4,9-Diaminoacridines and 4-Aminoacridines as Dual-Stage Antiplasmodial Hits

Article abstract of DOI:10.1002/cmdc.202000740

Multi-stage drugs have been prioritized in antimalarial drug discovery, as targeting more than one process in the Plasmodium life cycle is likely to increase efficiency, while decreasing the chances of emergence of resistance by the parasite. Herein, we disclose two novel acridine-based families of compounds that combine the structural features of primaquine and chloroquine. Compounds prepared and studied thus far retained the in vitro activity displayed by the parent drugs against the erythrocytic stages of chloroquine-sensitive and -resistant Plasmodium falciparum strains, and against the hepatic stages of Plasmodium berghei, hence acting as dual-stage antiplasmodial hits.

Full text of DOI:10.1002/cmdc.202000740

Accepted Article
Title: 4,9-diaminoacridines and 4-aminoacridines as dual-stage
antiplasmodial hits
Authors: Mélanie Fonte, Natália Tassi, Diana Fontinha, Inés Bouzón-
Arnáiz, Ricardo Ferraz, Maria J. Araújo, Xavier Fernàndez-
Busquets, Miguel Prudêncio, Paula Gomes, and Cátia
Teixeira
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemMedChem 10.1002/cmdc.202000740
Link to VoR: https://doi.org/10.1002/cmdc.202000740
01/2020

10.1002/cmdc.202000740
ChemMedChem
COMMUNICATION
4,9-diaminoacridines and 4-aminoacridines as dual-
stage antiplasmodial hits
Mélanie Fonte,[a],# Natália Tassi,[a]# Diana Fontinha,[b] Inés Bouzón-Arnáiz,[c],[d]
Ricardo Ferraz,[a],[e] Maria J. Araújo,[a] Xavier Fernàndez-Busquets,[c],[d] Miguel
Prudêncio,[b] Paula Gomes,[a] Cátia Teixeira[a]*
[a]
M. Fonte, N. Fagundes, Dr. R. Ferraz, Prof. Dr. M. J. Araújo, Prof Dr. P. Gomes, Dr. C. Teixeira
LAQV-REQUIMTE, Departamento de Química e Bioquímica
Faculdade de Ciências, Universidade do Porto
R. do Campo Alegre, 4169-007 Porto (Portugal)
E-mail: catia.teixeira@fc.up.pt
[b]
[c]
Dr. D. Fontinha, Dr. M. Prudêncio
Instituto de Medicina Molecular João Lobo Antunes
Faculdade de Medicina, Universidade de Lisboa
Av. Prof. Egas Moniz, 1649-028 Lisboa (Portugal)
I. Bouzón-Arnáiz, Dr. X. Fernàndez-Busquets
Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC)
The Barcelona Institute of Science and Technology
Baldiri Reixac, 10-12, 08028 Barcelona (Spain)
I. Bouzón-Arnáiz, Dr. X. Fernàndez-Busquets
Barcelona Institute for Global Health (ISGlobal),
Hospital Clínic-Universitat de Barcelona (Spain)
Dr. R. Ferraz
[d]
[e]
Ciências Químicas e das Biomoléculas
Escola Superior de Saúde, Politécnico do Porto
R. Dr. António Bernardino de Almeida 400, 4200-072 Porto (Portugal)
# These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
1
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10.1002/cmdc.202000740
ChemMedChem
COMMUNICATION
Abstract: Multi-stage drugs have been prioritized in antimalarial
drug discovery, as targeting more than one process in the
Plasmodium life cycle is likely to increase efficiency, while
decreasing the chances of emergence of resistance by the parasite.
Herein, we disclose two novel acridine-based families of compounds
that combine the structural features of primaquine and chloroquine.
Compounds prepared and studied thus far retained the in vitro
activity displayed by the parent drugs against the erythrocytic stages
of chloroquine-sensitive and -resistant P. falciparum strains, and
against the hepatic stages of P. berghei, hence acting as dual-stage
antiplasmodial hits.
and safety were far superior to those of QN.[2] Interestingly,
“disassembly” of the QN structure shows it as a “merge” of the
structure of CQ with the heterocycle core of primaquine (PQ,
Figure 1). PQ is another emblematic antiplasmodial, active
against all liver forms of the parasite, and able to block parasite
transmission from the human host to the mosquito vector.[2] In
view of this, and based on previous promising results for similar
compounds,[9] we hypothesized that 4,9-diaminoacridines (1)
and 4-aminoacridines (2) might act as multi-target
antiplasmodials, since compounds 1 embed the structures of
both CQ and PQ, and compounds 2 combine the heterocyclic
core of CQ with PQ.
