Synthesis and in vitro antiplasmodial activity of ferrocenyl aminoquinoline derivatives

Article abstract of DOI:10.1016/j.ejmech.2014.11.065

The aim of this study was to synthesize a series of ferrocenyl 4-aminoquinolines and to evaluate their activities against Plasmodium falciparum F32 (chloroquine-sensitive) and FCB1 and K1 (chloroquino-resistant). Some of the ferrocenyl compounds exhibited

Full text of DOI:10.1016/j.ejmech.2014.11.065

European Journal of Medicinal Chemistry 90 (2015) 519e525
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and in vitro antiplasmodial activity of ferrocenyl
aminoquinoline derivatives
,
Gabin Mwande Maguene a b, Jean-Bernard Lekana-Douki c, Elisabeth Mouray d,
Till Bousquet a, Philippe Grellier d, Sylvain Pellegrini a, Fousseyni Samba Toure Ndouo c,
,
*
a
,
*
Jacques Lebibi b , Lydie Pelinski
ꢀ
a
ꢀ
ꢀ
ꢀ
Universite Lille Nord de France, Universite de Lille 1, Unite de Catalyse et de Chimie du Solide, UMR CNRS 8181, ENSCL, B.P. 108, 59652 Villeneuve d'Ascq,
France
b
ꢀ
Universite des Sciences et Techniques de Masuku, BP 901 Franceville, Gabon
c
ꢀ
ꢀ
Centre International de Recherches Medicales de Franceville (CIRMF), Unite de Parasitologie, BP 769 Franceville, Gabon
FRE 3206 CNRS MCAM, Museum National d'Histoire Naturelle, Departement Regulations, Developpement, Diversite Moleculaire, CP 52, 61 rue Buffon,
d
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
75231 Paris Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The aim of this study was to synthesize a series of ferrocenyl 4-aminoquinolines and to evaluate their
activities against Plasmodium falciparum F32 (chloroquine-sensitive) and FCB1 and K1 (chloroquino-
resistant). Some of the ferrocenyl compounds exhibited in vitro antiplasmodial activity in the nM range.
In particular, (1R,4R)-N1-(7-chloroquinolin-4-yl)-N4-(ferrocenylmethyl)-N4-methylcyclohexane-1,4-
diamine 17 presented the lowest IC50 value (26 nM) against CQ-resistant strains.
Received 26 August 2014
Received in revised form
30 October 2014
Accepted 30 November 2014
Available online 3 December 2014
© 2014 Elsevier Masson SAS. All rights reserved.
Keywords:
Quinoline
Ferrocene
Antimalarial assay
Cytotoxicity
1. Introduction
(quinine, primaquine), arylaminoalcohols (mefloquine, halofan-
trine, lumefantrine), hydroxynaphthoquinones (e.g. atovaquone),
Malaria remains the most common parasite disease in tropical
and subtropical regions affecting more than 207 million people
with 627.000 deaths in 2013 [1,2]. Human malaria, transmitted by
female Anopheles mosquitoes, is caused by five species of Plas-
modium, which are Plasmodium falciparum, Plasmodium vivax,
Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi.
However, most cases of malaria and deaths are caused by
P. falciparum. Since its discovery, Chloroquine (CQ) was the best
antimalarial drug according to its safety, affordability, and efficacy.
Despite this, the emergence and rapid widespread of P. falciparum
CQ resistance have created an urgent need to discover new anti-
malarial agents [3,4]. Nowadays, most important antimalarial drugs
include diaminopyrimidines (e.g. pyrimethamine), biguanides (e.g.
proguanil), sulfonamides (e.g. sulfadoxine) and sulfones, quinolines
artemisinin and its semisynthetic derivatives [5,6]. Among these,
the interesting 4-aminoquinoline scaffold continues to be intro-
duced in synthesized compounds [7e10]. Particularly, hybrid
molecules are obtained by combining 4-aminoquinoline with other
pharmacophore possessing an antimalarial activity [11e16]. This
type of molecules may overcome drug resistance problems.
The use of metal complexes enhancing the biological activity of
compounds has become a relevant strategy of research in both
organometallic chemical and biological communities. In fact, the
introduction of metals leads to profound changes in drugs biolog-
ical activities [17e22]. Many different metal complexes have been
incorporated into antimalarial drugs. Particularly, Ferroquine (FQ,
SSR97193), a molecule with a ferrocenyl moiety inserted within the
side chain of CQ is currently developed by Sanofi-Aventis [23e27].
Following this work, a variety of ferrocenyl antimalarial compounds
was investigated and validated the ferrocene as an important entity
for the design of new drugs [28e33]. A representative series of
Ferroquine analogous is presented in Fig. 1. Usually, the ferrocenyl
* Corresponding authors.
E-mail addresses: jlebibi@hotmail.com (J. Lebibi), lydie.pelinski@univ-lille1.fr
ꢀ
(L. Pelinski).
http://dx.doi.org/10.1016/j.ejmech.2014.11.065
0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.

520
G. Mwande Maguene et al. / European Journal of Medicinal Chemistry 90 (2015) 519e525
cells (Table 1). The selectivity index of the compounds was calcu-
lated as the ratio of cytotoxicity LD50 to antiplasmodial IC50
.
All tested compounds exhibited modest to excellent activities on
the CQ-sensitive F32, CQ-resistant FCB1 and K1 strains with IC50
ranging from 26 to 292 nM for F32, 18e217
mM for FCB1 and
26e261 nM for K1. Except for molecules 11 and 21, all ferrocenyl
quinolines were more efficient than CQ in inhibiting the CQ-
resistant strains FcB1 and K1 with IC50 ranging from 18 to 34 and
25e32 nM respectively. Furthermore, they displayed similar IC50
values than FQ and ART toward all strains tested.
