Synthesis and Structure-Activity Relationship of Dehydrodieugenol B Neolignans against Trypanosoma cruzi

Article abstract of DOI:10.1021/acsinfecdis.0c00523

Trypanosoma cruzi is the etiologic agent of Chagas disease, which affects over seven million people, especially in developing countries. Undesirable side effects are frequently associated with current therapies, which are typically ineffective in the treatment of all stages of the disease. Here, we report the first synthesis of the neolignan dehydrodieugenol B, a natural product recently shown to exhibit activity against T. cruzi. Using this strategy, a series of synthetic analogues were prepared to explore structure-activity relationships. The in vitro antiparasitic activities of these analogues revealed a wide tolerance of modifications and substituent deletions, with maintained or improved bioactivities against the amastigote forms of the parasite (50% inhibitory concentration (IC50) of 4-63 μM) and no mammalian toxicity (50% cytotoxic concentration (CC50) of >200 μM). Five of these analogues meet the Drugs for Neglected Disease Initiative (DNDi) "hit criteria"for Chagas disease. This work has enabled the identification of key structural features of the natural product and sites where scaffold modification is tolerated.

Full text of DOI:10.1021/acsinfecdis.0c00523

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pubs.acs.org/journal/aidcbc
Letter
Synthesis and Structure−Activity Relationship of Dehydrodieugenol
B Neolignans against Trypanosoma cruzi
Claire E. Sear, Pauline Pieper, Maiara Amaral, Maiara M. Romanelli, Thais A. Costa-Silva,
̃
Marius M. Haugland, Joseph A. Tate, Joao H. G. Lago, Andre G. Tempone,* and Edward A. Anderson*
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ABSTRACT: Trypanosoma cruzi is the etiologic agent of Chagas disease, which
affects over seven million people, especially in developing countries. Undesirable
side effects are frequently associated with current therapies, which are typically
ineffective in the treatment of all stages of the disease. Here, we report the first
synthesis of the neolignan dehydrodieugenol B, a natural product recently shown
to exhibit activity against T. cruzi. Using this strategy, a series of synthetic
analogues were prepared to explore structure−activity relationships. The in vitro
antiparasitic activities of these analogues revealed a wide tolerance of
modifications and substituent deletions, with maintained or improved bioactivities against the amastigote forms of the parasite
(50% inhibitory concentration (IC50) of 4−63 μM) and no mammalian toxicity (50% cytotoxic concentration (CC50) of >200 μM).
Five of these analogues meet the Drugs for Neglected Disease Initiative (DNDi) “hit criteria” for Chagas disease. This work has
enabled the identification of key structural features of the natural product and sites where scaffold modification is tolerated.
KEYWORDS: Trypanosoma cruzi, Chagas disease, natural product, neolignan, SAR
hagas disease, a neglected tropical disease caused by the
Ckinetoplastid parasite Trypanosoma cruzi, affects 6−7
million people worldwide and causes ∼14 000 deaths per
year.1,2 It is endemic in Latin American countries and is
spreading further worldwide due to human and vector
migration.3 The disease consists of a mostly asymptomatic
acute stage, which is typified by the presence of parasites in the
blood, and a chronic stage, where the level of parasite in the
blood is low/undetectable due to their predominant location
in the heart and digestive system. While the chronic phase can
persist undetected for decades,4 30−40% of patients suffer
severe failure of vital organs (e.g., cardiomyopathy and
gastrointestinal disease), leading to major disability or
death.5 Current treatments (nifurtimox and benznidazole)
cause severe side effects and are inefficient in the chronic stage
of the disease, and parasite resistance is emerging.6 Despite
efforts to develop new antiparasitic agents,7,8 the current
pipeline for chemical entities against T. cruzi is limited, and as
such, there is an ongoing need for new drug candidates.9,10
Natural products are a proven source of drugs, either in their
Figure 1. Structures of the dehydrodieugenol natural products and
planned SAR/synthesis strategy.