The eradication of malaria, one of the deadliest infectious
diseases in the world,[1] remains to be achieved. This is partly
due to the emergence of parasite resistance to virtually all the
antimalarial drugs introduced in the clinic over the last
decades.[1-2] In endemic areas, where chloroquine-resistant P.
falciparum prevails, artemisinin combination therapies (ACT) are
the antimalarial treatment currently recommended by the WHO.
However, reported resistance to ACT in western Cambodia and
across the Greater Mekong sub-region is threatening the
efficacy of these first-line therapies, for which suitable
alternatives remain unavailable.[1-3] Therefore, while an effective
antimalarial vaccine remains elusive,[4] new efforts bend towards
the discovery of multi-target antiplasmodials, capable of
targeting more than one process in the malaria parasite’s life
cycle.[5] In the pursuit of such efforts, one must bear in mind that
only cost-effective approaches towards affordable medicines will
have a real impact in the fight against malaria, which mainly
affects low to middle income countries. Thus, priority should be
given to the repurposing of existing drugs for malaria,[6] or to the
rescuing of antimalarial pharmacophores towards the
development of new multi-target compounds.[7]
Figure 1. Structures of antimalarials quinacrine (QN) chloroquine (CQ), and
primaquine (PQ)
– top row; and of 4,9-diaminoacridines (1) and 4-
aminoacridines (2) in this work – bottom row.
Quinacrine (QN, Figure 1) was the first clinically tested
synthetic antimalarial drug;[8] it is a potent blood schizonticide,
but its serious adverse effects led to its rapid replacement by
chloroquine (CQ, Figure 1), whose efficiency, oral bioavailability,
2
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10.1002/cmdc.202000740
ChemMedChem
COMMUNICATION
Scheme 1. Synthetic routes towards 4,9-diaminoacridines 1 and 4-aminoacridines 2. Reagents and conditions: (i) phenol (15 equiv.), Cs2CO3 (1 equiv.),
anhydrous DMSO, 4 Å molecular sieves, 100 ºC, 2 h, then diamine (4 equiv.), 100 °C, 4 h; (ii) SnCl2 (5 equiv.), 37% aq. HCl, 0→40 ºC, 30 min; (iii) N-(n-
bromoalkyl)phthalimide (3 equiv.), CH3COONa (3 equiv.), CH3CH2OH, microwave (MW) heating (100 W, 120 °C) in a pressurized vial (100 psi), 2.5 h; (iv)
hydrazine monohydrate (40 equiv.), tetrahydrofuran (THF), 60 °C, 72 h; (v) H2 (50 psi), Pd/C, CH3OH, rt, 5 h; (vi) p-TSH (1 equiv.), CHCl3, rt, 24 h; (vii) hydrazine
monohydrate (10 equiv), Pd/C (10% wt), CH3OH, 80 º C, 1 h – 3 h; (viii) ethylene glycol/H2O (3:1), Na2CO3 (0.0625 M), 95 ºC, 1.5 h; (ix) N-(n-
bromoalkyl)phthalimide (3 equiv.), Et3N (3 equiv.), CH3CH2OH, MW heating (100 W, 120 °C) in a pressurized vial (100 psi), 3 h.
3
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10.1002/cmdc.202000740
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COMMUNICATION
In view of the above, we have synthesized 4,9-
diaminoacridines 1a-c and 4-aminoacridines 2a-c, as depicted in
Scheme 1. The synthetic route towards 4,9-diaminoacridines 1
had been previously reported by us,[10] whereas the synthesis of
4-aminoacridines 2 starting from 3, the common precursor to
both compounds 1 and 2, was established in the present work,
as follows. The first step was the reduction of the nitro group,
along with the removal of chlorine in position 9 of the acridine
ring in 6,9-dichloro-2-methoxy-4-nitroacridine 3; classical
catalytic hydrogenation using H2(g) and Pd/C (step v in Scheme
1) did not afford the desired compound, as non-selective
removal of the two chlorine atoms occurred (data not shown).
