Structure-activity relationship of new growth inhibitors of Trypanosoma cruzi

Article abstract of DOI:10.1021/jm970860z

Several drugs bearing the 4-phenoxyphenoxy skeleton and other closely related structures were designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the etiologic agent of Chagas' disease. The new class of drugs was envisioned by modifying the nonpolar 4-phenoxyphenoxy moiety replacing selected aromatic protons by different groups via electrophilic aromatic substitution reactions as well as introducing a sulfur atom at file polar extreme. Of the designed compounds, sulfur-containing derivatives were shown to be potent antireplicative agents against T. cruzi. Among these drugs, 4-phenoxyphenoxyethyl thiocyanate (compound 56) proved to be an extremely active growth inhibitor of the epimastigote forms of T. cruzi and displayed an IC₅₀0 of 2.2 μM. Under the same assay conditions, this drug was much more active than Nifurtimox, one of the drugs currently in clinical use to control this disease. This thiocyanate derivative was also a very active inhibitor against the intracellular form of the parasite at the nanomolar level. Other sulfur derivatives prepared also exhibited very potent antiproliferative action against T. cruzi. The presence of a sulfur atom at the polar extreme for this family of compounds seems to be very important for biological action because this atom was always associated with high inhibition values. 4-Phenoxyphenoxyethyl thiocyanate presents very good prospective not only as a lead drug but also as a potential chemotherapeutic agent.

Full text of DOI:10.1021/jm970860z

1540
J . Med. Chem. 1998, 41, 1540-1554
Str u ctu r e-Activity Rela tion sh ip of New Gr ow th In h ibitor s of Tr ypa n osom a
cr u zi
Gu¨endalina M. Cinque,‡ Sergio H. Szajnman,‡ Li Zhong,† Roberto Docampo,† Andrea J . Schvartzapel,‡
J uan B. Rodriguez,*,‡ and Eduardo G. Gros‡
Departamento de Quı´mica Orga´nica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires,
Pabello´n 2, Ciudad Universitaria, 1428 Buenos Aires, Argentina, and Laboratory of Molecular Parasitology, Department of
Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, 2001 South Lincoln Avenue,
Urbana, Illinois, 61801
Received December 29, 1997
Several drugs bearing the 4-phenoxyphenoxy skeleton and other closely related structures were
designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi,
the etiologic agent of Chagas’ disease. The new class of drugs was envisioned by modifying
the nonpolar 4-phenoxyphenoxy moiety replacing selected aromatic protons by different groups
via electrophilic aromatic substitution reactions as well as introducing a sulfur atom at the
polar extreme. Of the designed compounds, sulfur-containing derivatives were shown to be
potent antireplicative agents against T. cruzi. Among these drugs, 4-phenoxyphenoxyethyl
thiocyanate (compound 56) proved to be an extremely active growth inhibitor of the epimastigote
forms of T. cruzi and displayed an IC50 of 2.2 µM. Under the same assay conditions, this drug
was much more active than Nifurtimox, one of the drugs currently in clinical use to control
this disease. This thiocyanate derivative was also a very active inhibitor against the
intracellular form of the parasite at the nanomolar level. Other sulfur derivatives prepared
also exhibited very potent antiproliferative action against T. cruzi. The presence of a sulfur
atom at the polar extreme for this family of compounds seems to be very important for biological
action because this atom was always associated with high inhibition values. 4-Phenoxyphe-
noxyethyl thiocyanate presents very good prospective not only as a lead drug but also as a
potential chemotherapeutic agent.
