Discovery of Potent N-Ethylurea Pyrazole Derivatives as Dual Inhibitors of Trypanosoma brucei and Trypanosoma cruzi

Article abstract of DOI:10.1021/acsmedchemlett.9b00218

Trypanosoma brucei (T. brucei) and Trypanosoma cruzi (T. cruzi) are causative agents of parasitic diseases known as human African trypanosomiasis and Chagas disease, respectively. Together, these diseases affect 68 million people around the world. Current

Full text of DOI:10.1021/acsmedchemlett.9b00218

Letter
pubs.acs.org/acsmedchemlett
Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Discovery of Potent N‑Ethylurea Pyrazole Derivatives as Dual
Inhibitors of Trypanosoma brucei and Trypanosoma cruzi
‡
§
‡
Swapna Varghese,‡ Raphael ∥Rahmani, Stephanie Russell, Girdhar Singh Deora,∇ Lori Ferrins,‡
̈
§
∥
⊥
́
Arthur Toynton, Amy Jones, Melissa Sykes, Albane Kessler, Amanda Eufrasio,
Artur Torres Cordeiro,∇ Julian Sherman,# Ana Rodriguez,# Vicky M. Avery,∥ Matthew Piggott,*,§
and Jonathan B. Baell*,‡,†,○,⊗
†School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China
‡Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
§Chemistry, School of Molecular Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, Perth, Western
Australia 6009, Australia
∥Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, Queensland 4111, Australia
⊥GlaxoSmithKline, 28760 Tres Cantos, Spain
∇Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials, Campinas, Sao
̃
Paulo 13083-970,
Brazil
#Anti-Infectives Screening Core, New York University School of Medicine, New York 10016, United States
○ARC Centre for Fragment-Based Design, Monash University, Parkville, Victoria 3052, Australia
⊗Australian Translational Medicinal Chemistry Facility (ATMCF), Monash University, Parkville, Victoria 3052, Australia
S
* Supporting Information
ABSTRACT: Trypanosoma brucei (T. brucei) and Trypanosoma
cruzi (T. cruzi) are causative agents of parasitic diseases known as
human African trypanosomiasis and Chagas disease, respectively.
Together, these diseases affect 68 million people around the
world. Current treatments are unsatisfactory, frequently asso-
ciated with intolerable side-effects, and generally inadequate in
treating all stages of disease. In this paper, we report the
discovery of N-ethylurea pyrazoles that potently and selectively
inhibit the viability of T. brucei and T. cruzi. Sharp and logical
SAR led to the identification of 54 as the best compound, with an
in vitro IC50 of 9 nM and 16 nM against T. b. brucei and T. cruzi, respectively. Compound 54 demonstrates favorable
physicochemical properties and was efficacious in a murine model of Chagas disease, leading to undetectable parasitemia within
6 days when CYP metabolism was inhibited.
KEYWORDS: Human African trypanosomiasis, Chagas disease, dual inhibitors, neglected disease, N-ethylurea pyrazole
been substantially decreased. WHO aims to eliminate HAT by
2020 if the current progress is sustained.4 However,
reemergence of the disease is always a threat, as current
treatments are not effective against all stages and subspecies of
the disease and are either toxic, contraindicative in pregnancy, or
difficult to use in remote endemic areas,5 which can lead to
issues with compliance.6 A new drug, Fexinidazole, has most
recently been discovered; however, the European Medicines
eglected tropical diseases affect approximately one billion
Npeople across 149 countries and are responsible for
around 534,000 deaths every year.1 These diseases are prevalent
in the poorest countries, where access to medication is
unavailable or unaffordable. Trypanosoma species cause human
African trypanosomiasis (HAT) and Chagas disease, while
Leishmania species cause leishmaniasis.1 HAT is endemic to sub-
Saharan Africa and has resulted in several epidemics over the last
century. In addition to causing fever, joint aches, and
neurological and endocrinal disorder,2 HAT affects the host
circadian clock, thereby leading to changes in the timing of
sleep.3 The World Health Organization (WHO) estimates that
61 million people are at risk of HAT in 36 countries. About
10,000 new cases were reported in 2009; however, with proper
intervention and disease control strategies, the disease toll has
Special Issue: Women in Medicinal Chemistry
Received: May 29, 2019
Accepted: September 9, 2019
Published: September 9, 2019
© XXXX American Chemical Society
A
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Agency has only approved it for the treatment of infection with
T. b. gambiense.7
substituted analogues 25a and 25b, using methyl crotonate (for
R1 methyl) and methyl methacrylate (for R2 methyl).