Alternatively, we applied a procedure early reported by Scovill et
al.,[9] whereby 3 was converted into the p-toluene sulfonyl
falciparum two-fold and twelve-fold, respectively. In turn,
changes in the side chain at position 9 did not significantly affect
activity against the 3D7 strain, but the IC50 value against the W2
strain decreased by nearly ten-fold when changing from four
(1a) to three (1b) carbon atoms. Yet, since these two
compounds also differ in R1 (methyl in 1a and hydrogen in 1b),
we cannot establish, at this stage, which of these two structural
features, or both, lead to the observed difference, and why.
Intermediates 4a, 5a and 6a also showed interesting results,
particularly against the CQ-sensitive 3D7 strain. Remarkably,
neither any of these synthetic precursors of 1a, nor any of the
target compounds 1a-c or 2a-c were haemolytic up to 10 µM
(Figure S1, Supp. Information).
hydrazide (p-TSH)
7
(step vi). This intermediate was
Table 1. In vitro activity of 1a-c, 2a-c, and 9-11a, against blood-stage P.
falciparum (CQ-sensitive and -resistant strains 3D7 and W2, respectively) and
liver-stage P. berghei parasites. Data for reference drugs are also included, for
comparison.
subsequently reduced to aniline 8, for which either SnCl2/HCl
(step ii) or hydrazine hydrate and Pd/C (step vii) were used. In
both cases, the desired product was obtained, at 18 and 30%
yields, respectively. An alternative two-step (steps viii and vii)
procedure, via cleavage of the p-TSH moiety in 7 using Na2CO3
in aqueous ethylene glycol to give 9 and subsequent reduction
of the latter with hydrazine hydrate and Pd/C to afford 8,
increased the overall yield to 40%. Aniline 8 was next alkylated
with the appropriate N-(N-bromoalkyl)phthalimide, as previously
reported by us.[10] This afforded compounds 10a-c in moderate
yields (30-60%), which were quantitatively converted into the
respective final 4-aminoacridines 2a-c by hydrazinolysis (step iv)
IC50 (μM) blood-stage[c]
Compound
IC50 (μM) liver-stage[c]
Pf 3D7
Pf W2
4a
5a
0.28 ± 0.20 0.91 ± 0.23
0.45 ± 0.22 0.49 ± 0.24
0.16 ± 0.22 0.98 ± 0.24
0.68 ± 0.24 6.17 ± 0.23
0.44 ± 0.21 0.66 ± 0.25
0.26 ± 0.35 0.49 ± 0.23
5.64 ± 0.22 5.14 ± 0.23
ND[a]
ND
6a
ND
1a
11.02 ± 0.44
using
excess
hydrazine
monohydrate
in
refluxing
1b
1c
ND
tetrahydrofuran (THF). Detailed procedures and relevant
spectroscopic data on intermediate and final compounds are
given in the Supplementary Information.
ND
Target compounds 1a-c and 2a-c, as well as 4a, 5a, and 6a,
all of which are synthetic precursors of 1a, were evaluated in
vitro for their (i) activity against erythrocytic forms of CQ-
sensitive 3D7, and CQ-resistant W2 P. falciparum strains, (ii)
haemolytic effects, (iii) activity against the hepatic stages of P.
berghei, and (iv) toxicity to human hepatic cells (Huh7 cell line).
All the compounds exhibited antimalarial activity against blood
forms of CQ-sensitive (3D7) and CQ-resistant (W2) P.
falciparum parasites (Table 1), although those of 4-
aminoacridines 2 were quite modest. Interestingly, the 4,9-
diaminoacridines 1 showed better activity than compounds 2,
emphasizing the importance of the aminoalkyl chain in position 9
of the acridine ring, in close similarity to the structures of QN and
CQ. Also, our data suggest that the length of the side chains at
both positions 9 and 4 of the acridine ring influences the activity
of 4,9-diaminoacridines 1. Specifically, increasing the length of
the side chain at position 4 from four (1a) to six (1c) carbons
improved the activity against 3D7 and W2 strains of P.
