Incorporation of a 3-(2,2,2-Trifluoroethyl)-γ-hydroxy-γ-lactam motif in the side chain of 4-aminoquinolines. Syntheses and antimalarial activities

Article abstract of DOI:10.1021/jm301076q

In this paper we report the synthesis and antimalarial properties of two series of fluoroalkylated γ-lactams derived from 4-aminoquinoline as potent chemotherapeutic agents for malaria treatment. These molecules obtained in several steps resulted in the identification of very potent structures with in vitro activity against Plasmodium falciparum clones of variable sensitivity (3D7 and W2) in the range of 19-50 nM with resistance indices in the range of 1.0-2.5. In addition, selected molecules (50, 51, 58, 60, 63, 70, 72, 74, 78, 81, 84, and 87) that are representative of the two series of compounds did not show cytotoxicity in vitro when tested against human umbilical vein endothelial cells up to a concentration of 100 μM. The most promising compounds (82 and 84) showed significant IC₅₀ values close to 26 and 19 nM against the chloroquino-sensitive strain 3D7 and 49 and 42 nM against the multi-drug-resistant strain W2. Furthermore, two model compounds (50 and 70) were found to be quite stable over 48 h at pH 7.4 and 5.2. Overall, our preliminary data indicate that this class of structures contains promising candidates for further study.

Full text of DOI:10.1021/jm301076q

Article
pubs.acs.org/jmc
Incorporation of a 3‑(2,2,2-Trifluoroethyl)-γ-hydroxy-γ-lactam Motif
in the Side Chain of 4‑Aminoquinolines. Syntheses and Antimalarial
Activities
Damien Cornut,†,‡ Hugues Lemoine,†,‡ Oleksandr Kanishchev,† Etsuji Okada,§ Florian Albrieux,⊥
Abdoul Habib Beavogui,‡,∥ Anne-Lise Bienvenu,‡,∥ Stephane Picot,‡,∥ Jean-Philippe Bouillon,*,†
́
and Maurice Medebielle*,‡
́
†Equipe “Biomolec
́
ules Fluoree
́
s”, Chimie Organique Bioorganique Rea
Chimie Organique Fine de Rouen (IRCOF), UMR CNRS 6014, Universite
Rouen, F-76821 Mont Saint Aignan Cedex, France
́
ctivite
́
et Analyses (COBRA), Institut de Recherche en
s (INSA) de
́
et Institut National des Sciences Appliquee
́
‡Equipe “Synthes
Supramolec
Lyon, Batiment Curien, 43 bd du 11 Novembre 1918, F-69622 Villeurbanne, France
̀
e de Molec
́
ules d’Inter
́
et
̂
Ther
́
apeutique (SMITH)”, Institut de Chimie et Biochimie Molec
́
ulaires et
́
ulaires (ICBMS), UMR CNRS-UCBL-INSA Lyon 5246, Universite
́
Claude Bernard Lyon 1 (UCBL), Universite de
́
̂
§Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai-cho, Nada-ku,
Kobe 657-8501, Japan
∥Malaria Research Unit (MRU), Faculte
France
́
de Med
́
ecine, Universite
́
Claude Bernard Lyon 1, 8 avenue Rockefeller, F-69373 Lyon Cedex,
⊥ICBMS and Centre Commun de Spectromet
́
rie de Masse (CCSM), Universite
́
Claude Bernard Lyon 1, Batiment Curien, 43 bd du
̂
11 Novembre 1918, F-69622 Villeurbanne, France
S
* Supporting Information
ABSTRACT: In this paper we report the synthesis and antimalarial properties
of two series of fluoroalkylated γ-lactams derived from 4-aminoquinoline as
potent chemotherapeutic agents for malaria treatment. These molecules
obtained in several steps resulted in the identification of very potent structures
with in vitro activity against Plasmodium falciparum clones of variable sensitivity
(3D7 and W2) in the range of 19−50 nM with resistance indices in the range of
1.0−2.5. In addition, selected molecules (50, 51, 58, 60, 63, 70, 72, 74, 78, 81,
84, and 87) that are representative of the two series of compounds did not show
cytotoxicity in vitro when tested against human umbilical vein endothelial cells
up to a concentration of 100 μM. The most promising compounds (82 and 84)
showed significant IC50 values close to 26 and 19 nM against the chloroquino-
sensitive strain 3D7 and 49 and 42 nM against the multi-drug-resistant strain
W2. Furthermore, two model compounds (50 and 70) were found to be quite stable over 48 h at pH 7.4 and 5.2. Overall, our
preliminary data indicate that this class of structures contains promising candidates for further study.
antimalarial drugs,1−4 and new agents with improved activity
INTRODUCTION
■
against CQ-resistant (CQR) strains have been introduced via
synthetic modifications of the CQ side chain.5−10 Another
current strategy to overcome the resistance mechanism of 4-
aminoquinolines is to develop dual drugs based on the 7-
chloro-4-aminoquinoline skeleton, such as the trioxaquines and
other hybrid molecules.11−14 The search for new CQ analogues
that are equally active against CQ-sensitive (CQS) and CQR
strains has received increasing attention during recent years.
Various studies have revealed that most of the structural
changes of the 7-chloroquinoline ring in the CQ reduce the
activity, whereas alterations of the CQ side chain appear to be a
Malaria is an infectious disease that affects approximately 300
million people annually, causing about 1 million deaths (mostly
young children). It is most common in tropical and subtropical
areas, and 90% of all cases are found in sub-Saharan Africa.
Antimalarial drug resistance, particularly the widespread
resistance of many Plasmodium falciparum strains to most
readily available drugs, including the recent artemisin-based
combined therapies, hinders malaria control and is therefore a
major public health problem. Resistance to antimalarial drugs
has increased the global cost of controlling the disease.
Resistance, as well as the absence of a vaccine, causes an
urgent need for new effective, safe, and affordable drugs. 7-
Chloro-4-aminoquinoline derivatives, including chloroquine
(CQ) and amodiaquine (AQ), were among the most potent
Received: July 24, 2012
© XXXX American Chemical Society
A
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promising approach. One modification that is of current
interest is to replace the basic tertiary nitrogen atom of CQ
with other functionalities which may give rise to molecules with
improved metabolic stability and induce better resistance
profiles.
For some years we have been developing methodologies to
generate fluoroalkylated heterocycles using perfluoroketene
dithioacetals as versatile building blocks.15−24 Among the
different heterocyclic structures that have been disclosed, γ-
lactams bearing a trifluoroethyl moiety were readily obtained
from the reaction of primary amines and several α,β-
unsaturated γ-lactones,18 as well as from the treatment of
fluoroalkylated γ-ketothioesters with diisopropylamine followed
by addition of various primary amines (Figure 1).22
To the best of our knowledge, the methodologies presented in
this study have not been used before for the design of
antiplasmodials, and no synthetic, non-natural γ-hydroxy-γ-
lactams have been evaluated as potent antimalarials. When the
project was initiated in 2008, only one paper describing the
parallel synthesis of 4-aminoquinoline γ-lactams through an
intramolecular multicomponent reaction (Ugi three-compo-
nent four-center reaction, Ugi 3C/4C)27 using levulinic acid,
commercially available tert-butyl isocyanide, or cyclohexyl
isocyanide and 7-chloroquinoline-derived diamines was consid-
ered to be relevant to our study (Figure 3).28
Figure 3. Antimalarial 4-aminoquinoline γ-lactams.
In this paper we present the first results of our efforts
directed to the synthesis and antimalarial evaluation of two
series (A and B) of new γ-hydroxy-γ-lactams bearing a 4-
aminoquinoline skeleton using readily available perfluoroketene
dithioacetal building blocks. The general structure of our
targets is depicted in Figure 4.
Figure 1. γ-Lactam derivatives with a trifluoroethyl moiety.
The resulting 3-substituted 5-hydroxypyrrolin-2-ones are a
class of compounds that are found in many natural products
and bioactive derivatives.25 Interestingly, some, but a few, of
these γ-hydroxy-γ-lactams from natural sources have been
screened as potent antiplasmodial agents, and a number of
them displayed interesting antimalarial activities (Figure 2).26
Figure 4. Our targeted 4-aminoquinoline γ-hydroxy-γ-lactams.