Ch a r t 1. Current Drugs for the Treatment of Chagas’
Disease and Blood Sterilization
In tr od u ction
It has been estimated that around 16-18 million
people are infected with Trypanosoma cruzi, the etio-
logic agent of American trypanosomiasis (Chagas’ dis-
ease), that 2-3 million individuals have the clinical
symptoms that characterize the chronic stage of Chagas’
disease, and that 45 000 of them die each year.1,2
The parasite has a complex life cycle involving blood-
sucking Reduviid insects and mammals.3 It multiplies
in the insect gut as an epimastigote form and is spread
as a nondividing metacyclic trypomastigote from the
insect feces by contamination of intact mucosa or
wounds produced by the blood-sucking activity of the
vector. In the mammalian host, T. cruzi multiplies
intracellularly in the amastigote form and is subse-
quently released into the blood stream as a nondividing
trypomastigote.3 Transmission of Chagas’ disease could
also occur via the placenta or blood transfusion.3 This
latter mechanism is responsible for the occurrence of
Chagas’ disease in developed countries where the dis-
ease is not endemic.4,5
symptoms and the negativization of parasitemia and
serology.6-8 However, results of treatment trials for
acute infections have not been homogeneous in the
different countries,6,7 probably because of the different
drug sensitivity of the distinct T. cruzi strains. In
addition, both drugs produce serious side effects.9
Treatment duration is another drawback as both drugs
have to be given for prolonged periods. The usefulness
of these drugs for parasitological cure in the indeter-
minate or chronic stage of the infections has also been
questioned; after treatment, serology remains positive
in most cases even when parasitemia is absent.10
Gentian Violet (N-{4,4-bis[[4-(dimethylamino)phenyl]-
methylene]-2,5-cyclohexadien-1-ylidene}-N-methylam-
monium chloride, 3) is the only drug available as a
Two drugs, Nifurtimox (4-[(5-nitrofurfurylidene)-
amino]-3-methylthiomorpholine 1,1-dioxide, 1) and Ben-
znidazole (N-benzyl-2-nitro-1-imidazoleacetamide, 2)
(Chart 1), have been shown to cure at least 50% of recent
infections as demonstrated by the disappearance of
* Corresponding author. Phone: (54 1) 782-0529. Fax: (54 1) 787-
2696. E-mail: J BR@qo.fcen.uba.ar.
‡ Universidad de Buenos Aires.
† University of Illinois at UrbanasChampaign.
S0022-2623(97)00860-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/04/1998

SAR of New Growth Inhibitors of T. cruzi
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9 1541
Ch a r t 2. Chemical Structures of Fenoxycarb and Four
Inhibitors of T. cruzi Proliferation Taken as Lead Drugs
Ra tion a le
The presence of the 4-phenoxyphenoxy moiety at the
nonpolar extreme of a number of selected drugs is
crucial to maintain high growth inhibitory action against
T. cruzi.28-30 Replacement of the phenoxy group by a
methoxy or a benzoyl groups accomplishes a dramatic
impairing in the biological activity.30 The design and
synthesis of the new compounds in this work was
encouraged by the potent antiparasitic activity shown
by compounds 5-816,28,29 taken as lead drugs. There-
fore, a new set of related compounds possessing the
4-phenoxyphenoxy moiety and closely related frames
and a sulfur derivative at the polar end of these drugs
were designed, prepared, and evaluated against the
epimastigote form of T. cruzi which is, by far, the
preferred model to screen new drugs.
chemoprophylactic agent to prevent blood transmission
of Chagas’ disease.11 However, this drug is carcinogenic
in animals, and safety concerns have been raised
against its use (Chart 1).12
Then, bearing in mind that the 4-phenoxyphenoxy
skeleton showed a marked influence in modulating
biological activity, it seemed interesting to replace an
aromatic hydrogen atom by different atoms or groups
in order to see their influence on biological activity.
Employing 4-phenoxyphenol as starting material, the
more attractive positions to carry out this idea were the
ortho position (C-2) to the phenol group at the A ring
for being a favorite site for electrophilic aromatic
substitution and the para position (C-4′) at the B ring
by partial deactivation of the A ring with an electron-
withdrawing group (Scheme 1). Accordingly, bromine,
chorine, nitro, and iodine functions were selected as
suitable units to be introduced at the aromatic ring. It
was decided to use tetrahydropyranyl and allyl ethers
as terminal polar ends due to the high activity previ-
ously presented by these groups.30 Thus, treatment of
4-phenoxyphenol with bromine in toluene in the pres-
ence of tert-butylamine at low temperature led to a
monobromo derivative at the ortho position (compound
10) and a small amount of the dibromo derivative 11.31
Analysis of the 13C NMR spectrum of 10 indicated the
presence of 10 nonequivalent carbons. These data,
together with the corresponding chemical shifts and the
mass spectrum showing the pattern for monobromina-
tion, were quite in agreement with the substitution at
C-2. Drugs 12 and 13 were straightforwardly prepared
by treatment with bromoethyl tetrahydropyranyl ether
and allyl ether, respectively, by a modified Williamson
methodology.32 On the other hand, the presence of an
acetyl group at C-1 (compound 14) deactivated the A
ring in such a way that the preferred site for an
electrophilic aromatic substitution was the C-4′ position.