2a
2.22 ± 0.51
2b
2c
>10
>10
4.17 ± 0.23
2.39 ± 0.24
0.23[b]
1.64 ± 0.30
2.04 ± 0.38
CQ
QN
PQ
0.02[b]
0.10[b]
-
-
-
0.16[b]
-
7.5[b]
[a]
[b]
[c]
ND: Not determined;
Value taken from our previous work.[11]
;
IC50
determination was carried out in two independent biological replicates. In each
determination, all compound concentrations were tested in three technical
replicates.
4
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10.1002/cmdc.202000740
ChemMedChem
COMMUNICATION
Infection
Confluency
200
150
100
50
200
150
100
50
0
0
Figure 2. Activity of 1a-c, 2a-c, 5a, and 6a against liver forms of P. berghei, and toxicity towards human hepatocytes (Huh7 cell line). PQ used as reference drug.
The effects of the compounds on hepatic P. berghei
parasites and their host cells (Huh7) were further evaluated at 1
and 10 μM. As shown in Figure 2, 4-aminoacridines 2 appears to
be slightly more active at 1 µM, except for 2b that is inactive,
than compounds 1 against liver stage P. berghei. On the other
hand, at 10 µM both compounds 1 and 2 present similar
activities, except for 1a that is less active, but compounds 2
were not cytotoxic at that concentration unlike compounds 1.
The activities of compounds selected as most promising based
on activity and cytotoxicity were quantitatively compared (Table
1). Relevantly, IC50 values of compounds 2 were roughly 3 to 5
times lower than that of the reference liver stage antiplasmodial
drug, PQ. This indicates the relevance of having the side chain
at position 4 of the acridine ring, in close similarity with the
structure of PQ itself, to retain selective action against liver-
stage forms of Plasmodia, and which should be further
confirmed with a more complete structure-activity relationships
(SAR) study. Moreover, these results suggest that fusion of the
chlorobenzene ring (affording the 4-aminoacridine moiety) to the
original 8-aminoquinoline ring of parent PQ is advantageous for
liver stage activity, with no apparent increase in compound
cytotoxicity (PQ vs. 2a-c, Figure 2). Regarding compounds 1
and their respective precursors, all but 1a were significantly
active at 10 μM, although some 4,9-diaminoacridines (1c, 5a
and 6a) were highly cytotoxic at this concentration. Although the
data set is not large enough to establish solid SAR, it seems that
a decrease in length of the side chain at position 9 from 1a to 1b
increases activity at the expense of a small increase in
cytotoxicity. Interestingly, such small structural changes in the
side chain at position 9, important to blood-stage activity, leads
also to an increase in liver-stage activity (Figure 2). These
results emphasize the importance of conducting an extensive
SAR study to establish how liver stage activity can be modulated
through structural changes at position 9. We also observed that
increasing length of the side chain at position 4 (1a vs. 1c)
seems to improve liver stage activity and cause a significant
increase in cytotoxicity.
Collectively, our findings show that the compounds reported
herein, which can be regarded as a structural merge between
classical antimalarial drugs PQ and CQ, and also as analogues
of QN, define two novel classes of antimalarial hits. Logically,
optimization of these structures is needed towards the
development of more potent dual-stage antiplasmodial action
and lower cytotoxicity. Yet, the robust synthetic routes now
established for both families, and the in vitro data obtained thus
far pave the way to the attainment of this goal. Also, the most
promising compounds will be further evaluated for their
gametocytocidal activity, which may hopefully establish them as
triple-stage antimalarial hits.
Experimental Section
Compounds 1 and 3-6 were prepared as previously described,
and their structural analyses (Supp. Information) agreed with
formerly reported data.[10]
Synthesis
of
6-chloro-2-methoxy-4-nitro-9-[(p-
solution of p-
toluenesulfonyl)hydrazine]acridine (7):
a
toluenesulfonyl hydrazide in CHCl3 was added dropwise to a
solution of compound 3 in CHCl3. After stirring for 24 h, product
7 was precipitated with cold CHCl3 and isolated in quantitative
yield by vacuum filtration.
Synthesis of 6-chloro-2-methoxy-4-aminoacridine (8):
compound 7 and Pd/C (10% wt) were suspended in CH3OH and
the mixture refluxed at 80 ºC. Hydrazine hydrate (10 equiv.) was
5
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10.1002/cmdc.202000740
ChemMedChem
COMMUNICATION
then added and the reaction mixture kept in reflux for 3 h or 1 h
(step xiii or step xv, respectively). Pd/C was next removed by
filtration through Celite, and the filtrate evaporated to dryness.