natural form, as synthetic/semisynthetic derivatives, or as a
basic pharmacophore.11 Parasitic diseases are no excep-
tion,12−15 with the frontline treatments for malaria (artemisi-
Received: July 21, 2020
nin) and visceral leishmaniasis (amphotericin B and
paromomycin) themselves being natural products.16,17 As
part of a program to identify new antitrypanosomal agents,
we previously reported the isolation of dehydrodieugenol B (1,
Figure 1) and methyl dehydrodieugenol B (2) from the plant
Nectandra leucantha and their bioactivity against T. cruzi.18,19 A
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© XXXX American Chemical Society
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A

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Letter
series of semisynthetic analogues was subsequently inves-
tigated,20 which were accessed by modification of the phenol
and allyl side chains of dehydrodieugenol B. This suggested
that at least one nonpolar side chain is required for activity, as
the introduction of polar functionalities onto both (a necessary
consequence of this semisynthesis approach) resulted in a
notable reduction in bioactivity.
Table 1. Optimization of Ullmann Coupling Reaction
Conditions
To establish a more detailed structure−activity relationship
(SAR) for dehydrodieugenol B, we targeted a concise and
robust strategy that would enable facile modification of the
natural product core, including selective substitution/deletion
of key structural features. We were attracted to a copper-
catalyzed biaryl ether formation as a key disconnection
(Ullmann coupling, Figure 1), as this would segment the
natural product into the readily available eugenol (3) and
eugenol-derived iodide (4); analogues would be accessed by
the variation of either partner. From an SAR perspective, three
sets of modifications were targeted: (1) the phenol/OMe
group at C2 on the A-ring (substituent S1, green); (2) the allyl
side chains (substituents S2, blue); (3) the methoxy groups
(substituents S3, orange). Here, we describe the development
of this synthetic strategy to access natural products 1 and 2, its
application to prepare 21 analogues (5−25), and the
evaluation of their bioactivity against T. cruzi.
Copper-catalyzed Ullmann coupling represents an attractive
method to access biaryl ethers.21−23 However, this particular
C−O bond formation is challenged by the need for an
electron-rich halide and steric hindrance (ortho-substitution)
on both coupling partners. The need for basic reaction
conditions leads to an additional concern, which has been
encountered in work toward related natural products,24
namely, isomerization of the allylic side chain to the more
thermodynamically favored internal alkene.
CuCl
TMHD
temp (°C), yield
a
b
entry (mol %) (mol %)
solvent
NMP
NMP
NMP
dioxane
time (h)
(%)
27:28
1
2
3
4
5
50
50
50
50
50
10
10
10
10
10
120, 16
120, 42
80, 16
80, 64
80, 24
33
25
63
37
84
1:2.5
0:1
c
1:0.07
1:<0.01
1:0.02
dioxane/
d
NMP
6
7
8
25
50
50
10
10
50
dioxane/
80, 24
80, 22
80, 22
66
53
90
1:0.03
1:0.01
1:<0.01
d
NMP
dioxane/
e
NMP
dioxane/
e
NMP
a
b
1
Isolated yield. Determined by H NMR spectroscopic analysis of
the crude reaction mixture. Using 2-bromoanisole. 1:1 ratio. 2:1
ratio.
c
d
e
Scheme 1. Synthesis of Natural Products 1 and 2 and
Analogues 5−10
a
The Ullmann coupling conditions described by Buck et al.
