Antileishmanial bis-arylimidamides: DB766 analogs modified in the linker region and bis-arylimidamide structure-activity relationships

Article abstract of DOI:10.1016/j.bmcl.2012.06.037

Analogs of the lead antileishmanial bis-arylimidamide DB766 were prepared that possess unsymmetrical substitutions on the diphenylfuran linker, and an additional compound was synthesized that contains isopropoxy groups meta to the central furan. These agents all displayed nanomolar in vitro potency against intracellular Leishmania with selectivity indexes >100 compared to J774 macrophages. While the unsymmetrical analogs were toxic to mice when given ip at 30 mg/kg/day, the compound bearing the meta isopropoxy groups was well tolerated by mice and showed activity in a murine model of visceral leishmaniasis when administered ip at 30 mg/kg/day for five days.

Full text of DOI:10.1016/j.bmcl.2012.06.037

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6806–6810
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Antileishmanial bis-arylimidamides: DB766 analogs modified in the linker
region and bis-arylimidamide structure–activity relationships
Carolyn S. Reid a, , Abdelbasset A. Farahat b,c, , Xiaohua Zhu a, Trupti Pandharkar a, David W. Boykin b,
,
⇑
Karl A. Werbovetz a,
⇑
a Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
b Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA
c Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 16 June 2012
Analogs of the lead antileishmanial bis-arylimidamide DB766 were prepared that possess unsymmetrical
substitutions on the diphenylfuran linker, and an additional compound was synthesized that contains
isopropoxy groups meta to the central furan. These agents all displayed nanomolar in vitro potency
against intracellular Leishmania with selectivity indexes >100 compared to J774 macrophages. While
the unsymmetrical analogs were toxic to mice when given ip at 30 mg/kg/day, the compound bearing
the meta isopropoxy groups was well tolerated by mice and showed activity in a murine model of visceral
leishmaniasis when administered ip at 30 mg/kg/day for five days.
In dedication to Professor Timothy
Macdonald for his many contributions to
the fields of Organic and Medicinal
Chemistry
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Leishmania
Drug discovery
Leishmaniasis is a disease that manifests in several forms, the
two most common being a life-threatening visceral form and a
cutaneous variety. Approximately one quarter of the estimated
two million new cases of leishmaniasis occurring annually are of
the visceral form, with the majority of these cases occurring on
the Indian subcontinent, Sudan, and Brazil.1 About three quarters
of the new leishmaniasis cases are of the cutaneous variety, with
most occurring in the Middle East, Afghanistan, Brazil, and Peru.1
This spectrum of disease is caused by species of the genus Leish-
mania, a protozoan parasite. Regarding the worldwide burden in-
flicted by protozoan parasitic diseases, leishmaniasis is second
only to malaria in terms of mortality and the total number of
cases.2,3 Although several classes of antimalarial drug candidates
are in various stages of preclinical development or in clinical tri-
als,4 the same cannot be said for antileishmanial drug candidates.
While the treatment of visceral leishmaniasis on the Indian sub-
continent has improved over the last few years due to the registra-
tion of paromomycin5 and the demonstration of the efficacy of
single dose liposomal amphotericin B,6 no new chemical entities
are in clinical trials against leishmaniasis, and few new candidates
are in the development pipeline.7 Considering the limitations of
the existing drugs, the dearth of new antileishmanial drug candi-
dates requires renewed efforts to find small molecules capable of
meeting the unmet needs in antileishmanial chemotherapy and a
restored commitment to support these important drug discovery
and development efforts.
As part of our efforts to identify new antileishmanial drug can-
didates, compounds were prepared inspired by diamidine antimi-
crobials that showed exceptional in vitro potency against
intracellular Leishmania.8 These molecules were originally termed
reversed amidines because, unlike pentamidine and other diami-
dine antimicrobials, their imino group is bound to an anilino nitro-
gen instead of being directly attached to an aromatic ring. This
compound class, now known by the more chemically descriptive
name arylimidamides (AIAs), has produced numerous potent
antileishmanial molecules,8–10 including the hydrochloride salts
DB766 and DB1852 (see Fig. 1 for structures) and their correspond-
ing mesylate salts that were considered as candidates for preclini-
cal development against visceral leishmaniasis.11,12 All of the AIAs
reported thus far are symmetrical bis-AIAs (compounds containing
two terminal heteroaromatic groups). Those that advanced the far-
thest as antileishmanial candidates, DB766 and DB1852, possess
isopropoxy and cyclopentyloxy groups ortho to the furan ring of
the diphenylfuran linker. The goals of the present study are to
examine the effects of (1) preparing unsymmetrical bis-AIAs re-
lated to DB766 and (2) positioning the isopropoxy groups of
DB766 meta to the central furan of the linker.