Increasing the length of the side alkyl chain from two or three to
four methylene units in compounds 9e11 decreased the anti-
plasmodial activity (entries 4 and 5 vs 6). Similar effect was
observed for 20 and 21 (entries 11 vs 12). But the effect of chain
length was not observed with the linear 10 and branched 12 pro-
pylamino chain derivatives (entries 10 and 12). As already
described [34], 1,4-diaminocyclohexyl compounds showed an in-
crease of relative activity against CQ. Indeed, ferrocenyl derivative
16 exhibited excellent activities of 31e32 nM for the three strains
(entry 9). Changing the position of the two amines in the cyclohexyl
for 14 led to similar activities than 16 (entries 8 and 9). The anti-
plasmodial activity is not affected by the N-methylation of the ni-
trogen atom in compound 16 (entries 9 vs 10).
Fig. 1. Structures of Ferroquine (FQ) and analogous.
moiety is introduced between the two amino groups or at the end
of the linear or branched aliphatic N-alkylamino side chain of the 4-
aminoquinoline. To our knowledge, no ferrocenyl compounds
possessing a cyclic entity have been previously synthesized.
However, previous studies have shown that the incorporation of
a cyclohexane, piperidine or piperazine group in the side chain of
the 4-aminoquinoline provided good antimalarial drugs [34e36].
As part of our ongoing interest in development of novel ferrocenyl
drugs [37e39], we introduced cyclic moiety in the design of fer-
rocenyl compounds (Fig. 2). Their antiplasmodial activity was
evaluated on CQ-sensitive- and CQ-resistant P. falciparum strains.
The resistance index values provide a quantitative measurement
of the antimalarial activity against chloroquine-resistant strains
(FcB1 and K1) relative to that against sensitive strain (F32). All
ferrocenyl compounds exhibited lower resistance index than those
of CQ in a range of 0.6e1.2 (FcB1) and 0.7e1.1 (K1) (Table 1).
2.3. Cytotoxicities on MCR-5 cells
2. Results and discussion
The cytotoxicities of the ferrocenyl compounds were evaluated
upon MCR-5 cells. The values allowed us to calculate the selectivity
index corresponding to the ratio of cytotoxicity and antimalarial
activity for the different strains. The results are summarized in
Table 1.
Unfortunately, most of the ferrocenyl derivatives appeared to be
cytotoxic with LD50 ranging from 17 to 683 nM. Although 11 and 21
were the less cytotoxic compounds, they were also the less active
on P. falciparum strains. Only ferrocenyl compound 17 could
constitute good candidate for further pharmacological studies with
selectivity indexes over 259 upon the CQ-sensitive strain F32 and
over 317 upon CQ-resistant strains FcB1 and K1.
2.1. Chemistry
Ferrocenyl ketone 3 was first synthesized by reaction of ferro-
cenyl ammonium salt 1 with 4-piperidone chloride 2 in the pres-
ence of potassium carbonate (Scheme 1). In addition, condensation
of diamines with 4,7-dichloroquinoline 4 afforded the primary
amines 5e8 [40]. Ferrocenyl quinoline amines 9e12 were then
obtained in 74e95% yields by condensation of amines 5e8 on the
ketone 3, followed by a reduction with NaBH4 (Scheme 1).
The ferrocenyl diamines 14 and 16 were prepared by a two-step
reaction in 86 and 83% global yield respectively including a
nucleophilic substitution of 4,7-dichloroquinoline 4 and a reductive
amination in the presence of ferrocene carboxaldehyde (Scheme 2).
The methylation of the secondary amine 16 by reaction of formal-
dehyde followed by a reduction with NaBH4 afforded to 17 in 90%
yield. Finally, condensation of amine 15 with either N-Boc-2-
bromoethylamine or 3-bromopropylamine followed by N-Boc
deprotection led to amines 18 and 19 in 26 and 56% global yields.
The incorporation of a ferrocenyl group in 18 and 19 was achieved
by reductive amination in the presence of ferrocene carbox-
aldehyde and furnished the ferrocenyl amines 20 and 21 in 95%
yield (Scheme 2).
3. Conclusion
Novel series of ferrocenyl 4-aminoquinolines were synthesized
and tested for their activities against P. falciparum F32 (chloro-
quine-sensitive) and FCB1 and K1 (chloroquine-resistant). Most of
the ferrocenyl compounds showed interesting antiplasmodial ac-
tivity in the nM range. In particular, the biological results led to
highlight the ferrocenyl quinoline 17 as a lead compound in this
series and could be a good candidate for further pharmacological
studies. In addition, this work emphasizes the importance of the
ferrocenyl entity as a good scaffold for designing antimalarial
compounds. Further in vivo testing of ferrocenyl quinoline 17 will
also be performed on murine models of malaria.
2.2. In vitro antiplasmodial activities
The in vitro antiplasmodial activity of ferrocenyl 4-
aminoquinolines were evaluated against the CQ-sensitive F32
4. Experimental
(IC50 CQ ¼ 0.019
m
M) and CQ-resistant FcB1 (IC50 ¼ 0.111
mM) and
K1 (IC50 ¼ 0.160
m
M) P. falciparum strains. The potencies of the
4.1. Chemistry
ferrocenyl compounds, as indicated by their IC50 values, are sum-
marized in Table 1. The IC50 values were compared to Chloroquine
(CQ), Ferroquine (FQ) and Artemesinine (ART). In parallel, the
cytotoxicity of the compounds was evaluated with human MCR-5
All commercial reagents and solvents were used without further
purification. Melting points were determined with a Barnstead
Electrothermal (BI 9300) capillary melting point apparatus and are

G. Mwande Maguene et al. / European Journal of Medicinal Chemistry 90 (2015) 519e525
521
Fig. 2. Structures of ferrocenyl 4-aminoquinolines.
Scheme 1. Reagents and conditions: (a) K2CO3, methanol, reflux, 12 h (98%); (b) diamine, 135 ꢁC, 4 h (80e98%); (c) 3, methanol, reflux, 4 h then NaBH4 (74e95%).