Therefore, treatment of acetate 14 with aqueous bro-
mine gave rise to monobromo derivative 1533 that when
treated under these modified Williamson conditions
with the appropriate halides brought about acetyl
cleavage producing drugs 16 and 17 in good yields,
respectively. Monochlorophenol derivative 18 was suc-
cessfully prepared in moderate yield treating phenol 9
with N-chlorosuccinimide in refluxing benzene.34 This
product was transformed into drugs 19 and 20 by
reaction of the respective halides. The preparation of
the chloro derivative at the C-4′ position (compound 21)
was achieved via the respective acetate 14 by treatment
with 1-chlorobenzotriazole with moderate yield.35 Trans-
formation of 21 into 22 was carried out by treatment
with allyl bromide. Phenol 9 reacted with 70% nitric
The above findings stress the need of having chemo-
therapeutic and chemoprophylactic agents that are
effective against all strains of T. cruzi and with less or
no side effects than those currently available.12,13
In the present study, we investigated the trypano-
static activity of the lead structures (compounds 4-8)
(Chart 2) which present a dual action, as juvenile
hormone analogues of Chagas’ disease vector Triatoma
infestans14,15 and as potent growth inhibitors of T. cruzi
proliferation.16 J uvenile hormones are crucial com-
pounds for maintaining larval stages and maturation
of the reproductive system in the female.17 These
compounds have been studied as a consequence of the
finding that after treatment of the insects with the well-
known insect growth regulator Fenoxycarb18 (ethyl
N-{2-[(4-phenoxyphenoxy)ethyl]}carbamate, 4), they were
more resistant to infection with T. cruzi.19 Some
modified structures having the 4-phenoxyphenoxy moi-
ety were found later to be more active than Fenoxycarb
against T. cruzi cells. Preliminary studies on the mode
of action of these drugs have provided evidence that they
could be inhibitors of the sterol biosynthetic path-
way.20,21 Very recently, we have found that this class
of inhibitors blocks the sterol biosynthetic pathway at
an early stage.22 Since this pathway is different in T.
cruzi from that present in mammalian cells,23 we
anticipate a lower toxicity of these compounds toward
the host cells. It is interesting to note that sterol
biosynthesis inhibitors have been postulated to be
potential chemotherapeutic agents against Chagas’
disease.23-25
Compound 6, one of the representative members of
our designed drugs and structurally related to Fenoxy-
carb, was a very effective agent against the intracellular
form of the parasite,26 and, as occurs with other
ergosterol biosynthesis inhibitors,25 it exhibited vanish-
ing action to eradicate the nonproliferative trypomas-
tigotes.27
As part of our efforts to improve the antireplicative
activity of these inhibitors against T. cruzi, and in order
to investigate their structure-activity relationship, we
prepared a series of new derivatives structurally related
to our lead drugs (compounds 5-8) and evaluated their
biological activity (Chart 2).

1542 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9
Cinque et al.
Sch em e 1a
a
Reagents: (a) Br2/t-BuNH2, toluene, -70 °C (45%); (b) NCS, benzene, reflux, 48 h (46%); (c) 70% HNO3/AcOH, rt, 15 min (70%); (d)
H2, 10% Pd/C, EtOAc, 3 atm, rt, 1 h (92%); (e) H2SO4/H2O, NaNO2, 0 °C, i. NaI, CuCl, rt (20%); (f) BrCH2CH2OTHP, KOH/DMSO, rt (33%
for 12, 60% for 16, 74% for 19); (g) allyl bromide, KOH/DMSO, rt (88% for 13, 81% for 17, 75% for 20, 68% for 22, 17% for 25, 65% for 27,
80% for 34, 54% for 36, 38% for 38, 79% for 41); (h) Ac2O/py, rt, overnight (63%); (i) Ac2O/py, rt, 16 h (87%); (j) Br2/H2O, rt, 2 h (58% for
15), 1-chlorobenzotriazole, CH2Cl2, rt, 6 d (49% for 21); (k) S2C, CH3COCl, AlCl3, -5 °C, 2 h (26% for 37), S2C, PhCOCl, AlCl3, -5 °C, 2
h (15% for 40); (l) 1-chloro-4-nitrobenzene, DMSO/KOH, CuCl, 70 °C, 16 h (45%); (m) CH3CH2SH, AlCl3, 0 °C, 3 h (91%).
acid in glacial acetic acid36 to give mononitrophenol 23
as the main product in good yield and the 2,6-dinitro
derivative 25 as a side product. Compound 23 on
treatment with allyl bromide was transformed into drug
25. The nitro compound 23 was reduced by catalytic
hydrogenation employing palladium on charcoal as
catalyst37 to afford aminophenol 26, which on reaction
with allyl bromide gave rise to allyl ether 27 as the main
product and the undesired N-alkyl products 28 and 29
as minor components. Compound 26 was converted into
the amide 30 by treatment with acetic anhydride.
