Cinnamic Acid/Chloroquinoline Conjugates as Potent Agents against Chloroquine-Resistant Plasmodium falciparum

Full text of DOI:10.1002/cmdc.201200257

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DOI: 10.1002/cmdc.201200257
Cinnamic Acid/Chloroquinoline Conjugates as Potent Agents against
Chloroquine-Resistant Plasmodium falciparum
Bianca Pꢀrez,[a] Cꢁtia Teixeira,[a, b] Jiri Gut,[c] Philip J. Rosenthal,[c] Josꢀ R. B. Gomes,[b] and Paula Gomes*[a]
Malaria, particularly the cases of the disease caused by Plasmo-
dium falciparum, is the most widespread and deadly parasitic
disease, causing approximately one million deaths each year.
Strains of P. falciparum have emerged that are commonly re-
sistant to many available drugs, including chloroquine (1) and
antifolates, which have been classical antimalarial agents for
over half a century;[1] however, drug therapy remains a main-
stay of malaria control. Most clinically available antimalarial
agents target the blood-stage parasite, but specific mecha-
nisms of action are, in many cases, unknown.[2] Still, the major
mechanism of action of 1 is quite well understood—it is be-
lieved to block the biocrystallization of heme, the main process
through which Plasmodia eliminate toxic heme after it is re-
leased from parasite digestion of host erythrocyte hemoglo-
bin.[3]
A recent rational approach of antimalarial drug design char-
acterized as “covalent bitherapy” involves linking two mole-
cules with individual intrinsic activity to create a single agent,
thus packaging dual activity into a single hybrid molecule.[4,5]
In this regard, we have synthesized twelve novel compounds
(7) with the heteroaromatic core of 1, 4-amino-7-chloroquino-
line, linked to differently substituted cinnamoyl groups (CIN)
through a flexible aminobutyl spacer (Scheme 1a). Compound
Scheme 1. Synthesis of a) 4-amino-7-chloroquinoline/cinnamic acid conju-
design rationale was based on 1) relevance of 6 for inhibition
of heme biocrystallization, and consequently, of the develop-
ment of erythrocytic malaria parasites;[3] and 2) previous re-
ports on cinnamic acid derivatives with promising antimalarial
properties.[6–8] Moreover, we have recently demonstrated that
1) a spacer between the chloroquinoline and cinnamoyl moiet-
ies is required for antiplasmodial activity, as conjugates 5, bear-
ing a dipeptide spacer between those moieties were active,
whereas their counterparts 4 lacking such spacer were not;
and 2) the higher the lipophilicity of conjugates 5, the higher
the antiplasmodial activity.[7] Additionally, it is known that
a basic nitrogen together with a flexible polymethylene chain
gates 7 and b) 8-amino-6-methoxyquinoline analogue 8 (for details of sub-
stituent R, see Table 1). Reagents and conditions: a) 1008C, 2 h, 64%;
b) TBTU/DIEA, RT, 24 h, 8–67%; c) TBTU/DIEA, RT, 24 h, 78% (R=p-iPr).
linked to the aminoquinoline core favor drug accumulation in
the acidic parasite digestive vacuole and, consequently, have
a positive effect of the antiplasmodial activity of the com-
pound.[9] Therefore, we designed second-generation conju-
gates 7, where both the chloroquinoline and cinnamoyl cores
were preserved, but where the rigid and hydrophilic dipeptide
spacer of first-generation conjugates 5 has been replaced by
a flexible and more hydrophobic butyl chain, which also in-
creases the overall basicity of the compounds.
Compounds 7 were evaluated in vitro as inhibitors of 1) the
development of intraerythrocytic parasites of the chloroquine-
resistant P. falciparum W2 strain, 2) heme biocrystallization, and
3) falcipain-2 (FP2) activity. As shown in Table 1, all compounds
7 were exceptionally active against erythrocytic parasites, with
IC50 values ranging from 11 to 59 nm. All compounds were sig-
nificantly more active than 1, and two of them (7c and 7h)
were about as active as artemisinin (2), the prototype for the
most important new class of antimalarial agents.