The design of these new molecules was based on different
structural variations that can lead to the generation of a diverse
set of molecules. Overall, our study was expected to establish
which primary substitutions are tolerated on the γ-lactam and
the 4-aminoquinoline moieties and how these modifications
provide potential hits with low cytotoxicity and a good
resistance profile. Molecules thus generated were based on
(a) the variation of the length of the spacer, (b) the
introduction of a basic nitrogen moiety(ies) in the spacer to
potentially increase food vacuole accumulation and also to
generate a hydrogen bond acceptor as well as induce better
solubility via possible salt formulation, (c) substitution on the
quinoline ring at the C-3 position (R1 = H or COCF3) since we
already know from our previous work29 that 7-chloro-3-
(trifluoroacetyl)-4-((3-(dimethylamino)propyl)amino)-
quinoline showed an antimalarial effect against Plasmodium
berghei in mice with a 2-fold intraperitoneal injection dose of
100 mg/kg with a 60% survival rate after 14 days and an
infection rate of erythrocytes of 2.1% after three days and
16.6% after seven days (for comparison CQ has 0% and <1%
infection rates after three and seven days) as well as at the C-7
position (X = Cl, H),29 (d) the introduction of different
aromatic, aliphatic, benzyl, or heteroraryl moieties (R2, R3, R4,
and R′4) to study the impact of hydrophobic and lipophilic
moieties on activity, and (e) the introduction of a
fluoroalkylated moiety (R5) that may help to some extent to
Figure 2. γ-Hydroxy-γ-lactam derivatives from natural sources with
known antimalarial activities.
Introducing such γ-lactam scaffolds using our current
methodologies,18,22 with different possible functionalities,
including fluorine moieties, in the side chain of 4-aminoquino-
lines in a first exploratory study, may provide molecules with
interesting antimalarial activities, possible new modes of action
with an ultimate aim then to extend the syntheses and data
generated in this study to other more or less complex structures
without the typical 4-aminoquinoline skeleton; such a γ-lactam
skeleton may be well adapted to (a) decrease potential
metabolic dealkylation processes due to the presence of a
tertiary nitrogen, (b) provide simpler analogues than those
found in natural products, and (c) generate molecular diversity
for structure−activity relationships and hit to lead optimization.
B
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Figure 5. Targeted molecules, series A and B, and retrosynthetic analysis.
a
decrease some possible metabolism processes as well as to
potentially increase bioavailability.30
Scheme 1
CHEMISTRY
■
On the basis of our experience with the synthesis of fluorinated
γ-lactams,18,22 we envisaged to prepare two series of structures,
A and B (Figure 5). The two sets of molecules differ in their
substitutions on the γ-lactam and quinoline rings to generate
more diversity. They are prepared in 7−8 steps from
commercially available perfluoroalkyl esters 1−3. The first
key perfluoroketene dithioacetal building blocks 4−
1017,18,21,22,24 (6 and 8 are new compounds) were obtained
in three steps (Scheme 1) using our published procedures from
the reduction of the esters 1−3 using lithium aluminum
hydride in diethyl ether at 0 °C followed by aqueous acid
hydrolysis to give the corresponding aldehyde hydrates, which
are directly treated with appropriate thiols in the presence of
TiCl4 in dichloromethane to provide the corresponding
dithioacetals. HF elimination of the latter in the presence of
potassium hydroxide under phase transfer catalysis yielded the
compounds 4−10. These intermediates were purified by
distillation under reduced pressure or were pure enough to
be used directly in the two next steps to provide the γ-
ketothioesters 20−2821,22,24 (24−27 are new compounds) by
substitution of the vinylic fluoride with the appropriate
potassium enolate of ketones in THF at 0 °C and final
hydrolysis in the presence of trifluoroacetic acid and water
under refluxing conditions (Scheme 1 and Table 1).
a
Reagents and conditions: (a) LiAlH4 in Et2O at 0 °C, then aq H2SO4,
EtOH; (b) R6SH (2.0 equiv) + TiCl4 (3 equiv) in CH2Cl2; (c) aq
KOH + cat Bu4NBr in CH2Cl2; (d) R7COMe/KH in THF at 0 °C;
(e) CF3CO2H/H2O, reflux (see Table 1 for the different substitutions
and yields).
starting materials 2931 and 3029,32 with 1-(trifluoroacetyl)-4-
(dimethylamino)pyridinium trifluoroacetate (generated in situ)
followed by aromatic nucleophilic substitution (N−N exchange
reaction) of the 4-dimethylamino moiety with commercially
available diamines. The 4-aminoquinoline amines 33−35 were
obtained in 76−92% isolated yields and were found to be pure
enough to be engaged in the final step of the synthesis (traces
of the corresponding dimers were observed by mass
spectrometry, but these impurities were removed at the latest
stage of the chemical synthesis). Amines 36−3828,34,35 (39−41
are new compounds; 41 was mentioned in a patent without the
Appropriate amines 33−35 (Scheme 2) bearing a trifluor-
oacetyl moiety were prepared using our published procedure,31
via the trifluoroacetylation of 4-(dimethylamino)quinoline
C
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Journal of Medicinal Chemistry
Article
experiments were carried out twice with wells in triplicate.
Data are reported as mean IC50 values (Figures S1−S2 of the
Supporting Information).
Table 1. Synthesis of γ-Ketothioesters 20−28
a
γ-ketothioester
RF
CF3
R7
CH3
R6
C6H5
yield (%)
20
21
22
23
24
25
26
27
28
60
62
51
86
53
64
72
65
61
Selected compounds (50, 51, 58, 60, 63, 70, 72, 74, 78, 81,
84, and 87) were also tested for cytotoxicity against human
umbilical vein endothelial cell (HUVEC) lines. Endothelial cells
were used for these experiments to reproduce the physiological
conditions associated with the use of an antimalarial drug
against blood stage parasites. These cells are the major target of
parasitized red blood cells, and any additional injury may
counteract the beneficial effect of antimalarial drugs. The lack of
cytotoxicity against endothelial cells is expected to be a major
benefit for any new drug. All experiments were carried out
twice.
CF3
CH3
p-ClC6H4
p-BrC6H4
C2H5
CF3
CH3
CF3
CH3
CF3
CH3
CH2C6H5
C2H5
CF3
C6H5
p-BrC6H4
CH3
CF3
C2H5
C2F5
H(CF2)2
C2H5
CH3
C2H5
a
Overall isolated yield for the last two steps (from compounds 4−10).
procedure and spectral data36) were prepared following known
procedures (the piperazine diamine precursor to prepare 41
was prepared as described in the literature33).
Finally, the stability of two representative compounds (50
and 70) in pH 5.2 and 7.4 buffers was evaluated over 48 h using
LC/MS (Figures S3−S7 of the Supporting Information).