Nitration at the C-4′ of 4-phenoxyphenol was performed
employing a nucleophilic aromatic substitution as the
key step. Then, 4-methoxyphenol (compound 31) was
condensed with 4-nitrochlorobenzene in the presence of
cuprous ion38 to give the mononitro derivative 32.
Demethylation of 32 by treatment with mercaptoethanol
and aluminum chloride39 gave free phenol 33, which on
reaction with allyl bromide led to 34 in good yields. The
synthesis of the o-iodo derivative 36 was achieved
employing aminophenol 26 as intermediate.40 Then, on
treatment with sodium nitrite in sulfuric acid followed
by addition of sodium iodide in the presence of cuprous
chloride and further reaction with allyl bromide, 26 was
converted into drug 36 (Scheme 1). Acyl derivatives at
the C-4′ position were carried out via Friedel-Crafts
methodology employing 4-phenoxyphenol (9) as starting
material. This compound when treated with either
acetyl or benzoyl chloride in carbon disulfide using
aluminum chloride as catalyst41 led to the acylated
product at the hydroxyl group as main products in both
cases (compounds 14 and 40, respectively) and the
desired C-4′ acylated compounds 37 and 39 as minor
products. On reaction with allyl bromide, these com-
pounds were converted into drugs 38 and 41 (Scheme
1).
Since compounds with an isoprenic skeleton had
presented potent inhibitory action against T. cruzi
proliferation, it was decided to prepare two drugs
bearing sulfur atoms at their polar ends using geraniol
as the isoprenic source. Then, geraniol (compound 42)
was treated with ethyl chlorothiolformate to give 43 that
after treatment with m-chloroperbenzoic acid led to
epoxy derivative 44. To investigate the influence of the
oxygen atom between the phenyl groups on the biologi-
cal activity, it was decided to replace it by a sulfur atom.
Therefore, phenol (45) was treated with recently pre-
pared benzenesulfinic acid (46) to afford 47 in moderate
yield.42 After reaction with allyl bromide, 47 was
transformed into 48 (Scheme 2).
Some related modification was also contemplated by
adding two extra chlorine atoms at the A ring and
deleting the phenoxy group to determine the control of
this phenoxy unit on biological activity. Then, 2,4-
dichlorophenol (compound 49) was converted into 50
and 51 in the usual way (Scheme 3).

SAR of New Growth Inhibitors of T. cruzi
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9 1543
Sch em e 2a
Sch em e 4a
a
Reagents: (a) ClC(O)SEt/py, rt, 16 h (93%); (b) m-CPBA,
Cl2CH2, 0 °C, 3 h (93%); (c) 60 °C, 1 h (19%); (d) allyl bromide,
KOH/DMSO, rt, 3 h (96%).
Sch em e 3a
a
Reagents: (a) ClTs/py, rt, 4 h (70% for 54, 17% for 55); (b)
KSCN, DMF, 100 °C, 3 h (73%); (c) NaOCH3/CH3OH, rt, 2 h (98%);
(d) Zn/AcOH, 11 °C, 1 h (91%); (e) EtNCO/py, rt, overnight (56%
for 59), ClCOOEt/py, rt, overnight (55% for 60), ClCOOi-Bu/py,
rt, overnight (40% for 61), ClC(O)SEt/py, rt, overnight (44% for
62); (f) KSC(S)OEt/DMSO, 90 °C, 2 h (86%); (g) i. DBU, S2C, DMF,
rt, 20 min, ii. allyl bromide, rt, 30 min (39%).