[a] B. Pꢀrez,+ Dr. C. Teixeira,+ Prof. P. Gomes
Centro de Investigażo em Quꢁmica, Departamento de Quꢁmica e Bioquꢁ-
mic
Faculdade de CiÞncias da Universidade do Porto
R. do Campo Alegre, 4169-007 Porto (Portugal)
E-mail: pgomes@fc.up.pt
[b] Dr. C. Teixeira,+ Dr. J. R. B. Gomes
CICECO, Departamento de Quꢁmica, Universidade de Aveiro
Campus Universitꢂrio de Santiago, Aveiro 3810-193 (Portugal)
[c] J. Gut, Prof. P. J. Rosenthal
Department of Medicine, San Francisco General Hospital
University of California, San Francisco
PO Box 0811, CA 94143 (USA)
Compounds 7 did not display any enzymatic activity up to
50 mm and thus, do not exert their potent antiplasmodial activ-
ity through FP2 inhibition. This was expected, as first-genera-
tion compounds 5 were not FP2 inhibitors either.[7] Computa-
tional studies run in our group support this finding by predict-
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201200257.
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ophilic attack of compounds 7 increases from ~3.5 to ~5–5.5 ꢃ
(Figure S2 in the Supporting Information). As such, the interac-
tion between the enzyme and compounds 7 is predicted to be
insufficiently strong enough to form a stable complex, eventu-
ally leading to irreversible alkylation of the enzyme, as the
ligand rapidly moves away from the catalytic Cys. Hence, it
was not surprising that compounds 7 do not inhibit FP2
(Table 1). Still, replacing the dipeptide spacer in conjugates 5
by the more flexible and hydrophobic butyl chain, producing
conjugates 7, led to the anticipated increase in antiplasmodial
potency.
The remarkable activities of compounds 7 against erythro-
cytic parasites, along with their general ability to inhibit heme
biocrystallization, suggest that these compounds share their
antimalarial mechanism of action with chloroquine. To test
this, we prepared and evaluated compound 8 (Scheme 1b), an
analogue of 7c (R=p-iPr), where the 4-amino-7-chloroquino-
line moiety is replaced by 8-amino-6-methoxyquinoline, the
heteroaromatic ring of the antimalarial primaquine (3), which
is not an efficient inhibitor of heme biocrystallization.[2] Such
replacement led to loss of heme biocrystallization inhibitory
activity, providing evidence that this activity is mainly due to
the chloroquine part of the molecule and not to the cinnamoyl
moiety. Still, the ability of compounds 7 to inhibit heme bio-
crystallization did not fully correlate with their antimalarial ac-
tivity; that is to say, the most active antiplasmodial agents
were not necessarily the best inhibitors of biocrystallization in
vitro. For instance, compound 7b, which did not inhibit heme
biocrystallization, was determined to have antimalarial activity
(16.9 nm) comparable to that of compound 7i (18.2 nm), which
is one of the best inhibitors of heme biocrystallization.
ing that compounds 7 are inappropriate ligands for FP2. Al-
though docking calculations showed that the vinyl bond in 7
is placed at a distance that allows the formation of a covalent
bond between the ligand and the catalytic Cys residue of the
enzyme (Figure S1 in the Supporting Information), molecular
dynamics determined that, after a few picoseconds, the dis-
tance between the catalytic Cys and the putative site of nucle-
Based on literature accounts, the antimalarial activities
might be ascribed to the presence of the 4-amino-7-chloroqui-
noline as a heme-targeted pharmacophore, with the remaining
structure acting as a potential pharmacophore targeting the
new permeability pathways (NPP), created on red blood cells
(RBCs) by erythrocytic P. falciparum parasites.[10,11] Induced in
the host RBC plasma membrane several hours after parasite in-
vasion, NPP are a single or set of routes that have the function-
al characteristics of chloride channels, being also able to trans-
port a range of other structurally unrelated molecules.[10] They
have been proposed to play roles in nutrient uptake (e.g.,
sugars, amino acids and nucleotides), waste removal (e.g.,
lactic acid), volume regulation, and ion balance.[11] Because the
properties of the NPP are significantly different to channels
found in normal human RBCs, they are considered to be an im-
portant antimalarial drug target.