Of the 40 compounds tested, 10 compounds showed
reasonable potency (IC50 < 100 nM) against the CQ-sensitive
3D7 strain and CQ-resistant W2 strain with roughly equipotent
activity against the two strains. Two compounds (85, 87)
exhibited high activity (IC50 = 49 and 42 nM, respectively)
against the CQ-resistant W2 strain, while the activity against
CQ-sensitive 3D7 was on the same order as that of chloroquine
(IC50 = 26 and 19 nM, respectively). The length of the spacer
had generally a dramatic influence on the activity, with three
methylene spacers better than four and six methylene spacers;
introduction of a basic nitrogen in the spacer (−NMe, −NH,
and piperazine, 58, 60, 61, 63, 72, and 83) greatly improved
the activity on both strains, as long as the R2 moiety was not a
sulfonyl one, which induced decreased reactivity on the CQ-
resistant W2 strain. The beneficial effect of such a basic
nitrogen as well as the length of the spacer has already been
demonstrated in other studies.7−9 The sulfur atom in series A
and B may raise some concern for potential in vivo
metabolization to the sulfoxide and sulfone; while we have
not yet prepared the sulfoxide analogues, our current data
indicate that the sulfonyl derivatives (at least in series A) are
less active on the CQ-resistant W2 strain but not to a great
extent and have almost similar activity on the CQ-sensitive 3D7
strain. The trifluoroacetyl moiety in 64−68 was a “poor”
The γ-ketothioesters 20−22, when treated with diisopropyl-
amine in diethyl ether, give rise to sulfides 42−44 and sulfones
45−47 (after mCPBA oxidation in dichloromethane), γ-
lactones, according to our published methodology18,21 or
furan intermediates from γ-ketothioesters 23−28 using our
standard conditions in the presence of diisopropylamine in
diethyl ether.22 The coupling reactions (lactamization) in
anhydrous THF (room temperature or refluxing conditions) of
amines 33−41 with γ-lactones 42−47 gave final target
compounds of series A (48−68, Table 2), while furan
intermediates, which are usually not isolated (their formation
can be followed by 19F NMR analysis of the reaction mixture),
can be in situ trapped with appropriate amines 36 and 38−40
to give the final target compounds 69−83 of series B (Table 3).
γ-Lactams containing a fluoroalkene moiety (74−76) were
obtained from in situ base induced HF elimination. Aqueous
soluble citrate salts 84−88 were finally obtained in excellent
yields from the reaction of 58, 59, 62, 72, and 83 with citric
acid in acetone (Scheme 3).
BIOLOGICAL TESTING
■
All the compounds thus synthesized (40 new derivatives) were
evaluated against 3D7 chloroquino-sensitive and W2 chlor-
oquino-resistant strains of P. falciparum (Table 4). All
a
Scheme 2
a
Reagents and conditions: (a) 1-(trifluoroacetyl)-4-(dimethylamino)pyridinium trifluoroacetate in xylene, reflux, 31 (87%), 32 (95%); (b)
H2NCH2YCH2NH2 (5.0 equiv) in acetonitrile, room temperature or reflux, 33 (92%, reflux, 1 h), 34 (76%, room temperature, 2 h), 35 (83%, room
temperature, 2 h); (c) H2NCH2YCH2NH2 (3.0−3.5 equiv), neat, 90−135 °C, 2−4 h, 36 (>90%), 37 (>90%), 38 (>90%), 39 (23%), 40 (>95%), 41
(76%).
D
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a
Table 2. 4-Aminoquinoline-Derived γ-Hydroxy-γ-lactams, Series A
a
Reagents and conditions for the reaction: (a) i-Pr2NH (2 equiv), Et2O, rt, 15 h, 42 (51%), 43 (72%), 44 (27%); (b) mCPBA (3 equiv), CH2Cl2,
room temperature, 16 h, 45 (76%), 46 (65%), 47 (67%); (c) appropriate amine (2 equiv), THF, room temperature, 6 h (for 45−47), or reflux, 20−
b
36 h (for 42−44). Isolated yield.
substitution since the compounds were not active up to 1600
nM; this may be due to a lack of protonation of the nitrogen of
the quinoline ring (N-1) that resulted from the mesomeric
effect of the lone pair of the −NH on the electron-withdrawing
COCF3 substituent. Within this set of molecules bearing the
trifluoroacetyl moiety, molecules having either a chlorine or a
hydrogen were devoid of activity. Halogen substitution on the
aryl moiety R6 in series A has no great influence on activity if
compared to hydrogen (see, for example, 61 versus 60 and 58);
such halogens may offer some advantage in blocking potential
metabolization (for example, through cytochrome P450
oxidation), but may also increase the lipophilicity and potential
liability, especially with a bromine atom. A fluorine substitution
will be preferred, but these types of molecules have not yet
been synthesized. Generally, the compounds produced from
series B are to some degree less active than those generated in
series A. Fluoroalkene moieties in 74−76 seem not appropriate
since IC50 values higher than 100 nM were observed; this may
be due to their prononced reactivity (as possible Michael
acceptors) toward endogeneous nucleophiles that can produce
less potent and/or toxic metabolites.
Selected representative compounds (50, 51, 58, 60, 63, 70,
72, 74, 78, 81, 84, and 87) were evaluated against a mammalian
cell line (HUVECs) using final concentrations ranging from
E
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a
Table 3. 4-Aminoquinoline-Derived γ-Hydroxy-γ-lactams, Series B
b
compd
Y
R2
CH3
R5
R4
CF3
R′4
yield (%)
c
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
−CH2−
−SC2H5
−SC2H5
−SC2H5
−SC2H5
−SC2H5
−SC2H5
−SC2H5
−SC2H5
−SC2H5
−SCH2Ph
−SC2H5
−SC2H5
−SC2H5
−SC2H5
−SC2H5
H
H
H
H
H
36
c
−(CH2)2−
−(CH2)4−
−CH2NMeCH2−
−CH2NHCH2−
−CH2−
CH3
CF3
CF3
CF3
CF3
25
c
CH3
52
c
CH3
26
c
CH3
19
d
CH3
−CR4R′4 = −CCFCF2H
22
22
18
d
−(CH2)4−
−CH2−
CH3
−CR4R′4 = −CCFCF2H
d
CH3
−CR4R′4 = −CCFCF3
c
−CH2−
−CH2−
−CH2−
CH3
−CF2CF3
CF3
H
H
H
H
H
H
H
17
c
CH3
28
c
C6H5
C6H5
p-BrC6H4
p-BrC6H4
p-BrC6H4
CF3
46
c
−(CH2)4−
−CH2−
−(CH2)4−
−CH2NMeCH2−
CF3
37
c
CF3
20
c
CF3
16
c
CF3
18
a
Reagents and conditions for the reaction: (a) i-Pr2NH (2 equiv), Et2O, room temperature, 15 h; (b) appropriate amine (1.2 equiv), MeOH, room
b
c
d
temperature, 8−17 h. Isolated yield from γ-ketothioester. Diastereoisomeric mixture (for the ratio, see the Experimental Section). E stereoisomer.
a
Scheme 3
a
Reagents and conditions: (a) citric acid (1.0 equiv) in acetone at room temperature for 24 h, 84 (salt of 58, 93%), 85 (salt of 59, 97%), 86 (salt of
62, 94%), 87 (salt of 72, 93%), 88 (salt of 83, 76%).
0.01 to 100 μmol/L. We did not detect significant cytotoxicity,
and no relevant IC50 could be obtained in the concentration
range tested. On the basis of these data, we extrapolate a
minimum cytotoxicity value over the 10−100 μmol/L range for
all tested coumpounds, leading to an excellent selectivity
against parasites (both strains).
Two model compounds (50 and 70) were found to be quite
stable at pH 5.2 and 7.4 over 48 h with LC/MS monitoring; the
hemiaminal function in these series does not seem to be a
critical issue at these pH values since no dehydrated compound
or ring-opening product was observed (Figures S3−S7 of the
Supporting Information). For both compounds at pH 7.4, there
is an indication of formation of traces of new species; in the
case of 50 ([M + H]+ = 600.0) the new species at 15.0 min has
a molecular weight of [M + H]+ = 412.1 (89, Figure S4), which
may correspond to a loss of the p-bromothiophenol moiety. As
for compound 70 ([M + H]+ = 488.1), the new species at 15.9
min has a molecular weight of [M + H]+ = 468.1 (90, Figures
S6 and S7), which may correspond to the loss of a HF
molecule. Since these two species (89 and 90) are observed in
very minor amounts, no attempts to isolate them and to
confirm their structures have been made so far. In addition, for
compound 70, the ratio of diastereomers did not change
significantly for both pH values, with an equilibration of the
ratio of such isomers at pH 7.4 after 48 h (Figure S5).