The situation is not as promising in South America, where
Chagas disease (American trypanosomiasis) affects 6−7 million
people. Among them, 10% will develop digestive and neuro-
logical deteriorations and 30% cardiac alterations, which may
lead to progressive heart failure and sudden cardiac arrest.8 The
current drugs used to treat Chagas disease have associated
toxicity and have variable efficacy in the chronic phase of the
disease.9,10 Chagas disease transmission is confined to Latin
America, but migration of chronic patients to other continents
contributes to the urgent need for control and treatment.5
In both forms of trypanosomiasis, the diseases evolve in two
stages. The first stage is rarely diagnosed due to nonspecific
symptoms, and the second stage is most debilitating and not
easily treated.5,11 With no immediate prospect for vaccines,
chemotherapy is the only way to fight these trypanosomes. In
this context, in 2012 we described an HTS campaign against T.
b. brucei12 which led to the identification of a novel series of
thiazoles with broad spectrum trypanocidal activity13 (T. b.
brucei is a human noninfective strain of the parasite responsible
for HAT and presents as an excellent model for the human
infective strains, namely T. b. rhodesiense and T. b. gambiense).
Such dual activity offers potential development cost advantages
for drugs against both diseases, thus driving us to explore this
chemotype further. In particular, we wished to investigate
whether the thiazole core (Figure 1A) could be replaced by a
In order to understand the SAR around the LHS phenyl
group, substituents varying in size and electronic properties were
introduced at the ortho, meta, and para positions (Scheme 3). 2-
Nitropyrazole (26) was first alkylated with N-(2-bromoethyl)-
phthalimide (27), and then the nitro group was reduced to form
the aminopyrazole 29. A Sandmeyer reaction installed the
bromine at the 3-position, before being reduced and converted
to the ureas 32a−d. Finally, Suzuki coupling reactions were used
to introduce the substituted phenyl group, providing targets
33−57.
All target compounds were subjected to biological evaluation
against T. b. brucei, and a selection were assessed against T. cruzi
parasites. Table 1 represents compounds with RHS modifica-
tions; our starting point, benzamide 8, had moderate activity
(IC50 = 0.61 μM) against T. b. brucei, while an aliphatic ring led
to a loss in activity in 9. Consistent with our previous work,13
urea analogs showed a distinct boost in activity against T. b.
brucei, with the piperidine urea (11) demonstrating an almost
10-fold potency increase compared with both the benzamide
(8), and the slightly smaller pyrrolidine urea (10). The
introduction of a more hydrophilic morpholine moiety (12)
was detrimental for activity, and so was increasing the size of the
ring as in 13. The acyclic urea analog (14) and the isopropyl urea
(15) also had reduced activity, while the carbamate (17) had
modest activity, highlighting the importance of a cyclic urea
substituent at the RHS. The ureas 11 and 13 were also potent
inhibitors of T. cruzi viability. The drop-in potency against this
species compared to T. b. brucei may be a result of poorer
compound penetration through the host mammalian cell
membrane; the T. b. brucei assay is on free parasites, while the
T. cruzi assays are intracellular.
Exploring the tolerance of other groups and space around the
RHS, we investigated sulfonamide 16 and reverse amide 19;
however, these modifications led to complete loss of activity.
Reduction of the amide to amine 20 also led to a complete loss in
activity, highlighting the importance of the carbonyl group.
Thus, we saw sharp SAR trends for the RHS modifications with a
distinct preference for a piperidine urea. This group was thus
maintained in subsequent investigations around other parts of
the molecule.
Modifications to the linker and the LHS were then explored.
