Synthesis and Activity of a New Series of Antileishmanial Agents

Article abstract of DOI:10.1021/acsmedchemlett.7b00039

We have determined that tetrahydroindazoles such as 1 show potent activity against Leishmania donovani, the causative agent of leishmaniasis. While the Hsp90 activity and anticancer properties of 1 have previously been explored, we present here our effort

Full text of DOI:10.1021/acsmedchemlett.7b00039

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Letter
Synthesis and Activity of a New Series of Antileishmanial Agents
Ankush Kanwar, Benjamin J. Eduful, Linda Barbeto, Piero Carletti Bonomo, Andrea Lemus,
Brian Andrew Vesely, Tina S. Mutka, Ala Azhari, Dennis E Kyle, and James W. Leahy
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00039 • Publication Date (Web): 31 Jul 2017
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Synthesis and Activity of a New Series of Antileishmanial Agents
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Ankush Kanwar†, Benjamin J. Eduful†, Linda Barbeto†, Piero Carletti Bonomo†, Andrea Lemus†, Briꢀ
an A. Vesely‡, Tina S. Mutka‡, Ala Azhari‡, Dennis E. Kyle‡┴ and James W. Leahy†,§,#*
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†
Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Avenue, Tampa, FL 33620
‡ Department of Global Health, College of Public Health, University of South Florida, 3720 Spectrum Boulevard, Suite 304,
Tampa, FL 33612
§
Florida Center of Excellence for Drug Discovery and Innovation, University of South Florida, 3720 Spectrum Boulevard,
Suite 303, Tampa, FL 33612
Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, MDC 7, 12901 Bruce B.
#
Downs Boulevard, Tampa, FL 33612
KEYWORDS Antiinfectives, Leishmaniasis, Hsp90, Chaperone
ABSTRACT: We have determined that tetrahydroindazoles such as 1 show potent
activity against Leishmania donovani, the causative agent of leishmaniasis. While the
Hsp90 activity and anticancer properties of 1 have previously been explored, we preꢀ
sent here our efforts to optimize their activity against L. donovani via the synthesis of
novel analogs designed to probe the hydrophobic pocket of the protozoan Hsp90
ortholog, specifically through the auspices of functionalization of an amine embedded
into the scaffold.
Neglected tropical diseases (NTDs) represent an undeniꢀ
activity, and a prodrug analog (SNX5422, 2) is currently in
11,12
1,2
able threat to human health. The World Health Organizaꢀ
tion has prioritized 17 diseases that affect more than 1.5 bilꢀ
lion people around the world, the vast majority of whom are
multiple clinical trials for oncology indications.
The bioꢀ
chemical target of 1 is Hsp90, a ubiquitous chaperone protein
known to facilitate protein folding and one that is often overꢀ
3
13
impoverished. One of these diseases is leishmaniasis, a zoꢀ
expressed in stressed cells. It is the putative target of
1
4
onotic parasitic infection caused by protozoa of the genus
Leishmania. This parasite is transmitted to humans through
the bite of phlebotomine sandflies, and there are estimated to
known bioactive natural products such as radicicol, and has
proven to be a viable focus for oncology drug discovery. A
number of Hsp90 inhibitors have been investigated in human
clinical trials such as breast cancer, colorectal cancer and
4
be more than 12 million people currently infected. The disꢀ
15
ease is manifested in three primary forms: cutaneous, mucoꢀ
cutaneous and visceral leishmaniasis. Visceral leishmaniasis
hepatic cancer. Given that Hsp90 or related orthologs have
been identified not just in mammals but in organisms from
bacteria to yeast, it seemed reasonable that it could therefore
serve as a viable target for the development of antiprotozoal
agents. Indeed, there have been a number of reports of Hsp90
inhibitors that also possess activity against protozoan paraꢀ
(
VL), which is also known as kalaꢀazar, represents the most
5
lethal form of the disease, and is fatal if left untreated. The
most common method for treating VL is through the injecꢀ
tion of pentavalent antimonials such as meglumine antimoniꢀ
ate or sodium stibogluconate, though resistance is reaching
16
sites, including Trypanosoma brucei (African sleeping
6
17,18
18,19
alarming levels. Other treatment options have been exꢀ
sickness),
Leishmania spp. (leishmaniasis). We therefore sought to
explore the prospects of optimizing this
Plasmodium falciparum (malaria)
and
2
0
plored, including miltefosine (Figure 1), liposomal amphoꢀ
tericin B, paromomycin and pentamidine, but each is accomꢀ
7
panied by its own set of challenges. There therefore remains
a significant need for the discovery and development of new
Figure 1 – Structures of miltefosine and radicicol
potential therapeutic agents for the treatment of leishmaniaꢀ
sis.
We have been actively engaged in an ongoing screening
effort for the identification of potential new antiprotozoal
agents. As part of these efforts, we recently found that
8,9
SNX2112 (1, Figure 2) showed potent activity in a high
10
throughput axenic L. donovani amastigote assay. This
compound was previously known to have potent antitumor
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Figure 2 – Interactions of 1 with Hsp90
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O
Asp 93
OR
O
O
H
O
Thr 184
H
2
N
N
O
H
H
N
HN
H
N
N
OH
N
F3C
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O
F3C
1
2
(R = H)
(R =
O
)
NH2
H
O
O
Tyr 139
initial hit as a potential antileishmanial agent. Critical to theꢀ
se efforts would be to ensure that any analogs would demonꢀ
strate this activity without demonstrating significant cytotoxꢀ
icity, which would mitigate the potential usefulness of these
agents as selective antileishmanial agents.
The initial discovery of 1 focused primarily on modificaꢀ
tions to the anthranilamide portion in an attempt to optimize
2
1
for pharmacokinetic parameters. This decision was based in
part on docking studies that suggested the anthranilamide
contributed to two of the three critical hydrogen bonds with
the target and the apparent solvent exposure of the amine
substituent. Notably, little attention was paid to the geminal
methyl substituents other than to note that their presence was
essential for activity. Given that their presence was primarily
a result of the use of dimedone as the starting material for the
synthesis of the initial lead series, we felt that this portion
warranted additional consideration.
2
3
a coꢀcrystal in AutoDock 1.5.6 suggested that 11 would fit
well into the active site, and that the geminal methyl substitꢀ
uents would access a hydrophobic pocket that might be exꢀ
ploited for additional activity or selectivity (Figure 2). We
therefore set out to prepare analogs that would allow us to
introduce diversity late in the synthesis in order to evaluate
their activity. We also considered the typical
Lipinski/physicochemical parameters for each of these anaꢀ
logs in order to maximize the likelihood that any active comꢀ
pounds would have a reasonable chance at achieving acꢀ
In order to confirm the initial hit compound, we prepared
compounds 9 – 11 (Scheme 1). We eschewed the CF subꢀ
3
stituent in the hopes of restricting the cytotoxicity in this
21
24
series. As expected, analog 9 displayed potent and selecꢀ
ceptable oral bioavailability.
tive activity in the axenic amastigote assay, while the
desmethylated 10 showed no activity at 25 ꢀM. We also
prepared quinazoline 11, which restricted the majority of the
rotatable bonds to facilitate docking studies. Since this comꢀ
pound also displayed activity in our initial assay, we felt that
it was an excellent candidate for docking into the active site
We envisioned that an appropriately adorned pyrazoꢀ
lo[3,4ꢀc]pyridine core would serve as a suitable replaceꢀ
22
of Hsp90. Using publicly available coordinates (3D0B) for
Figure 2 – Minimized Poses of 11 in Hsp90 Showing the Geminal Methyl Groups Pointing Toward Hydrophobic Pockets
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Compound 11 docked into Hsp90. The ball and stick (left) and surface (center) models show how the compound accesses the acꢀ
tive site. The right panel shows a channel that exposes the geminal methyl groups that should accommodate modifications at this
site.
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monitrile (15), which was able to undergo Buchwaldꢀ
Hartwig amination and nitrile hydration to afford tertiary
amine 16. The benzyl group could be reductively removed
under acidic conditions to give 17, which served as a viable
intermediate for the generation of substituted analogs. Acylaꢀ
tion of 17 was able to be conducted with a series of readily
available acid chlorides (Scheme 3). Similarly, sulfonylation
was
easily
achieved.
Urea
formation
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was conducted through the auspices of a benzyl carbamate,
which could be debenzylated to give the parent 26.
In addition to evaluating these analogs in the initial high
throughput axenic amastigote assay, we also investigated
their activity in a high content screening (HCS) infected
macrophage assay using transformed J774 murine macroꢀ
phages that also allows us to evaluate cytotoxicity and ensure
that the activity we see is not a general cytotoxic phenomeꢀ
28
non. The results of these evaluations are displayed in Table
. Clearly, the ostensible hydrophobic pocket accommodates
1
a fair amount of substitution at this position. The HCS data
indicates that the secondary and tertiary amines (17 and 16)
are not particularly active, though it is noteworthy that the
more substituted benzyl amine is the more active of the two
which suggests a preference for greater substitution. This
diminished activity preꢀsumably arises from the physiologiꢀ
cal protonation of the amine under the assay conditions.
More significantly, all of the amides showed reasonable HCS
activity, and acetamide 18 was nearly equipotent with the
ment for the initial scaffold such that the amine would proꢀ
vide a versatile handle for the installation of functionality
that could probe this pocket. Toward that end, alkylation of
the ethyl ester of Nꢀ benzylglycine with chloroacetone folꢀ
lowed by tertꢀbutoxide promoted cyclization gave cyclic βꢀ
2
5,26
diketone 13 (Scheme 2).
CꢀAcylation of this material
proved more difficult than we anticipated, but the initial mixꢀ
parent
(9).
By
contrast,
sulfonꢀ
ture of Cꢀ and Oꢀacylated compounds could be converted to
2
7
the desired 14 by cyanide equilibration. Condensation of
this material with the arylhydrazine gave the requisite broꢀ
Table 1. Biological and Physicochemical Data For All Analogs
IC50 (ꢀM)
Lipinski/Physicochemical Properties (DruLiTo)
Compound
J 774
Axenic
Amastigote Macrophage
Infected
Molecular
Weight
Hꢀbond
acceptors
Hꢀbond
donors
Rotatable
bonds
cLogP
tPSA
Cytotoxicity
Miltefosine
Radicicol
3.26
0.62
1.43
0.29
>50
2.35
408
365
8.7
2.4
4
6
0
2
55.43
96.36
20
0
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9
10
11
16
0.42
0.65
> 25
2.42
2.29
3.90
13.9
6.43
1.90
4.48
2.99
2.60
> 20
> 20
> 20
0.61
0.88
> 10
1.33
6.33
> 10
1.06
3.54
3.54
3.58
1.52
1.75
5.38
> 10
> 10
< 0.06
3.52
> 50
> 50
> 50
> 50
> 50
> 50
37.3
> 50
> 50
26.3
25.5
> 50
> 50
437
356
332
302
418
334
374
386
398
402
422
446
410
460
376
2.9
1.8
0.7
0.9
0.9
0.0
ꢀ0.4
ꢀ0.1
0.2
ꢀ0.9
1.0
1.1
ꢀ0.6
0.4
ꢀ1.2
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10
10
4
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49.74
58.97
58.97
57.39
62.21
58.97
79.28
79.28
79.28
88.51
79.28
79.28
104.73
79.28
79.28
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pound that demonstrated an excellent ADME/PK profile, this
is an early drug discovery project and we will continue to
assess these parameters as we seek a lead compound with
optimal properties.
amide 24 was considerably less active, and neither of the
ureas showed any activity. It should also be noted that none
of the compounds prepared demonstrated any significant
cytotoxicity, suggesting that the activity was specific to the
Leishmania amastigotes. Notably, some analogs such as 18
and 24 show considerably more activity in the infected macꢀ
rophage assay than in our initial axenic amastigote assay.
This type of behavior has previously been observed with
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
29
opioid receptor antagonists, suggesting more than one tarꢀ
get could be involved in the observed macrophage activity.
Experimental details for the preparation of all compounds, how
the assays were performed, the Hsp90alpha activity and the kinetꢀ
ic solubility data for 18 (PDF)
Since the ultimate goal of this work is to identify a comꢀ
pound that not only demonstrates antileishmanial activity but
also has the potential to be orally bioavailable, we considered
the typical Lipinski “rule of 5” parameters for each of the
compounds evaluated (Table 1). Furthermore, we also conꢀ
sidered other factors such as the number of rotatable bonds
AUTHOR INFORMATION
Corresponding Author
Corresponding Author
*Phone: (813) 974ꢀ4642. Email jwleahy@usf.edu.
2
4
and the total polar surface area (tPSA). These evaluations
were completed using the DruLiTo drug likeness tool open
3
0
Funding Sources
source calculator. With the exception of the number of roꢀ
tatable bonds for 25, each of the compounds fell within acꢀ
ceptable parameters for oral bioavailability. We tested our
most active Nꢀlinked analog 18 in a kinetic solubility assay
to confirm that these modifications did not result in a deleteꢀ
rious effect on the physicochemical properties of the original
lead, and were pleased to see that it demonstrates excellent
solubility (> 490 ꢀM) in PBS buffer (pH 7.4).
We gratefully acknowledge support for this research from the
University of South Florida Office of Research and Innovation
and the Florida Center of Excellence for Drug Discovery and
Innovation.
Present Address
┴ (D. E. K.) Center for Tropical & Emerging Global Diseases,
University of Georgia, Athens, GA 30602.
We also sought to determine whether the antileishmanial
activity could be tied to Hsp90 inhibition. However, we were
surprised to find that none of the new analogs prepared disꢀ
ACKNOWLEDGMENT
We would like to thank Gabriela Chiosis and Hardik Patel at the
Memorial Sloan Kettering Cancer Center for analyzing these
compounds in their Hsp90 alpha assay. We would also like to
thank Wentao Zhang and Sean Wu of Quintara Biosciences for
obtaining the kinetic solubility data of 18.
31
played significant inhibitory activity against human Hsp90.
In fact, unsubstituted analog 10 was more potent against
Hsp90 than any of the compounds that were active in the
antileishmanial assays. Among the possible explanations for
this are that these compounds are selective for the protozoan
ortholog for Hsp90 (Hsp83) over human Hsp90 or that they
are exerting their antileishmanial activity through a different
mechanism.
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