were chosen as a starting point to study biaryl ether
formation,25 as they were successfully employed using
electron-rich halides and sterically hindered substrates. In
order to optimize the conditions for our system, commercially
available 2-iodoanisole (26) was first used as a coupling
partner with eugenol (Table 1). Under the reported
conditions,25 isomerization of the allylic side chain proved to
be a significant problem (Entry 1), with desired product 27
being the minor component of the product mixture. The use of
bromoanisole (Entry 2) exacerbated this problem due to the
extended reaction time required. However, lowering the
reaction temperature to 80 °C dramatically reduced the
proportion of isomerized product 28 (Entry 3), and switching
to a less polar solvent (dioxane,26 Entry 4) eliminated this
problem entirely but at the cost of a significantly reduced
reaction rate. A solvent mixture of dioxane and NMP (1:1)
resulted in shorter reaction times and greatly reduced the levels
of isomerization (Entries 5 and 6). An increase in the
proportion of dioxane (2:1) further reduced isomerization but
also conversion (Entry 7), while a copper/ligand ratio of 1:1
maximized the reaction efficiency while maintaining minimal
isomerization (Entry 8, 90%, <1% isomerization).
a
Reagents and conditions: (a) MOMCl (1.5 equiv), i-Pr2EtN,
CH2Cl2; (b) s-BuLi (1.5 equiv), TMEDA, THF, 0 °C to rt; I2 (1.5
equiv); (c) CuCl (50 mol %), TMHD (50 mol %), Cs2CO3 (2 equiv),
dioxane/NMP (2:1), 80 °C; (d) 2 M HCl/MeOH (1:10); (e)
PMBCl (1.2 equiv), K2CO3(2.5 equiv), DMF, 100 °C; (f) MeI (1.4
equiv), K2CO3 (4 equiv), DMF; (g) 1 M HCl/EtOH (1:2.5), 80 °C;
(h) H2, Pd/C (30 mol %), EtOH.
With optimized conditions in hand, attention turned to the
natural products, which would require the coupling of a
suitable iodinated derivative of eugenol (e.g., 4, Figure 1). This
was prepared by straightforward ortho-lithiation/iodination of
MOM-protected eugenol (Scheme 1).27 The application of our
optimized conditions to the coupling of 4 with eugenol
resulted in low yields of product 5 due to the unexpected
lability of the MOM protecting group under the reaction
conditions. However, switching from MOM to PMB (30) or
B
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Letter
a
to Me (31, as required for natural product 2) overcame this
problem, affording 6 and 2 in 59% and 58% yields, respectively.
Interestingly, the more electron-rich “left-hand” side chain was
found to be more prone to alkene isomerization during the
coupling. Fortunately, the acidic conditions required for
deprotection of the PMB group to deliver natural product 1
(67%) also removed any traces of this isomerized byproduct
via selective hydration of the styrenyl double bond, which is
activated to protonation by the electron-rich arene. This
synthetic strategy could be scaled up to enable access to 1 in
gram quantities. A series of synthetic derivatives of the natural
products, featuring allyl or benzyl ethers at substituent S1 (7,
8) and/or double saturation at S3 (9, 10), was also prepared
for reference, with 7−9 having been studied in our earlier
work.20
Scheme 2. Synthesis of Analogues 11−25
The modular nature of this route means it can readily be
applied to the synthesis of a range of analogues not accessible
from the natural products themselves in order to explore
structure−activity relationships of dehydrodieugenol B. A
series of 14 further compounds 11−25 was thus prepared,
featuring systematic selective modification of substituents S1,
S2, and S3 (Scheme 2). First, a variation of the B-ring was
carried out by coupling of various aryl iodides (4, 30, and 31)
with “saturated” eugenol (32). This gave analogues 11−13,
which allowed the investigation of the importance of B-ring
side chain unsaturation on bioactivity compared to 1, 2, and 6.
The need for either the B-ring methoxy substituent or the
three-carbon side chain was probed through analogues 14/15
and 16/17, respectively, which were prepared by coupling with
the requisite partners 33 and 34 (we note in passing that 15 is
itself a natural product, namely, 3-methylobovatol).27−29
Equivalent variation of A-ring functionality was achieved by
coupling of eugenol with n-propyl iodoarene 36, which gave
analogues 18 and 19. Deletion of the A-ring three-carbon side
chain and methoxy group was explored through analogues 20−
22 and 23/24. Interestingly, when halide 40 (lacking a
methoxy group ortho to the MOM ether) was used in the
Ullmann coupling, no cleavage of the MOM group was
observed as had been the case with the equivalent coupling of
3 with 4 (see Scheme 1). We suggest that this can be
rationalized by a steric effect where the MOM group is now
able to rotate away from the Lewis-acidic copper atom during
the coupling reaction, presumably a more reactive conforma-
tion for the coupling process. Finally, deletion of the C1-
phenol (25) was accomplished by coupling of 3,5-dibromoa-
nisole with 3, followed by palladium-catalyzed Kumada
coupling with allylmagnesium chloride.