Scheme 2. Reagents and conditions: (a) 1,2- or 1,4-diaminocyclohexane, ethanol, reflux, 24 h (90% for 13 and 87% for 15); (b) Ferrocene carboxaldehyde, methanol, reflux, 4 h then
NaBH4 (95%); (c) Formaldehyde (37% aq), methanol, 2 h, reflux then NaBH4, 0 ꢁC, 2 h (90%); (d) N-Boc aminoalkyl bromide, dioxane, potassium carbonate, 100 ꢁC then 12 h HCl, i-
PrOH, CHCl3, rt, 12 h (26% for 18 and 56% for 19, two steps); (e) Ferrocene carboxaldehyde, methanol, reflux, 4 h then NaBH4 (95%).
uncorrected. The 1H and 13C NMR spectra were recorded on a
Bruker AC300 spectrometer at 300 and 75.5 MHz respectively. Thin
layer chromatography (TLC) was carried out on aluminum-baked
MachereyeNagel silica gel 60. Column chromatography was per-
formed on silica gel (230e400 mesh). Elemental analyses were
performed with a varioMICRO analyzer.
4.1.1. N-ferrocenylmethyl-4-piperidone 3
Ferrocenyl ammonium iodide 1 (8.8 mmol, 3.38 g) and 4-
piperidone chloride (4.6 mmol, 0.455 g) were dissolved in aceto-
nitrile (30 mL) in the presence of K2CO3 (4.6 mmol, 0.634 mg). The
resulting solution was heated at reflux for 12 h. The mixture was
hydrolyzed by an aqueous NaOH solution (1 M, 20 mL) and
extracted with CH2Cl2 (3 ꢀ 20 mL). The organic layer was dried over
Na2SO4 and evaporated under vacuum to give a yellow solid. The

522
G. Mwande Maguene et al. / European Journal of Medicinal Chemistry 90 (2015) 519e525
Table 1
In vitro sensitivity of P. falciparum strains and in vitro cytotoxicity on MRC-5 cells of ferrocenyl compounds 9e12, 14, 16e17 and 20e21.
Entry
Compd
P. falciparum strains IC50 values (nM)a
MRC-5 cells LD50 (nM)b
Selectivity indexc
Resistance indexd
F32
FcB1
K1
F32
FcB1
K1
FcB1
K1
1
2
3
4
CQ
FQ
ART
9
19
29
31
111
20
18
160
31
29
50000
NT
NT
e
e
e
e
e
e
0.7
0.6
1.2
1.1
0.7
0.8
1.0
1.0
0.8
1.0
0.6
1.1
0.9
1.0
0.8
0.7
0.9
0.9
1.0
0.8
0.9
0.9
26
32
27
17
0.7
0.5
0.6
5
6
7
8
10
11
12
14
16
17
20
21
30
319
35
33
31
33
33
292
32
217
27
34
32
27
33
174
25
215
30
30
32
26
32
261
683
5520
551
59
52
8570
67
22.7
17.3
15.7
1.8
21.3
25.4
20.4
1.7
27.3
25.6
18.3
2.0
9
1.7
1.6
1.6
10
11
12
259.7
2.0
30.5
317.4
2.0
51.1
329.6
2.1
34.1
8900
a
IC50 values were measured on the chloroquine-sensitive strain F32/Tanzania and the chloroquine-resistant strains FcB1/Colombia and K1/Thailand. The results are
expressed as IC50 values at least one experiment for F32, three independent experiments for FCB1, two experiments for K1.
b
LD50 lethal dose, indicating concentration which reduced the number of viable cells by 50%.
Selectivity index (SI) was defined as the ratio between the LD50 value on the MRC-5 cells and the IC50 value against the P. falciparum F32, FcB1 et K1 strains.
IC50(FcB1)/IC50(F32) and IC50(K1)/IC50(F32).
c
d
product was purified by recrystallization to give 3 (1.33 g, 98%). 1H
4.1.2.3. N1-(1-ferrocenylmethylpiperidin-4-yl)-N4-(7-
NMR (300 MHz, CDCl3)
d
4.18 (s, 2H, Cp), 4.12 (s, 2H, Cp), 4.11 (s, 5H,
chloroquinolin-4-yl)butane-1,4-diamine 11. Yield: 85%, yellow solid,
Cp0), 3.50 (s, 2H, FcCH2), 2.70 (t, J ¼ 6.0 Hz, 2H, CH2), 2.41 (t,
mp 62 ꢁC. 1H NMR (300 MHz, CDCl3)
d
8.29 (d, J ¼ 6.7 Hz, 1H, HAr),
J ¼ 6.0 Hz, 2H, CH2). 13C (75.5 MHz, CDCl3)
d 209.2, 82.3, 70.2, 68.6,
8.12 (d, J ¼ 9.3 Hz, 1H, HAr), 7.79 (s, 1H, HAr), 7.23 (d, J ¼ 9.3 Hz, 1H,
68.3, 57.4, 52.4, 41.1. HRMS (ESI): m/z (M þ H)þ calcd for
H
Ar), 6.19 (d, J ¼ 7.0 Hz, 1H, HAr), 5.9 (s, 1H, NH), 4.12 (s, 2H, Cp), 4.11
C
16H20FeNO: 298.0894, found: 297.0881.
(s, 7H, Cp, Cp0), 3.39 (s, 2H, FcCH2), 3.21 (m, 2H, CH2), 2.85 (m, 4H,
CH2), 2.71 (m, 1H, CH), 2.18 (m, 2H, CH2),2.01 (m, 4H, CH2), 1.95 (m,
4H, CH2). 13C NMR (75 MHz, CDCl3)
d 156.5,151.5, 147.9, 135.8, 125.4,
4.1.2. General procedure for ferrocenyl amines 9e12
123.4, 126.7, 111.4, 98.2, 81.3, 70.4, 68.6, 68.3, 57.6, 54.8, 50.9, 42.5,
To a solution of amine (1.3 mmol) in methanol (20 mL) was
added ferrocene carboxaldehyde (1.3 mmol). After stirring under
reflux for 4 h, the mixture was allowed to reach to room temper-
ature and NaBH4 (4 mmol) was slowly added. After 1 h 30, the
mixture was hydrolyzed by an aqueous NaOH solution (1 M, 20 mL)
and extracted with CH2Cl2 (3 ꢀ 20 mL). The organic layer was dried
over Na2SO4 and evaporated under vacuum to give a yellow solid.