Table 1. In vitro data for compounds 7 against P. falciparum (W2 strain).
Chloroquine (1) and artemisinin (2) were used as reference drugs; com-
pound 8, the primaquine analogue of 7c, is also included for compari-
son.
Compd
R
b-Heme inhibition[a] IC50[b] [nm]
clogP[c] Yield [%]
7a
7b
7c
7d
7e
7 f
7g
7h
7i
H
NA
NA
+
46.6Æ5.5 4.51
16.9Æ1.2 4.90
52
p-Me
p-iPr
p-OMe
p-NH2
m-F
p-F
p-Cl
p-Br
o-NO2
m-NO2
p-NO2
p-iPr
32
28
30
52
52
34
16
16
67
36
8
11.0Æ6.2 5.72
20.0Æ2.6 4.45
58.8Æ1.5 3.77
34.1Æ4.2 4.68
19.7Æ0.4 4.69
11.6Æ0.4 5.12
18.2Æ2.8 5.26
38.3Æ4.2 4.37
26.2Æ5.0 4.41
23.5Æ1.3 4.43
+
NA
+
+
+
+ +
+
7j
7k
7l
NA
+ +
NA
ND
+ +
8
4840
5.56
78
–
–
Kanaani et al. found that cinnamic acid derivatives (e.g., 9)
inhibit the growth of intraerythrocytic P. falciparum by inhibit-
ing the NPP induced in the host cell membrane by the para-
site.[14] Interestingly, they observed that NPP inhibitory activity
was correlated with the hydrophobic character of the mole-
cules. Additionally, several compounds that have previously
been shown to inhibit anion transport pathways, such as 5-
nitro-2-(3-phenylpropylamino)benzoic acid (NPPB; 10), also in-
hibit NPP.[10] Generally, these compounds have a heterocyclic
moiety linked to another aromatic ring through a flexible poly-
Artemisinin
Chloroquine
9.5
138[e]
2.86 (2.90)
4.49 (4.63)
[a] b-Heme inhibition was determined as the ability of a compound to in-
hibit hemozoin formation in vitro. Results were calculated as a percentage
of the inhibitory effect displayed by chloroquine in the same experiment.
Test compounds were ranked as follows: 50–75% (+); ꢀ75% (+ +); not
active (NA); [b] IC50 values were determined in P. falciparum (W2 strain).
Data represent the meanÆSD of at least three independent assays;
[c] clogP was calculated using ALOGPS 2.1 (http://www.vcclab.org/lab/
alogps/). Experimental values for artemisinin and chloroquine are given in
parentheses; [d] Value taken from Ref. [12].
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for H (7a), p-Me (7b) and p-iPr (7c) substituents, respective-
ly.[12] Ongoing studies on the NPP inhibitory activity of com-
pounds 7 will provide grounds to confirm the above theories,
but at this stage we cannot exclude the possibility that these
compounds have alternative mechanism(s) of action within the
infected cell, such as, for example, bypassing the chloroquine
resistance transporter (PfCRT).
It has been shown that resistance to chloroquine is not due
to loss of activity against the chloroquine therapeutic target,
heme. Rather, it is due to mutations in a putative transmem-
brane chloroquine transporter, PfCRT, which appears to allow
the drug to rapidly efflux from the parasite digestive vacuole,
preventing sufficient inhibition of heme polymerization to
block parasite development. Chloroquine chemosensitizers,
also known as chloroquine-resistance-reversing agents, are
thought to interact with PfCRT in such a way that drug efflux
is impeded.[18,19] Compounds 7 described here match relevant
structural factors of chloroquine-chemosensiziting agents re-
cently reported by Kelly[9] and Lavrado,[20] such as a hydrogen-
bond acceptor (nitrogen) or aminobutyl chains between the
heterocyclic core of the compound and its N-substituted termi-
nal amine. Therefore, we cannot rule out that conjugates 7 act
also through this mechanism.