The residue obtained was dissolved in CH2Cl2 and the solution
obtained was washed with saturated aq. NaCO3 (3 × 50 mL)
followed by saturated aq. NaCl (1 × 50 mL). The organic layer
was isolated and next dried over anhydrous NaSO4, filtered, and
the filtrate evaporated to dryness under reduced pressure. The
crude product thus obtained was further purified by column
chromatography on silica gel, using CH2Cl2 as mobile phase,
affording 8.
anhydrous Na2SO4, filtered, and the filtrate evaporated to
dryness under reduced pressure to afford the target compounds
2a-c. The compounds used in biological assays were confirmed
to have at least 95% purity, based on peak areas obtained
through HPLC analyses that were run as detailed in the
Supporting Information.
In vitro liver-stage assays: In vitro inhibition of liver-stage
infection by test compounds was determined by measuring the
luminescence intensity in Huh7 cells infected with a firefly
luciferase-expressing P. berghei line, PbGFP-Luccon, as
previously described.[12] Huh7 cells were cultured in RPMI 1640
medium supplemented with 10% v/v fetal calf serum, 1% v/v
nonessential amino acids, 1% v/v penicillin/streptomycin, 1% v/v
Synthesis
of
6-chloro-2-methoxy-4-nitroacridine
(9):
compound 7 and Na2CO3 (6.25x10-2 M) were dissolved in
ethylene glycol/water (18/9 mL). The reaction mixture was kept
under reflux at 95 ºC for 1,5 h. Next, the mixture was poured
onto cold water, and the resulting black precipitate was isolated
by vacuum filtration and next dissolved in CH2Cl2. The resulting
solution was washed with saturated aq. NaHCO3 (3 × 50 mL)
followed by saturated aq. NaCl (1 × 50 mL). The organic layer
was isolated and then dried over anhydrous Na2SO4, and the
filtrate evaporated to dryness under reduced pressure. The
crude product thus obtained was purified by column
chromatography on silica gel, using CH2Cl2 as mobile phase,
affording 9.
glutamine,
and
10
mM
4-(2-hydroxyethyl)-1-
piperazineethanesulfonic acid (HEPES), pH 7, and maintained
at 37 °C with 5% CO2. For infection assays, Huh7 cells were
seeded in 96-well plates the day before drug treatment and
infection. Culture medium in the wells was replaced by infection
medium (culture medium supplemented with 50 µg/mL
gentamicin and 0.8 µg/mL amphotericin B) containing the
appropriate concentration of each compound approximately 1 h
prior to infection with sporozoites freshly obtained through
disruption of salivary glands of infected female Anopheles
stephensi mosquitoes. For control cells, culture medium was
replaced by medium containing equivalent amounts of DMSO,
the compounds solvent. After 48 h of infection, inhibition of
infection was measured and the effect of the compounds on the
viability of Huh7 cells was assessed by the AlamarBlue assay
(Invitrogen, UK) using the manufacturer’s protocol. Nonlinear
regression analysis was employed to fit the normalized results of
the dose-response curves, and IC50 values were determined
using GraphPad Prism 8.0 (GraphPad software, La Jolla
California USA).
Synthesis of compounds 10a-c: triethylamine (3 equiv.) and
the relevant N-(n-bromoalkyl)phthalimide (3 equiv.) were added
to a solution of 8 in CH3CH2OH. The reaction mixture was
transferred into a reaction vial that was next sealed and
subjected to microwave (MW) irradiation (100 W); the reaction
proceeded under MW heating for 3 h at 120 °C and 100 psi.
Aliquots of triethylamine (3 equiv.) and the relevant N-(n-
bromoalkyl)phthalimide (3 equiv.) were added to the reaction vial
every 30 min. Once the reaction was halted, the solvent was
removed under reduced pressure and the residue was next
dissolved in CH2Cl2. The resulting solution was washed with
saturated aq. NaHCO3 (3 × 50 mL) and then with saturated aq.