The crude product was purified by recrystallization or by column
chromatography (eluant: ethyl acetate/triethylamine: 7/3).
30.9, 29.2, 25.2, 24.0. HRMS (ESI): m/z (M þ H)þ calcd for
C29H36ClFeN4: 531.1978, found: 531.1988.
4.1.2.4. N1-(1-ferrocenylmethylpiperidin-4-yl)-N3-(7-
chloroquinolin-4-yl)2,2-dimethyl
propane-1,3-diamine
12.
8.44
Yield: 74%, yellow solid, mp 58 ꢁC. 1H NMR (300 MHz, CDCl3)
d
(d, J ¼ 6.9 Hz, 1H, HAr), 8.33 (s, 1H, NH), 7.91 (d, J ¼ 2.1 Hz, 1H, HAr),
7.70 (d, J ¼ 9.2 Hz,1H, HAr), 7.29 (dd, J ¼ 8.9 and 2.1 Hz,1H, HAr), 6.26
(d, J ¼ 6.9 Hz, 1H, HAr), 4.16 (m, 2H, Cp), 4.11 (s, 2H, Cp), 4.10 (s, 5H,
Cp0), 3.37 (s, 2H, FcCH2), 3.13 (s, 2H, CH2), 2.85 (m, 2H, CH2), 2.69 (s,
2H, CH2), 2.37 (m, 1H, CH),1.95 (m, 4H, CH2), 1.21 (m, 2H, CH2), 1.06
4.1.2.1. N1-(1-ferrocenylmethylpiperidin-4-yl)-N2-(7-chloroquinolin-
4-yl)ethane-1,2-diamine 9. Yield: 95%, yellow solid, mp 66 ꢁC. 1H
NMR (300 MHz, CDCl3)
d
8.40 (d, J ¼ 5.4 Hz, 1H, HAr), 7.81 (d,
(s, 6H, CH3). 13C NMR (75 MHz, CDCl3)
d 152.1, 150.8, 149.1, 134.5,
J ¼ 2.1 Hz, 1H, HAr), 7.64 (d, J ¼ 8.9 Hz, 1H, HAr), 7.20 (dd, J ¼ 8.7 and
2.1 Hz, 1H, HAr), 6.27 (d, J ¼ 5.4 Hz, 1H, HAr), 5.20 (s, 1H, NH), 4.07 (s,
2H, Cp), 4.02 (s, 2H, Cp), 4.01 (s, 5H, Cp0), 3.29 (s, 2H, FcCH2), 3.18 (t,
J ¼ 6.0 Hz, 2H, CH2), 2.74 (t, J ¼ 6.0 Hz, 2H, CH2), 2.35 (m, 4H, CH2),
128.5, 124.7, 122.4, 117.7, 97.8, 82.7, 70.4, 68.5, 68.0, 58.2, 55.9, 51.9,
33.5, 32.7, 25.0. Anal. Calcd for C30H37ClFeN4: C 66.12, H 6.84, N
10.28, found: C 66.01, H 6.79, N 10.20.
1.85 (m,1H, CH),1.78 (m, 4H, CH2). 13C NMR (75 MHz, CDCl3)
d 151.9,
149.9, 148.9, 134.7, 128.4, 125.1, 121.5, 117.4, 99.1, 82.2, 70.3, 68.5,
68.0, 58.3, 54.2, 51.7, 44.2, 42.3, 32.7. Anal. Calcd for C27H31ClFeN4: C
64.49, H 6.21, N 11.14, found: C 64.58, H 6.01, N 11.23.
4.1.3. (1R,2R)-N1-(7-chloroquinolein-4-yl)cyclohexane-1,2-
diamine 13
A mixture of 4,7-dichloroquinoline (0.28 g, 1.4 mmol) and
(1R,2R)-1,2-diaminocyclohexane (0.5 mL, 4.2 mmol) was heated to
110 ꢁC for 24 h. After cooling to room temperature, water (30 mL)
was then added and the mixture was extracted with CH2Cl2. The
organic layers were washed with water (50 mL), dried over anhy-
drous MgSO4. The mixture was evaporated to give a brown oil
4.1.2.2. N1-(1-ferrocenylmethylpiperidin-4-yl)-N3-(7-
chloroquinolin-4-yl)propane-1,3-diamine 10. Yield: 80%, yellow
solid, mp 64 ꢁC. 1H NMR (300 MHz, CDCl3)
d
8.43 (d, J ¼ 5.3 Hz, 1H,
H
Ar), 7.88 (d, J ¼ 2.0 Hz, 1H, HAr), 7.81 (d, J ¼ 8.9 Hz, 1H, HAr), 7.32
(dd, J ¼ 9.2 and 2.0 Hz, 1H, HAr), 6.25 (d, J ¼ 5.4 Hz, 1H, HAr), 5.22 (s,
1H, NH), 4.15 (s, 2H, Cp), 4.11 (s, 2H, Cp), 4.09 (s, 5H, Cp0), 3.39 (s, 2H,
FcCH2), 3.29 (t, J ¼ 5.7 Hz, 2H, CH2), 2.85 (m, 4H, CH2), 2.79 (t,
J ¼ 7.1 Hz, 2H, CH2), 2.5 (m, 1H, CH), 1.50 (m, 2H, CH2), 1.21 (m, 4H,
(0.346 g, 90%). 1H NMR (300 MHz, MeOD-d4)
d
8.38 (d, J ¼ 5.6 Hz,
1H, HAr), 8.21 (d, J ¼ 9.0 Hz, 1H, HAr), 7.75 (s, 1H, HAr), 7.38 (d,
J ¼ 8.9 Hz,1H, HAr), 6.67 (d, J ¼ 5.7 Hz,1H, HAr), 5.50 (s, 3H, NH), 3.65
(m, 1H, CH), 3.22 (m, 1H, CH), 2.16 (m, 2H, CH2), 1.84 (m, 2H, CH2),
CH2). 13C NMR (75 MHz, CDCl3)
d 151.4, 150.7, 144.4, 134.9, 127.8,
125.1, 125.6, 122.5, 117.4, 98.2, 82.1, 70.3, 68.5, 68.1, 58.1, 55.4, 51.6,
43.5, 34.4, 31.9, 27.2. Anal. Calcd for C28H33ClFeN4: C 65.06, H 6.44,
N 10.84, found: C 65.24, H 6.31, N 10.65.
