Evaluation of diarylureas for activity against plasmodium falciparum

Article abstract of DOI:10.1021/ml100083c

A library of diarylurea insulin-like growth factor 1 receptor inhibitors was screened for activity against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. The 4-aminoquinaldine-derived diarylureas displayed pro

Full text of DOI:10.1021/ml100083c

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Evaluation of Diarylureas for Activity Against
Plasmodium falciparum
Yiqun Zhang,† Marc Anderson,‡ Jennifer L. Weisman,§, Min Lu,† Cindy J. Choy,^
Vincent A. Boyd,† Jeanine Price,† Martina Sigal,† Julie Clark,† Michele Connelly,†
Fangyi Zhu,† W. Armand Guiguemde,† Cynthia Jeffries,† Lei Yang,† Andrew Lemoff,†
Ally P. Liou,§ Thomas R. Webb,† Joseph L. DeRisi,§ and R. Kiplin Guy*,†
†Chemical Biology & Therapeutics Department, St. Jude Children's Research Hospital, 262 Danny Thomas Place,
Memphis, Tennessee 38105, ‡Department of Chemistry and Biochemistry, San Francisco State University, San Francisco,
California 94132-4163, §Department of Biochemistry and Biophysics, and Department of Cellular and
Molecular Pharmacology, University of California, San Francisco, California 94143-2280, and
^Department of Chemistry, Washington State University, Pullman, Washington 99164-4630
ABSTRACT A library of diarylurea insulin-like growth factor 1 receptor inhibitors
was screened for activity against chloroquine-sensitive (3D7) and chloroquine-
resistant (K1) strains of Plasmodium falciparum. The 4-aminoquinaldine-derived
diarylureas displayed promising antimalarial potency. Further exploration of the B
ring of 4-aminoquinaldinyl ureas allowed identification of several quinaldin-4-yl
ureas 4{13, 39} and 4{13, 58} sufficiently potent against both 3D7 and K1 strains to
qualify as bone fide leads.
KEYWORDS Malaria, diarylurea
alaria affects roughly 250 million people and causes
over 800000 deaths annually, with most deaths being
attributed to infection by Plasmodium falciparum.1
diarylureas and, with the preliminary data developed from
that study, to carry out more extensive structure activity and
pharmacophore determination studies to map the elements
that are responsible for antimalarial activity. Here, we report
the results of these studies against chloroquine-sensitive
(3D7) and chloroquine-resistant (K1) P. falciparum strains.
A straightforward synthesis of diarylureas has been pre-
viously reported.15 The diarylurea library was generated in
parallel by coupling of aryl amines 1{x} (A ring) with aryl
isocyanates 2{y} (B ring), as shown in Figure 1. Phenyl iso-
cyanates 2{y} were either commercially available or freshly
prepared by treating commercial available aryl amines 3{y}
with 1,10-carbonyldiimidazole (Scheme 1). After all com-
pounds were purified by preparative reverse phase high-
pressure liquid chromatography (RP-HPLC), the identifica-
tion and purity of each compound were estimated by liquid
chromatography coupled to mass spectrometry (LC-MS)
(Table 1 in the Supporting Information). Novel compounds,
not previously reported in the literature, were characterized
by both nuclear magnetic resonance spectroscopy (NMR)
and LC-MS. This facile synthesis allowed us to produce a
library of diarylureas 4{x, y} with over 90% purity.
M
Drug resistance has been reported against almost all avail-
able antimalarial drugs.2-4 Therefore, it remains essential
to develop and discover new effective and affordable anti-
malarial drugs.
Diarylureas derivatives have been reported to have anti-
malarial activity.5-10 Jiang and co-workers identified a series
of diphenylureas in a plasmepsin-directed screening campaign.5
Although the authors proposed the antimalarial activity of
diphenylureas as inhibition of plasmepsin, the mechanism
of action in P. falciparum remains unclear due to poor cor-
relation between in vitro and in vivo structure-activity relation-
ships (SARs).11 -13 Baldwin and co-workers disclosed dia-
rylureas as inhibitors of dihydroorotate dehydrogenase,7
an enzyme in the pyrimidine biosynthetic pathway, although
no correlations between enzymatic and cellular SAR were
presented.14 Domínguez and co-workers reported that phe-
nylurenyl chalcones had activity against chloroquine-resis-
tant strains of P. falciparum. The phenylurenyl chalcones
exerted their antimalarial activity through multiple
mechanisms.8 While there is clearly some potential for
diarylureas, the mechanism or mechanisms of action re-
main unclear, and most of these studies revealed either poor
correlation between the enzyme target and the cellular
potencies or relatively poor potencies or both.
The originally reported IGF-1R targeted library of diarylur-
eas was tested for the antimalarial activity against chloroquine-
sensitive (3D7) and chloroquine-resistant (K1) strains in
replicate dose-response experiments to generate 50%
We had previously examined diarylureas as inhibitors
of the IGF-1R kinase for the treatment of cancer, an area
that has also been explored by industrial groups.15 The work
mentioned above led us to screen our existing collection of
Received Date: April 20, 2010
Accepted Date: August 23, 2010
Published on Web Date: September 09, 2010
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Figure 1. Library composition of diarylurea compound chemset 4{x, y}.
Scheme 1. General Synthetic Routes for Diarylureasa
showed modest activities with EC50 values of 5-15 μM
against both stains. With the exception of compound 4{4, 5},
these classes were nontoxic against all four mammalian cell
lines or weakly toxic with LD50 values between 10 and 25 μM.
All compounds in these classes were generally poorly soluble
in aqueous buffer at pH 7.4, and some of compounds were
reasonably permeable.
The quinoline and the pyridine-containing diarylurea
series 4{10-17, 1-9} had more compounds with modest
activity and substituents on the B ring influenced the anti-
malarial activity. For example, compounds 4{13, 1-2} and
4{13, 7-9}, carrying chloro substituents on the B ring, were
more potent than 4{13, 4-5}, which lacked chloro groups.
The most potent compound 4{13, 1} (EC50 = 0.053 μM vs
a Conditions: (a) DMSO, room temperature, 2 h. (b) DMSO, room
temperature, 5-10 min.
3D7) gave an equivalent potency to chloroquine (EC50
=
0.047 ( 0.004 μM vs 3D7) under the same assay conditions
in vitro. Although the 4-aminopyridine-derived diarylureas
4{16, 1-8} possessed a pyridine ring structurally equivalent
to that in the 4-aminoquinaldine series 4{13, 1-9}, only one
compound 4{16, 8} among eight 4-aminopyridine-derived
compounds demonstrated an EC50 value lower than 5 μM
against 3D7 strain. Thus, the activity requires both the hydro-
gen bonding and the hydrophobic functions. In general, the
4-aminoquialdine-derived diarylureas showed only weak
cytotoxicity. Most compounds 4{10-17, 1-9} had reason-
able permeability (>50 ꢀ 10-6 cm/s), and the pyridine-
derived compounds 4{14-17, 1-8} possessed better aqueous
solubility than the quinoline-derived diarylureas 4{10-13,
1-9}.
inhibitory concentrations (EC50). Simultaneously, the cyto-
toxicity of all diarylureas was investigated against four human
cell lines [human fibroblast cells (BJ), human embryonic
kidney 293 cells (HEK293), human hepatocellular liver
carcinoma cells (HEP G2), and human Burkitt's lymphoma
cells (Raji)]. In addition, the passive permeability and solubility
were examined to provide a survey of structure-property
relationships for the series. The results are summarized in a
heat map (Figure 2).
One class of diarylureas, the 4-aminoquinaldine-derived
diarylureas 4{13, 1-9}, showed fairly strong antimalarial
potency. All other classes showed weak antimalarial potency
at best, although a number of compounds had EC50 values in
the range of 5-15 μM similar to many of the diarylureas
The set of diarylureas 4{18-20, 1-9} containing two
heteroatoms on the A ring was only weakly active. Only
the 2-aminobenzimidazole-derived compounds 4{18, 1-4}
(EC50 = 5-15 μM) gave measurable potencies. All com-
pounds, except 4{18, 2} and 4{18, 4}, were nontoxic on four
;
reported in other studies.
Diarylureas including the subclasses of diphenyl ureas 4
{1-7, 1-8} or naphthyl phenyl ureas 4 {8-9, 1-7} exhib-
ited weak antimalarial activity. Eleven individual compounds
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Figure 2. Antimalarial activity, cytotoxicity, permeability, and solubility of diarylurea chemset 4{1-20, 1-9}. (1) Data represent median
EC50 values of parasite growth inhibition against 3D7 and K1 strains of P. falciparum, from replicate experiments, shown in a color gradient
scale with darker squares indicating a higher antimalarial potency. The positive control for the antimalarial assay was chloroquine (EC50
=
0.047 ( 0.004 μM against 3D7, and EC50 = 1.23 ( 0.07 μM against K1). (2) Cytotoxicity data represent median EC50 values of growth
inhibition against BJ, HEK-293, Hep G2, and Raji cell lines, from replicate experiments, and are shown in a color gradient with darkersquares
indicating a more potent mammalian cytotoxicity. (3) The parallel artificial membrane permeability assay (PAMPA) passive permeability
assay results at pH 7.4 are shown in a color gradient with darker purple squares indicating a higher permeability. (4) Aqueous solubility at
pH 7.4 in isotonic buffer is shown in olive scale with darker squares indicating a higher solubility.
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mammalian cell lines. Although this setof diarylureas did not
show promising antimalarial activity, the presence of benz-
imidazole, imidazole, and thiazole moieties enhanced both
permeability and aqueous solubility of the compounds.
The most promising compounds from the original test
contained the 4-aminoquinaldine system. Therefore, this
ring was fixed as the A ring and variation of the B ring
explored to examine the possibility of improving both the
antimalarial potencyand the physicochemical properties. All
compounds in this series possessed good selectivity against
malaria parasites and mammalian cells. The antimalarial
potency, cytotoxicity, and physicochemical properties are
summarized in Figure 3. Of the substituted phenyl rings
surveyed in this series, the chloro or fluoro substitutents
(4{13, 1-3} and 4{13, 7-20}) gave the best antimalarial
potencies with select compounds, giving EC50 values in the
mid or high nanomolar range against the 3D7 strain, equiva-
lent to chloroquine. Some SARs were evident. For example,
compound 4{13, 7}, with a 3-Cl substituent on the B ring,
gave an EC50 of 0.60 μM, 5-fold more potent than compound
4{13, 10} with a 4-Cl substituent. Compounds 4{13, 8-9}
and 4{13, 11}, bearing two chloro substituents on the B ring,
displayed weaker antimalarial potency as compared to 4{13, 7}.
Introduction of a 2-OMe group to 4{13, 7} afforded 4{13, 1}
with an improved EC50 value of 0.053 μM against 3D7.
However, moving the methoxy group of 4{13, 1} from the
2- to the 4-position (4{13, 3}) resulted in a 23-fold decrease
in potency against 3D7. Compound 4{13, 2} incorporating
the 3-Cl and 4-Me groups exhibited an EC50 value of 0.22 μM,
which was 3-fold more potent than 4{13, 7}. Notably,
compound 4{13, 12} containing the 4-Cl and 3-CF3 substit-
uents displayed an antimalarial potency of 0.47 μM. All
compounds 4{13, 13-20}, containing the fluoro substitu-
tents on the B ring, maintained similar levels of potency, in
the range of 0.7-3.37 μM. Compounds 4{13, 26} and 4{13, 39},
bearing 3-CF3 and 3-NMe2, respectively, showed EC50 values
of 0.32 and 0.031 μM against 3D7, illustrating the preference
for electron-donating substitutents. Compounds 4{13, 43-54},
containing hydroxyl, amino, or carbonyl-derived functional
groups, showed weak growth inhibitory activities against
malaria (5-15 μM) or displayed no activity at the highest
assay concentration (15 μM). Next in the study, we explored
a series of heteroaromatic rings 4{13, 55-60} as replace-
ments for the phenyl ring. The most promising compound
4{13, 58} carried the benzisothiadiazolyl ring and displayed
an EC50 value of 0.016 μM against 3D7, 3-fold more potent
than chloroquine. Meanwhile, compound 4{13, 58} was also
active againstchloroquine-resistant K1 strain (EC50=0.079μM).
In general, the entire 4-aminoquinaldine-derived series 4{13,
1-60} showed slightly more potency against chloroquine-
sensitive strain 3D7 than chloroquine-resistant strain K1.
With respect to structure-property relationships, there was
a general correlation between potent antimalarial activity
and decreasing aqueous solubility with the compounds with
EC50 values below 5 μM showing poor aqueous solubility
(<10 μM in 5% DMSO in aqueous buffer). However, the
highly active compounds had an aqueous solubility roughly
100-1000-fold higher than their EC50 values, indicating that
this is a liability that needs careful management but is not
an inherent block to further development. Although we
observed a wide range of permeability values, most com-
pounds had reasonable permeability.
A preliminary analysis of pharmacophores in the series is
illustrated with the three most active compounds 4{13, 1},
4{13, 39}, and 4{13, 58}. The conformers of each com-
pound were generated by systematic conformation search
using MOE software with lowest energy conformations
being used to generate pharmacophore features (Figure 1
in the Supporting Information). One clear pharmacophore
element is the aromatic moiety on the A ring (F2: Aro) and
the aromatic nitrogen (F1: Acc) as they relate to the oxygen
(F3: Acc), a distance of 4.86 Å from the centroid of the ring.
Another important pharmacophore feature of 4{13, 1} and
4{13, 39} appears to be a hydrophobic site (F5: Hyd, in
Figure 1 in the Supporting Information), on the B-ring, which
overlaid with 3-chloro group and 3-dimethylamino group,
respectively. In the case of the fused heteroaromatic ring, it
may be the case that a slightly less favorable conformation
also fulfills this hydrophobe by rotating the ring inward.
These pharmacophore elements can serve as a helpful tool
in further designing new diarylureas.
While several antimalarial targets have been proposed for
the diarylureas, including plasmepsin II,5 dihydroorate
dehydrogenase,7 plasmodial cysteine proteases, and hemo-
globin hydrolysis, the mechanism of action of diarylureas in
parasites has not been understood clearly.8 To date, we have
been unable to confirm any of these targets as the one acted
upon by our series of compounds. We have previously
investigated the use of diarylurea compounds as inhibitors
of the human receptor tyrosine kinase IGF-1R, which is
important in all stages of the development of breast and
other cancers. The inhibitory potencies of diarylureas
against P. falciparum can be compared with potency against
the human IGF-1R. Interestingly, while the 4-aminoquinaldine-
derived diarylureas were active against IGF-1R, overall,
the compounds were significantly less potent (IC50 = 9.7-
36.7 μM).15 According to these results, we tentativelysuggest
that the 4-aminoquinaldine-derived diarylureas may also
inhibit kinases present in Plasmodium that contain similar
catalytic domains. However, despite attempting to do so,
we have been unable to validate any individual malarial kinase
as the target of these compounds. Because the 4-animo-
quinaldine-derived diarylureas likely target kinases of
P. falciparum, it is important to know whether those com-
pounds inhibit any kinases of the human host besides IGF-
1R. One compound 4{13, 34}, which had some albeit
;
weak measurable mammalian cytotoxicity was submitted
;
for comprehensive screening against 402 human kinases by
Ambit Biosciences (Table 4 in the Supporting Information).
Compound 4{13, 34} bound to only one kinase, DDR1, outof
402 screened human kinases at concentration 10 μM (Figure 2
in the Supporting Information.). Protein kinases of parasite
Plasmodium are divergent from their human host.16-18 In
the case that the diarylureas target kinases of Plasmodium, it
is highly possible that the diarylureas selectively inhibit
kinases of Plasmodium over the human host since the most
active antimalarial diarylureas essentially failed to bind to
mammalian kinases. Further studies will be carried out to
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Figure 3. Antimalarial activity, cytotoxicity, permeability, and solubility of the 4-aminoquinaldine-derived diarylurea compounds 4{13,
1-60}. (1) Data represent median EC50 values of parasite growth inhibition against 3D7 and K1 strains of P. falciparum, from replicate
experiments, shown in a color gradient scale with darker squares indicating a higher antimalarial potency. The positive control for the
antimalarial assay was chloroquine (EC50 = 0.047 ( 0.004 μM against 3D7, and EC50 = 1.23 ( 0.07 μM against K1). (2) Cytotoxicity data
represent median EC50 values of growth inhibition against BJ, HEK 293, Hep G2, and Raji cell lines, from replicate experiments, and are
shown in a color gradient with darker squares indicating a more potent mammalian cytotoxicity. (3) PAMPA passive permeability assay
results at pH 7.4 areshown in a color gradient with darker purple squares indicating a higher permeability. (4) Aqueous solubility at pH 7.4 in
isotonic buffer is shown in olive scale with darker squares indicating a higher solubility.
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validate the targets of diarylureas and understand their
action in parasites. Additionally, further structural optimiza-
tion of diarylureas will be required to overcome concerns for
physicochemical properties and cross-resistance.
(4)
(5)
Kessl, J. J.; Meshnick, S. R.; Trumpower, B. L. Modeling the
molecular basis of atovaquone resistance in parasites and
pathogenic fungi. Trends Parasitol. 2007, 23 (10), 494–501.
Jiang, S.; Prigge, S. T.; Wei, L.; Gao, Y.; Hudson, T. H.; Gerena,
L.; Dame, J. B.; Kyle, D. E. New Class of Small Nonpeptidyl
Compounds Blocks Plasmodium falciparum Development In
Vitro by Inhibiting Plasmepsins. Antimicrob. Agents Chemother.
2001, 45 (9), 2577–2584.
Leban, J.; Pegoraro, S.; Dormeyer, M.; Lanzer, M.; Aschenbrenner,
A.; Kramer, B. Sulfonyl-phenyl-ureido benzamidines: A novel
structural class of potent antimalarial agents. Bioorg. Med.
Chem. Lett. 2004, 14, 1979–1982.
Baldwin, J.; Michnoff, C. H.; Malmquist, N. A.; White, J.; Roth,
M. G.; Rathod, P. K.; Phillips, M. A. High-throughput Screening
for Potent and Selective Inhibitors of Plasmodium falciparum
Dihydroorotate Dehydrogenase. J. Biol. Chem. 2005, 280,
21847–21853.
Herein is reported the evaluation of a library of diarylureas
for antimalarial activity against two strains of P. falciparum
(3D7 and K1). The most promising subseries of diarylureas
contained a 4-aminoquinaldinyl moiety (A ring) as one of the
aryl rings of the urea, a novel structural feature in the class.
The further investigation on the B ring of this series revealed
compounds in this series that were more active against the
chloroquine-sensitive strain 3D7 than the chloroqine-resistant
strain K1 and with absolute potencies in 3D7 equivalent to
chloroquine. The major liability observed in this class of
compounds is that they tend to be quite insoluble. To enable
clinical development, this liability will need to be addressed
in future studies.
(6)
(7)
ꢀ
(8)
(9)
Domínguez, J. N.; Leon, C.; Rodrigues, J.; Domínguez,
N. G. d.; Gut, J.; Rosenthal, P. J. Synthesis and Evaluation of
New Antimalarial Phenylurenyl Chalcone Derivatives. J. Med.
Chem. 2005, 48, 3654–3658.
Madapa, S.; Tusi, Z.; Sridhar, D.; Kumar, A.; Siddiqi, M. I.;
Srivastava, K.; Rizvi, A.; Tripathi, R.; Puri, S. K.; Keshava,
G. B. S.; Shukla, P. K.; Batra, S. Search for new pharmaco-
phores for antimalarial activity. Part I: Synthesis and anti-
malarial activity of new 2-methyl-6-ureido-4-quinolinamides.
Bioorg. Med. Chem. 2009, 17, 203–221.
SUPPORTING INFORMATION AVAILABLE Synthetic pro-
cedures for diarylureas; complete LC-MS characterization data of
all diarylureas; complete antimalarial data, cytotoxicity data, per-
meability, and solubility data for all listed compounds; pharmaco-
phore feature profile; kinase binding profile data; 1H NMR spectra
and chromatographic data of novel compounds 4{12, 1-4}, 4{13, 7},
4{13, 12}, 4{13, 21-24}, 4{13, 27-28}, 4{13, 41-45}, 4{13, 49-50},
4{13, 60}, 4{19, 1-4}, and 4{19, 8-9}. This material is available
free of charge via the Internet at http://pubs.acs.org.