would show the respective peak at lower fields (∼130
ppm).46 Saponification of 56 with sodium methoxide45
gave rise to the disulfide derivative (compound 57) as
the main product and a small amount of the desired
product, the mercaptane 58. Treatment of this mixture
of products with zinc in boiling acetic acid47 led to pure
compound 58 with excellent yield. Mercaptane 58 was
the common intermediate for the preparation of thiol-
carbonate and thiolcarbamate derivatives. Therefore,
compound 58 reacted with ethyl isocyanate, ethyl chlo-
roformate, isobutyl chloroformate, and ethyl chlorothi-
olformate to give compounds 59, 60, 61, and 62,
respectively, in moderate yields. To study the influence
of an extra sulfur atom, the preparation of xanthate
derivatives was the second modification considered by
replacing the oxygen atom of the carbonyl group by a
sulfur atom. Two types of sulfur derivatives were
prepared, the first with the sulfur atom on the same
side of the aliphatic chain (carbon-1) and the second
with it on the opposite position. Therefore, tosylate 54
was treated with potassium O-ethyl xanthate32 to afford
xanthate derivative 63 in good yield. On the other
hand, on reaction with 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) and carbon disulfide48 followed by addition
of allyl bromide, 55 was converted into xanthate 64
(Scheme 4).
a
Reagents: (a) allyl bromide, KOH/DMSO, rt, 3 h (73% for 50),
BrCH2CH2OTHP, KOH/DMSO, rt (28% for 51); (b) n-BuLi, THF,
2 °C (28%).
As the allyl ether group is frequently found in drugs
with high inhibitory action, it was interesting to study
the biological activity of its isomer vinyl ether (com-
pound 52). This drug was easily obtained by treatment
of 5 with n-butyllithium in tetrahydrofuran43 (Scheme
3).
Another structural variation was the replacement of
the oxygen atom at carbon-1 of the aliphatic chain by a
sulfur atom, giving rise to a series of thiolcarbamate,
thiolcarbonate, and xanthate derivatives, to study their
influence on the biological activity. The synthesis of
analogues of compounds 5-8 having a sulfur atom at
the polar end was carried out employing as starting
material the readily available alcohol 53, which was
straightforwardly prepared from 4-phenoxyphenol.15
Therefore, alcohol 53 was treated with tosyl chloride to
afford the expected tosylate 54 with good yield and the
undesired chloride derivative (compound 57) as a side
product (Scheme 4). Tosylate 54 was transformed into
the thiocyanate derivative 56 by treatment with potas-
sium thiocyanate44 in N,N-dimethylformamide at 100
°C. Thiocyanates are able to undergo thermal rear-
rangements under these conditions,45 but no formation
of the undesired isothiocyanate product was detected.
Analysis of the 13C NMR spectrum for compound 56
showed a signal corresponding to the thiocyanate group
at 113.47 ppm, which agreed perfectly with the single
formation of this compound.46 Alkyl isothiocyanates
Since preliminary biological assays had indicated the
strong influence of a sulfur atom on biological activity,
especially the thiocyanate group, it was decided to
prepare a set of closely related compounds so as to find
an optimal structure. It was interesting to assess the
influence of the aliphatic chain length on biological
activity by increasing it in one carbon. This transfor-
mation was carried out from the readily available
alcohol 65,29 which was treated with tosyl chloride to

1544 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9
Cinque et al.
Sch em e 5a
Ta ble 1. Growth Inhibition against T. cruzi (Epimastigotes)
compd
IC50 (µM)
compd
IC50 (µM)
1, Nifurtimox
8.6
67
85
5
13
17
20
25
34
38
43
48
51
56
60
62
64
69
74
79
221
182
>250
>250
185
230
300
298
324
93
12
16
19
22
30
36
41
44
50
52
59
61
63
67
71
76
143
>250
97
91
>330
>380
282
>440
17.0
19.1
41.9
3.5
2.2
15.1
37.7
96.1
3.9
8.1
13.4
121
282
ethanol. A control without drug was performed with
each group that was tested.
To calculate percent inhibition, the following formula
was used:
(∆Ad x 100)
100 -
) percent inhibition
∆Ac
where ∆Ac and ∆Ad are the differences in the absorbance
of control cultures and drug-treated cultures, respec-
tively, at the beginning and at the end of the experi-
ment. The maximum amount of solvent used (1%
ethanol) did not have any significant effect on the
epimastigote growth. The values of IC50 were estimated
by linear and polynomial regression. The results are
presented in Table 1.