1.44 (m, 4H, CH2). 13C NMR (75 MHz, MeOD-d4)
d 152.5, 152.2,
149.5, 136.5, 127.3, 126.1, 124.9, 119.1, 100.2, 57.2, 54.9, 32.9, 31.9,
25.6, 25.5.

G. Mwande Maguene et al. / European Journal of Medicinal Chemistry 90 (2015) 519e525
523
4.1.4. (1R,2R)-N1-(7-chloroquinolin-4-yl)-N2-(ferrocenylmethyl)
cyclohexane-1,2-diamine 14
under reflux for 2 h, the mixture was allowed to room temperature
and NaBH4 (1.68 mmol, 63 mg) was slowly added at 0 ꢁC. After 2 h,
the mixture was hydrolyzed by water (20 mL) and extracted with
CH2Cl2 (3 ꢀ 20 mL). The organic layer was dried over Na2SO4 and
evaporated under vacuum to give a yellow solid. The crude product
was purified by column chromatography (eluant: ethyl acetate/
triethylamine: 7/3) to give a yellow solid (367 mg, 90%). M.p. 90 ꢁC.
To a solution of diamine 13 (1.2 mmol, 0.300 g) in methanol
(20 mL) was added ferrocene carboxaldehyde (1.3 mmol, 0.286 g).
After stirring under reflux for 4 h, the mixture was allowed to reach
to room temperature and NaBH4 (2.6 mmol, 100 mg) was slowly
added. After 1h30, the mixture was hydrolyzed by an aqueous
NaOH solution (1 M, 20 mL) and extracted with CH2Cl2 (3 ꢀ 20 mL).
The organic layer was dried over Na2SO4 and evaporated under
vacuum to give a yellow solid. The crude product was purified by
column chromatography (eluant: ethyl acetate/triethylamine: 7/3)
to give a yellow solid (0.539 g, 95%). M.p. 50 ꢁC. 1H NMR (300 MHz,
1H NMR (300 MHz, CDCl3)
d
8.43 (d, J ¼ 5.3 Hz, 1H, HAr), 7.87 (d,
J ¼ 1.8 Hz, 1H, HAr), 7.53 (d, J ¼ 8.9 Hz, 1H, HAr), 7.25 (dd, J ¼ 8.8 and
1.8 Hz, 1H, HAr), 6.35 (d, J ¼ 5.4 Hz, 1H, HAr), 4.72 (d, J ¼ 7.1 Hz, 1H,
NH), 4.10 (s, 2H, Cp), 4.00 (s, 7H, Cp þ Cp0), 3.49 (s, 2H, FcCH2), 3.48
(m, 1H, CH), 2.52 (m, 1H, CH), 2.25 (s, 3H, CH3), 2.18 (m, 2H, CH2),
1.98 (m, 2H, CH2), 1.26 (m, 4H, CH2). 13C NMR (75 MHz, CDCl3)
CDCl3)
d
8.41 (d, J ¼ 5.4 Hz, 1H, HAr), 7.85 (d, J ¼ 2.1 Hz, 1H, HAr), 7.41
(d, J ¼ 8.9 Hz, 1H, HAr), 7.19 (dd, J ¼ 8.9 and 2.1 Hz, 1H, HAr), 6.40 (d,
J ¼ 5.4 Hz, 1H, HAr), 5.10 (s, 1H, NH), 4.05 (m, 4H, Cp), 3.95 (s, 5H,
Cp0), 3.57 (d, J ¼ 13.1 Hz, 1H, FcCH2), 3.31 (d, J ¼ 13.4 Hz, 1H, FcCH2),
3.16 (m, 1H, CH), 2.19 (m, 4H, CH2), 1.75 (m, 1H, CH), 1.35 (m, 4H,
d
151.9, 149.3, 148.6, 134.8, 128.9, 125.2, 120.7, 117.0, 99.3, 84.0, 70.2,
68.8, 68.2, 60.4, 53.7, 51.7, 37.9, 31.9, 27.2. Anal. Calcd for
27H30ClFeN3: C 66.47, H 6.20, N 8.61, Found 66.21, H 6.12, N 8.45.
C
CH2), 1.16 (m, 4H, CH2). 13C NMR (75 MHz, MeOD-d4)
d
152.0, 149.9,
4.1.8. (1R,4R)-N1-(2-aminoethyl)-N4-(7-chloroquinolin-4-yl)
cyclohexane-1,4-diamine 18
149.3, 134.7, 128.8, 125.2, 121.3, 117.6, 99.8, 87.3, 68.4, 68.1, 67.8,
60.5, 56.7, 45.6, 31.7, 24.7. HRMS (ESI): m/z (M þ H)þ calcd for
To a solution of diamine 15 (1.21 mmol, 0.332 g) in dioxane
(20 mL) was added ter-butyl-2-bromoethylcarbamate (1.33 mmol,
0.296 g) in the presence of K2CO3 (400 mg). After stirring at 100 ꢁC
for 12 h, the mixture was allowed to room temperature and the
solvent was evaporated. The residue was hydrolyzed by HCl (1 M,
20 mL) and extracted with CH2Cl2 (3 ꢀ 20 mL). The organic layer
was dried over Na2SO4 and evaporated under vacuum to give yel-
low oil. The crude product was purified by column chromatography
(eluant: ethyl acetate/triethylamine: 7/3) to give a yellow oil
C
26H28ClFeN3: 473.1321, found: 473.1302.
4.1.5. Trans-N1-(7-chloroquinolein-4-yl)cyclohexane-1,4-diamine
15
A mixture of 4,7-dichloroquinoline (1.4 mmol, 0.28 g) and trans-
1,4-diaminocyclohexane (4.2 mmol, 0.5 mL) was heated to 110 ꢁC
for 24 h. After cooling to room temperature, water (30 mL) was then
added and the mixture was extracted with CH2Cl2. The organic
layers were washed with water (50 mL), dried over anhydrous
MgSO4 and evaporated under reduced pressure. The mixture was
purified by flash chromatography (eluent: ethyl acetate/MeOH/
triethylamine: 7/1/2) to give a brown oil (0.335 g, 87%). 1H NMR
(0.258 g, 51%). 1H NMR (300 MHz, CDCl3)
d
8.71 (d, J ¼ 4.7 Hz, 1H,
H
Ar), 8.10 (d, J ¼ 9.1 Hz, 1H, HAr), 8.03 (s, 1H, HAr), 7.52 (d, J ¼ 8.9 Hz,
1H, HAr), 7.52 (d, J ¼ 4.6 Hz, 1H, HAr), 4.92 (s, 1H, NH), 4.52 (s, 1H,
NH), 3.63 (m, 2H, CH2), 3.52 (m, 2H, CH2), 3.39 (m, 1H, CH), 3.21 (m,
1H, CH), 2.18 (m, 2H, CH2), 2.01 (m, 2H, CH2), 1.95 (m, 4H, CH2), 1.38
(300 MHz, MeOD-d4)
d
8.29 (d, J ¼ 5.6 Hz, 1H, HAr), 8.07 (d,
J ¼ 8.8 Hz, 1H, HAr), 7.73 (s, 1H, HAr), 7.30 (d, J ¼ 9.0 Hz, 1H, HAr), 6.47
(d, J ¼ 5.6 Hz, 1H, HAr), 4.94 (s, 3H, NH), 3.48 (m, 1H, CH), 2.69 (m,
1H, CH), 2.09 (m, 2H, CH2), 1.94 (m, 2H, CH2), 1.45 (m, 2H, CH2), 1.30
(s, 9H, CH3). 13C NMR (75 MHz, CDCl3)
d 155.6, 150.9, 150.4, 148.4,
134.8,126.1,124.3,123.0,117.4, 98.5, 85.3, 50.9, 49.5, 42.3, 35.2, 33.6,
32.4, 28.3.
(m, 2H, CH2). 13C NMR (75 MHz, MeOD-d4)
d
150.9, 150.3, 148.4,
To a solution of N-protected amine (0.500 mg, 1.18 mmol) in
CHCl3 (10 mL) was added HCl (10 M in i-PrOH, 10 mL). After stirring
at 20 ꢁC for 18 h, the mixture was hydrolyzed by water (50 mL),
neutralized by NaOH and extracted with CHCl3 (3 ꢀ 20 mL). The
organic layer was dried over Na2SO4 and evaporated under vacuum
to give yellow oil. The crude product was purified by column
chromatography (eluant: ethyl acetate/triethylamine: 7/3) to give a
134.8, 126.1, 124.3, 123.0, 117.3, 98.5, 50.9, 49.5, 34.0, 30.4.
4.1.6. Trans-N1-(7-chloroquinolin-4-yl)-N4-(ferrocenylmethyl)
cyclohexane-1,4-diamine 16
To a solution of diamine 15 (1.2 mmol, 0.300 g) in methanol
(20 mL) was added ferrocene carboxaldehyde (1.3 mmol, 0.286 g).
After stirring under reflux for 4 h, the mixture was allowed to room
temperature and NaBH4 (2.6 mmol, 100 mg) was slowly added.
After 1h30, the mixture was hydrolyzed by an aqueous NaOH so-
lution (1 M, 20 mL) and extracted with CH2Cl2 (3 ꢀ 20 mL). The
organic layer was dried over Na2SO4 and evaporated under vacuum
to give a yellow solid. The crude product was purified by column
chromatography (eluant: ethyl acetate/MeOH/triethylamine: 7/1/
2) to give a yellow solid (0.539 g, 95%). M.p. 187 ꢁC. 1H NMR
yellow oil (193 mg, 51%). 1H NMR (300 MHz, CDCl3)
d 8.23 (d,
J ¼ 5.5 Hz, HAr), 8.04 (d, J ¼ 9.0 Hz, HAr), 7.65 (s, 1H, HAr), 7.27 (d,
J ¼ 9.0 Hz, HAr), 6.46 (d, J ¼ 5.9 Hz, HAr), 3.45 (s,1H, NH), 2.90 (m,1H,
CH), 2.60 (m, 1H, CH), 2.10 (m, 2H, CH2), 2.08 (m, 2H, CH2), 1.45 (m,
4H, CH2), 1.06 (m, 2H, CH2), 1.04 (m, 2H, CH2). 13C NMR (75 MHz,
CDCl3)
d 152.4, 151.8, 148.7, 136.4, 127.5, 125.9, 124.5, 118.8, 100.0,
51.8, 50.8, 49.8, 48.1, 32.3, 31.2.
(300 MHz, CDCl3)
d
8.45 (d, J ¼ 6.7 Hz, 1H, HAr), 8.12 (d, J ¼ 9.3 Hz,
4.1.9. (1R,4R)-N1-(2-aminopropyl)-N4-(7-chloroquinolin-4-yl)
cyclohexane-1,4-diamine 19
1H, HAr), 7.79 (s, 1H, HAr), 7.23 (d, J ¼ 9.4 Hz, 1H, HAr), 6.39 (d,
J ¼ 7.0 Hz, 1H, HAr), 4.88 (d, J ¼ 7.2 Hz, 1H, NH), 4.22 (s, 2H, Cp), 4.11
(s, 2H, Cp), 4.10 (s, 5H, Cp0), 3.60 (s, 2H, FcCH2), 3.21 (m, 1H, CH),
2.85 (m, 1H, CH), 2.18 (m, 2H, CH2), 2.01 (m, 2H, CH2), 1.83 (s, 1H,
To a solution of diamine 15 (1.21 mmol, 0.332 g) in dioxane
(20 mL) was added ter-butyl-2-bromopropylcarbamate (1.33 mmol,
0.315 g) in the presence of K2CO3 (400 mg). After stirring at 100 ꢁC
for 12 h, the mixture was allowed to reach to room temperature and
the solvent was evaporated. The residue was hydrolyzed by HCl
(1 M, 20 mL) and extracted with CH2Cl2 (3 ꢀ 20 mL). The organic
layer was dried over Na2SO4 and evaporated under vacuum to give
yellow oil. The crude product was purified by column chromatog-
raphy (eluant: ethyl acetate/triethylamine: 7/3) to give a yellow oil
NH), 1.37 (m, 4H, CH2). 13C NMR (75 MHz, CDCl3)
d 152.0, 149.3,
148.6, 134.8, 129.7, 125.2, 120.8, 117.1, 99.4, 87.0, 68.4, 68.3, 67.8,
55.7, 53.4, 51.5, 46.3, 31.8, 31.3. HRMS (ESI): m/z (M þ H)þ calcd for
C
26H29ClFeN3: 474.1399, found: 474.1407.
4.1.7. (1R,4R)-N1-(7-chloroquinolin-4-yl)-N4-(ferrocenylmethyl)-
N4-methylcyclohexane-1,4-diamine 17
To a solution of amine 16 (0.84 mmol, 0.400 g) in methanol
(20 mL) was added methanal (1 mL, 37% in H2O). After stirring
(355 mg, 68%). 1H NMR (300 MHz, CDCl3)
Ar), 7.86 (s, 1H, ArH), 7.56 (d, J ¼ 8.9 Hz, 1H, HAr), 7.26 (d, J ¼ 8.5 Hz,
1H, HAr), 6.35 (d, J ¼ 5.2 Hz, 1H, HAr), 5.23 (s, 1H, NH), 4.60 (s, 1H,
d
8.43 (d, J ¼ 5.3 Hz, 1H,
H

524
G. Mwande Maguene et al. / European Journal of Medicinal Chemistry 90 (2015) 519e525
NH), 3.45 (m, 2H, CH2), 3.16 (m, 1H, CH), 2.49 (m, 2H, CH2), 2.10 (m,
1H, CH), 2.04 (m, 2H, CH2), 1.64 (m, 2H, CH2), 1.41 (m, 2H, CH2), 1.38
4.2. Biological testing assay
(s, 9H, CH3), 1.28 (m, 4H, CH2). 13C NMR (75 MHz, CDCl3)
d
168.5,
4.2.1. In vitro P. falciparum culture and drug assays
151.9, 149.3, 148.5, 134.8, 128.8, 125.2, 120.0, 117.0, 99.3, 85.1, 50.9,
49.5, 42.3, 35.2, 35.1, 32.7, 31.2, 28.4.
P. falciparum strains were maintained continuously in culture on
human erythrocytes [41]. In vitro antiplasmodial activity was
determined by following [3H]hypoxanthine incorporation by the
parasite [42]. P. falciparum CQ-sensitive (F32/Tanzania) and CQ-
resistant (FcB1/Colombia and K1/Thailand) strains were used in
sensitivity testing. Stock solutions of chloroquine diphosphate,
artemisinine and test compounds were prepared in sterile distilled
water and DMSO, respectively. Drug solutions were serially diluted
with culture medium and introduced to asynchronous parasite
cultures (1% parasitemia and 1% final hematocrit) in 96-well plates
To a solution of N-protected amine (1 mmol, 0.432 g) in CHCl3
(10 mL) was added HCl (10 M in i-PrOH, 10 mL). After stirring at
20 ꢁC for 18 h, the mixture was hydrolyzed by water (50 mL),
neutralized by NaOH and extracted with CHCl3 (3 ꢀ 20 mL). The
organic layer was dried over Na2SO4 and evaporated under vacuum
to give yellow oil. The crude product was purified by column
chromatography (eluant: ethyl acetate/triethylamine: 7/3) to give a
yellow oil (272 mg, 82%). 1H NMR (300 MHz, CDCl3)
d 8.93 (d,
J ¼ 5.5 Hz, HAr), 8.36 (d, J ¼ 9.7 Hz, HAr), 8.15 (s, 1H, HAr), 7.98 (d,
J ¼ 9.6 Hz, HAr), 7.84 (d, J ¼ 5.9 Hz, HAr), 3.5 (s, 1H, NH), 3.45 (s, 2H,
NH), 2.92 (m, 1H, CH), 2.65 (m, 1H, CH), 2.10 (m, 2H, CH2), 2.08 (m,
2H, CH2),1.45 (m, 4H, CH2),1.36 (m, 2H, CH2),1.24 (m, 2H, CH2), 0.86
for 24 h at 37 ꢁC prior to the addition of [3H]hypoxanthine (0.5
mCi
per well, 1e5 Ci mmolꢂ1) for 24 h. The growth inhibition for each
drug concentration was determined by comparison of the radio-
activity incorporated into the treated culture with that in the
control culture (without drug) maintained on the same plate. In-
hibition concentration, IC50 (the drug concentration that reduced
the number of P. falciparum parasites by 50%) and IC90 were ob-
tained from the drug concentrationeresponse curve and the results
are expressed as the mean determined from several experiments.
IC90 values were reported in Table 1 in Supporting information.
(m, 2H, CH2). 13C NMR (75 MHz, CDCl3)
d 151.9; 149.3, 148.5, 134.8,
128.8, 125.2, 120.0, 117.0, 99.3, 50.9, 49.5, 42.3, 35.2, 35.1, 32.7, 31.2.
4.1.10. (1R,4R)-N1-(7-chloroquinolin-4-yl)-N4-(3-
(ferrocenylmethylamino)ethyl)cyclo hexane-1,4-diamine 20
To a solution of amine 18 (0.34 mmol, 0.108 mg) in methanol
(20 mL) was added ferrocene carboxaldehyde (0.37 mmol, 80 mg).
After stirring under reflux for 4 h, the mixture was allowed to reach
to room temperature and NaBH4 (0.68 mmol, 26 mg) was slowly
added. After 2 h, the mixture was hydrolyzed by water (20 mL) and
extracted with CH2Cl2 (3 ꢀ 20 mL). The organic layer was dried over
Na2SO4 and evaporated under vacuum to give a yellow solid. The
crude product was purified by column chromatography (eluant:
ethyl acetate/triethylamine: 7/3) to give a yellow solid (115 mg,
4.3. In vitro cytotoxicities against MCR-5 cells
Synthesized compounds were tested against MRC-5 human
diploid embryonic lung cells, using tetrazolium salt MTT (3-[4,5-
dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; Sigma_)
colorimetric method based on reagent cleavage by mitochondrial
dehydrogenase in viable cells [43]. Five thousand cells per well were
seeded into 96-well microplates containing culture medium
95%). M.p. 155 ꢁC. 1H NMR (300 MHz, CDCl3)
d
8.42 (d, J ¼ 8.8 Hz,
(DMEM þ 10% SVF þ 2 mM
L
-glutamine þ penicillin/streptomycin/
neomycin: 0.5/0.5/1 g /ml) as previously described [44]. The results
m
H
H
Ar), 7.87 (s, 1H, HAr), 7.52 (d, J ¼ 10.0 Hz, HAr), 7.25 (d, J ¼ 10.0 Hz,
were expressed as the median lethal dose LD50 (the drug concen-
tration that reduced the number of viable human cells MCR-5 by
50%). LD50 were obtained from the drug concentration-response
curve and the results are expressed as the mean determined from
three experiments. A selectivity index (SI) corresponding to the ratio
between the cytotoxic and antiparasitic activities of each compound
was calculated as follows: SI Plasmodium ¼ (LD50MRC-5)/(IC50Plasmodium).
Ar), 6.34 (d, J ¼ 8.6 Hz, HAr), 4.76 (s, 1H, NH), 4.25 (s, 1H, NH), 4.15
(s, 2H, Cp), 4.08 (s, 2H, Cp), 4.06 (s, 5H, Cp0), 4.01 (s, 2H, FcCH2), 2.55
(m, 2H, CH), 2.18 (m, 4H, CH2), 1.99 (m, 4H, CH2), 1.28 (m, 4H, CH2).
13C NMR (75 MHz, CDCl3)
d 152.2, 151.9, 144.7, 144.7, 129.0, 125.2,
122.5, 120.7, 114.0, 99.3, 81.7, 68.5, 68.3, 68.0, 60.7, 57.0, 55.5, 51.4,
46.1, 31.4, 31.2. Anal. Calcd for C28H33ClFeN4: C 65.06, H 6.44, N
10.84, found: C 64.89, H 6.32, N 10.97.
Acknowledgment
4.1.11. (1R,4R)-N1-(7-chloroquinolin-4-yl)-N4-(3-
The authors are thankful to the institutions that support our
(ferrocenylmethylamino)propyl)cyclo hexane-1,4-diamine 21
To a solution of amine 19 (0.29 mmol, 0.096 g) in methanol
(20 mL) was added ferrocene carboxaldehyde (0.32 mmol, 68 mg).
After stirring under reflux for 4 h, the mixture was allowed to reach
to room temperature and NaBH4 (0.58 mmol, 22 mg) was slowly
added. After 2 h, the mixture was hydrolyzed by water (20 mL) and
extracted with CH2Cl2 (3 ꢀ 20 mL). The organic layer was dried over
Na2SO4 and evaporated under vacuum to give a yellow solid. The
crude product was purified by column chromatography (eluant:
ethyl acetate/triethylamine: 7/3) to give a yellow solid (146 mg,
ꢀ
laboratory (Centre National de la Recherche Scientifique, Universite
ꢀ
de Lille1). This research was supported by the “Conseil Regional
Nord-Pas de Calais” (grant for GMM and program PRIM), the
Museum d'Histoire Naturelle de Paris, the Centre International de
Recherches Medicales de Franceville and Universite des Sciences et
Techniques de Masuku (USTM). The authors also gratefully
acknowledge Faustin Lekoulou, Julie Pontarollo and Sonya Estelle
Zang-Edou for parasitological assistance.
ꢀ
ꢀ
95%). M.p. 90 ꢁC. 1H NMR (300 MHz, CDCl3)
d
8.52 (d, J ¼ 8.8 Hz,
Appendix A. Supplementary data
H
H
Ar), 7.96 (s, 1H, HAr), 7.62 (d, J ¼ 10.2 Hz, HAr), 7.34 (d, J ¼ 9.2 Hz,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.11.065.
Ar), 6.44 (d, J ¼ 8.1 Hz, HAr), 4.88 (s, 1H, NH), 4.35 (s, 1H, NH), 4.25
(s, 1H, NH), 4.20 (s, 2H, Cp), 4.17 (s, 2H, Cp), 4.14 (s, 5H, Cp0), 4.10 (s,
2H, FcCH2), 2.70 (m, 2H, CH), 2.27 (m, 3H, CH þ CH2), 2.08 (m, 2H,
CH2), 1.35 (m, 4H, CH2), 1.27 (m, 4H, CH2), 0.86 (m, 2H, CH2). 13C
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