Table 2 illustrates that substitution at either position on the
linker led to considerable loss in activity. Table 3 illustrates the
SAR of LHS with substituted phenylpyrazoles. The ortho
position was mostly tolerant to lipophilic groups. The 2-
fluorophenyl analogue 33 was equipotent to the parent
compound 11. A chloro or a methyl group at the ortho position
was also tolerated (for T. b. brucei and T. cruzi); however, the
introduction of the slightly larger 2-methoxy group (36) led to a
40-fold drop in activity and the electron withdrawing cyano
group (37) led to a 80-fold decrease in activity against T. b.
brucei (60-fold decrease against T. cruzi). In summary, small
lipophilic groups, although tolerated at the ortho position, did
not offer any improvement in potency. Fluoro and chloro
substituents were also well tolerated at the meta position, while
nonhalogen groups such as methyl (40) and methoxy (41) led
to a 6-fold and 20-fold decrease in potency, respectively, against
T. b. brucei.
Figure 1. (A) Hit discovered from HTS.12 (B) General structure of
pyrazole compounds synthesized in this study. (SI = selectivity index vs
HEK293 (T. b. brucei) and H9c2 cells (T. cruzi)).
pyrazole (Figure 1B), as thiazoles have a reputation for
toxicogenic potential whereas pyrazoles are privileged structural
motifs in medicinal chemistry.14,15 In addition, the thiazoles
suffer from relatively high rates of phase-I metabolism, curtailing
their clinical potential. Herein we report our SAR investigation
of pyrazole-based compounds (Figure 1B) as potent dual
inhibitors of the viability of T. b. brucei and T. cruzi with
improved metabolic stability and efficacy in a mouse model of
Chagas disease.
Informed by our previous investigations on the series with a
thiazole core,13 we wanted to explore modifications of the amide
moiety (RHS as drawn), linker modifications, and modifications
of the pyrazole 3-substiuent (LHS as drawn) as shown in Figure
1B.
The key primary amine dihydrochloride 6 upon acylation gave
target amides (8, 9, 12) and upon treatment with
benzenesulfonyl chloride gave 16 (Scheme 1). Compound 6
was also converted to the activated urea 7, which was converted
to various ureas (10, 11, 13−15) and carbamate 17. The early
synthetic precursor 3 was saponified and subjected to amide
coupling conditions to obtain the reverse amide 19, and 8 was
reduced to give 20. Scheme 2 shows the synthesis of the linker-
Although, a cyano group also led to loss in activity, it was more
tolerated at the meta position (42) compared with the ortho
position (37). At the para position, the introduction of a fluorine
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a
Scheme 1. Synthetic Route for RHS SAR Exploration
a
Reagents and conditions: (a) K2CO3, DMF, 73%; (b) NH4OH, 60 °C, 60%; (c) PhI(OAc)2, MeOH, 60%; (d) 4 M HCl, reflux, 99%; (e) CDI,
MeCN/DMF, 46%; (f) RCOCl, Et3N, DCM, 57−98%; (g) PhSO2Cl, DIPEA, DCM, 34%; (h) R1R2NH, Et3N, DCM, 75−94%; (i) i-PrOH, NaH/
DMF, 59%; (j) LiOH, H2O, 88%; (k) PhNH2, DMF, HBTU, DIPEA, 57%; (l) 1 M BH3·THF, THF, reflux, 32%.
a
Scheme 2. Synthetic Route for Linker-Modified Targets
a
Reagents and conditions: (a) Methyl crotonate or methyl methacrylate, DBU, ACN, 50 °C; (b) LiOH, H2O, THF; (c) DPPA, Et3N, t-BuOH,
reflux; (d) TFA, DCM, rt; (e) (i) p-nitrophenyl chloroformate, Et3N, DCM, rt, (ii) Piperidine, rt. (a) R1 = Me, R2 = H, (b) R1 = H, R2 = Me.
atom (43) was tolerated while the bigger chlorine (44) led to a
20-fold loss in activity for T. b. brucei. The methyl group at the
C
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a
Scheme 3. Synthetic Route for the SAR Exploration of LHS-Modified Targets
a
Reagents and conditions: (a) K2CO3, DMF, 50 °C, 54%; (b) Pd/C, NH4HCOO, MeOH, reflux, 95%; (c) (i) NaNO2, HBF4, H2O/ACN (3:1),
(ii) CuBr, 50 °C, 11%; (d) NH2NH2, EtOH; (e) (i) p-nitrophenyl chloroformate, Et3N, DCM, (ii) R2 (piperidine or pyrrolidine or substituted
pyrrolidines), 36−63%; (f) R1boronic acid, K2CO3, TBAB, Pd(dppf)Cl2, dioxane/H2O (4:1), 24−87%.
