Macrofilaricidal Benzimidazole-Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness: Part 2. Ketone Linked Analogs

Article abstract of DOI:10.1021/acsinfecdis.9b00397

The optimization of a series of benzimidazole-benzoxaborole hybrid molecules linked via a ketone that exhibit good activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis, also known as river blindness, is desc

Full text of DOI:10.1021/acsinfecdis.9b00397

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Letter
Macrofilaricidal Benzimidazole-Benzoxaborole Hybrids as an Approach
to the Treatment of River Blindness. Part 2. Ketone Linked Analogs.
David S. Carter, Robert Toms Jacobs, Yvonne Freund, Pamela Berry, Tsutomu
Akama, Eric E. Easom, Christopher S. Lunde, Fernando L. Rock, Rianna Stefanakis,
James H. McKerrow, Chelsea Fischer, Christina Bulman, Kee Chong Lim, Brian
M. Suzuki, Nancy Tricoche, Judy Sakanari, Sara Lustigman, and Jacob J. Plattner
ACS Infect. Dis., Just Accepted Manuscript • DOI: 10.1021/acsinfecdis.9b00397 • Publication Date (Web): 26 Dec 2019
Downloaded from pubs.acs.org on December 30, 2019
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Macrofilaricidal Benzimidazole-Benzoxaborole Hybrids as an
Approach to the Treatment of River Blindness. Part 2. Ketone
Linked Analogs.
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David S. Cartera, Robert T. Jacobsa*, Yvonne R. Freunda, Pamela W. Berrya, Tsutomu Akamaa, Eric E.
Easoma, Christopher S. Lundea, Fernando Rocka, Rianna Stefanakisa, James McKerrowb, Chelsea
Fischerc, Christina A. Bulmanc, Kee Chong Limc, Brian M. Suzukib, Nancy Tricoched, Judy A.
Sakanaric, Sara Lustigmand, Jacob J. Plattnera
a Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA;
b Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La
Jolla, CA 92093-0657
c Dept. of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th Street, San Francisco, CA 94158,
USA
d Lindsley F. Kimball Research Institute, New York Blood Center, 310 E. 67th Street, New York, NY 10065, USA
*rtjacobs7158@gmail.com
Keywords: onchocerciasis, lymphatic filariasis, flubendazole, tubulin, organoboron
Supporting Information Placeholder
programs including ivermectin, albendazole and/or
diethylcarbamazine,2-5 there remains a need to identify
new treatments that can kill specifically adult worms
using a short course of treatment and not just
Optimization of
a
series of benzimidazole-
benzoxaborole hybrid molecules linked via a ketone are
described that exhibit good activity against Onchocerca
volvulus, a filarial nematode responsible for the disease
onchocerciasis, also known as River Blindness. The
lead identified in this series, AN15470, was found to
have acceptable pharmacokinetic properties to enable
evaluation following oral dosing in an animal model of
onchocerciasis. AN15470 was effective in killing
worms implanted in Mongolian gerbils when dosed
orally as a suspension at 100 mg/kg/day for 14 days, but
not when dosed orally at 100 mg/kg/day for 7 days.
microfilariae.4-7
In
addition,
co-infection
of
onchocerciasis or LF patients with the eye worm Loa
loa can limit the utility of treatment with ivermectin due
to significant side effects resulting from rapidly killing
the Loa loa microfilarae.8,9
The strategy of our program was based on the known
benzimidazole carbamate flubendazole (3), an inhibitor
of tubulin polymerization that had shown antifilarial
activity.10-13 Flubendazole (3) is a member of a larger
class
of
benzimidazole
carbamate
tubulin
polymerization inhibitors and contains a 4-fluorophenyl
substituent linked to the benzimidazole core via a
ketone at C(6). One of the main limitations of
flubendazole as an antifilarial is the limited
Previous work from our laboratory has described the
discovery and development of
a
series of
benzimidazole-benzoxaborole hybrid molecules that
were effective in inhibiting the molting in vitro of the
parasitic filarial worm Onchocerca volvulus as well as
killing Brugia malayi and B. pahangi adult worms in
vivo. O. volvulus, Wuchereria bancrofti, B. malayi and
B. timori are responsible for the diseases known as river
blindness (onchocerciasis) and elephantiasis (lymphatic
filariasis, LF) that are endemic in the developing
world.1 Despite significant and long-term efforts to limit
the impact of these parasitic infections on the
population through mass drug administration (MDA)
bioavailability of this molecule, most likely
a
consequence of poor aqueous solubility.14, 15 We sought
to overcome this limitation by utilization of the
benzoxaborole in place of the 4-fluorophenyl
substituent. This boron-containing heterocycle can exist
in equilibrium between a trigonal, neutral boron atom
(1) and a tetrahedral, negatively charged boron atom (2)
under physiologically relevant conditions which have
improved aqueous solubility (Figure 1).16-27
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OH
B
O
7
4
1
2
3
4
5
6
M+OH-
HO
7
4
OH
M+
6
5
B-
O
6
5
3
3
1
2
7
8
9
Figure 1. Equilibrium between trigonal and tetrahedral
boron in the benzoxaboroles
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19
20
21
22
23
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In addition, flubendazole has been found to be an
aneugen in both in vitro and in vivo micronucleus tests,
although it has been argued that the lack of
clastogenicity of flubendazole in these tests will limit
the risk of carcinogenicity to patients.28 However,
metabolism of flubendazole by reduction of the ketone
leads to short-lived clastogenic metabolites at low levels
that may pose a minimal risk.28 Though extensive
metabolite ID studies on our lead compounds,
particularly compound 21, have not observed significant
metabolism of these compounds in either in vitro or in
vivo experiments, suggesting that this risk may be
reduced in the benzoxaborole-benzimidazole hybrids
(vide infra).
Scheme 1.
Benzimidazole Hybrid Molecule.
Synthesis of 6-Oxobenzoxaborole-
O
Br
CO2H
a
b
Br
O
5
6
O
O
c
Br
NO2
d
Br
NO2
O
NH2
8
7
O
O
f
e
Br
NO2
N(Boc)2
Br
NO2
Br
N(Boc)2
10
9
O
g
O
O
h
Br
NO2
N(Boc)2
The lead compound identified in our earlier work,
AN8799 (4), was a hybrid molecule wherein the
benzimidazole and benzoxaborole moieties were
connected via an amide linker.
B
NO2
N(Boc)2
O
AcO
HO
AcO
11
12
O
O
HO
O
i
NO2
NH2
O
B
N
B
O
NH
O
S
N
H
H3CO2
C
CO2CH3
N
N
H
15
13
14
O
O
HO
O
O
O
O
N
B
N
Reagents and conditions: (a) SOCl2, DCM, DMF (cat.),
N
NH
O
NH
H
then anisole, AlCl3, DCM, 60%; (b) HNO3, H2SO4,
DCM, 55%; (c) NH3, iPrOH, 100 oC, sealed tube, 52%;
(d) Boc2O, pyridine, THF, 62%; (e) NBS, AIBN, CCl4,
87%; (f) NaOAc, DMF, 23%; (g) B2pin2, KOAc,
Pd(dppf)Cl2, 1,4-dioxane, 97%; (h) NaOH, MeOH, then
HCl, H2O, THF, 45%; (i) Fe(0), NH4Cl, EtOAc, H2O,
then 14, AcOH, 29%.
N
H
N
H
F
3
4
Figure 2. Structures of flubendazole (3) and AN8799 (4)
While this compound was found to exhibit good in vitro
antiparasitic activity and selectivity relative to effects on
mammalian cells, we discovered that it was only active
in in vivo models of LF following sub-cutaneous
administration. This limitation was understood on the
basis of the pharmacokinetic properties of 4,
specifically that it was subject to efflux via the P-
glycoprotein transport (Pgp), limiting its oral
bioavailability. We describe here subsequent efforts to
explore ketone-linked benzoxaborole-benzimidazole
hybrids designed to overcome Pgp efflux.
Starting with 3-bromo-4-methylbenzoic acid (5),
conversion to the acid chloride followed by Friedel-
Crafts acylation of anisole afforded the diaryl ketone
(6). Nitration, followed by displacement of the 4-
methoxy substituent provided the nitroaniline (8), which
was protected as the di-tertbutyl carbonate (9).
Benzylic bromination with NBS/AIBN followed by
displacement with sodium acetate gave the key
intermediate aryl bromide (11), which was converted to
the benzoxaborole (13) via palladium mediated
borylation, hydrolysis and ring closure. Reduction of
the nitro group and condensation with the isothiourea
derivative (14) completed the synthesis of the ketone
hybrid linked via C(5) of the benzimidazole and C(6) of
the benzoxaborole (15). Additional benzoxaborole
The synthesis of ketone-linked benzimidazole-
benzoxaborole hybrids was based on the well-known
route to flubendazole and close analogs.29 For example
the optimized route to the 6-oxobenzoxaborole isomer
is shown in Scheme 1.
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isomers were prepared in similar sequences starting
from the appropriate bromotoluic acids shown in
Scheme 2.
amide linker, as this has been shown in the literature to
1
2
3
4
5
6
7
8
34
be
a
contributor to recognition by Pgp.33,
Consequently, we were encouraged to find that both 15
and 20 exhibited improvement in permeability in an
MDCK-MDR1 cell monolayer assay, but we were
disappointed to find that this did not translate into
significantly improved exposure following oral
administration to gerbils (Table 2). Metabolic stability
in both gerbil and human microsomes was good, with
Clint values < 15 L/min/mg for both compounds,
suggesting that rapid metabolism was not responsible
for the poor exposure. We have observed in other
benzoxaborole classes that 3,3-dimethyl substituted
analogs frequently provide improved pharmacokinetics
over 3,3-unsubstituted analogs,22 hence we prepared
these analogs of 15 and 20. We were disappointed to
find that the 5-linked analog 22 was poorly selective
and the 6-linked analog 23 was only weakly active.
Encouragingly, both compounds exhibited significantly
improved permeability, suggesting that continued effort
in the ketone-linked series was warranted. As had been
observed in the amide-linked series, increasing the
length of the linker between the benzoxaborole and
benzimidazole cores as in 32 and 33 resulted in high
potency in the G2/M arrest assay, rendering these
compounds unattractive to progress forward due to lack
of selectivity.
Additionally,
hybrid
molecules
where
the
benzimidazole ring was linked ring via C(4), C(5) or
C(7) of the benzoxaborole ring (19 – 21) were prepared
in an analogous manner from appropriately substituted
bromotoluic acids (16 - 18). Also prepared were several
compounds containing substituents on the benzoxborole
ring (22 – 30) and two analogs where the linker between
the benzimidazole and benzoxaborole ring was
extended by two or three atoms (31, 32), as we had
observed that ether, thioether or simple alkyl linkers had
provided very potent macrofilaricides (unpublished
data).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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Scheme 2. Synthetic Approach to 4-, 5- and 7-
Oxobenzoxaborole-Benzimidazole Hybrids.
O
B
O
O
4
Br
CO2H
HO
O
N
NH
N
H
16
19
O
O
5
CO2H
O
N
O
NH
B
N
H
Br
17
HO
20
Moving the ketone linker to the 4-position of the
benzoxaborole ring provided 19, which was less potent
in the O. volvulus molting assay but exhibited good
permeability. Much more encouraging data was
obtained for the hybrid linked via the 7-position of the
benzoxaborole, 21, which showed very good activity in
the O. volvulus molting assay (IC50 = 100 nM), low
activity in the G2/M arrest assay (IC50 > 38 M) and
very high permeability (Papp = 56.6 x 10-6 cm/sec). We
hypothesize that the high permeability of this isomer is
the result of an intramolecular hydrogen bond between
the B-OH and ketone carbonyl which effectively masks
this hydrogen bond donor. This hypothesis is supported
by the observation that other 7-linked ketones (26 – 31)
prepared in the project showed similarly high
permeability.
OH
7
Br
O
O
B
O
CO2H
O
N
NH
N
H
18
21
As summarized in Table 1, we were encouraged to
find that the initial ketone analogs prepared, namely 15
(6-linked) and 20 (5-linked) were quite active in an O.
volvulus molting assay we used as a primary indicator
31
of antiparasitic activity,30,
active a G2/M arrest
and were only weakly
32
indicative of interaction with
mammalian tubulin. As described above, our hypothesis
was to reduce Pgp efflux liability through elimination of
the hydrogen-bond donor associated with the N-H of the
Table 1. In vitro Data for Ketone-Linked Benzoxaborole–Benzimidazole Analogs
HO
7
O
B
O
6
O
O
N
n
NH
5
4
3
N
H
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Clint in microsomes
1
2
3
O.v IC50
G2/M IC50
MDCK-MDR1 Papp
(A-B,  106 cm/sec)
Link
atom
(L/min/mg)
ID
n
R
(M)
(M)
4
5
gerbil
human
6
7
8
9
3
NA, flubendazole
0.004
0.118
1.59
0.67
12.3
>100
9.8
<4
8.25
NT
11.7
NT
NT
NT
NT
<4
NT
<4
15.6
6.0
15
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
6
4
5
7
5
6
6
6
7
7
7
7
7
7
6
6
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2
3
--
--
5.56
<4
28.3
11.7
56.6
26.2
20.7
NT
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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--
0.112
0.10
5.90
NT
NT
NT
<4
--
38.4
0.28
>100
>100
>100
30.3
22.0
>100
5.6
3,3-Me2
3,3-Me2
3-Me (R*)
3-Me (S*)
4-F
0.01
>1.0 (note 1)
>1.0 (note 2)
0.04
15.5
21.7
32.0
NT
11.6
<4
11.1
<4
0.02
5-F
0.27
NT
<4
NT
<4
6-F
1.31
3-Me (R*)
3-Me (S*)
4-Cl
0.10
57.2
34.3
28.0
16.0
NT
<4
<4
0.11
12.2
11.6
0.46
0.02
<4
<4
0.03
26.7
NT
7.63
NT
3,3-Me2
3,3-Me2
0.29
NT
Note 1. 0% inhibition at 1 M. Note 2. 2% inhibition at 1 M.
Most importantly, 21 was found to exhibit very good
exposure when dosed orally to gerbils (Table 3). We
observed that 21 provided very high blood
concentrations that were maintained for several hours
following oral dosing and that exposure was dose
proportional up to 100 mg/kg.
concentrations achieved at these doses were well in
excess of the O. volvulus IC50, a requirement for in vivo
activity that we had hypothesized based on earlier work
in the amide-linked series. Finally, we observed that
once daily dosing of 21 to gerbils over seven days was
well tolerated and no accumulation of compound was
observed over this time period, providing confidence to
progress this compound to a series of in vivo efficacy
In addition, the
assays
in
infected
gerbils.
Table 2. Pharmacokinetic Properties of Benzoxaborole-Benzimidazole Analogs in Mongolian Gerbils.
AUC0-24
Bioavailability
(%F)
Compound
Dose
Route
Cmax (g/mL)
(hg/mL)
15
15
20
20
21
21
2
10
2
IV
PO
IV
2.26
0.27
2.00
0.48
1.56
5.75
0.88
0.79
1.16
0.99
5.95
61.7
18%
17%
10
2
PO
IV
10
PO
~100%
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26
26
30
30
2
10
2
IV
PO
IV
10.9
1.69
7.58
14.0
18.6
23.5
14.6
141
1
2
3
4
24%
10
PO
~100%
5
6
7
8
Table 3. Pharmacokinetic Properties of 21 in Mongolian Gerbils by IV, PO and SC Routes.
9
Cmax
(µg/mL)
Clint
(mL/hr/kg)
AUC0-last
(hr-µg/mL)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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40
41
42
43
44
45
46
47
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49
50
51
52
53
54
55
56
57
58
59
60
Route
Dose
Vdss (mL/kg)
%F
IV
SC
PO
PO
PO
PO
2
10
10
30
60
100
1.56
3.13
5.75
17.2
26.3
34.5
289
NA
NA
NA
NA
NA
3188
NA
NA
NA
NA
NA
5.95
35.7
61.7
196
361
479
NA
100
100
NC
NC
NC
NA = Not applicable. NC = Not calculated
For our in vivo model, gerbils were infected by
injecting B. pahangi third-stage larvae (L3) that were
subsequently allowed to develop to adult worms over
several months. Once stable infections had been
established, 21 was administered as a suspension via
once-daily oral gavage at a dose of 100 mg/kg for either
7, 14 or 28 days. All animals were maintained until day
63 after start of dosing, at which time adult worms were
recovered from the peritoneal cavity and microfilariae
were quantified in blood samples. Flubendazole (5
mg/kg, SC x 5 days) was included as a positive control
in this study.
3). As anticipated, flubendazole given SC worked as
expected, with no worms recovered from this positive
control group. Differential sensitivity of male and
female Brugia was also observed when infected jirds
were given oral doses of an amorphous solid dispersion
formulation (ASD) of flubendazole.35 Female worms
were reduced by 52%-93% in animals dosed with 0.2 –
15 mg/kg ASD flubendazole for 5 days. Similar to
ASD flubendazole, the extended exposure of worms to a
tubulin inhibitor such as 21 may cause more extensive
damage to female worms than male worms.
To further explore this possibility, we progressed 21
to more extensive evaluation in additional in vivo
efficacy models that included evaluation of worm
damage through transmission electron microscopy
(TEM) studies of worms recovered from jirds. These
studies will be reported in due course.
We were encouraged to find that 21, when dosed for
14 or 28 days, was 99% effective in killing female
worms, although effects on male worms was less
Interestingly, very little effect was
observed when 21 was dosed for only 7 days. (Figure
impressive.
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1
2
3
4
5
6
7
8
Avg Female Worms
Avg Male Worms
40
35
30
25
20
15
10
5
25.2
22.8
9
21.8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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32
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13.0
11.4
11.1
0.6
0.1
0.0 0.0
0
21 (PO)
21 (PO)
100 mg/kg
14 days, QD
21 (PO)
100 mg/kg
7 days, QD
Flubendazole (SC) Vehicle (PO)
100 mg/kg
28 days QD
10 mg/kg
5 days, QD
14 Days QD
Figure 3. In vivo efficacy of 21 in a Brugia pahangi model.
Supporting Information.
pharmacokinetics studies. CF, CAB, KCL, BMS and NT
conducted in vitro and in vivo biological assays, which
were designed and coordinated by YRF, CSL, FR, KJ, SL
and JAS. The manuscript was edited by RTJ, DSC, YRF,
PWB, SL, CAB and JAS.
File 1: Synthesis methods for benzimidazole-
benzoxiborole hybrids and methods for testing compounds
in larval molt assay and in vivo studies.
AUTHOR INFORMATION
Funding Sources
Corresponding Author
There are no competing financial interests to declare. The
authors would like to thank the Bill & Melinda Gates
Foundation for funding of this program through awards to
Anacor (Contract Number 23629) and the University of
California San Francisco (OPP1017584).
Robert T. Jacobs, rtjacobs7158@gmail.com
Present Addresses
Robert T. Jacobs, PhD, Jacobs Scientific Consulting, LLC,
1849 Old College Circle, Wake Forest, NC 27587
Author Contributions
ACKNOWLEDGMENT
RTJ, DSC, YRF and JAS wrote the manuscript and
contributed equally to the design and execution of the
project. DSC, TA, RTJ and JJP designed and coordinated
synthesis of the compounds. RTJ, KJ, YRF, CSL, EE, FR,
JJP, RS, JM, AH, JAS and SL provided scientific
leadership and management of the project. PWB designed,
coordinated and interpreted in vitro and in vivo
We thank Richard Elliott and Ken Duncan of the Bill &
Melinda Gates Foundation for their support and guidance,
Jason Zhang and his team at Acme Bioscience, Inc. for
their contributions to the medicinal chemistry and Chris
Franklin for his help with the graphics.
Saunders: 2014; pp 737-765.
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Ichimori, K.; King, J. D.; Engels, D.; Yajima, A.;
1.
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