methylene chain. Kirk and Horner reported NPPB derivatives
with an aromatic moiety bearing an anionic head group and
an uncharged tail of varying size and polarity as NPP inhibi-
tors.[15] According to the same authors, the ability of these
NPPB derivatives to inhibit NPP improves with the length and
lipophilicity of the hydrophobic tail. Chalcones like 11 are
structurally related to the cinnamoyl moiety and were also re-
ported as NPP inhibitors by Go et al.[16] and Sisodia et al.[17]
In compounds 7, the heterocyclic core is linked to a butyl-
cinnamoyl group that reasonably matches relevant structural
factors described above, reinforcing the structural suitability of
the compounds as NPP inhibitors. Heme seems to be a main
target of compounds 7, which agrees with their structural simi-
larity to chloroquine. Hence, the activity of 7 could be attribut-
ed to a dual mode of action (heme biocrystallization + NPP in-
hibition), unveiling the butyl-cinnamoyl building block as an
NPP inhibitor chemotype. Furthermore, results with known
NPP inhibitors are consistent with the NPP having hydrophobic
components and with the observation that the pathway shows
a higher permeability to hydrophobic solutes than to hydro-
philic solutes of similar sizes.[10]
In summary, novel chloroquine analogues in which the
chloroquinoline core is linked to a cinnamoyl motif through
a flexible aminobutyl chain have been found to be highly
active against erythrocytic P. falciparum parasites. The in vivo
activity of the two most potent compounds is presently under
investigation, and preliminary data indicate that these chloro-
quine derivatives are nontoxic in vitro to human Huh7 hepato-
ma cells (data not shown). Compounds 7, like 1, inhibit heme
biocrystallization; however, such inhibitory activity does not
fully account for the potent antiplasmodial activities recorded
against the chloroquine-resistant P. falciparum strain used. Our
results strongly suggest that 1) the mode of action of 7 is simi-
lar to that of chloroquine, and 2) the butyl-cinnamoyl moiety
possibly acts as a NPP inhibitor and/or a chemosensitizer
motif. Confirmation of these hypotheses is being pursued in
ongoing studies, and preliminary data (not shown here) are
promising regarding the NPP-inhibitory ability of these com-
pounds. This will, hopefully, establish a novel family of dual
action P. falciparum inhibitors, bringing new insights in to the
development of new antimalarial agents and offering new po-
tential for chloroquine-related compounds in malaria therapy.
Thus, it is reasonable to assume that bulkiness and lipophi-
licity of the putative NPP inhibition motif in 7 would favor anti-
plasmodial activity. In fact, there is a clear correlation between
IC50 values found for 7 and compound lipophilicity, as estimat-
ed by calculated logP (Table 1 and Figure 1). A similar correla-
tion is also found between the IC50 value and the Charton’s
steric parameter (n)[12] of p-alkyl substituents on the aryl ring in
7, as shown for a subset of these compounds, derivatives 7a–
c, with Charton’s steric parameter values of 0.0, 0.52 and 0.76,
Experimental Section
4-(N-Aminobutyl)amino-7-chloroquinoline:
1,4-Diaminobutane
(10 equiv) and 4,7-dichloroquinoline (1 equiv) were stirred at
1008C for 3 h. After cooling to RT, the mixture was diluted with
CH2Cl2 (25 mL), and the solution was washed with 5% aq Na2CO3
(ꢄ3). The organic layer was separated, dried over anhyd Na2SO4, fil-
tered and concentrated to yield the title compound. Further purifi-
cation was not required.
General procedure for the synthesis of 7a–l: A solution of substi-
tuted cinnamic acid (1.1 equiv), O-(benzotriazol-1-yl)-N,N,N’,N’-tetra-
methyluronium tetrafluoroborate (TBTU; 1.1 equiv) and N-ethyl-
Figure 1. Plot of IC50 versus clogP values for compounds 7.
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N,N-diisopropylamine (DIPEA; 2.2 equiv) in N,N-dimethylformamide
(DMF; 5 mL) was stirred at 08C for 10 min. Then, a solution of 4-(N-
aminobutyl)amino-7-chloroquinoline (1.1 equiv) in DMF was added,
and the reaction proceeded at RT for an additional 24 h. The mix-
ture was diluted with CH2Cl2 (25 mL), and the solution was washed
with 5% aq Na2CO3 (ꢄ3). The organic layer was separated, dried
over anhyd Na2SO4, filtered and concentrated. The crude product
was purified by column chromatography (EtOAc/MeOH, 4:1 v/v) to
give the desired compound 7. Compound 8, the primaquine ana-
logue of 7c, was prepared by a similar method. Full spectrocopic
and analytical data on the synthesized compounds are given in the
Supporting Information.