Table 1. Antitrypanosomal Activities of Pyrazole Derivatives with RHS Modifications
a
b
c
IC50 values are the average of two independent experiments standard deviation. SI = selectivity index relative to HEK293 cells. SI = selectivity
index relative to H9c2 cells. ND = not determined. NA = not active (IC50 value could not be determined).
para position was again tolerated but led to a less active
compound. 4-Methoxy or -cyano groups were not favorable for
activity, presumably for steric reasons.
Overall, only minor changes could be integrated in the LHS
phenyl group. In all cases the small lipophilic fluorine atom was
well tolerated. In order to explore potential additive SAR
D
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leishmaniasis, and malaria, respectively, with known antiproto-
zoal drugs as positive controls (Supporting Information, Table
S1). These compounds were also tested against T. cruzi, to get an
independent reconfirmation of activity, and rat skeletal muscle
cell line L6, for cytotoxicity assessment. It was reassuring that all
the tested compounds reconfirmed activity against T. cruzi and
also displayed activity against T. b. rhodesiense; however, they
only demonstrated modest activity against L. donovani and P.
falciparum. Compound 54 was again the most active compound
against T. cruzi and T. b. rhodesiense, considerably more so than
the Chagas drug benznidazole and as active as the very toxic
HAT agent melarsoprol.
Time to kill T. cruzi assays of compounds 11 and 54 were
performed to understand the kinetics and mode of action of
these compounds (Figure 2). Two positive controls, namely
benznidazole and posaconazole, were used. Benznidazole is a
trypanosomacidal (fast-killing) prodrug activated by trypano-
somal type 1 nitroreductase resulting in the formation of glyoxal
reactive forms that have a nonspecific cytotoxic effect.
Posaconazole on the other hand has a trypanosomastatic
(slow-killing) mode of action as it inhibits trypanosomal sterol
biosynthesis by targeting CYP51 activity. Compounds 11 and
54 show a fast-killing profile against T. cruzi intracellular forms,
similar to that observed for benznidazole. Both compounds
caused a reduction in the number of infected cells in the first 24 h
after addition of drug. The precise mechanism of action,
however, remains to be determined.
Table 2. Antitrypanosomal Activities of Pyrazole Derivatives
with Linker Modifications
a
b
a
c
Compd
IC50 μM (SI ) T. b. brucei
IC50 μM (SI ) T. cruzi
25a
25b
0.23 0.04 (358)
0.64 0.12 (131)
0.20 0.004 (251)
1.0 0.23 (50)
a
All IC50 values are the average of two independent experiments
standard deviation. SI = selectivity index relative to HEK293 cells.
SI = selectivity index relative to H9C2 cells.
b
c
features, we synthesized difluoro analogues 48 and 49. Clearly
the additive features were beneficial for activity, with the 3,4-
difluoro analogue (49) demonstrating improved activity against
both T. b. brucei and T. cruzi parasites.
Thus, through a series of systematic SAR studies, we identified
very potent compounds. Evidently, LHS fluoro substitutions
were well tolerated in terms of potency and were also expected to
improve metabolic stability.16,17 The RHS substituent was
briefly revisited to probe substituted pyrrolidine groups. This led
to the synthesis of compounds 50 and 51, which showed
considerable boosts in potency from unsubstituted pyrrolidine
derivative 10 (Table 4).
Physicochemical and metabolic parameters of some of the
most active compounds were determined (Supporting In-
formation, Table S2). Most properties were in accord with the
guidelines suggested by the Drugs for Neglected Diseases
Initiative (DNDi) for progression to in vivo studies. The polar
surface area of all compounds is below 85 Å2, which is favorable
for traversing the blood−brain barrier. The compounds
generally also had a desirable balance of water solubility and
lipophilicity, as indicated by their cLogD values. The solubility
of one of the compounds (51) was limited (12.5−25 μg/mL);
however; both the other compounds tested had good solubility
(>20 μg/mL) at pH values of 2 and 6.5.