a
Reagents and conditions: (a) CuCl (50 mol %), TMHD (50 mol %),
Cs2CO3 (2 equiv), dioxane/NMP (2:1), 80 °C; (b) 2 M HCl/MeOH
(1:10); (c) 1 M HCl/EtOH (1:2.5), 80 °C; (d) coupled using CuI
(10 mol %), N,N-dimethylglycine hydrochloride (30 mol %), K2CO3
(2 equiv), DMSO, 80 °C;26 (e) PMBCl (1.2 equiv), K2CO3 (2.5
equiv), DMF, 100 °C; (f) Pd2(dba)3 (1 mol %), BINAP (1 mol %),
AllylMgCl (2.5 equiv), dioxane.
Our attention next turned to an evaluation of the activity of
the various natural product analogues against T. cruzi
amastigotes (evaluated microscopically using an ex vivo
intracellular model with mice macrophages)20 and trypomas-
tigotes (resazurin in vitro assay).30 Among the compounds
featuring sole modification of the S1 substituent (5−8 and 25,
Table 2), four of the five presented improved activity against
the amastigotes compared to the natural products, with 50%
inhibitory concentration (IC50) values of 4−24 μM, while only
one demonstrated activity against the trypomastigotes (5, 6.5
4.9 μM). Analogue 6 (OPMB) showed the most promising
of the phenol with a variety of groups, which offers a scope for
future modification, the deletion of this S1 substituent also
enhanced bioactivity compared to the parent natural products
(25, 10.9 μM). It is noteworthy that all modifications of the S1
substituent did not lead to mammalian cytotoxicity for the
highest tested concentration of 200 μM.
activity (4.0
1.4 μM), being approximately 20-fold more
Considering modification of the S2 hydrocarbon side chains
(Table 3), we first questioned whether the saturation of either
or both alkenes would affect the biological activity, a
potentially important consideration from a synthetic perspec-
tive where saturation would avoid the problem of alkene
potent than the natural product 1 against the amastigotes and
with a selectivity index >50 and activity equivalent to
benznidazole, a drug in clinical use against Chagas disease.
Interestingly, in addition to the tolerance of functionalization
C
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a
Table 2. Anti-T. cruzi Activity and Mammalian Cytotoxicity of Synthetic Analogues with a Variation of S1 Substitution
b
IC50 (μM) SD
c
d
entry
compound
S1
OH
OMe
OMOM
OPMB
OAllyl
OBn
trypomastigote
amastigote
CC50 (μM) SD
SI
e
1
2
3
4
5
6
7
8
1
38.6 8.3
NA
6.5 4.9
NA
NA
NA
86.5 16.2
NA
24.4 10.3
4.0 1.4
NA
9.5 1.3
10.9 6.5
5.0 1.5
>200
>200
>200
>200
>200
>200
>200
190.6 13.4
>2.3
ND
>8.2
>50
e
2
5
6
7
8
f
f
ND
>21.1
>18.3
38.1
25
H
NA
17.7 1.9
benznidazole
a
b
c
d
SD: standard deviation; ND: not determined; NA: not active. IC50: 50% inhibitory concentration. CC50: 50% cytotoxic concentration. SI:
e
f
selectivity index, given by the ratio between CC50 in NCTC cells and IC50 in intracellular amastigotes. Published in ref 18. Published in ref 20.