Calculated physicochemical properties of the most potent
structures (not the citrate salts) were obtained (Table 5) using
ChemAxon software37 to assess if they were compliant with the
Lipinski “rule of five” criteria38 (Table 5); the data showed that
all molecules have (a) a molecular weight in the range of 517−
658, which is higher than the accepted 500, (b) a log P close to
or higher than 5.0, which may indicate that the compounds are
too lipophilic, and (c) a log D at pH 7.4 (permeability) usually
in the range of 1.2−2.8 except for two molecules with values
F
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Table 4. In Vitro Data of Compounds 48−88
Table 5. Calculated Physical Properties of the Best Active
Antimalarial Compounds
a
a
IC50(W2)
(nM)
IC50(3D7)
(nM)
IC50(W2)/
b
a
compound
IC50(3D7)
log D
(pH
7.4)
no. of H-
bond
donors
no. of H-
bond
acceptors
no. of
Lipinski
violations
chloroquine
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
750
110
210
302
810
391
>1000
796
395
391
391
55
30
107
102
351
297
273
>1000
800
335
275
500
47
25.0
1.0
2.1
0.9
2.7
1.4
a
compd
MW
log P
CQ
58
60
61
63
72
81
83
319.9
565.0
599.5
643.9
620.1
517.0
628.9
657.9
0.88
1.18
1.78
1.95
1.08
2.81
6.36
5.29
3.93
1
2
2
2
2
2
2
2
3
6
6
6
6
6
5
6
0
1
2
2
1
1
3
3
4.69
5.30
5.46
4.54
3.57
6.60
6.05
1.0
1.2
1.4
0.8
1.2
4.8
1.0
0.9
2.4
1.2
a
All calculations were performed using MarvinSketch 5.8.1 from
ChemAxon.
360
57
75
55
of potent antimalarials; a number of such molecules were found
to be quite potent when tested in vitro against P. falciparum
clones of variable sensitivity (3D7 and W2) with activities in
the range of 19−50 nM.39 None of the tested molecules were
found to be cytotoxic, and resistance indexes were usually close
to 1.0−2.0. Two model compounds were found to be
chemically stable at pH 5.2 and 7.4 over 48 h. Overall, our
data for these new series demonstrate that the incorporation of
a γ-lactam plays a significant role in biological activity.
Therefore, these results warrant further effort and studies.
Work is now under way to (a) demonstrate in vivo oral efficacy
of our best derivatives as well as optimize the current structures
especially by reducing the log P and also study a murine model
of their pharmacokinetics, (b) establish the mechanism of
action especially by checking if the molecules are found to
inhibit β-hematin production as the current 4-aminoquinolines
do, and (c) extend the in vitro data to a more comprehensive
series of P. falciparum clones (Dd2, NF54, HB3, 7G8) to
establish if the molecules are not impaired by the chloroquine
resistance phenotype. Synthetic current efforts have already
been successful in producing (a) a new family of 7-chloro-4-
aminoquinolines bearing a different γ-hydroxy-γ-lactam in the
side chain with excellent in vitro activity, a good resistance
index, and no relevant cytotoxicity, demonstrating that the
combination of these two skeletons yields new potent
antimalarials, and (b) other new pharmacophores not bearing
the 7-chloro-4-aminoquinoline skeleton based on a γ-lactam
unit that shows very promising activities. These results will be
published in forthcoming papers.
42
45
211
51
89
43
>1000
>1000
>1000
>1000
>1000
283
413
226
73
>1000
>1000
>1000
>1000
>1000
141
377
180
56
2.0
1.1
1.3
1.3
8.6
1.9
1.1
1.6
1.4
1.3
1.2
0.9
1.0
1.0
1.3
3.3
1.9
5.7
2.2
1.2
496
667
298
266
125
178
290
306
79
58
351
270
168
87
138
250
326
79
97
99
74
58
287
49
86
26
233
42
41
19
135
118
a
Values are means determined from at least two experiments. Effective
b
concentration for 50% inhibition. Resistance index (RI) = IC50(W2)/
IC50(3D7).
EXPERIMENTAL SECTION
■
Chemistry. Solvents were of the highest purity and anhydrous and
were purchased from Acros Organics and Sigma-Aldrich. Reagents
were obtained commercially (Acros Organics, Sigma-Aldrich) and
used without further purification. Infrared spectra were recorded on an
FT-IR Perkin-Elmer PARAGON 500 with a KBr pellet for a solid and
higher than 5.0. All derivatives are compliant with hydrogen
bond properties. The compounds that are almost compliant
with the Lipinski rule of five criteria are 58 and 72 (data shown
in bold in Table 5), which are not the most active in vitro
(Table 4). The results of this informative analysis do not
suggest that any of the compounds should be discarded from
this computational assessment and should be taken into
account when progressing further potential hits.
1
a film for an oil. H, 19F, and 13C NMR spectra were recorded with a
Bruker Avance 300 or a DRX300 spectrometer (in acetone-d6, CDCl3,
CD3OD, or DMSO-d6) at 300, 282, and 75 MHz, respectively.
Chemical shifts are given in parts per million (ppm) relative to the
residual peak of the solvent or CFCl3 (19F). The following
abbreviations are used to describe peak patterns: s (singlet), d
(doublet), dd (double doublet), t (triplet), m (multiplet), q
(quadruplet), and br (broad). Coupling constants are given in hertz.
High- and low-resolution mass spectra were recorded using a
FINIGAN MAT 95 (electronic ionization (EI) and chemical
ionization (CI) modes) and MicroTOF-Q II (electrospray ionization
(ESI) mode). The purities of the target compounds were ≥95%,
CONCLUSION
■
Two new series of 4-aminoquinoline derivatives bearing a γ-
hydroxy-γ-lactam in the side chain were synthesized using
methodologies that have not been previously used in the design
G
dx.doi.org/10.1021/jm301076q | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Article
measured by LC/MS, which was performed on an Agilent 1200 series
HPLC system connected to a Bruker MicroTOF-Q II (Bremen,
Germany) mass spectrometer. Separations were carried out on a
Macherey Nagel Nucleodur C18 HTec column (3 μm, 2 × 125 mm)
with a flow rate of 0.4 mL/min at 20 °C. Two mobile phases (mobile
phase A, 100% water with 0.1% acetic acid; mobile phase B, 100%
methanol with 0.1% acetic acid) were employed to run a gradient
condition from 95% A and 5% B to 100% B in 30 min which was held
for 5 min, and back to the initial conditions in 5 min, which was held
for 5 min. An injection volume of 10 μL was used. The mass spectra
were acquired by scanning from 50 to 1000 amu in the positive ion
mode with a spray voltage of 5 kV. The calibration of the mass
spectrometer was performed by using formiate buffer; the measured
mass precision is less than 5 ppm. Samples were prepared by mixing 10
μL of a 1 mg/mL concentration of the compound in methanol in 1
mL of water. Thin-layer chromatography (TLC) was performed on
silica gel GF254 plates. Macherey-Nagel silica gel 60M (0.04−0.063
mm) was used for silica gel chromatography. Melting points
134.9 (s, Cq Ph), 135.4 (s, Cq quinoline), 146.5 (s, CH lactam),
148.5 (s, Cq quinoline), 149.9 (s, Cq quinoline), 151.3 (s, CH
quinoline), 168.5 (s, Cq, CO). MS (ESI+): m/z = 565 [M + H]+, 567
[M(37Cl) + H]+. HRMS (ESI+): m/z calcd for [M + H]+
C27H29ClF3N4O2S 565.1652, found 565.1659. Anal. Calcd for
C27H28ClF3N4O2S: C, 57.39; H, 4.99; N, 9.92. Found: C, 57.65; H,
4.98; N, 9.72.