(10) Madapa, S.; Tusi, Z.; Mishra, A.; Srivastava, K.; Pandey, S. K.;
Tripathi, R.; Puri, S. K.; Batra, S. Search for new pharmaco-
phores for antimalarial activity. Part II: Synthesis and anti-
malarial activity of new 6-ureido-4-anilinoquinazolines.
Bioorg. Med. Chem. 2009, 17, 222–234.
(11) Francis, S. E.; Sullivan, D. J., Jr.; Goldberg, D. E. Hemoglobin
metabolism in the malaria parasite Plasmodium falciparum.
Annu. Rev. Microbiol. 1997, 51, 97–123.
AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. Tel: 901-595-9050. Fax: 901-595-5715. E-mail: kip.guy@
stjude.org.
(12) Coombs, G. H.; Goldberg, D. E.; Klemba, M.; Berry, C.; Kay, J.;
Mottram, J. C. Aspartic proteases of Plasmodium falciparum
and other parasitic protozoa as drug targets. Trends Parasitol.
2001, 17, 532–537.
(13) Francis, S. E.; Banerjee, R.; Goldberg, D. E. Biosynthesis and
Maturation of the Malaria Aspartic Hemoglobinases Plas-
mepsins I and II. J. Biol. Chem. 1997, 272, 14961–14968.
(14) Seymour, K. K.; Lyons, S. D.; Phillips, L.; Rieckmann, K. H.;
Christopherson, R. I. Cytotoxic Effects of Inhibitors of de Novo
Pyrimidine Biosynthesis upon Plasmodium falciparum. Bio-
chemistry 1997, 33, 5268–5274.
(15) Anderson, M. O.; Yu, H.; Penaranda, C.; Maddux, B. A.;
Goldfine, I. D.; Youngren, J. F.; Guy, R. K. Parallel synthesis
of diarylureas and their evaluation as inhibitors of insulin-like
growth factor receptor. J. Comb. Chem. 2006, 8, 784–790.
(16) Ward, P.; Equinet, L.; Packer, J.; Doerig, C. Protein kinases of
the human malaria paratiste Plasmodium falciparum: The
kinome of a divergent eukaryote. BMC Genomics 2004, 5 (1),
79.
Funding Sources: This work was supported by the National
Institute of Allergy and Infectious Disease at NIH (AI075517), the
American Lebanese Syrian Associated Charities (ALSAC), and St.
Jude Children's Research Hospital.
ACKNOWLEDGMENT We are grateful to Taosheng Chen and
Jimmy Cui from High Throughput Screening Core, Chemical Biology
& Therapeutics Department, St. Jude Children's Research Hospital,
for their support in antimalarial and cytotoxicity screening. We are
also grateful to High Throughput Synthesis Core and High Through-
put Analytical Core, Chemical Biology & Therapeutics Department,
St. Jude Children's Research Hospital, for their support in the syn-
thesis and purification of diarylureas.
REFERENCES
(1)
(2)
(3)
WHO Malarial Report 2008; World Health Organization:
Geneva, Switzerland, 2008.
Hyde, J. E. Drug-resistant malaria. Trends Parasitol. 2005,
21 (11), 494–498.
Dondorp, A. M.; Nosten, F.; Yi, P.; Das, D.; Phyo, A. P.; Tarning,
J.; Lwin, K. M.; Ariey, F.; Hanpithakpong, W.; Lee, S. J.; Ringwald,
P.; Silamut, K.; Imwong, M.; Chotivanich, K.; Lim, P.; Herdman,
T.; An, S. S.; Yeung, S.; Singhasivanon, P.; Day, N. P. J.; D.M.,
N. L.; Socheat, D.; White, N. J. Artemisinin Resistance in
Plasmodium falciparum Malaria. N. Engl. J. Med. 2009, 361,
455–467.
(17) Anamika, N. S.; Krupa, A. A genomic perspective of protein
kinases in Plasmodium falciparum. Proteins 2005, 58 (1), 180–
189.
(18) Doerig, C.; Meijer, L. Antimalarial drug discovery: targeting
protein kinases. Expert Opin. Ther. Targets 2007, 11 (3), 279–
290.
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