⇑
Corresponding authors. Tel.: +1 404 413 5498; fax: +1 404 413 5505 (D.W.B.);
tel.: +1 614 292 5499; fax: +1 614 292 2435 (K.A.W.).
E-mail addresses: dboykin@gsu.edu (D.W. Boykin), werbovetz.1@osu.edu (K.A.
Werbovetz).
These two authors equally contributed to this work.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.06.037

C. S. Reid et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6806–6810
6807
2HCl
2HCl
O
O
O
O
NH
HN
NH
HN
O
O
N
N
N
N
H
H
H
H
N
N
N
N
DB766
DB1852
Figure 1. Structures of DB766 and DB1852.
For the preparation of unsymmetrical DB766 analogs (shown in
Scheme 1), the synthesis of the key intermediate 1-bromo-2-iso-
propoxy-4-nitrobenzene (1) was achieved starting with the bro-
mination of commercially available 2-amino-5-nitrophenol using
sulfamic acid and sodium nitrite in aqueous HBr to form 2-bro-
mo-5-nitrophenol in modest yield.13 The phenolic group was then
alkylated with 2-iodopropane in the presence of cesium carbonate/
acetone to give 1 in 55% overall yield. Stille coupling between 1 and
2-(tributylstannyl)furan (2)14 in the presence of catalytic Pd(PPh3)4
in anhydrous 1,4-dioxane followed by bromination of the interme-
diate with NBS in DMF afforded nitrophenylfuran 3 in good yield.
Aryl boronate esters 4a–d were obtained in low yields from the
reaction of the corresponding commercially available 1-bromo-4-
nitrobenzenes, bis(pinacolato)diboron, potassium acetate and cat-
alytic PdCl2(dppf) in DMSO.15 Suzuki coupling between 3 and 4a–d
in the presence of catalytic PdCl2(dppf) or Pd(PPh3)4 gave the de-
sired unsymmetrical dinitrophenylfurans 5a–d in excellent yields.
Reduction of 5a–d through catalytic hydrogenation yielded the
corresponding diamino intermediates, which then reacted with
S-(2-naphthylmethyl)-2-pyridylthioimidate hydrobromide in eth-
anol/acetonitrile to provide target compounds 6a–d.8,14
The synthesis of a DB766 analog containing isopropoxy groups
meta to the furan attachment point (shown in Scheme 2) required
the preparation of key intermediate 4-iodo-2-isopropoxy-1-nitro-
benzene (7). Toward this end, 3-iodophenol was nitrated with
sodium nitrite in glacial acetic acid to form 5-iodo-2-nitrophenol
in low yield.16 The alkylation of the phenolic group was carried
out under conditions similar to those described above to afford 7
in almost quantitative yield. 2,5-Bis(tri-n-butylstannyl)furan (8)
was prepared from furan via lithiation with n-butyllithium and
O
O
Br
B
O
O
R
a, b
c
Sn(Bu)3
O
Br
O
O2N
NO2
NO2
1
2
3
4a-d
2CH3SO3H
O
R
O
R
O
4-6a
: R = H
4-6b: R = F
d, e
O
4-6c: R = CH3
4-6d: R = OCH3
NH
O2N
NO2
HN
HN
NH
5a-d
6a-d
N
N
Scheme 1. Reagents and conditions: (a) 1,4-dioxane, Pd(PPh3)4, reflux, overnight (68–85%); (b) DMF, NBS, rt, overnight (72–83%); (c) DMSO, KOAc, PdCl2(dppf), 100 °C,
overnight or Pd(PPh3)4, Na2CO3, toluene/MeOH/water, reflux, overnight (56–69%); (d) H2, Pd/C, EtOAc, EtOH (85–96%); (e) (i) S-(2-naphthylmethyl)-2-pyridylthioimidate
hydrobromide, EtOH/MeCN, rt; (ii) CH3SO3H, CH2Cl2 (41–55%).
Br
O
O
a
(Bu)3Sn
Sn(Bu)3
O
O
O
O2N
NO2
NO2
7
8
9
2CH3SO3H
O
O
O
b, c
NH
HN
HN
NH
N
10
N
Scheme 2. Reagents and conditions: (a) 1,4-dioxane, Pd(PPh3)4, reflux, overnight (41–55%); (b) H2, Pd/C, EtOAc, EtOH; (c) (i) S-(2-naphthylmethyl)-2-pyridylthioimidate
hydrobromide, EtOH/MeCN, rt; (ii) CH3SO3H, CH2Cl2 (55%).

6808
C. S. Reid et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6806–6810
Table 1
In vitro biological activity (nM) of AIAsa
Compound
IC50 versus intracellular L. donovani
IC50 versus intracellular L. amazonensis
IC50 versus J774 macrophages
6a
6b
6c
6d
10
DB766
5.3 1.2
150 30
21 18
7.0 1.7
26 14
36 5b
93 28
190 120
49 19
11,000 1000
27,000 5000
13,000 3000
14,000 2000
10,000 2000
Not tested
110 50
290 80
87 15b
Amphotericin B
podophyllotoxin
45
8
120 30
Not tested
Not tested
Not tested
18 14
a
Mean standard deviation of at least three determinations.
Values taken from Ref. 11.
b
subsequent treatment with tri-n-butyltin chloride as previously
described.17 Stille coupling between 7 and 8 provided the corre-
sponding 2,5-bis(4-nitrophenyl)furan 9, which was reduced by cat-
alytic hydrogenation to yield the corresponding diamine. This
diamine then reacted with two equivalents of S-(2-naphthyl-
methyl)-2-pyridylthioimidate hydrobromide in ethanol/acetoni-
trile to yield target compound 10.
tremors. Because of the high toxicity of these compounds at the
30 mg/kg dose and because the lead compound DB766 required a
30 mg/kg ip dose to show good in vivo antileishmanial efficacy,
compounds 6a–d were not tested at lower doses. Compound 10,
on the other hand, was well tolerated when given ip at 30 mg/kg/
Compounds 6a–d and 10 were evaluated for their activity
against both L. donovani and L. amazonensis intracellular amastig-
otes (please see Table 1) using methods that have been described
previously.18,19 Each of these target compounds displayed IC50 val-
ues in the nanomolar range against Leishmania parasites. The
in vitro potency of these molecules was similar to that of ampho-
tericin B, the clinical antileishmanial drug exhibiting the greatest
in vitro activity, and was also in the range of that reported for
the AIA lead compound DB766 (IC50 values of 36 and 87 nM against
L. donovani and L. amazonensis intracellular amastigotes, respec-
tively).11 Consistent with our previous observations for other AIAs,
the target compounds were generally more potent against intracel-
lular L. donovani than against L. amazonensis.10,11 Comparing the
four unsymmetrical AIAs (6a–d), the steric bulk of the R group
did not have a major effect on potency, as both compounds 6a
and 6d displayed single digit nanomolar IC50 values against intra-
cellular L. donovani and possessed IC50 values ꢀ100 nM against L.
amazonensis. The electronics of the R group appeared to have a
greater influence on potency, as fluorinated congener 6b was the
least active in this series against both Leishmania species. Symmet-
rical AIA 10 displayed an IC50 value against L. donovani similar to
that reported for DB766 and in the range of the IC50 values ob-
served for 6a–d. Compound 10 was less active than DB766 and
the unsymmetrical AIAs against L. amazonensis, however. Dose–re-
sponse curves for 6a and 10 in the intracellular Leishmania assays
are given in Figure 2. In terms of mammalian cell toxicity, com-
pounds 6a–d and 10 exhibited IC50 values from 10,000 to
27,000 nM against J774 macrophages, providing in vitro selectivity
indexes (IC50 vs J774/IC50 vs Leishmania) of 180–2075 against L.
donovani and 115–265 against L. amazonensis.
Considering the outstanding potency of these AIAs against intra-
cellular Leishmania and their in vitro selectivity against intracellular
parasites, 6a–d and 10 were evaluated for toxicity to female BALB/c
mice to determine an appropriate dose for in vivo antileishmanial
efficacy assays (all animal protocols used in the course of this work
were approved by the Institutional Animal Care and Use Committee
of The Ohio State University; 6a–d and 10 were dissolved in water
for in vivo administration). Compounds 6a–d were toxic to the mice
when administered at an ip dose of 30 mg/kg/day. Mice given a sin-
gle 30 mg/kg ip dose of 6a died within 24 h of compound adminis-
tration; necropsy of these animals revealed signs of severe toxicity
to the gastrointestinal tract (black and swollen stomach, intestine
and colon). Animals receiving 6b–d were euthanized after either
the second or third dose of compound due to hyperactivity and
Figure 2. Dose–response curves showing the susceptibility of intracellular Leish-
mania to 6a and 10. Experiments pictured above were performed in triplicate as
indicated in Table 1, with the results of a representative experiment shown. Panel A,
susceptibility of L. donovani and L. amazonensis to 6a. In the L. donovani assay, the
uninfected control average absorbance was 0.11 and the infected control average
absorbance was 0.28. In the L. amazonensis assay, the uninfected control average
absorbance was 0.11 and the infected control average absorbance was 0.53. Panel B,
susceptibility of L. donovani and L. amazonensis to 10. In the L. donovani assay, the
uninfected control average absorbance was 0.11 and the infected control absor-
bance average was 0.28. In the L. amazonensis assay, the uninfected control average
absorbance was 0.13 and the infected control average absorbance was 0.54.

C. S. Reid et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6806–6810
6809
containing 5-imidazolyl and 2-pyrrolyl rings were at least an order
of magnitude less active than the corresponding 2-pyridyl com-
pound, while the 4-(2-methylthiazolyl) compound retained the
in vitro (but not in vivo) activity of the corresponding 2-pyridyl
congener.9 Regarding the linker, a bis-AIA with a phenyl linker
was inactive against intracellular Leishmania, but bis-AIAs bearing
4,40-biphenyl and 4,40-diphenyl ether linkers were as potent as the
corresponding bis-AIAs containing a 4,40-diphenylfuran linker.10
Concerning substitution on the diphenylfuran linker, inclusion of
halogen, alkyl or alkoxy groups on the phenyl rings improves po-
tency compared to the diphenylfuran derivative lacking such sub-
stitutions.8,9 The alkoxy groups on the phenyl rings can be quite
large, as the cyclopentyloxy-containing compound DB1852 retains
mid-nanomolar in vitro potency against intracellular Leish-
mania,9,12 but the benzyloxy derivative was 3-fold and sixfold less
potent than DB1852 and DB766, respectively.9 Our present study
indicates that bis-AIAs bearing unsymmetrical substitutions on
the diphenylfuran linker retain the nanomolar antileishmanial po-
tency of their symmetrical bis-AIA counterparts (Table 1).
Of the considerable number of bis-AIAs possessing potent
in vitro activity against intracellular Leishmania, only derivatives
bearing relatively large alkoxy substituents on a diphenylfuran lin-
ker such as DB766, DB1852, and compound 10 are relatively well
tolerated in mice. In a previous report, we examined the in vivo
properties of both DB766 and DB745, a compound identical in
structure to DB766 except that the isopropoxy groups were re-
placed by smaller ethoxy groups.11 DB745 displayed in vitro and
in vivo antileishmanial efficacy similar to DB766 but was signifi-
cantly more toxic to mice, despite the fact that comparable doses
of these compounds resulted in significantly higher exposure for
DB766. Considering that the in vivo toxicity data for compounds
6a–6d, like DB745, fit our structure–toxicity relationship outlined
above, we do not believe that it is justified to sacrifice more ani-
mals to measure the pharmacokinetics of these toxic compounds.
Like the lead compound DB766, its regioisomer 10 displayed no
overt toxicity to mice when given ip at 30 mg/kg/day ꢁ 5, but
was less effective than DB766 at reducing the liver parasite burden
in L. donovani-infected mice (Fig. 3). Previous work showed that
micromolar levels of DB766 and related AIAs accumulate in the
livers of mice after a single dose.11,12 If this is also the case for
10, sufficient compound should be present in the liver to eradicate
the parasites (Fig. 2B). Within hepatic tissue, L. donovani reside
within Kupffer cells, the macrophages of the liver. Since Kupffer
cells comprise only 2% of the liver cell population23 and AIA levels
have not been measured in this cell type, it is possible that 10 and
other AIAs do not reach sufficient concentrations within the para-
sites to eliminate infection. Testing this hypothesis will require the
isolation of Kupffer cells from animals dosed with an AIA and the
determination of compound levels within these cells.
Figure 3. Efficacy of 10 in a murine model of visceral leishmaniasis. Compound 10
and the antileishmanial standard drug miltefosine were administered in five daily
doses to L. donovani-infected BALB/c mice as indicated in the text, then animals
were euthanized and liver parasitemia was determined microscopically. Data are
presented as the percentage reduction of liver parasitemia compared to infected,
untreated control animals. Bars and error bars indicate the means and standard
deviations, respectively, of groups of four animals. ⁄P <0.05 compared to untreated
control.
day for five days. This dosing regimen was thus selected for the
evaluation of 10 in a murine model of visceral leishmaniasis
(Fig. 3). Antileishmanial efficacy was assessed by established meth-
ods in which L. donovani-infected BALB/c mice were treated with
test compound or vehicle daily for five days starting one week post
infection and liver parasitemia was assessed microscopically two
weeks post infection.19 Compound 10 reduced the liver parasite
burden by 32%, whereas the standard antileishmanial drug miltefo-
sine decreased liver parasitemia by 96% when administered orally
at a dose of 10 mg/kg/day ꢁ 5 (Fig. 3). A previous study showed that
the lead AIA DB766 reduced liver parasitemia by 63% when given ip
at a dose of 30 mg/kg/day ꢁ 5.11
AIAs display outstanding in vitro activity against intracellular
Leishmania as demonstrated in previous work8–11 and as shown
in Table 1. We are unaware of another structural class of molecules
that contains as many compounds possessing nanomolar potency
against intracellular Leishmania, although phospholipid analogs,20
arylisoquinolinium salts,21 and cyanines18,22 also exhibit mid-
nanomolar in vitro potency against Leishmania within host macro-
phages. Given the range of bis-AIAs that have been prepared and
tested for activity against intracellular Leishmania in vitro, a de-
tailed structure–activity relationship can now be outlined for these
compounds (Fig. 4). Regarding terminal groups containing a six
membered aromatic ring, 2-pyridyl groups are preferred over phe-
nyl,8 2-pyrimidinyl, or 2-pyrazinyl groups,9 and substitution of the
2-pyridyl terminal group at the para position with a halogen (but
not a methoxy) group reduces potency.9 For AIAs with a 5-mem-
bered heteroaromatic ring as the terminal group, compounds
Despite the potency of the AIAs against intracellular Leishmania
and the favorable distribution of members of this class of com-
pounds, we have thus far been unable to identify an AIA with the
combination of safety and efficacy required to progress to preclinical
Unsymmetrical bis-AIA (R2
When R2 = R3 = o-i-Pr and
either ortho or meta to the
furan, compounds are
active and well tolerated
Compared to compounds with
= o-i-Pr, R3 = H, F, Me,
unsubstituted (R2
= = H)
R3
OMe) are active but toxic
linkers, potency is improved when
R3
R
2 = R3 = halogen, alkyl or alkoxy
R2
NH
NH
R1
O
Activity is optimal
R1
N
N
H
when R1 = 2-pyridyl or
H
4-(2-methylthiazole)
A phenyl linker abolishes activity; compounds
with unsubstituted diphenylfuran, biphenyl, or
diphenyl ether linkers are active but toxic
Figure 4. Structure–activity map for AIAs against intracellular Leishmania.

6810
C. S. Reid et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6806–6810
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development against leishmaniasis. Thus far, our published work
has focused on bis-AIAs (compounds containing two terminal het-
eroaromatic groups). Initial studies indicate that mono-AIAs also
show activity against intracellular Leishmania and no overt toxicity
to mice. Further work concerning the antileishmanial activity of
mono-AIAs will be reported in due course. Mechanism of action
studies are also in progress to identify the molecular target or targets
of the AIAs in Leishmania. If a specific target can be found for the AIAs,
it may be possible to design inhibitors of this target that retain the
antileishmanial potency of the AIAs while achieving greater
in vivo antileishmanial efficacy and an acceptable toxicity profile.
This may be the best strategy to capitalize on the outstanding
in vitro antileishmanial potency of the AIAs.
Acknowledgment
This work was supported by the Bill and Melinda Gates Founda-
tion. The sponsor had no role in designing the study, in data collec-
tion/analysis, or in the decision to publish this work.
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Supplementary data
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Supplementary data (experimental procedures for the synthesis
of all new compounds, along with the complete chemical charac-
terizations for these molecules) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/
j.bmcl.2012.06.037.
References and notes
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