1-(2-((2-((7-Chloroquinolin-4-yl)amino)ethyl)piperazin-1-yl)-
ethyl)-5-hydroxy-5-((phenysulfanyl)methyl)-3-(2,2,2-trifluor-
oethyl)-1H-pyrrol-2(5H)-one (63). The yield was 21% after
purification by silica gel column chromatography (MeCN/MeOH =
80/20, Rf = 0.2), viscous oil. 1H NMR (CDCl3): δ 2.38 (dm, J = 15.4
Hz, 1H, CH2), 2.44−2.97 (m, 12H, 6 × CH2), 3.12 (q, J = 10.6 Hz,
2H, CH2CF3), 3.26 (d, J = 14.0 Hz, 1H, SCHAHB), 3.31 (m, 2H,
CH2), 3.43 (d, J = 14.0 Hz, 1H, SCHAHB), 3.73 (dm, J = 15.4 Hz, 1H,
CH2), 5.79 (br s, 1H, NH), 6.37 (d, J = 5.4 Hz, 1H, CH quinoline),
6.83 (s, 1H, CH lactam), 7.19−7.34 (m, 5H, Ph), 7.37 (dd, J = 9.0
and 1.9 Hz, 1H, CH quinoline), 7.63 (d, J = 9.0 Hz, 1H, CH
quinoline), 7.96 (d, J = 1.9 Hz, 1H, CH quinoline), 8.53 (d, J = 5.4 Hz,
1H, CH quinoline), 9.07 (br s, 1H, OH). 19F NMR (CDCl3): δ −65.3
(t, J = 10.6 Hz). 13C NMR (CDCl3): δ 29.9 (q, J = 31.6 Hz, CCF3),
36.5 (s, CH2), 39.0 (s, CH2), 41.7 (s, CH2S), 51.9 (s, 2 × CH2
piperazine), 53.2 (br s, 2 × CH2 piperazine), 55.4 (s, CH2), 57.0 (s,
CH2), 89.0 (s, Cq, C(OH)CH3), 99.4 (s, CH quinoline), 117.4 (s, Cq
quinoline), 121.0 (s, CH quinoline), 125.3 (q, J = 276.6 Hz, CF3),
125.4 (s, CH quinoline), 127.0 (s, CH Ph), 128.0 (q, J = 3.0 Hz, Cq
lactam), 128.8 (s, CH quinoline), 129.1 (s, 2 × CH Ph), 130.7 (s, 2 ×
CH Ph), 134.9 (s, Cq Ph), 135.6 (s, Cq quinoline), 146.4 (s, CH
lactam), 149.0 (s, Cq quinoline), 149.6 (s, Cq quinoline), 152.1 (s, CH
quinoline), 168.6 (s, CO). HRMS (ESI+): m/z calcd for [M + H]+
C30H34ClF3N5O2S 620.2074, found 620.2064. Anal. Calcd for
C30H33ClF3N5O2S: C, 58.10; H, 5.36; N, 11.29. Found: C, 58.29; H,
5.51; N, 11.05.
(uncorrected) were determined in capillary tubes on a Buchi
̈
apparatus.
General Procedure for the Preparation of γ-Lactams 48−68.
To a solution of γ-lactones 42−47 (0.126 mmol) in THF (20 mL)
under an inert atmosphere were added the appropriate amines (0.252
mmol, 2 equiv). The reaction mixture was stirred at room temperature
for 6 h (for γ-lactones 45−47) or was refluxed for 20−36 h (for γ-
lactones 42−44) until total conversion (the reactions were monitored
by 19F NMR). After evaporation of the solvent, the residue was
purified by silica gel column chromatography and recrystallized,
affording the desired γ-lactams 48−68.
1-(3-((7-Chloroquinolin-4-yl)amino)propyl)-5-hydroxy-5-
[(phenylthio)methyl]-3-(2,2,2-trifluoroethyl)-1H-pyrrol-2(5H)-
one (48). The yield was 66% after purification by silica gel column
chromatography (AcOEt, Rf = 0.58) followed by recrystallization
1
(petroleum ether/MeOH), solid, mp 180 °C. H NMR (CDCl3): δ
Typical Procedure for the Preparation of γ-Lactams 69−83.
To a solution of γ-ketothioester 23 (120 mg, 0.48 mmol) in diethyl
ether (3 mL) was added diisopropylamine (134 μL, 0.96 mmol). The
reaction mixture was stirred at room temperature for 15 h (the
formation of a furan intermediate was monitored by 19F NMR of the
crude). Amine 36 (170 mg, 0.72 mmol) and MeOH (0.5 mL) were
added to the reaction mixture. After total conversion (monitoring by
19F NMR), the solvents were evaporated under reduced pressure, and
2.03 (m, 2H, NCH2CH2), 3.1−3.3 (m, 3H, CH2CF3 + NCHAHB), 3.42
(d, J = 13.9 Hz, 1H, CHAHBS), 3.3−3.5 (m, 3H, NCH2 + NCHAHB),
3.52 (d, J = 13.9 Hz, 1H, CHAHBS), 6.52 (d, J = 5.9 Hz, 1H
quinoline), 6.84 (s, 1H, CH lactam), 7.1−7.3 (m, 5H Ph), 7.42 (dd,
J = 9.0 and 2.2 Hz, 1H quinoline), 7.78 (d, J = 2.2 Hz, 1H quinoline),
8.10 (d, J = 9.0 Hz, 1H quinoline), 8.32 (d, J = 5.9 Hz, 1H quinoline).
19F NMR (CDCl3): δ −65.1 (t, J = 11.6 Hz). 13C NMR (CDCl3): δ
28.3 (s, NCH2CH2), 30.3 (q, J = 31.5 Hz, CH2CF3), 37.5 (s, CH2),
40.9 (s, CH2), 41.4 (s, CH2), 92.3 (s, Cq, COH), 99.7 (s, CH
quinoline), 118.8 (s, Cq quinoline), 124.3 (s, CH quinoline), 126.1 (s,
CH quinoline), 126.9 (q, J = 276.1 Hz, CF3), 127.5 (s, CH quinoline),
127.8 (s, CH Ph), 130.1 (s, 2 × CH Ph), 130.3 (q, J = 3.3 Hz,
CCH2CF3), 131.4 (s, 2 × CH Ph), 136.4 (s, Cq quinoline), 137.1 (s,
Cq, Ph), 147.8 (s, CH lactam), 149.6 (s, Cq quinoline), 152.4 (s, CH
quinoline), 152.6 (s, Cq quinoline), 171.0 (s, Cq, CO). IR (KBr,
cm−1): 3401, 2925, 1678, 1590, 1458, 1370, 1269, 1139. MS (ESI+):
m/z = 522 [M + H]+, 524 [M(37Cl) + H]+. HRMS (ESI+): m/z calcd
for [M + H]+ C25H23ClF3N3O2S 522.1230, found 522.1235.
then the residue was purified by silica gel column chromatography
(AcOEt/MeOH = 95/5, Rf = 0.32) followed by recrystallization
(CH2Cl2/petroleum ether), affording the desired γ-lactam 69.