NaCl (1 × 50 mL). The organic layer was collected, dried over
anhydrous Na2SO4 and filtered. The filtrate was next evaporated
to dryness under reduced pressure, to afford the crude product
that was partially purified by column chromatography on silica
gel using hexane/ethyl acetate (4:1 v/v) as mobile phase.
Fractions containing the target product were pooled and the
solvent removed under reduced pressure. The residue was
dissolved in CH2Cl2, 85.5% aq. H3PO4 was added dropwise, and
the solution stirred for approximately 30 min. The liquid phase
was removed by decantation and the precipitate formed, and it
was washed three times with CH2Cl2, every time discarding the
solvent also by decantation. Aq. 2 M NaOH was then added to
the solid residue and the resulting solution was extracted with
CH2Cl2 (3 × 50 mL). The organic layer was collected, dried over
anhydrous Na2SO4 and filtered. The filtrate was next evaporated
to dryness under reduced pressure to afford compounds 10a-c.
Cytotoxicity was inferred from the cell confluency data. As a
control, Huh7 cells were infected in the presence of
a
percentage of DMSO that mimics that of compound samples
(0.01%), and that is known to not be cytotoxic. All compound
data was then normalized to the DMSO control. Therefore, a
reduction in cell confluency, as compared to the DMSO control,
is indicative of cytotoxicity.
Ethics statement: The human blood used in this work was
commercially obtained from the Banc de Sang
i Teixits
(www.bancsang.net). Blood was not specifically collected for this
research; the purchased units had been discarded for
transfusion, usually because of an excess of blood relative to
anticoagulant solution. Prior to their use, blood units underwent
the analytical checks specified in the current legislation. Before
being delivered to us, unit data were anonymized and
irreversibly dissociated, and any identification tag or label had
been removed in order to guarantee the non-identification of the
blood donor. No blood data were or will be supplied, in
accordance with the current Spanish Ley Orgánica de
Protección de Datos and Ley de Investigación Biomédica. The
blood samples will not be used for studies other than those
made explicit in this research. The studies reported here were
performed in accordance with the current Spanish Ley Orgánica
de Protección de Datos and Ley de Investigación Biomédica and
under protocols reviewed and approved by the Ethical
Synthesis of compounds 2a-c:To a solution of the relevant
compound 15 in THF, NH2NH2.H2O (40 equiv.) was added. The
reaction mixture was left under stirring at 60 °C until the reaction
was completed, according to TLC analysis (approximately 48 h).
The solvent was removed by evaporation under reduced
pressure, the residue dissolved in CH2Cl2, and washed with
saturated aq. NaHCO3 (3 × 50 mL) and saturated aq. NaCl (1 ×
50 mL). The organic layer was collected and dried over
6
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10.1002/cmdc.202000740
ChemMedChem
COMMUNICATION
Committee on Clinical Research from the Hospital Clínic de
Barcelona (Reg. HCB/2018/1223, January 23, 2019).
Acknowledgements
Funding Sources
This work was developed within scope of projects
UIDB/50006/2020,
PTDC/BTM-SAL/29786/2017
and
PTDC/SAU-INF/29550/2017, funded by Fundação para
a
Ciência e Tecnologia (FCT, Portugal). XF-B was funded by (i)
Spanish Ministry of Science, Innovation and Universities
(http://www.ciencia.gob.es/), grant number RTI2018-094579-B-
I00 (which included FEDER funds), and (ii) Generalitat de
Catalunya, Spain (http://agaur.gencat.cat/), grant number 2017-
SGR-908.
MF
thanks
FCT
for
doctoral
grant
SFRH/BD/147345/2019.
Keywords: acridines • antimalarial activity • blood-stage • liver-
stage • malaria • Plasmodium • synthesis
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J. Janse, B. M. Franke-Fayard, PLoS One 2009, 4,
e7881.
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10.1002/cmdc.202000740
ChemMedChem
COMMUNICATION
Graphical abstract
We disclose two novel acridine-based families of compounds that combine the structural features of primaquine and chloroquine.
Compounds prepared and studied thus far retained the in vitro activity displayed by the parent drugs against the erythrocytic stages
of chloroquine-sensitive and -resistant P. falciparum strains, and against the hepatic stages of P. berghei, hence acting as dual-stage
antiplasmodial hits.
8
This article is protected by copyright. All rights reserved.