a
Table 3. Anti-T. cruzi Activity and Mammalian Cytotoxicity of Synthetic Analogues with a Variation of S2 Substitution
b
IC50 (μM) SD
c
d
entry
compound
13
S1
OH
OH
OMe
OMe
OPMB
OPMB
OPMB
OMe
S2-A
S2-B
trypomastigote
amastigote
CC50 (μM) SD
SI
1
2
3
4
5
6
7
8
Allyl
n-Pr
Allyl
n-Pr
n-Pr
Allyl
n-Pr
Allyl
H
n-Pr
Allyl
n-Pr
n-Pr
n-Pr
n-Pr
Allyl
H
Allyl
H
Allyl
Allyl
7.6 1.9
4.6 3.8
21.9 6.1
NA
NA
NA
16.6 1.0
10.5 8.3
11.7 7.0
13.3 1.2
5.5 3.5
8.6 2.1
13.4 5.4
NA
25.7 12.2
NA
NA
NA
5.0 1.5
42.0 3.8
14.2 0.1
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
190.6 13.4
2.5
1.3
19
11
>17.1
>15.0
>36.4
>23.3
>14.9
ND
>7.8
ND
ND
e
9
10
12
18
16
20
17
21
22
NA
20.3 0.4
63.1 6.2
NA
NA
NA
9
OMe
10
11
12
13
OPMB
OPMB
OAllyl
Allyl
H
H
ND
38.1
benznidazole
17.7 1.9
a
b
c
d
SD: standard deviation; ND: not determined; NA: not active. IC50: 50% inhibitory concentration. CC50: 50% cytotoxic concentration. SI:
e
selectivity index, given by the ratio between CC50 in NCTC cells and IC50 in intracellular amastigotes. Published in ref 20.
a
Table 4. Anti-T. cruzi Activity and Mammalian Cytotoxicity of Synthetic Analogues with S3 Deletions
b
IC50 (μM) SD
c
d
entry
compound
23
24
15
14
S1
OH
OPMB
OH
S3-A
S3-B
trypomastigote
amastigote
CC50 (μM) SD
SI
1
2
3
4
5
H
H
OMe
OMe
OMe
OMe
H
2.5 1.3
NA
4.6 3.0
NA
7.7 1.3
11.6 8.4
22.5 18.8
11.0 2.3
128.6 5.2
>200
123.4 9.4
>200
16.7
>17.2
5.5
>18.2
38.1
OPMB
H
benznidazole
17.7 1.9
5.0 1.5
190.6 13.4
a
b
c
d
SD: standard deviation; ND: not determined; NA: not active. IC50: 50% inhibitory concentration. CC50: 50% cytotoxic concentration. SI:
selectivity index, given by the ratio between CC50 in NCTC cells and IC50 in intracellular amastigotes.
isomerization during Ullmann coupling. Pleasingly, a con-
sistent and potent activity was observed against T. cruzi
amastigotes irrespective of which side chain was hydrogenated
(or indeed both, 5.5−16.6 μM, Entries 1−7). For the phenols
13 and 19, significant mammalian toxicity was observed,
although alkylation of the phenol as methyl or PMB ether
avoided this problem. In contrast, analogue 11 was the only
derivative of this subset aside from 13 and 19 to display
activity against the trypomastigote form. We next examined
whether deletion of the S2 side chains was tolerated. For
activity against amastigotes, this revealed that both side chains
are likely required (Entries 8−12), with only analogue 18
displaying appreciable bioactivity (albeit reduced compared to
derivatives featuring two side chains, Entries 1−7). It is curious
that this deletion led to activity for compound 16, a direct
analogue of 2, which in its native form is apparently inactive
(Table 1, Entry 2). Finally, the effect of S3 deletion was
studied through analogues 23/24 (A-ring) and 14/15 (B-
ring). In all cases (Table 4), appreciable activity was observed
against the amastigote form of the parasite and also against
D
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Letter
trypomastigotes for the free phenols, albeit again at a cost of
mammalian toxicity. Given the improved efficiency of Ullmann
coupling of iodide 41 (Scheme 2), which lacks the A-ring
methoxy substituent, this deletion may again offer a synthetic
benefit for access to further natural product analogues.
The Drugs for Neglected Disease Initiative (DNDi) defines
the “hit criteria” for Chagas disease as a compound accessed by
a synthetic pathway of up to 8 steps, with an IC50 value against
amastigotes lower that 10 μM and a selectivity index of at least
10.31 Among the 21 analogues studied in this work, five meet
these criteria, displaying a potency equivalent to the current
therapeutic agent benznidazole, and a further seven display
activity of <15 μM. Only those analogues possessing a free
phenol exhibited mammalian toxicity. In general, low activity
was observed against the extracellular trypomastigotes
compared to the intracellular amastigotes, which may suggest
that the compounds’ mode of action is implicated in
amastigote replication or a possible immunomodulatory effect
whereby the compounds activate the macrophage, rather than
acting on the parasite directly.
much flexibility and promise for the discovery of bioactive
natural-product based antiparasitic agents.
METHODS
■
Ethics Statement. BALB/c mice were obtained from the
animal breeding facility at the Instituto Adolfo Lutz, Brazil.
The animals were maintained in sterilized cages under a
controlled environment and received water and food ad
libitum. All procedures performed were previously approved by
the Animal Care and Use Committee from Instituto Adolfo
Lutz, Secretary of Health of Sao Paulo State (Project number
CEUA 05/2018) in agreement with the Guide for the Care
and Use of Laboratory Animals from the National Academy of
Sciences.
Parasites and Mammalian Cell Maintenance. Macro-
phages were collected from the peritoneal cavity of BALB/c
mice by washing them with RPMI-1640 medium supple-
mented with 10% fetal calf serum and were maintained at 37
°C in a 5% CO2 humidified incubator. Trypomastigotes of
T. cruzi (Y strain) were maintained in Rhesus monkey kidney
cells (LLC-MK2, ATCC CCL 7) and cultivated in RPMI-1640
medium supplemented with 2% fetal calf serum at 37 °C in a
5% CO2 humidified incubator. Murine conjunctive cells
(NCTC clone 929, ATCC) were maintained in RPMI-1640
supplemented with 10% FBS at 37 °C in a 5% CO2 humidified
incubator.20
The following trends against the amastigote form of T. cruzi
emerge from the SAR study (Figure 2): (1) The presence of
Antitrypomastigote Assay. LLC-MK2-derived trypomas-
tigotes were seeded (1 × 106 cells/well) in 96-well plates and
incubated with the compounds serially diluted 2-fold (up to
100 μM) for 24 h in RPMI 1640 medium at 37 °C in a 5%
CO2 humidified incubator. Subsequently, resazurin (0.011% in
PBS) was added for 24 h to check the parasite viability.30 The
optical density was determined in the FilterMax F5 (Molecular
Devices) at 570 nm. Benznidazole was used as the standard.
Antiamastigote Assay. Peritoneal macrophages (1 × 105
cells/well), collected from the peritoneal cavity of the BALB/c
mice, were seeded in 16-well chamber slides (NUNC, Thermo
Fisher Scientific) and infected with trypomastigotes (10:1,
parasite/macrophage ratio). After 2 h, the compounds (in
concentrations of 30−0.23 μM) were incubated with infected
macrophages for 48 h at 37 °C in a 5% CO2 humidified
incubator. The slides were fixed with MeOH, stained with
Giemsa, and observed under a light microscope (EVOS
M5000, Termo, USA) with digital image equipment. The 50%
inhibitory concentration (IC50) values were determined by the
infection index.20 >90% infection of macrophages was
established in this assay.
Cytotoxicity against Mammalian Cells. Fibroblast
NCTC cells (clone 929) (6 × 104 cells/well) were seeded in
96-well plates and incubated with the compounds (200−1.56
μM) for 48 h at 37 °C in a 5% CO2 humidified incubator. The
50% cytotoxic concentration (CC50) was determined by the
MTT colorimetric assay.32 The selectivity index (SI) was
determined as CC50/IC50 against amastigotes.