Comparison of the activity of 43 and 49 with 50 and 51
suggests that LHS prefers a fluoro substitution and also that
further optimization of the RHS urea with an intermediately
sized substituent may be beneficial for activity. Our previous
observations of preference for small electronegative substituents
at the meta-position of benzamides13 led us to incorporate 3-
fluoro substituents at the RHS, as in 52−57. Clearly, the activity
of these compounds improved with RHS fluoro substitution.
The combination of LHS 3,4-difluorophenyl and RHS (S)-
fluoro pyrrolidine was particularly favorable, with 54 showing 9
nM potency for T. b. brucei (16 nM for T. cruzi).
A selection of active compounds was tested against other
protist parasites, namely T. b. rhodesiense, Leishmania donovani,
and Plasmodium falciparum, the causative agents of HAT,
Compounds 43, 51, and 54 show slight improvement in the
metabolic stability in human liver microsome over compound
Table 3. Antitrypanosomal Activities of Pyrazole Derivatives with LHS Substitution
a
b
a
c
a
b
a
c
Compd
R
IC50 μM (SI ) T. b. brucei IC50 μM (SI ) T. cruzi Compd
R
IC50 μM (SI ) T. b. brucei IC50 μM (SI ) T. cruzi
11
33
34
35
36
37
38
39
40
H
2-F
2-Cl
2-Me
2-OMe
2-CN
3-F
3-Cl
3-Me
0.06 0.00 (1349)
0.06 0.00 (185)
0.12 0.03 (361)
0.35 0.11 (240)
2.6 0.58 (32)
0.25 0.12 (32)
ND
0.13 0.02 (398)
0.32 0.10 (158)
ND
13 0.89 (4)
ND
0.13 0.0 (398)
0.32 0.04 (158)
41
42
43
44
45
46
47
48
49
3-OMe
3-CN
4-F
4-Cl
4-Me
4-OMe
4-CN
2,4-difluoro
3,4-difluoro
1.2 0.13 (67)
0.35 0.10 (236)
0.06 0.00 (161)
1.2 0.13 (35)
5.3 1.45 (16)
7.1 1.78 (12)
ND
4.0 0.09 (13)
0.40 0.01 (126)
ND
1.0 0.14 (50)
10 1.9 (5)
25 7.6 (2)
40 0.0 (1)
ND
4.7 0.69 (18)
0.05 0.00 (197)
0.13 0.01 (327)
0.36 0.14 (232)
0.045 0.00 (1875)
0.027 0.01 (2912)
d
0.119 0.026* (616)
a
b
c
All IC50 values are the average of two independent experiments standard deviation. SI = selectivity index relative to HEK293 cells. SI =
*
d
selectivity index relative to H9c2 cells. Protocol B (Supporting Information). SI = selectivity index relative to 3T3 cells. ND = not determined.
E
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Table 4. Antitrypanosomal Activities of Pyrazole Derivatives with LHS and RHS Modifications
a
b
c
All IC50 values are the average of two independent experiments standard deviation. SI = selectivity index relative to HEK293 cells. SI =
selectivity index relative to H9c2 cells.
Figure 2. T. cruzi time to kill assay for 11 (0.312 μM), 54 (0.078 μM), benznidazole (20 μM), posaconazole (0.04 μM), and DMSO.
11, pointing toward the positive effect of fluorine substitution.
The methyl substituted linker compounds (25a and 25b) were
synthesized to investigate the effects on both conformational
restriction and metabolic stability but exhibited low microsomal
stability; as such, this strategy was not pursued further. It was
rewarding to find that 54, the most potent compound in this
series, was also the most stable compound when tested in
(human, mouse) liver microsomes. As anticipated, the pyrazole
series demonstrated better pharmacokinetic properties than our
previous thiazole series;13 54 demonstrated a 3-fold increase in
the half-life (from 8 to 23 min in human) and a significant
improvement in the microsome predicted EH (from 0.90 to 0.75
in humans) when compared with the most active compound in
the thiazole series.
Compound 54 was subjected to in vivo efficacy studies using
benznidazole as the positive control. Mice acutely infected with
T. cruzi were treated orally with vehicle as control or with the
CYP-inhibitor 1-aminobenzotriazole (ABT) (intraperitoneal)
followed by compound 54 orally 30 min later. (ABT is a CYP
inhibitor which slows down drug metabolism without affecting
T. cruzi parasite viability (unpublished data)). The treatment
resulted in a sharp decrease of parasitemia, with parasites
undetectable after 6 days of treatment, as illustrated in Figure 3.
