(90 mg, 3 eq) according to the general procedure. The crude product was purified by chromatography
on silica gel (DCM/5% NH3 in MeOH: 99.5/0.5) to give 61 mg (77% yield) of white solid. m.p. 167 ◦C;
ν
max: 2952, 2918, 2847, 1715, 1607, 1542, 1434, 1282, 1105, 890, 768, 703 cm−1
;
[α]2D6
= −67.9 (c 0.1, DCM);
ee = 99% (column Chiralpak IG, heptane/iPrOH: 9/1, 1mL/min, tR(R) = 11.5 min, tR(S) = 32.3 min);
HRMS (ESI, m/z): calculated for [M + H] C23H21N2O3F6, 487.1456, found 487.1459; 1H NMR (400 MHz,
Chloroform-d)
δ
8.18 (d, 3J = 8.6 Hz, 1H), 8.16 (d, 3J = 7.4 Hz, 1H), 8.09 (s, 1H), 7.90 (d, 3J = 8.3 Hz, 2H),
7.71 (t, 3J = 7.9 Hz, 1H), 7.28 (d, 3J = 8.2 Hz, 2H), 5.45 (dd, 3J = 8.8 Hz,3J = 3.5 Hz, 1H), 3.92 (s, 3H), 3.18
(dd, 2J = 12.5 Hz, 3J = 3.7 Hz, 1H), 3.11–2.93 (m, 2H), 2.91–2.85 (m, 2H), 2.73 (dd, 2J = 12.6 Hz, 3J = 8.8
Hz, 1H).13C NMR (101 MHz, Chloroform-d) 166.9, 148.8 (2JC-F = 35.7 Hz), 144.7, 130.0, 128.7, 128.7,
δ
127.1, 126.8, 126.5, 114.5, 67.4, 55.4, 52.1, 50.2, 36.6.
Methyl (S)-4-(2-((2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-hydroxyethyl)amino)ethyl)benzoate (4l)
(S)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline was reacted with methyl 4-(2-aminoethyl)benzoate
(90 mg, 3 eq) according to the general procedure. The crude product was purified by chromatography
on silica gel (Et2O then Et2O/5% NH3 in MeOH: 99/1 to 97/3) to give 42 mg (53% yield) of white solid.
[α]2D6 = +55.4 (c 0.1, DCM); ee = 94% (column Chiralpak IG, heptane/iPrOH: 9/1, 1mL/min, tR(R) =
11.6 min, tR(S) = 32.1 min); HRMS (ESI, m/z): calculated for [M + H] C23H21N2O3F6, 487.1456, found
487.1463. NMR, IR spectra and mp were the same as 4k.
(R)-4-(2-((2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-hydroxyethyl)amino)ethyl)benzonitrile (4m)
4-(2-aminoethyl)benzonitrile hydrochloride (90 mg, 3 eq) was quenched by NaOH 1M then extracted
with ethyl acetate. The combined organic layers were dried and the resulting solid was reacted with
(R)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline (50 mg, 1 eq) according to the general procedure.
The crude product was purified by chromatography on silica gel (Et2O then Et2O/5% NH3 in MeOH:
96.5/3.5) to give 64 mg (86% yield) of white solid. m.p. 140 ◦C;
988, 889, 830, 763, 703 cm−1
[α]2D6
63.6 (c 0.1, DCM); ee = 99% (column Chiralpak IG, heptane/iPrOH:
9/1, 1mL/min, tR(R) = 13.8 min, tR(S) = 39.8 min); HRMS (ESI, m/z): calculated for [M + H] C22H18N3OF6,
νmax: 2855, 2233, 1605, 1457, 1308, 1110,
;
=
−

Pharmaceuticals 2019, 12, 91
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454.1354, found 454.1350; 1H NMR (400 MHz, Chloroform-d)
δ
8.21 (d, 3J = 8.5 Hz, 1H), 8.19 (d, 3J = 8.5
Hz, 1H), 8.11 (s, 1H), 7.74 (t, 3J = 7.9 Hz 1H), 7.63 (d, 3J = 8.2 Hz, 2H), 7.34 (m, 2H), 5.49 (dd, 3J = 3.6 Hz,
3J = 8.8 Hz,1H), 3.21 (dd, 2J = 12.6 Hz, 3J = 3.7 Hz, 1H), 3.10–2.96 (m, 2H), 2.94–2.90 (m, 2H), 2.78 (dd,
2J = 12.6 Hz, 3J = 8.7 Hz, 1H).13C NMR (101 MHz, Chloroform-d)
δ
151.0, 148.8 (2JC-F= 35.4 Hz), 150.0,
143.7, 132.4, 129.5, 128.8 (3JC-F = 5.8 Hz), 127.1, 126.8, 123.5 (1JC-F = 274.7 Hz), 121.1 (1JC-F = 276.7 Hz),
119.9, 114.5 (3JC-F = 2.0 Hz), 67.5, 55.4, 50.0, 36.7.
(S)-4-(2-((2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-hydroxyethyl)amino)ethyl)benzonitrile (4n)
4-(2-aminoethyl)benzonitrile hydrochloride (90 mg, 3 eq) was quenched by NaOH 1M then extracted
with ethyl acetate. The combined organic layers were dried and the resulting solid was reacted with
(S)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline (50 mg, 1 eq) according to the general procedure.
The crude product was purified by chromatography on silica gel (Et2O then Et2O/5% NH3 in MeOH:
96/4) to give 62 mg (84% yield) of white solid. [α]2D6 = +45.1 (c 0.1, DCM); ee = 90% (column Chiralpak
IG, heptane/iPrOH: 9/1, 1mL/min, tR(R) = 13.9 min, tR(S) = 39.2 min); HRMS (ESI, m/z): calculated for
[M + H] C22H18N3OF6, 454.1354, found 454.1353. NMR, IR spectra and mp were the same as 4m.
(R)-4-(2-((2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-hydroxyethyl)amino)ethyl)benzoic acid (4o)
Methyl (R)-4-(2-((2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-hydroxyethyl)amino)ethyl)benzoate 4k
(560 mg, 1 eq) was solved in THF/H2O (2 mL, v/v: 1/1), then LiOH.H2O (100 mg, 2 eq) was added. The
mixture was heated at 68 ◦C during 16H. The crude product was quenched by HCl until pH=7. The
precipitate formed during neutralization was filtered and washed with water. Thirty-nine milligrams
(72 % yield) of a white solid were obtained. m.p. 217 ◦C;
1104, 767 cm−1
[α]2D6
26.1 (c 0.1, MeOH); HRMS (ESI, m/z): calculated for [M + H] C22H19N2O3F6,
473.1300, found 473.1295; 1H NMR (400 MHz, Methanol-d4)
νmax: 3392, 2925, 1592, 1546, 1372, 1310,
;
=
−
δ
8.46 (d, 3J = 8.5 Hz, 1H), 8.19 (d, 3J = 7.2
Hz, 1H), 8.11 (s, 1H), 7.82 (d, 3J = 8.0 Hz, 2H), 7.81 (t, 3J = 8.4 Hz, 1H), 7.21 (d, 3J = 8.0 Hz, 2H), 5.78 (dd,
3J = 2.9 Hz, 3J = 9.7 Hz, 1H), 3.29 (dd, 2J = 12.8 Hz, 3J = 2.8 Hz, 1H), 3.20–3.12 (m, 2H), 3.07 (dd, 2J =
12.8 Hz, 3J = 9.7 Hz, 1H), 2.96 (t, 3JH16/H15 = 7.8 Hz, 2H). 13C NMR (101 MHz, Methanol-d4)
δ 150.9,
147.9, 140.6, 129.7, 129.0, 128.2, 128.0, 127.7, 114.6, 65.3, 52.9, 48.5, 31.9.
(S)-4-(2-((2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-hydroxyethyl)amino)ethyl)benzoic acid (4p)
Methyl (S)-4-(2-((2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2 hydroxyethyl)amino)ethyl)benzoate 4l
(560 mg, 1 eq) was solved in THF/H2O (2 mL, 1:1 v/v), then LiOH.H2O (100 mg, 2 eq) was added.
The mix was heated at 68 ◦C during 16H.The crude product was quenched by HCl until pH=7. The
precipitate formed during neutralization was filtered and washed with water. Forty-five milligrams
(68% yield) of a white solid were obtained. [α]2D6 = +43.6 (c 0.1, MeOH); HRMS (ESI, m/z): calculated
for [M + H] C22H19N2O3F6, 454.1300, found 454.1297. NMR, IR spectra and mp were the same as 4o.
(R)-4-(2-((2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-hydroxyethyl)amino)ethyl)benzamide (4q)
(R)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline was reacted with 4-(2-aminoethyl)benzamide
(120 mg, 4.5 eq) according to the general procedure. The crude product was purified by chromatography
on silica gel (DCM then DCM/5% NH3 in MeOH: 96/4) to give 20 mg (26% yield) of white solid. m.p.
155 ◦C;
ν
max: 3363, 3281, 3170, 2928, 2534, 1629, 1425, 1308, 1103, 764 cm−1
;
[α]2D6
=
−
37.7 (c 0.1, MeOH);
HRMS (ESI, m/z): calculated for [M + H] C22H20N3O2F6, 472.1460, found 472.1466; 1H NMR (400 MHz,
Methanol-d4) δ
8.39 (d, 3J = 8.6 Hz, 1H), 8.14 (d, 3J = 7.3 Hz, 1H), 8.02 (s, 1H), 7.75 (t, 3J = 8.0 Hz, 1H),
7.70 (d, 3J = 8.0 Hz, 2H), 7.21 (d, 3J = 8.0 Hz, 2H), 5.55 (dd, 3J = 3.0 Hz, 3J = 8.0 Hz, 1H), 2.93–2.88 (dd,
2J = 12.8 Hz, 3J = 3.2 Hz, 1H), 2.87–2.76 (m, 4H), 2.75 (dd, 2J = 12.4 Hz, 3J = 8.6 Hz, 1H). 13C NMR
(101 MHz, Methanol-d4)
δ
171.9, 153.3, 147.7 (2JC-F = 34.4 Hz), 144.0, 143.4, 131.5, 128.8 (3JC-F = 6.1 Hz),
128.5, 127.6, 127.5, 127.3, 123.8 (1JC-F = 273.7 Hz), 121.1 (1JC-F = 275.7 Hz), 114.2, 68.1, 55.8, 50.1, 35.3.

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(S)-4-(2-((2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-hydroxyethyl)amino)ethyl)benzamide (4r)
(S)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline was reacted with 4-(2-aminoethyl)benzamide
(120 mg, 4.5 eq) according to the general procedure. The crude product was purified by chromatography
on silica gel (DCM then DCM/5% NH3 in MeOH: 96/4) to give 30 mg (39% yield) of white solid. [α]D26
=
+44.1 (c 0.1, MeOH); HRMS (ESI, m/z): calculated for [M + H] C22H20N3O2F6, 472.1460, found 472.1460.
NMR, IR spectra and mp were the same as 4q.
(R)-4-(2-((2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-hydroxyethyl)amino)ethyl)benzene
sulfonamide (4s)
(R)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline
was
reacted
with
4-(2-aminoethyl)
benzenesulfonamide (98 mg, 3 eq) according to the general procedure. The crude product
was purified by chromatography on silica gel (DCM then DCM/5% NH3 in MeOH: 97/3) to give 63 mg
(76% yield) of white solid. m.p. 203 ◦C;
ν
max: 3419, 3304, 2932, 2856, 1596, 1311, 1158, 1100, 830, 691
cm−1
found 508.1145; 1H NMR (400 MHz, Methanol-d4)
;
[α]2D6
=
−
40.0 (c 0.1, MeOH); HRMS (ESI, m/z): calculated for [M + H] C21H20N3O3F6S, 508.1130,
δ
8.53 (d, 3J = 8.4 Hz, 1H), 8.28 (d, 3J = 7.1 Hz, 1H),
8.15 (s, 1H), 7.89 (t, 3J = 8.0 Hz, 1H), 7.85 (d, 3J = 8.3 Hz, 2H), 7.43 (d, 3J = 8.3 Hz, 2H), 5.68 (dd, 3J = 3.0
Hz, 3J = 8.8 Hz, 1H), 3.03 (dd, 2J = 12.4 Hz, 3J = 3.2 Hz, 1H), 3.00–2.90 (m, 4H), 2.86 (dd, 2J = 12.4 Hz, 3J
= 8.8 Hz, 1H). 13C NMR (101 MHz, Methanol-d4)
δ
144.5, 143.4, 141.6, 129.0, 128.9 (3JC-F = 5.5 Hz),
127.7, 127.3, 126.6, 126.0, 121.1 (1JC-F = 275.5 Hz), 123.8 (1JC-F = 275.5 Hz), 114.2, 68.1, 55.8, 50.1, 35.3.
(S)-4-(2-((2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-hydroxyethyl)amino)ethyl)benzene
sulfonamide (4t)
(S)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline
was
reacted
with
4-(2-aminoethyl)
benzenesulfonamide (98 mg, 3 eq) according to general procedure. The crude product was
purified by chromatography on silica gel (DCM then DCM/5% NH3 in MeOH: 97/3) to give 64 mg
(77% yield) of white solid. [α]2D6 = +43.0 (c 0.1, MeOH); HRMS (ESI, m/z): calculated for [M + H]
C21H20N3O3F6S, 508.1130, found 508.1126. NMR, IR spectra and mp were the same as 4s.
(R)-2-((4-aminophenethyl)amino)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)ethan-1-ol (4u)
(R)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline was reacted with 4-(2-aminoethyl)aniline (68 µL,
3 eq) according to general procedure. The crude product was purified by chromatography on silica gel
(DCM/5% solution NH3 in MeOH 99:1 then DCM/5% NH3 in MeOH: 97/3) to give 64 mg (89% yield) of
white solid. m.p. 155 ◦C;
[α]2D6
444.1506; 1H NMR (400 MHz, Methanol-d4)
ν ;
max: 3286, 2928, 1606, 1514, 1433, 1372, 1305, 1101, 893, 829, 767, 702 cm−1
= 40.9 (c 0.1, MeOH); HRMS (ESI, m/z): calculated for [M + H] C21H20N3OF6, 444.1511, found
−
δ
8.08 (d, 3J = 8.2 Hz, 1H), 8.06 (d, 3J = 7.3 Hz, 1H), 8.00 (s,
1H), 7.62 (t, 3J = 8.2 Hz, 1H), 6.87 (d, 3J = 8.3 Hz, 2H), 6.53 (d, 3J = 8.3 Hz, 2H), 5.36 (dd, 3J = 3.6 Hz,
3J = 8.7 Hz, 1H), 3.05 (dd, 2J = 12.5 Hz, 3J = 3.7 Hz, 1H), 2.86 (m, 2H), 2.65–2.58 (m, 2H). 13C NMR
(101 MHz, Methanol-d4)
δ
148.7 (2JC-F = 35.1 Hz), 144.8, 143.5, 129.6, 129.0, 128.7 (3JC-F = 5.4 Hz), 127.3,
127.0, 126.5, 123.3 (1JC-F = 274.9 Hz), 120.9 (1JC-F = 275.6 Hz), 115.4, 114.5, 67.4, 55.4, 50.7, 35.3.
(S)-2-((4-aminophenethyl)amino)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)ethan-1-ol (4v)
(S)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline was reacted with 4-(2-aminoethyl)aniline (68
µL,
3 eq) according to the general procedure. The crude product was purified by chromatography on silica
gel (DCM/5% solution NH3 in MeOH: 99/1 to 97/3) to give 64 mg (89% yield) of white solid. [α]D26
= +53.4 (c 0.1, MeOH); HRMS (ESI, m/z): calculated for [M + H] C21H20N3OF6, 444.1511, found =
444.1508. NMR, IR spectra and mp were the same as 4u.

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3.3. Antibacterial Assays
The following strains were used for testing antibacterial susceptibility to 4a–4v and 3m/3n:
Escherichia coli DSM 1103 and Pseudomonas aeruginosa DSM 1117 for Gram-negative bacteria (Deutsche
Sammlung für Mikroorganismen, Braunschweig, Germany) and Staphylococcus aureus CIP 103.429
and Enterococcus faecalis CIP 103.214 (Collection de l’Institut Pasteur, Paris, France) for Gram-positive
bacteria. Bacteria were grown overnight at 35 ◦C in Tryptic Soy Broth and streaked on Tryptic Soy
Agar (TSA) (AES, Bruz, France). From these isolation plates, inocula were prepared according to
CLSI recommendations [27] and the broth microdilution technique carried out in Mueller–Hinton
Broth (pH 7.4) as advised using drug concentrations ranging from 0.0625 to 128 µg/mL obtained
from serial two-fold dilutions of stock solutions of compounds 3 or 4 in DMSO (Sigma-Aldrich,
Saint-Quentin Fallavier, France). Ciprofloxacin (Sigma-Aldrich, France) was used as control in each
series of experiments. The minimum inhibitory concentration (MIC) was determined as the lowest
concentration at which wells remained visually clear.
3.4. Antimycobacterial Tests
Susceptibility testing by broth microdilution technique was performed in duplicate on
Mycobacterium avium ATCC 700,898 (also known as « MAC 101 ») according to CLSI guidelines [28].
Inocula were prepared in saline solution using transparent colonies and standardized using
a nephelemeter, then diluted in the appropriate media to obtained a final solution around
5 × 105 CFU/mL. As recommended by CLSI, the susceptibility testing was first realized in CAMHB
medium (Sigma-Aldrich, France) complemented with 5% OADC (Becton, Dickinson and Company,
Le-Pont-de-Claix, France). Also, the same procedure was applied in MB 7H9 medium (Sigma-Aldrich,
Saint-Quentin Fallavier, France) + 5% OADC to avoid potential medium-dependent activity of the
tested compounds. Ninety-six-wells transparent polystyrene microplates (Thermo-Scientific, Illkirch,
France) were incubated static at 37 ◦C during 14 days before reading. A clarithromycin (Sigma-Aldrich,
France) stock solution in acetone was used as control in each series of experiments and results were
compared with CLSI breakpoints. Activities of the compounds synthetized during this study were
determined for high drug concentrations ranging from 2 to 64
lowest concentration at which wells remained visually clear.
µg/mL. The MIC was determined as the
4. Conclusions
We have prepared more than twenty novel quinoline-based drugs
synthesis with good enantiomeric excesses (>90%). These compounds were either active against
Gram-positive bacteria (MIC g/mL for 4c 4h and 4k 4l) or E. coli (MIC = 32–64 g/mL for 4q 4v
according to the global lipophilicity of the compounds. Unfortunately, these quinolines were weakly
active against M. avium. Interestingly, all compounds of the previously synthesized series were
efficient on M. avium with MIC = 2–16 g/mL, whatever the clogP value and the side chain length.
4 in a five-step asymmetric
≤
4
µ
–
/
µ
–
)
4
3
µ
This study has confirmed the strong antibacterial potential of quinoline-based drugs in relation with
their lipophilicity. Further studies are under progress in order to better understand their mechanism(s)
of action.
1
Supplementary Materials: All H and 13C NMR spectra of compounds 4a
–4u (Figures S1–S22) are available
online at http://www.mdpi.com/1424-8247/12/2/91/s1.
Author Contributions: The project was conceptualized, validated and under the supervision of A.D.-K. and P.S.
P.L. was in charge of synthesis and structural characterization of all the described compounds. S.D.-N. was in charge
of the mass spectra analysis of all the described compounds. The anti-bacterial activity against Gram-positive and
Gram-negative strains were carried out by P.L. under the supervision of C.M. The anti-mycobacterial assays were
performed by François Peltier under the supervision of S.C. and C.A. P.L., A.D.-K. and P.S. wrote the manuscript.
Funding: Pierre Laumaillé is the recipient of the Hauts-de-France region grant.
Conflicts of Interest: The authors declare no conflict of interest.

Pharmaceuticals 2019, 12, 91
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2019 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
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).