Statistical Analysis. IC50 and CC50 values were calculated
using a sigmoid dose−response curve in GraphPad Prism 6.0
software (GraphPad Software, San Diego, CA, USA). The
assays were repeated at least twice, and the samples were tested
in duplicate.
Figure 2. SAR trends for the dehydrodieugenol scaffold.
both S2 side chains is likely important for activity, although
one or both may be saturated. (2) Either of the S3 methoxy
groups may be removed without a significant effect on
antiparasitic activity, which may be of utility from a synthetic
perspective. (3) The S1 substituent may not be crucial (Table
3) but can also accommodate functionalization with various
ether groups, which in general reduce toxicity compared to the
equivalent phenols (e.g., 13 vs 11 or 12, 19 vs 18, 23 vs 24). In
particular, the most potent analogues (6, 8, 10, and 12) feature
benzylic ethers at this position, suggesting there is significant
scope for further exploration of this substituent vector. In all,
this study shows that the dehydrodieugenol framework offers a
robust platform for further analogue design, including the
synthesis of candidates featuring improved “drug-like” proper-
ties.
In conclusion, a robust synthetic route to the dehydrodieu-
genol natural products has been developed, which centers on
an Ullmann coupling to form the biaryl ether linkage. This
approach enabled the preparation of 21 synthetic analogues,
most of which are not accessible from the natural products
themselves. While further mechanism of action and pharma-
cokinetic studies as well as additional analogues that
encompass more significant variations on the aromatic rings
and their side chains will be needed to inform the design
process, the study shows that this biaryl ether scaffold has
E
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pubs.acs.org/journal/aidcbc
Letter
2018/10279-6, 2018/25128-3), Coordenaca̧ o de Aperfeico̧ a-
̃
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsinfecdis.0c00523.
■
́
mento de Pessoal de Nivel Superior (CAPES).
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ABBREVIATIONS
■
Synthetic procedures and copies of H and 13C NMR
data for all novel compounds (PDF)
1
BINAP, (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl);
CCL2, CC chemokine ligand 2; CCR2, CC chemokine
receptor 2; CCR5, CC chemokine receptor 5; DMF, N,N-
dimethylformamide; MOM, methoxymethyl; NMP, N-meth-
ylpyrrolidinone; TMEDA, N,N,N′,N′-tetramethylethylenedi-
amine; PMB, para-methoxybenzyl; TLC, thin layer chroma-
tography; TMHD, 2,2,6,6-tetramethyl-3,5-heptanedione
AUTHOR INFORMATION
Corresponding Authors
■
Andre G. Tempone − Centre for Parasitology and Mycology,
Instituto Adolfo Lutz, Sao Paulo 01246-000, Brazil;
̃
orcid.org/0000-0003-2559-7344; Email: atempone@
ial.sp.gov.br
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■
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Claire E. Sear − Chemistry Research Laboratory, Oxford OX1
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Pauline Pieper − Chemistry Research Laboratory, Oxford OX1
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Maiara Amaral − Faculdade de Medicina, Universidade de Sao
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors wish to thank Hannah Asiki for assistance with the
synthesis of compounds 32 and 35. C.E.S. thanks the EPSRC
Centre for Doctoral Training in Synthesis for Biology and
Medicine for a studentship (EP/L015838/1), generously
supported by AstraZeneca, Diamond Light Source, Defence
Science and Technology Laboratory, Evotec, GlaxoSmithKline,
Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex.
P.P. thanks the Swiss National Science Foundation for an
SNSF Fellowship and the Marie Skłodowska-Curie actions for
an Individual Fellowship (GA No. 832700). E.A.A. thanks the
Oxford Internal GCRF Research England Fund (Grant No.
0006019) and the EPSRC for additional support (EP/
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