F
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Figure 3. In vivo efficacy study. Balb/c mice infected with the trypomastigote form of the transgenic T. cruzi Brazil strain expressing firefly luciferase18
were treated by oral gavage twice daily with vehicle (PBS with 2% methylcellulose and 0.5% Tween 80) or 54 (50 mg/kg preceded by ip ABT 50 mg/kg
30 min prior) or benznidazole (30 mg/kg, oral gavage, once daily). (A) Parasite load from day 0 (3 days post infection) and day 6 of treatment. (B)
Bioluminescence imaging of the group of mice treated with 54 and ABT.
Signs of toxicity were observed in treated mice, including weight
loss and lethargy.
Girdhar Singh Deora: 0000-0001-9857-101X
Lori Ferrins: 0000-0001-8992-0919
HAT and Chagas disease exert a great burden on some of
society’s poorest people. Compounds with dual activity against
both diseases represent an efficient approach to therapeutic
development by cutting down the cost of drug discovery
research and manufacturing. Until recent publications by us and
others, it was not clear whether the availability of such
chemotypes was sufficient. Even with the advanced chemotypes
identified by Novartis19 and Sanofi,7 the pipeline of potential
dual-action drugs is desperately underpopulated.
Systematic SAR studies of the N-(2-(3-phenylpyrazol-1-
yl)ethyl)urea series led to the identification of derivatives with
low nanomolar levels of potency against T. b. brucei and T. cruzi
parasites with negligible toxicity to mammalian cells. This series
presents a step forward in dually active trypanosomacides with
increased potency, selectivity, and metabolic profile for this
particular subclass. Time-to-kill assays establish that these
compounds have a trypanosomacidal mode of action, similar to
benznidazole, while being 36 times more potent. In vivo studies
also showed that 54 led to a drastic reduction of parasite load in
T. cruzi infected mice within 6 days of twice daily treatment
when CYP metabolism was inhibited with ABT. Although
metabolic liabilities need further optimization, this series
represents a promising chemotype for these neglected diseases,
and further investigation and mechanism of action studies are
warranted.
Matthew Piggott: 0000-0002-5857-7051
Jonathan B. Baell: 0000-0003-2114-8242
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The National Health and Medical Research Council of Australia
(NHMRC) is thanked for research support for J.B.B. (2012-
2016 Senior Research Fellowship #1020411, 2017- Principal
Research Fellowship #1117602 and project grant #1079351).
Australian Translational Medicinal Chemistry Facility
(ATMCF) acknowledges the support of the Australian Govern-
ment’s National Collaborative Research Infrastructure Strategy
(NCRIS) program via Therapeutic Innovation Australia (TIA).
The Griffith University Postdoctoral Fellowship Scheme
(GUPF) provided research support for M.S.
ABBREVIATIONS
■
ABT, 1-aminobenzotriazole; ACN, acetonitrile; CDI, carbon-
yldiimidazole; CLint, intrinsic clearance; DBU, 1,8-diazabicyclo-
[5.4.0]undec-7-ene; DIPEA, N,N-diisopropylethylamine;
DNDi, Drugs for Neglected Diseases Initiative; DPPA, diphenyl
phosphorylazide; Dppf, 1,1′-ferrocenediyl-bis-
(diphenylphosphine); HAT, human African trypanosomiasis;
HBTU, N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)-
uraniumhexafluorophosphate; LHS, left hand side; RHS, right
hand side; T. b, Trypanosoma brucei; T. cruzi, Trypanosoma
cruzi; SI, selectivity index; WHO, World Health Organisation.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.9b00218.
REFERENCES
■
Experimental procedures for biological assays, activity
against other parasites, metabolic stability data, and
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AUTHOR INFORMATION
Corresponding Authors
*For J.B.B.: Phone, +61 3 9903 9044; E-mail, jonathan.baell@
monash.edu.
*For M.J.P.: Phone, +61 8 6488 3170; E-mail, matthew.
piggott@uwa.edu.au.
ORCID
■
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Swapna Varghese: 0000-0002-4613-7999
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DOI: 10.1021/acsmedchemlett.9b00218
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX