Evaluation of aromatic 6-substituted thienopyrimidines as scaffolds against parasites that cause trypanosomiasis, leishmaniasis, and malaria

Article abstract of DOI:10.1039/c4md00441h

Target repurposing is a proven method for finding new lead compounds that target Trypanosoma brucei, the causative agent of human African trypanosomiasis. Due to the recent discovery of a lapatinib-derived analog 2 with excellent potency against T. brucei (EC₅₀ = 42 nM) and selectivity over human host cells, we have explored other classes of human tyrosine kinase inhibitor scaffolds in order to expand the range of chemotypes for pursuit. Following library expansion, we found compound 11e to have an EC₅₀ of 84 nM against T. brucei cells while maintaining selectivity over human hepatocytes. In addition, the library was tested against causative agents of Chagas' disease, leishmaniasis, and malaria. Two analogs with sub-micromolar potencies for T. cruzi (4j) and Plasmodium falciparum (11j) were discovered, along with an analog with considerable potency against Leishmania major amastigotes (4e). Besides identifying new and potent protozoan growth inhibitors, these data highlight the value of concurrent screening of a chemical library against different protozoan parasites. This journal is

Full text of DOI:10.1039/c4md00441h

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CONCISE ARTICLE
Evaluation of aromatic 6-substituted
thienopyrimidines as scaffolds against parasites
that cause trypanosomiasis, leishmaniasis, and
malaria†
Cite this: DOI: 10.1039/c4md00441h
Jennifer L. Woodring,a Gautam Patel,a Jessey Erath,b Ranjan Behera,c Patricia J. Lee,d
Susan E. Leed,d Ana Rodriguez,be Richard J. Sciotti,d Kojo Mensa-Wilmotc
a
*
and Michael P. Pollastri
Target repurposing is a proven method for finding new lead compounds that target Trypanosoma brucei,
the causative agent of human African trypanosomiasis. Due to the recent discovery of a lapatinib-derived
analog 2 with excellent potency against T. brucei (EC50 ¼ 42 nM) and selectivity over human host cells,
we have explored other classes of human tyrosine kinase inhibitor scaffolds in order to expand the range
of chemotypes for pursuit. Following library expansion, we found compound 11e to have an EC50 of 84
nM against T. brucei cells while maintaining selectivity over human hepatocytes. In addition, the library
was tested against causative agents of Chagas' disease, leishmaniasis, and malaria. Two analogs with
sub-micromolar potencies for T. cruzi (4j) and Plasmodium falciparum (11j) were discovered, along with
an analog with considerable potency against Leishmania major amastigotes (4e). Besides identifying new
and potent protozoan growth inhibitors, these data highlight the value of concurrent screening of a
chemical library against different protozoan parasites.
Received 29th September 2014
Accepted 12th November 2014
DOI: 10.1039/c4md00441h
www.rsc.org/medchemcomm
homologous to essential parasite targets or pathways can
facilitate rapid development of structure–activity relationships
Introduction
(SAR), and accelerate “hit” optimization.
Human African trypanosomiasis (HAT) is a life-threatening
parasitic disease that places 70 million people at risk in parts of
sub-Saharan Africa. Caused by the protozoan parasite Trypa-
nosoma brucei, it is one of 17 neglected tropical diseases (NTDs)
highlighted by the World Health Organization as needing new
therapies. Current medicines for HAT are not orally bioavail-
able, have unfavorable toxicity proles and drug resistant
parasites are emerging.1
Phosphodiesterase and kinase target repurposing2 are rapid
and pragmatic methods of lead drug discovery explored in our
laboratory.3–8 Launching new antiparasitic drug discovery
efforts by redirecting inhibitors of human drug targets that are
Inhibition of human receptor tyrosine kinases (RTKs) is a
widely employed approach for cancer therapeutics.9–12 Speci-
cally, an epidermal growth factor receptor (EGFR) inhibitor
lapatinib (GW572016, Tykerb, 1, Fig. 1) was approved by the
FDA in 2007 for solid tumors and breast cancer.13–16 Compound
1 proved to be a promising lead for HAT due to its modest
potency against T. brucei with an EC50 of 1.54 mM, and its ability
to cure 25% of infected mice in a murine model of HAT.17
Beginning with lapatinib, extensive SAR studies led to
compound 2, which has an EC50 of 42 nM and excellent selec-
tivity over human cells. Importantly, compound 2 was orally
bioavailable in mice and had a modest effect on parasitemia
and life extension in a murine T. brucei bloodstream infection
despite exhibiting high plasma protein binding (>99%) and a
lack of central nervous system exposure.7 These observed
pharmacokinetic properties are not surprising due to its high
log P and molecular weight.
aNortheastern University Department of Chemistry
& Chemical Biology, 360
Huntington Avenue, Boston, MA 02115, USA. E-mail: m.pollastri@neu.edu; Tel: +1
617-373-2703
bNew York University School of Medicine, Department of Microbiology, Division of
Parasitology, 341 E. 25th St. New York, NY 10010, USA
cUniversity of Georgia, Department of Cellular Biology, Athens, GA 30602, USA
dExperimental Therapeutics, Walter Reed Army Institute for Research, 2460 Linden
Lane, Silver Spring, MD 20910, USA
The previous SAR explorations of the lapatinib chemotype
focused on the “head” and “tail” regions of the molecule,
described in Fig. 1. Historical tyrosine kinase inhibitor lead
discovery efforts have led to many quinazoline scaffold replace-
ments in cancer chemotherapy discovery.18–21 GW837016X (3)
possesses a related core scaffold and was also found to be potent
eAnti-Infectives Screening Core, New York University School of Medicine, New York, NY
10010, USA
† Electronic supplementary information (ESI) available: Synthetic preparations,
assay details, in vitro ADME data, and additional malaria screening data are
described in the ESI. See DOI: 10.1039/c4md00441h
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Fig. 1 Project strategy.
against T. brucei. It therefore seemed appropriate to utilize the 2,5-diol to produce the desired aminothiophene 13. Cyclization
thieno[3,2-d]pyrimidine (and the regioisomeric thieno[2,3-d] of the thiophene with formamide afforded intermediate 14,
pyrimidine) scaffolds to launch a crossover SAR study, preparing followed by sequential bromination (15), and chlorination to
analogs matched to those quinazoline-based inhibitors previ- provide 16. As before, aniline displacement of the chloride was
ously described7 (denoted in this article as 4b–m, Table 1).
effected smoothly, providing 17 for further diversication via
We recently demonstrated the value of simultaneously Suzuki reaction. For both scaffolds, intermediate 10 or inter-
testing compounds against related protozoan parasites, mediate 17 was coupled with boronic esters or acids using
wherein it became evident that producing parasite-dependent Suzuki reaction conditions to generate the respective nal
SAR could direct future work against each pathogen.8 In addi- compounds 11a–m and 18a–j, which are matched with corre-
tion to the screening of new compounds against T. brucei, sponding quinazoline analogs previously reported (Table 1).7
compounds were screened against the kinetoplastid parasites
Leishmania major (causative agent of cutaneous leishmaniasis)
and T. cruzi (which causes Chagas disease), as well as the
Results and discussion
malaria-causing parasite Plasmodium falciparum. In this report
Tests of the compounds against T. brucei revealed favorable
we disclose the results of our efforts to prepare and test thie-
growth inhibitory activity amongst three distinct scaffolds
nopyrimidine-based inhibitors, matching the “tail” replace-
shown in Table 1. To make the direct comparison with 2,
ments explored in the previous study that led to compound 2.7
replacement of the quinazoline with thieno[2,3-d]pyrimidine
(18a) yielded a 10ꢀ change in potency, whereas the thieno[3,2-d]
pyrimidine replacement (11a) resulted in a dramatic loss of
Synthetic procedure
potency. Removal of the morpholine altogether (4b, 11b, 18b) or
The requisite dihalo template precursors (9 and 16, Schemes 1 the tail altogether (4m, 11m) reduced the potency to the
and 2) of the thieno[3,2-d]pyrimidine and thieno[2,3-d]pyrimi- micromolar range.
dine scaffolds were made following previously disclosed
An additional atom linker between the phenyl and mor-
protocols.22–25 The thieno[3,2-d]pyrimidine intermediate 9 was pholine was more favored on the quinazoline scaffold (4j) than
synthesized starting from methyl 3-aminothiophene-2-carboxy- the thienopyrimidines (11j and 18j) but still showed reduced
late (5) as shown in Scheme 1. This commercially available potency. Evaluation of the morpholine regiochemistry revealed
material underwent formylation, followed by cyclization with that para (4k, 11k) was less potent than meta (2, 11a, 18a),
formamide and ammonium formate to afford intermediate 7. though alteration of this regiochemistry was better tolerated
The pyrimidinone 7 was chlorinated using phosphorous oxy- when attached to the thieno[3,2-d]pyrimidine (11k) than the
chloride to provide 8 and brominated using 1,2-dibromo- quinazoline scaffold (4k). The most potent compound from this
1,1,2,2-tetrauoroethane to yield the key thienopyrimidine 9. series is 11e, an 84 nM inhibitor of T. brucei cell growth. This
From this point, halide displacement with the requisite aniline “tail” was not as potent in the quinazoline scaffold (4e); the
in reuxing isopropanol produced the bromide intermediate morpholinophenyl tail present in 2 remains the most potent
10, amenable for subsequent Suzuki chemistry.
analog overall with an EC50 of 42 nM. For the most potent
The thieno[2,3-d]pyrimidine template was synthesized from analogs in the thieno[2,3-d]pyrimidine scaffold, both the 5-
commercially available methyl 2-cyanoacetate (12, Scheme 2), methyl-6-morpholinopyridin-3-yl tail (18e) and the morpholi-
which underwent Gewald reaction conditions with 1,4-dithiane- nophenyl tail (18a) were essentially equipotent with EC50 values
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Table 1 Antiparasitic activities of compounds against T. brucei, T. cruzi, L. major, and P. falciparum
L. major
T. brucei EC50 (mM) T. cruzi EC50 (mM)
P. falciparum
Cmpd Scaffolda
R
or % inh (at 5 mM)b or % inh (at 10 mM)b Amast EC50 (mM)c Promast EC50 (mM)c D6 EC50 (mM)d
2e
0.042 ꢁ 0.010
1.8 ꢁ 0.9
7.98 r2 ¼ 0.75
5.4 r2 ¼ 0.81
2.97 r2 ¼ 0.76
0.23 r2 ¼ 0.99
0.86 r2 ¼ 0.98
11a
18a
42%
>50
>20
0.40 ꢁ 0.05
2.2 ꢁ 0.4
2.60 r2 ¼ 0.94
>20
0.52 r2 ¼ 0.99
4be
3.9 ꢁ 0.3
2.8 ꢁ 0.1
1.7 ꢁ 0.2
1.8 ꢁ 0.1
0%
>15
>15
>15
4.05 r2 ¼ 0.85
8.14 r2 ¼ 0.86
>20
0.79 r2 ¼ 0.90
2.97 r2 ¼ 0.98
>20
11b
18bf
42%
4ce
4.7 ꢁ 0.2
1.2 ꢁ 0.1
0.5 ꢁ 0.2
6.4 ꢁ 4.0
0.67 ꢁ 0.06
>50.0
Ndg
Ndg
>20
>20
ng
11c
18c
2.37 r2 ¼ 0.92
1.07 r2 ¼ 0.96
>15
>15
4de
11d
18d
3.2 ꢁ 0.1
1.4 ꢁ 0.0
1.3 ꢁ 0.1
5.0 ꢁ 0.0
2.7 ꢁ 2.3
2.4 ꢁ 1.0
4.67 r2 ¼ 0.91
3.49 r2 ¼ 0.82
0.52 r2 ¼ 0.98
0.65 r2 ¼ 0.96
0.52 r2 ¼ 0.97
>3
>3
>15
11.75 r2 ¼ 0.90
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Table 1 (Contd.)
L. major
T. brucei EC50 (mM) T. cruzi EC50 (mM)
P. falciparum
Cmpd Scaffolda
R
or % inh (at 5 mM)b or % inh (at 10 mM)b Amast EC50 (mM)c Promast EC50 (mM)c D6 EC50 (mM)d
4e
1.0 ꢁ 0.1
49%
1.14 r2 ¼ 0.85
>20
>3
0.26 r2 ¼ 0.96
0.23 r2 ¼ 0.98
0.28 r2 ¼ 0.99
11e
18e
0.084 ꢁ 0.0
0.42 ꢁ 0.1
3.3 ꢁ 1.2
29%
>3
>3
>3
4f
0.22 ꢁ 0.00
0.89 ꢁ 0.10
1.6 ꢁ 0.0
2.2 ꢁ 0.4
30 ꢁ 13
17%
4.09 r2 ¼ 0.92
>20
>20
>20
0.60 r2 ¼ 0.96
1.65 r2 ¼ 0.98
7.79 r2 ¼ 0.93
11f
18f
>15
2.03 r2 ¼ 0.84
4ge
11g
18g
5.3 ꢁ 0.2
10%
Nd
>15
6.86 r2 ¼ 0.78
5.79 r2 ¼ 0.98
6.21 r2 ¼ 0.46
10.78 r2 ¼ 0.94
>50.0
45%
3.50 r2 ¼ 0.84
>20
>20
1.2 ꢁ 0.3
>15
4he
11h
18h
0.14 ꢁ 0.1
46%
>50.0
>15
>3
0.51 r2 ¼ 0.98
1.17 r2 ¼0.94
2.11 r2 ¼ 0.98
3.2 ꢁ 0.5
>50.0
3.10 r2 ¼ 0.93
>20
>20
0.33 ꢁ 0.03
>15
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Table 1 (Contd.)
L. major
T. brucei EC50 (mM) T. cruzi EC50 (mM)
P. falciparum
Cmpd Scaffolda
R
or % inh (at 5 mM)b or % inh (at 10 mM)b Amast EC50 (mM)c Promast EC50 (mM)c D6 EC50 (mM)d
4ie
6.0 ꢁ 0.2
8%
>50.0
>50.0
49%
>15
>15
>3
>20
>20
>3
0.91 r2 ¼ 0.99
11i
18i
>15
>4
2.9 ꢁ 0.3
4je,f
11j
18j
1.0 ꢁ 0.05
1.1 ꢁ 0.0
60%
0.60 ꢁ 0.15
>50.0
5.91 r2 ¼ 0.94
2.74 r2 ¼ 0.88
0.22 r2 ¼ 0.84
>20
0.063 r2 ¼0.99
0.027 r2 ¼ 0.97
0.089 r2 ¼ 0.81
>15.0
1.7 ꢁ 0.1
4.20 r2 ¼ 0.91
4ke,f
11k
1.9 ꢁ 0.9
10.1%
0%
>15
>15
4.40 r2 ¼ 0.82
0.27 r2 ¼ 0.98
3.10 r2 ¼ 0.98
0.47 ꢁ 0.25
>20
4le
6.5 ꢁ 1.0
2.2 ꢁ 0.1
>50.0
>15
>20
>20
>20
11l
0.75 ꢁ 0.02
1.58 r2 ¼ 0.83
0.44 r2 ¼ 0.98
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Table 1 (Contd.)
L. major
T. brucei EC50 (mM) T. cruzi EC50 (mM)
P. falciparum
Cmpd Scaffolda
R
or % inh (at 5 mM)b or % inh (at 10 mM)b Amast EC50 (mM)c Promast EC50 (mM)c D6 EC50 (mM)d
4m
1.3 ꢁ 0.1
2.4 ꢁ 0.2
27 ꢁ 3.5
12.36 r2 ¼ 0.78
1.75 r2 ¼ 0.77
5.68 r2 ¼ 0.94
5.33 r2 ¼ 0.69
16.4 r2 ¼ 0.93
H
11m
1%
>15
a
b
Ar is dened as 3-chloro-4-((3-uorobenzyl)oxy)phenyl. Compounds showing >75% growth inhibition at 5 or 10 mM for T. brucei or T. cruzi,
respectively, were tested for EC50 values. T. brucei EC50 values are the result of duplicate experiments, within ꢁ25%, with the exception of 11e
(ꢁ33%), and 11k (ꢁ52%). T. cruzi EC50 values are the result of duplicate experiments, within ꢁ50%, with the exception of 4c (ꢁ63%), and 11d
c
d
(ꢁ85%). Compounds screened against L. major amastigotes and promastigotes were tested in duplicate and had r2 values >0.75. Compounds
were tested in duplicate against P. falciparum (D6 strain) and had r2 values >0.90 except for 11g (r2 ¼ 0.46) and 18j (r2 ¼ 0.81) against P.
e
f
falciparum. Previously reported data utilizing the same assay as described in the ESI.7 All compounds were inactive against HepG2 cell lines
g
except for 4b (TC50 ¼ 4.9 mM), 4j (12.9 mM), 4k (9.6 mM), and 18b (10.0 mM). Not determined due to low solubility in the assay conditions.
of 420 and 400 nM respectively, but the 3-phenyl(piperidin-1-yl)
Fig. 2 displays the effect of changing the scaffold, while
methanone analog (18h) was slightly more potent with an EC50 maintaining the R-group substitution, upon anti-T. brucei
of 330 nM.
activity. We can make a few observations from this qualitative
analysis. First, in the majority of cases, switching from
Scheme 1 Synthesis of the thieno[3,2-d]pyrimidine template. Reagents and conditions: (a) HCO2H, Ac2O, 0 ꢂC to RT, 12 h, 79%; (b) HCONH2,
NH4HCO2, 150 ꢂC to RT, 17 h, 56%; (c) POCl3, 110 ꢂC, 12 h, 90%; (d) LDA, C2Br2F4, THF, ꢃ78 ꢂC to RT, 13 h, 94%; (e) 3-chloro-4-((3-fluorobenzyl)
oxy)aniline, IPA, 85 ꢂC, 12 h, 88%; (f) boronic ester, Na2CO3, Pd(PPh3)4, DME/EtOH (3 : 2), H2O, 80–85 ꢂC, 12 h, 8–36%.
Scheme 2 Synthesis of the thieno[2,3-d]pyrimidine template. Reagents and conditions: (a) 1,4-dithiane-2,5-diol, TEA, DMF, 45 ꢂC, 2 h, 58%; (b)
HCONH2, 170 ꢂC, 6 h, 38%; (c) Br2, AcOH, 80 ꢂC, 2 h, 79%; (d) POCl3, 100 ꢂC, 12 h, 75%; (e) 3-chloro-4-((3-fluorobenzyl)oxy)aniline, IPA, 85 ꢂC, 12
h, 88%; (f) boronic ester, Na2CO3, Pd(PPh3)4, DME/EtOH (3 : 2), H2O, 85 ꢂC, 12 h, 20–46%.
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T. cruzi, overall the thieno[3,2-d]pyrimidine analogs were more
potent in this study, with the best compounds being 4j (EC50
¼
0.60 mM), 11c (0.67 mM), and 11l (0.75 mM). Quinazolines
tolerated the removal of the morpholino group better than
either of the thienopyrimidines. Though the para-morpholino-
phenyl tail (4k, 11k) was inactive in this assay, adding an
intervening methylene group (4j and 11l) resulted in active
analogs.
Screening of more than 35 compounds against amastigotes
of Leishmania major failed to produce any sub-micromolar
compounds. The most potent analog across all 3 scaffolds
against Leishmania major amastigotes was 4e with an EC50 of
1.14 mM. Against promastigotes of L. major only 11j had sub-
micromolar potency (EC50 ¼ 220 nM). As seen with other drug
sensitivity studies, there is oen little-to-no correlation between
the effect of compounds on intracellular amastigotes and the
promastigote form of Leishmania.26
Most compounds showed no toxicity to the HepG2 cell line
except 4b, 4j, 4k, and 18b with TC50 values (concentration
leading to 50% growth inhibition of host cells) of 4.9, 12.9, 9.6,
and 10.0 mM respectively.
Fig. 2 Plot of anti-trypanosome activity as a function of R-group (X-
axis) and scaffold (black ¼ quinazoline, red ¼ thieno[2,3-d]pyrimidine;
green ¼ thieno[3,2-d]pyrimidine). R group letter corresponds to
compound substitutions listed in Table 1.
We tested the two most potent T. brucei growth inhibitors 2
and 11e in in vitro ADME assays, and observed that, as predicted
based on their high c log P (7.6 and 7.4 respectively), both have
poor solubility (<1 mM), high protein binding (>99%), and
modest metabolic stability (Table S3, ESI†). Nonetheless, as the
goal of this report was to describe SAR between the quinazoline
and thienopyrimidine scaffolds, we are encouraged by the
reasonable SAR tracking that is observed between the different
scaffolds. Work continues on all three scaffolds to improve their
physicochemical properties, primarily focused upon reducing
size and lipophilicity; results will be reported in due course.
quinazoline (black circles) to thieno[2,3-d]pyrimidine (red
circles) tends to improve compound potency (i.e., reduces EC50
3-fold or more). Second, when comparing matched analogs
between the quinazoline and thieno[3,2-d]pyrimidine scaffolds,
except for 18c versus 4c, which is about a 9-fold difference; 0.5
versus 4.7 mM, the difference in activity is seldom greater than
two-fold. This indicates that thieno[3,2-d]pyrimidines, unlike
thieno[2,3-d]pyrimidines, are equipotent to quinazolines when
tested against T. brucei. Third, the range of activities for
compounds with thienopyrimidine scaffolds is narrower
(0.084–2.9 mM) than the quinazolines (0.042–6.5 mM). Fourth,
for matched pairs of the [3,2-d] and [2,3-d] scaffold, there is
seldom more than a 2-fold difference in EC50 (the only exception
being 11j (EC50 ¼ 1.1 mM) vs. 18j, which only inhibits parasite
growth 60% at 5 mM).
Table 1 also shows the results of testing these analogs
against the other protozoan parasites. Compound 2 and its
related thienopyrimidine-derived analogs 11a and 18a had
shown sub-micromolar potency towards the malaria parasite
P. falciparum. Removal of the “tail” (4m, 11m) or of the mor-
pholine (4b, 11b, 18b) produced a signicant loss in potency
across all 3 scaffolds. Ortho substitution on the phenyl portion
of the tail was not well tolerated by any set tested. The three tails
that produced the most potent analogs were the meta
substituted methylsulfonyl (4d, 11d, 18d), the para substituted
methyl-pyridinylmorpholine (4e, 11e, 18e), and the para
substituted benzylmorpholine (4j, 11j, 18j). These tails consis-
tently showed sub-micromolar EC50 values across all three
scaffolds, suggesting that appropriately placed H-bond accep-
tors may be crucial to antimalarial activity in this region. These
compounds were also tested against two drug resistant strains
of malaria (W2, C235) and were generally found to show
potencies within 3-fold of the D6 strain (Table S2, Fig. S1 (ESI†)).
Although 2 and the corresponding thieno[2,3-d]pyrimidine
analog 18a displayed promising micromolar potency against
Conclusions
We have previously shown that some lapatinib-derived analogs
have high potency towards the HAT parasite T. brucei and with
little host cell toxicity, typied by 2 (EC50 ¼ 42 nM). In assessing
matched [3,2-d] and [2,3-d] thienopyrimidine scaffold replace-
ments, we have discovered analogs, such as 11e, that have
excellent potency against T. brucei cells (EC50 ¼ 84 nM). Also, a
multi-pathogen testing campaign using these T. brucei inhibi-
tors against select protozoan parasites produced compounds
with a variety of favorable potencies: 4j, T. cruzi EC50 ¼ 0.60 mM;
4e, L. major amastigote EC50 ¼ 1.14 mM and 11j, P. falciparum
EC50 ¼ 0.027 mM. While these data are indicative of good
starting points for antiparasite drug discovery, attention must
be paid to improvement of the physicochemical properties of
these agents in order to produce effective drugs.
Acknowledgements
This work was funded in part by NIH grants R01AI082577
(MPP), R56AI099476 (MPP and KM-W), and R21AI076647 (KM-
W). We thank GlaxoSmithKline for providing GW837016X that
was used in exploratory studies with T. brucei. We appreciate a
free academic license for the OpenEye suite of soware, and are
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grateful to AstraZeneca for performing the in vitro ADME 15 S. R. Johnston and A. Leary, Drugs Today, 2006, 42, 441–453.
experiments described in this manuscript.
16 B. Moy, P. Kirkpatrick, S. Kar and P. Goss, Nat. Rev. Drug
Discovery, 2007, 6, 431–432.
17 R. Behera, S. M. Thomas and K. Mensa-Wilmot, Antimicrob.
Agents Chemother., 2014, 58, 2202–2210.
References
1 World Health Organization Fact Sheet No. 259, http://
www.who.int/mediacentre/factsheets/fs259/en/, accessed 28
July 2014.
2 M. P. Pollastri and R. K. Campbell, Future Med. Chem., 2011,
3, 1307–1315.
18 A. G. Waterson, K. G. Petrov, K. R. Hornberger,
R. D. Hubbard, D. M. Sammond, S. C. Smith,
H. D. Dickson, T. R. Caferro, K. W. Hinkle, K. L. Stevens,
S. H. Dickerson, D. W. Rusnak, G. M. Spehar, E. R. Wood,
R. J. Griffin and D. E. Uehling, Bioorg. Med. Chem. Lett.,
2009, 19, 1332–1336.
19 K. L. Stevens, K. J. Alligood, J. G. Alberti, T. R. Caferro,
S. D. Chamberlain, S. H. Dickerson, H. D. Dickson,
H. K. Emerson, R. J. Griffin, R. D. Hubbard, B. R. Keith,
R. J. Mullin, K. G. Petrov, R. M. Gerding, M. J. Reno,
T. R. Rheault, D. W. Rusnak, D. M. Sammond, S. C. Smith,
D. E. Uehling, A. G. Waterson and E. R. Wood, Bioorg. Med.
Chem. Lett., 2009, 19, 21–26.
20 R. D. Hubbard, S. H. Dickerson, H. K. Emerson, R. J. Griffin,
M. J. Reno, K. R. Hornberger, D. W. Rusnak, E. R. Wood,
D. E. Uehling and A. G. Waterson, Bioorg. Med. Chem. Lett.,
2008, 18, 5738–5740.
21 E. R. Wood, L. M. Shewchuk, B. Ellis, P. Brignola,
R. L. Brashear, T. R. Caferro, S. H. Dickerson,
H. D. Dickson, K. H. Donaldson, M. Gaul, R. J. Griffin,
A. M. Hassell, B. Keith, R. Mullin, K. G. Petrov, M. J. Reno,
D. W. Rusnak, S. M. Tadepalli, J. C. Ulrich, C. D. Wagner,
D. E. Vanderwall, A. G. Waterson, J. D. Williams,
W. L. White and D. E. Uehling, Proc. Natl. Acad. Sci. U. S.
A., 2008, 105, 2773–2778.
3 N. D. Bland, C. Wang, C. Tallman, A. E. Gustafson, Z. Wang,
T. D. Ashton, S. O. Ochiana, G. McAllister, K. Cotter,
A. P. Fang, L. Gechijian, N. Garceau, R. Gangurde,
R. Ortenberg, M. J. Ondrechen, R. K. Campbell and
M. P. Pollastri, J. Med. Chem., 2011, 54, 8188–8194.
4 R. Diaz-Gonzalez, F. M. Kuhlmann, C. Galan-Rodriguez,
L. M. d. Silva, M. Saldivia, C. E. Karver, S. M. Beverley,
A. Rodriguez, M. Navarro and M. P. Pollastri, PLoS
Neglected Trop. Dis., 2011, 5, e1297.
5 J. D. Seixas, S. A. Luengo-Arratta, R. Diaz, M. Saldivia,
D. I. Rojas-Barros, P. Manzano, S. Gonzalez, M. Berlanga,
T. K. Smith, M. Navarro and M. P. Pollastri, J. Med. Chem.,
2014, 57, 4834–4848.
6 S. O. Ochiana, V. Pandarinath, Z. Wang, R. Kapoor,
M. J. Ondrechen, L. Ruben and M. P. Pollastri, Eur. J. Med.
Chem., 2013, 62, 777–784.
7 G. Patel, C. E. Karver, R. Behera, P. J. Guyett, C. Sullenberger,
P. Edwards, N. E. Roncal, K. Mensa-Wilmot and
M. P. Pollastri, J. Med. Chem., 2013, 56, 3820–3832.
8 G. Patel, N. E. Roncal, P. J. Lee, S. E. Leed, J. Erath,
A. Rodriguez, R. J. Sciotti and M. P. Pollastri,
MedChemComm, 2014, 5, 655–658.
22 T. R. Caferro, S. D. Chamberlain, K. H. Donaldson,
P. A. Harris, M. D. Gaul, D. E. Uehling and
D. E. Vanderwall, WO2003053446A1, 2003.
23 M. A. Benish, R. J. A. Budde and M. Lawless,
WO2002057271A2, 2002.
24 B. Buchmann, N. Braeuer, M. Koppitz, O. Peters, L. A. Ter,
B. Lindenthal, G. Langer and T. Wintermantel,
WO2009007421A1, 2009.
9 G. S. Cockerill and K. E. Lackey, Curr. Top. Med. Chem., 2002,
2, 1001–1010.
10 P. Traxler, Expert Opin. Ther. Targets, 2003, 7, 215–234.
11 J. Baselga and C. L. Arteaga, J. Clin. Oncol., 2005, 23, 2445–
2459.
12 N. E. Hynes and H. A. Lane, Nat. Rev. Cancer, 2005, 5, 341–
354.
25 Y. Huang, S. Wolf, M. Bista, L. Meireles, C. Camacho,
13 D. W. Rusnak, K. Lackey, K. Affleck, E. R. Wood,
K. J. Alligood, N. Rhodes, B. R. Keith, D. M. Murray,
W. B. Knight, R. J. Mullin and T. M. Gilmer, Mol. Cancer
Ther., 2001, 1, 85–94.
¨
T. A. Holak and A. Domling, Chem. Biol. Drug Des., 2010,
76, 116–129.
26 G. De Muylder, K. K. Ang, S. Chen, M. R. Arkin, J. C. Engel
and J. H. McKerrow, PLoS Neglected Trop. Dis., 2011, 5, e1253.
14 W. Xia, R. J. Mullin, B. R. Keith, L. H. Liu, H. Ma,
D. W. Rusnak, G. Owens, K. J. Alligood and N. L. Spector,
Oncogene, 2002, 21, 6255–6263.
Med. Chem. Commun.
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