Acknowledgements
The authors thank the Portuguese Foundation for Science and
Technology (FCT) for funding (PTDC/QUI-QUI/116864/2010). CT
and JRBG thank FCT for a postdoctoral grant (SFRH/BPD/62967/
2009) and Programa CiÞncia 2007, respectively
Keywords: aminoquinolines
permeability pathways · Plasmodium falciparum
· cinnamic acids · malaria ·
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In vitro heme biocrystallization inhibition assay: The assay was per-
formed as previously described.[21,22] Briefly, test compound in
DMSO at various concentrations (0.1–1 mm) was added to a solu-
tion of hemin chloride in DMSO (50 mL, 5.2 mgmLÀ1). Assays were
performed in triplicate. Controls contained equal volumes of water
(or DMSO). Biocrystallization was initiated by the addition of ace-
tate buffer (100 mL, 0.2m, pH 4.4), and the plates were incubated at
378C for 48 h. Samples were centrifuged (SIGMA 3–30 K) at
3000 rpm for 15 min. After discarding the supernatant, the pellet
was washed with DMSO (200 mLꢄ4) and then dissolved in 0.2m aq
NaOH (200 mL). The solubilized aggregates were further diluted
with 0.1m aq NaOH (1:6), and absorbance was recorded at 405 nm
(Biotek Powerwave XS with software Gen5 1.07).
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previously described.[23] Briefly, recombinant falcipain-2 (1 nm) was
incubated with various concentrations of test compound (taken
from 10 mm DMSO stock solutions) in sodium acetate (100 mm;
pH 5.5) and dithiothreitol (10 mm) for 30 min at room temperature
before addition of the substrate, benzoxycarbonyl-Leu-Arg-7-
amino-4-methyl-coumarin (final concentration 25 mm). Fluorescence
was continuously monitored for 30 min at room temperature in
a Labsystems Fluoroskan II spectrofluorometer, and IC50 values
were determined from plots of activity versus enzyme concentra-
tion created using GraphPad Prism software.
In vitro blood-schizontocidal activity determination: The activity was
determined using a method previous reported by us.[24] Synchron-
ized ring-stage W2 strain P. falciparum was cultured with test com-
pound at various concentrations (taken from 1000ꢄ DMSO stock
solutions) in RPMI 1640 medium containing 10% human serum or
0.5% Albumax serum substitute. After incubation for 48 h, when
control cultures contained new rings, parasites were fixed with 1%
formaldehyde in phosphate-buffered saline (PBS; pH 7.4) for 48 h
at room temperature and then labeled with YOYO-1 (1 nm; Molec-
ular Probes) in 0.1% Triton X-100 in PBS. Parasitemia was deter-
mined from dot plots (forward scatter versus fluorescence) ac-
quired on a FACSort flow cytometer using CELLQUEST software
(Becton Dickinson). Growth inhibition (IC50) was determined from
plots of parasitemia (%) against inhibitor concentration generated
using GraphPad Prism software. In each case, the curve fit present-
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Molecular docking and molecular dynamics simulations: Compu-
tational methods were used to predict the structures and stabilities
of 7–FP-2 complexes. Additional details about these calculations
are supplied in the Supporting Information.
Received: May 17, 2012
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Cinnamic acid derivatives containing
a 4-amino-7-chloroquinoline scaffold
(blue) and substituted cinnamoyl build-
ing blocks (green) linked through an
alkylamine chain (red) were found to
have potent (11–59 nm) in vitro activi-
ties against erythrocytic chloroquine--
resistant Plasmodium falciparum.
B. Pꢀrez, C. Teixeira, J. Gut, P. J. Rosenthal,
J. R. B. Gomes, P. Gomes*
&& – &&
Cinnamic Acid/Chloroquinoline
Conjugates as Potent Agents against
Chloroquine-Resistant Plasmodium
falciparum
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