1-(3-((7-Chloroquinolin-4-yl)amino)propyl)-3-(1-(ethylsul-
fanyl)-2,2,2-trifluoroethyl)-5-hydroxy-5-methyl-1H-pyrrol-
2(5H)-one (69). The yield was 36% as a mixture (52/48) of
nonseparated diastereomers, solid. The following are data for the major
diastereomer. 1H NMR (CDCl3): δ 1.26 (t, J = 7.5 Hz, 3H, CH3CH2),
1.62 (s, 3H, C(OH)CH3), 1.9−2.1 (m, 2H, CH2CH2N), 2.7−2.9 (m,
2H, CH2S), 3.0−3.8 (m, 4H, NCH2CH2CH2N), 4.28 (m, 1H,
CHCF3), 6.06 (d, J = 5.8 Hz, 1H, CH quinoline), 6.4−6.6 (br s,
1H, OH or NH), 6.99 (br s, 1H, CH lactam), 7.2 (m, 1H, CH
quinoline), 7.61 (d, J = 9.0 Hz, 1H, CH quinoline), 7.79 (d, J = 1.9 Hz,
1H, CH quinoline), 8.11 (d, J = 5.8 Hz, 1H, CH quinoline). 19F NMR
(CDCl3): δ −69.1 (d, J = 8.8 Hz). 13C NMR (CDCl3): δ 14.3 (s,
CH3CH2S), 22.8 (s, CH2CH2N), 23.7 (s, CH3C(OH)), 27.4 (s,
CH2S), 36.1 (s, CH2N), 40.3 (s, CH2N), 41.5 (m, CHCF3), 89.0 (s, Cq,
C(OH)), 98.3 (s, CH quinoline), 110.0 (s, Cq quinoline), 117.0 (s, Cq
quinoline), 115−125 (CF3), 122.4 (s, CH quinoline), 125.7 (s, CH
quinoline), 126.2 (s, CH quinoline), 130.6 (s, Cq, CCHCF3), 135.9 (s,
Cq quinoline), 146.7 (s, CH lactam), 149.7 (s, CH quinoline), 151.0
(s, Cq quinoline), 168.0 (s, Cq, CO). The following are selected data for
1-(2-((2-((7-Chloroquinolin-4-yl)amino)ethyl)methylamino)-
ethyl)-5-hydroxy-5-((phenylsulfanyl)methyl)-3-(2,2,2-trifluor-
oethyl)-1H-pyrrol-2(5H)-one (58). The yield was 46% after
purification by silica gel column chromatography (MeOH, Rf = 0.6),
1
viscous oil. H NMR (CDCl3): δ 2.35 (s, 3H, NCH3), 2.35 (m, 1H,
CH2), 2.70−3.05 (m, 6H, 2 × CH2 + CH2CF3), 3.28−3.41 (m, 4H,
CH2 + CH2S), 3.66 (dt, J = 15.3 and 2.7 Hz, 1H, CH2), 5.68 (br s, 1H,
OH or NH), 6.28 (d, J = 5.4 Hz, 1H, CH quinoline), 6.75 (br s, 1H,
CH lactam), 7.20−7.28 (m, 5H, Ph), 7.35 (dd, J = 9.0 and 2.1 Hz,
1H, CH quinoline), 7.86 (d, J = 9.0 Hz, 1H, CH quinoline), 7.93 (d, J
= 2.1 Hz, 1H, CH quinoline), 8.48 (d, J = 5.4 Hz, 1H, CH quinoline).
19F NMR (CDCl3): δ −65.4 (t, J = 10.7 Hz). 13C NMR (CD3OD): δ
29.4 (q, J = 31.5 Hz, CH2CF3), 36.9 (s, CH2), 39.7 (s, CH2), 41.2 (s,
CH2S), 41.6 (s, NCH3), 55.5 (s, CH2), 56.1 (s, CH2), 89.1 (s, Cq,
C(OH)CH3), 98.6 (s, CH quinoline), 117.2 (s, Cq quinoline), 122.4
(s, CH quinoline), 125.1 (q, J = 276.7 Hz, CF3), 125.0 (s, CH
quinoline), 126.9 (s, CH Ph), 127.6 (s, CH quinoline), 127.9 (q, J =
2.7 Hz, Cq, CCH2CF3), 129.0 (s, 2 × CH Ph), 130.5 (s, 2 × CH Ph),
1
minor diastereomer: H NMR (CDCl3): δ 1.34 (t, J = 7.4 Hz, 3H,
CH3CH2), 1.63 (s, 3H, C(OH)CH3), 1.9−2.1 (m, 2H, CH2CH2N),
2.7−2.9 (m, 2H, CH2S), 3.0−3.8 (m, 4H, NCH2CH2CH2N), 4.28 (m,
1H, CHCF3), 6.04 (d, J = 5.8 Hz, 1H, CH quinoline), 6.4−6.6 (br s,
1H, OH or NH), 6.99 (br s, 1H, CH lactam), 7.2 (m, 1H, CH
quinoline), 7.56 (d, J = 9.0 Hz, 1H, CH quinoline), 7.81 (d, J = 1.9 Hz,
1H, CH quinoline), 8.10 (d, J = 5.8 Hz, 1H, CH quinoline). 19F NMR
H
dx.doi.org/10.1021/jm301076q | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Article
(CDCl3): δ −68.7 (d, J = 8.8 Hz). 13C NMR (CDCl3): δ 14.2 (s,
CH3CH2S), 22.8 (s, CH2CH2N), 23.7 (s, CH3C(OH)), 27.4 (s,
CH2S), 36.1 (s, CH2N), 40.3 (s, CH2N), 41.5 (m, CHCF3), 89.2 (s, Cq,
C(OH)), 98.3 (s, CH quinoline), 110.0 (s, Cq quinoline), 117.0 (s, Cq
quinoline), 115−125 (CF3), 122.4 (s, CH quinoline), 125.7 (s, CH
quinoline), 126.2 (s, CH quinoline), 130.6 (s, Cq, CCHCF3), 135.9 (s,
Cq quinoline), 146.9 (s, CH lactam), 149.7 (s, CH quinoline), 151.0
(s, Cq quinoline), 168.0 (s, Cq, CO). IR (KBr, cm−1): 3383, 3070,
2935, 1686, 1585, 1453, 1254, 1147. MS (ESI+): m/z = 474 [M + H]+,
476 [M(37Cl) + H]+. HRMS (ESI+): m/z calcd for [M + H]+
C21H24ClF3N3O2S 474.1230, found 474.1233.
126.8 (s, Cq, p-BrC6H4), 127.9 (s, 2 × CH p-BrC6H4), 129.0 (s, Cq
quinoline), 129.1 (s, Cq quinoline), 132.1 (s, 2 × CH p-BrC6H4),
135.6 (m, Cq, CCHCF3), 137.1 (s, Cq quinoline), 137.3 (s, Cq
quinoline), 146.3 (s, CH lactam), 146.8 (s, CH lactam), 150.2
(s, CH quinoline), 150.3 (s, CH quinoline), 150.5 (s, Cq quinoline),
150.6 (s, Cq quinoline), 168.1 (s, CO), 168.2 (s, CO). HRMS (ESI+):
m/z calcd for [M + H]+ C28H30BrClF3N4O2S 657.0913, found
657.0904. Anal. Calcd for C28H29BrClF3N4O2S: C, 51.11; H, 4.44; N,
8.52. Found: C, 51.09; H, 4.43; N, 8.47.
Typical Procedure for the Preparation of Citric Salts 84−88.
To a solution of aminoquinoline derivative 58 (22 mg, 0.04 mmol) in
anhydrous acetone (1 mL) was added a solution of citric acid (8 mg,
0.04 mmol) in anhydrous acetone (1 mL). The corresponding
ammonium salt precipated spontaneously, and then the resulting
suspension was left for 1 day at room temperature until full
precipitation. After removal of the solvent, the solid was washed
with acetone (1 mL) and dried under reduced pressure, affording the
desired citric salt 84 (28 mg, yield 93%).
1-(2-((2-((7-Chloroquinolin-4-yl)amino)ethyl)amino)ethyl)-5-
hydroxy-5-((phenylsulfanyl)methyl)-3-(2,2,2-trifluoroethyl)-
1H-pyrrol-2(5H)-one Citrate (84). The title compound was a solid.
1H NMR (DMSO-d6): δ 2.54 (d, J = 15.3 Hz, 2H, 2 × CHAHB citrate),
2.63 (d, J = 15.3 Hz, 2H, 2 × CHAHB citrate), 3.03−3.53 (m, 12H, 6 ×
CH2), 6.62 (d, J = 5.4 Hz, 1H, CH quinoline), 6.92 (br s, 1H, CH
lactam), 7.19−7.30 (m, 5H, Ph), 7.55 (dd, J = 9.0 and 1.9 Hz, 1H, CH
quinoline), 7.84 (d, J = 1.9 Hz, 1H, CH quinoline), 8.25 (d, J = 9.0 Hz,
1H, CH quinoline), 8.47 (d, J = 5.4 Hz, 1H, CH quinoline). 19F NMR
(DMSO-d6): δ −63.4 (t, J = 10.3 Hz). Anal. Calcd for
C32H34ClF3N4O9S: C, 51.72; H, 4.61; N, 7.54. Found: C, 51.97; H,
4.59; N, 6.93.
1-(2-((2-((7-Chloroquinolin-4-yl)amino)ethyl)methylamino)-
ethyl)-3-(1-(ethylsulfanyl)-2,2,2-trifluoroethyl)-5-hydroxy-5-
methyl-1H-pyrrol-2(5H)-one (72). The yield was 26% (from γ-
ketothioester 23) as a mixture (0.85/1) of nonseparated diastereomers
after purification by silica gel column chromatography (MeOH, Rf =
0.55), solid. The following NMR data are for the mixture of
diastereomers. 1H NMR (CDCl3): δ 1.10 (t, J = 7.5 Hz, 3H, CH3CH2
major), 1.26 (t, J = 7.5 Hz, 3H, CH3CH2 minor), 1.52 (s, 2 × 3H, 2 ×
CH3), 2.34 (s, 3H, NCH3 minor), 2.36 (s, 3H, NCH3 major), 2.44−
2.90 (m, 6H, 2 × CH2 + CH2S), 3.23−3.35 (m, 3H, CH2), 3.96 (m,
1H, CH2), 4.15 (m, 1H, CHCF3), 5.94 (br s, 1H, OH or NH), 6.26 (d,
J = 5.4 Hz, 1H, CH quinoline minor), 6.27 (d, J = 5.4 Hz, 1H, CH
quinoline major), 6.95 (br s, 1H, CH lactam), 7.28−7.35 (m, 1H,
CH quinoline), 7.84−7.89 (m, 2H, CH quinoline), 8.42 (d, J = 5.4 Hz,
1H, CH quinoline). 19F NMR (CDCl3): δ −68.9 (d, J = 8.2 Hz,
minor), −69.0 (d, J = 8.2 Hz, major). 13C NMR (CDCl3): δ 13.9 (s,
CH3CH2S major), 14.0 (s, CH3CH2S minor), 24.0 (s, 2 × C(OH)
CH3), 27.2 (s, CH2 major), 27.3 (s, CH2 minor), 36.8 (s, CH2), 39.9 (s,
CH2 minor), 40.0 (s, CH2 major), 41.1 (q, J = 31.6 Hz, CHCF3 major),
41.2 (q, J = 31.6 Hz, CHCF3 minor), 41.7 (s, NCH3 minor), 41.9 (s,
NCH3 major), 55.7 (s, CH2 minor), 55.8 (s, CH2 major), 56.2 (s, CH2
major), 56.6 (s, CH2 minor), 87.1 (s, Cq, C(OH)CH3 major), 87.3 (s,
Cq, C(OH)CH3 minor), 98.6 (s, CH quinoline), 117.2 (s, Cq
quinoline minor), 117.3 (s, Cq quinoline major), 120.2 (s, Cq
quinoline minor), 120.3 (s, Cq quinoline major), 122.4 (s, CH
quinoline minor), 122.5 (s, CH quinoline major), 125.8 (q, J = 278.9
Hz, CF3), 127.4 (s, CH quinoline minor), 127.5 (s, CH quinoline
major), 129.5 (s, Cq quinoline), 135.1 (m, Cq, CCHCF3), 146.8 (s, 
CH lactam), 148.2 (s, CH quinoline minor), 148.3 (s, CH quinoline
major), 150.1 (s, Cq quinoline), 151.1 (s, CH quinoline), 167.0 (s, CO
major), 167.1 (s, CO minor). MS (ESI+): m/z = 517 [M + H]+, 519
[M(37Cl) + H]+. HRMS (ESI+): m/z calcd for [M + H]+
C23H29ClF3N4O2S 517.1652, found 517.1657. Anal. Calcd for
C23H28ClF3N4O2S: C, 53.43; H, 5.46; N, 10.84. Found: C, 53.68; H,
5.43; N, 11.06.
5-(4-Bromophenyl)-1-(2-((2-((7-chloroquinolin-4-yl)amino)-
ethyl)methylamino)ethyl)-3-(1-(ethylsulfanyl)-2,2,2-trifluor-
oethyl)-5-hydroxy-1H-pyrrol-2(5H)-one citrate (88). The yield
was 76% as a mixture (50/50) of nonseparated diastereomers, solid.
1
The following NMR data are for the mixture of diastereomers. H
NMR (DMSO-d6): δ 1.19 (t, J = 7.5 Hz, 3H, CH3CH2), 2.21 (s, 3H,
NCH3), 2.58 (d, J = 15.3 Hz, 2H, 2 × CHAHB citrate), 2.67 (d, J =
15.3 Hz, 2H, 2 × CHAHB citrate), 2.50−2.78 (m, 6H, 3 × CH2), 2.85−
2.95 (m, 1H, CH2), 3.45 (m, 3H, CH2), 4.47−4.60 (m, 1H, CHCF3),
6.66 (d, J = 5.4 Hz, 1H, CH quinoline), 6.93 (br s, 1H, CH lactam),
6.95 (br s, 1H, CH lactam), 7.17−7.22 (m, 2H, p-BrC6H4), 7.56−
7.63 (m, 3H, 2 × CH p-BrC6H4 + CH quinoline), 7.86 (m, 1H, CH
quinoline), 8.34 (d, J = 9.0 Hz, 1H, CH quinoline), 8.48 (d, J = 5.4 Hz,
1H, CH quinoline). 19F NMR (DMSO-d6): δ −67.1 (d, J = 8.2 Hz),
−67.5 (d, J = 8.2 Hz). Anal. Calcd for C34H37BrClF3N4O9S: C, 48.04;
H, 4.39; N, 6.59. Found: C, 48.38; H, 4.37; N, 6.18.
In Vitro Drug Sensitivity Assay with Cultured Parasites. After
they were taken out of liquid nitrogen, the cultured parasites were
grown for 10−12 days until a predominance of ring-stage parasites of
no less than 70% was reached. These parasites were used for the drug
sensitivity assays. Once the parasitemia levels of the in vitro cultures
reached an optimum density of 5−8%, the infected red blood cells
were centrifuged at 350g for 5 min; the supernatant was aspirated; and
the cells were suspended in RPMI with and without phenol red
(Invitrogen, Carlsbad, CA) supplemented with 0.5% Albumax I (0.005
g/mL), HEPES (5.94 g/L), and NaHCO3 (2.4 g/L). An aliquot of the
culture was diluted to reduce the parasitemia to 0.5%, and the
hematocrit was added to plates preloaded with serial dilution of tested
drugs. Negative control (RPMI) and positive control (chloroquine)
were systematically added to each plate. All tests were conducted in
triplicate, and the experiments were reproduced twice. The plates were
incubated in a humidified modular incubator chamber (Flow
Laboratories, Irvine, CA) at 37 °C under a gas mixture of 5% O2,
5% CO2, and 90% N2 for 72 h.
5-(4-Bromophenyl)-1-(2-((2-((7-chloroquinolin-4-yl)amino)-
ethyl)methylamino)ethyl)-3-(1-(ethylsulfanyl)-2,2,2-trifluor-
oethyl)-5-hydroxy-1H-pyrrol-2(5H)-one (83). The yield was 18%
(from γ-ketothioester 26) as a mixture (50/50) of nonseparated
diastereomers after purification by silica gel column chromatography
(EtOH, Rf = 0.55), solid. The following NMR data are for the mixture
of diastereomers. 1H NMR (CDCl3): δ 1.16 (t, J = 7.5 Hz, 3H,
CH3CH2), 1.31 (t, J = 7.5 Hz, 3H, CH3CH2), 2.22 (s, 3H, NCH3),
2.25 (s, 3H, NCH3), 2.34 (m, 1H, CH2), 2.63−2.95 (m, 6H, CH2),
3.47 (m, 2H, CH2), 3.98 (m, 1H, CH2), 4.24 (q, J = 8.2 Hz, 1H,
CHCF3), 5.8 (br s, 1H, OH or NH), 6.36 (m, 1H, CH quinoline), 6.91
(br s, 1H, CH lactam), 6.93 (br s, 1H, CH lactam), 7.24 (d, J =
8.5 Hz, 2H, p-BrC6H4), 7.37 (m, 1H, CH quinoline), 7.51 (d, J = 8.5
Hz, 2H, p-BrC6H4), 7.90−7.96 (m, 2H, CH quinoline), 8.51 (m, 1H,
CH quinoline). 19F NMR (CDCl3): δ −68.9 (d, J = 8.2 Hz), −69.1 (d,
J = 8.2 Hz). 13C NMR (CDCl3): δ 14.0 (s, CH3CH2S), 14.1 (s,
CH3CH2S), 27.3 (s, CH3CH2S), 27.4 (s, CH3CH2S), 37.5 (s, CH2),
39.9 (s, CH2), 41.0 (s, NCH3), 41.2 (s, NCH3), 41.2 (q, J = 31.5 Hz,
CHCF3), 41.4 (q, J = 31.5 Hz, CHCF3), 89.6 (s, Cq, C(OH)CH3),
89.7 (s, Cq, C(OH)CH3), 98.5 (s, CH quinoline), 98.6 (s, CH
quinoline), 117.1 (s, Cq quinoline), 117.2 (s, Cq quinoline), 122.6 (s,
CH quinoline), 122.7 (s, CH quinoline), 123.0 (s, Cq, p-BrC6H4),
123.1 (s, Cq, p-BrC6H4), 125.5 (s, CH quinoline), 125.6 (s, CH
quinoline), 125.8 (q, J = 278.9 Hz, CF3), 126.7 (s, Cq, p-BrC6H4),
IC50 Determination by the SYBR Green I Assay. Following
incubation, the plates were frozen and stored at −80 °C until the
SYBR green I assay was performed. The plates were thawed for 2 h at
room temperature, and each sample was mixed by pipetting. Briefly, a
total of 100 μL of the culture was transferred to a new 96-well plate,
followed by the addition of 100 μL of SYBR green I (Molecular
I
dx.doi.org/10.1021/jm301076q | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Article
Probes, Invitrogen, Carlsbad, CA) in lysis buffer (0.2 μL of SYBR
green I/mL of lysis buffer, which consisted of Tris 20 mM (pH 7.5),
EDTA (5 mM), saponin (0.008%, w/v), and Triton X-100 (0.08%, w/
v)).40 The plates were covered and incubated at room temperature for
1 h. The fluorescence intensity was measured from below with a
Twinkle fluorometer (Berthold, Thoiry, France) at excitation and
emission wavelengths of 485 and 535 nm, respectively. The IC50 values
obtained after incubation times of 48 and 72 h were calculated by
using the HN-nonlin V1.O5 Beta program.
Cytotoxicity. The cytotoxicity of the chemical compounds was
tested against HUVECs. Cells were maintained in cell medium EBM-2
(endothelial cell basal medium 2; Lonza) under a humidified
atmosphere in 5% CO2 at 37 °C. HUVECs were seeded in a 96-
well microplate in their exponential phase of growth (50 000 cells/
mL). The cells were incubated for 24 h with serial dilutions of the
compounds from 100 to 0.01 μmol/L. The stock solution of the
compounds was 200 mM in DMSO, and the successive dilutions were
made in culture medium. The DMSO final concentration in the well
never exceeded 0.5%. Growth controls were obtained using medium
alone and cytotoxicity controls using DMSO. After the incubation
period, 20 μL of Tryptan Blue dye (0.4%) was added to each well
during 3 min. Then the dye was removed, and the plates were
observed using an optical microscope. Blue-stained cells were
considered as dead. The proportion of dead cells in each well was
compared to the proportion of dead cells in the growth control.
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270−283.
ASSOCIATED CONTENT
* Supporting Information
■
S
(9) Natarajan, J. K.; Alumasa, J. N.; Yearick, K.; Ekoue-Kovi, K. A.;
Casabianca, L. B.; de Rios, A. C.; Wolf, C.; Roepe, P. D. 4-N-, 4-S-, and
4-O-Chloroquine analogues: influence of side chain length and
quinolyl nitrogen pKa on activity vs chloroquine resistant malaria. J.
Med. Chem. 2008, 51, 3466−3479.
Additional experimental details and description of compounds,
additional in vitro data, and LC/MS pH stability profile of
compounds 50 and 70. This material is available free of charge
via the Internet at http://pubs.acs.org.
(10) Dive, D.; Biot, C. Ferrocene conjugates of chloroquine and
other antimalarials: the development of ferroquine, a new antimalarial.
ChemMedChem 2008, 3, 383−391.
AUTHOR INFORMATION
Corresponding Author
■
*Phone: +33 4 7243 1989 (M.M.); +33 2 3552 2422 (J.-P.B.).
E-mail: maurice.medebielle@univ-lyon1.fr. (M.M.); jean-
philippe.bouillon@univ-rouen.fr (J.-P.B.).
(11) Dechy-Cabaret, O.; Benoit-Vical, F.; Loup, C.; Robert, A.;
́ ́
Gornitzka, H.; Bonhoure, A.; Vial, H.; Magnaval, J. -F.; Seguela, J. -P.;
Meunier, B. Synthesis and antimalarial activity of trioxaquine
derivatives. Chem.Eur. J. 2004, 10, 1625−1636.
Notes
(12) Bellot, F.; Cosledan, F.; Vendier, L.; Brocard, J.; Meunier, B.;
́
The authors declare no competing financial interest.
Robert, A. Trioxaferroquines as new hybrid antimalarial drugs. J. Med.
Chem. 2010, 53, 4103−4109.
ACKNOWLEDGMENTS
■
(13) Kumar, A.; Srivastava, K.; Kumar, S. R.; Siddiqi, M. I.; Puri, S.
K.; Sexana, J. K.; Chauhan, P. M. S. 4-Anilinoquinoline triazines: a
novel class of hybrid antimalarial agents. Eur. J. Med. Chem. 2011, 46,
676−690.
This investigation was supported by the Universite
́
de Lyon and
Claude Bernard Lyon 1, and
́
de Rouen, OSEO Haute-Normandie, by the Centre
Lyon Science Transfert, Universite
Universite
́
(14) (a) Rojas Ruiz, F. A.; García-San
Estupinan, S.; Gomez-Barrio, A.; Torres Amado, D. F.; Per
zano, B. M.; Nogal-Ruiz, J. J.; Martinez-Fernandez, A. R.;
́
chez, R. N.; Villabona
National de la Recherche Scientifique (CNRS), and in part by
the Agence National de la Recherche (Grant ANR-11-EMMA-
04-QUINOLAC). A. Demore, R. Rolff, K. Roussee, V.
Datinska, J. Gouteux, and S. Iikawa are thanked for their help
with some of the syntheses. A. Lavoignat, G. Bonnot, and G.
Herbet are warmly thanked for their contribution to the
different biological evaluations.
́
́
ez-
̃
Solor
́
́
Kouznetsov, V. V. Synthesis and antimalarial activity of new
heterocyclic hybrids based on chloroquine and thiazolidinone
scaffolds. Bioorg. Med. Chem. 2011, 19, 4562−4573. (b) Solomon, V.
R.; Srivastava, K.; Puri, S. K.; Katti, S. B. Synthesis and antimalarial
activity of side chain modified 4-aminoquinoline derivatives. J. Med.
Chem. 2007, 50, 394−398.
ABBREVIATIONS USED
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Fluorine-Containing Synthons; Soloshonok, V. A., Ed.; ACS Symposium
Series 911; Oxford University Press/American Chemical Society:
Washington, DC, 2005; Chapter 12, pp 232−247. (b) Portella, C.;
■
AQ, amodiaquine; CQ, chloroquine; CQS, chloroquino-
sensitive; CQR, chloroquino-resistant; CC50, concentration
for 50% cytotoxicity; IC50, concentration of inhibitor resulting
in 50% inhibition; HUVECs, human umbilical vein endothelial
cells; SAR, structure−activity relationship; RI, resistance index
(ratio IC50(W2)/IC50(3D7))
́
Muzard, M.; Bouillon, J.-P.; Brule, C.; Grellepois, F.; Shermolovich,
Yu, G.; Timoshenko, V. M.; Chernega, A. N.; Sotoca-Usina, E.; Parra,
M.; Gil, S. Perfluoroketene dithioacetals and perfluorodithiocarboxylic
acid derivatives: versatile tools for organofluorine synthesis. Heteroat.
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