a
Reagents: (a) ClTs/py, rt (60%); (b) KSCN, DMF, 100 °C, 3 h
(87% for 67, 47% for 69); (c) BrCH2CH2OTHP, KOH/DMSO, rt
(55% for 71, 65% for 76); (d) PPTs, MeOH, rt (82% for 72, 77% for
77); (e) ClTs/py, rt (82% for 73, 63% for 78); (f) KSCN, DMF, 100
°C (70% for 74, 52% for 79).
give 66, followed by nucleophilic displacement with
potassium thiocyanate to give 67. An episulfide group
was also attached to the same chain length by reaction
of epoxide 6829 with potassium thiocyanate49 to give 69
(Scheme 5). To study the influence of the spacial
alignment of the terminal phenyl group, a slight modi-
fication at the aromatic skeleton was also considering
by replacing the phenoxy moiety by a benzyloxy and
benzyl group keeping the thiocyanate function as the
polar end. Therefore, employing 4-(benzyloxy)phenol
and 4-benzylphenol (compounds 70 and 75, respectively)
as starting materials, these compounds were trans-
formed into tetrahydropyranyl derivatives 71 and 76,
which following a similar method as depicted for 56
were converted into thiocyanates 74 and 79 in good
yields (Scheme 5).
Experiments on the intracellular form of the parasite
were conducted on T. cruzi-infected L6E9 myoblasts as
described before.26
Confluent cell myoblast cell monolayers were pre-
pared on 0.9- × 0.9-cm coverslips in tissue culture
chambers (three coverslips per treatment). Myoblasts
was trypsinized and counted in a Neubauer hemacy-
tometer. The same amount of cells was inoculated in
each chamber. The monolayers were washed three
times with phosphate-buffered saline (PBS) at 37 °C
after 4 h. Some monolayers were exposed to a suspen-
sion of tissue culture-derived trypomastigotes in DMEM-
10% FBS (1 mL/chamber). The final concentration of
trypomastigotes was calculated based on a ratio of 8:1
parasites:L6E9 cells. The parasites were allowed to
internalize within the myoblast for 24 h. At this time,
a set T. cruzi-infected cultures was fixed and stained
with Giemsa and was designated as the 24-h control
culture. The media from the remaining slides were
removed, and fresh DMEM-10% FBS alone (control) or
containing drug 1 or 56 was added to the cultures. After
a further 24 h of incubation at 37 °C, a set of T. cruzi-
infected cultures (untreated control and drug-treated)
was fixed and stained with Giemsa. Media were
removed from other cultures, and again, fresh DMEM-
10% FBS alone (control) or containing compound 1 or
56 was added to the cultures. Cultures were incubated
(37 °C) for a further 24 h after which they were fixed
and stained with Giemsa. Infection was assessed by the
percentage of myoblasts with intracellular parasites and
by the number of parasites present in 100 myoblasts.
Dr u g Scr een in g
Biological assays on epimastigotes were performed as
previously described.30 T. cruzi epimastigotes (Y strain)
were grown in 20-mL screw-cap tubes at 28 °C in a
liquid medium containing brain-heart infusion (37 g/L),
hemin chlorohydrate (20 mg/L) (dissolved in 50% tri-
ethanolamine), and 10% newborn calf serum. The
initial inoculum contained (2-3) × 106 cells/mL (as
determined by counting in a Neubauer chamber) in a
final volume of 1 mL. The concentration of cells was
determined by measuring the absorbance of the culture
medium containing parasites at 600 nm against a blank
with culture medium alone. Each drug was tested at
four different concentrations (1, 10, 50 and 100 µg/mL),
each one in quadruplicate. Drugs were dissolved in

SAR of New Growth Inhibitors of T. cruzi
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9 1545
Ta ble 2. Growth Inhibition of Intracellular T. cruzi by 56
µM. The substitution at the B ring did not result in an
increase in the antiproliferative action; for example,
drugs 17, 22, 34, 38, and 41 presented vanishing
inhibition values. All of them were less active than 5
and 6.
% myoblasts
with parasites
no. of parasites/
drug 56
100 myoblasts (%R)a
none (24 h)
none (48 h)
0.1 (µg/mL)
0.5 (µg/mL)
1.0 (µg/mL)
none (72 h)
0.1 (µg/mL)
0.5 (µg/mL)
1.0 (µg/mL)
none (24 h)
none (48 h)
1.0 (µg/mL)
2.5 (µg/mL)
5.0 (µg/mL)
none (72 h)
1.0 (µg/mL)
2.5 (µg/mL)
5.0 (µg/mL)
26.0 ( 6.0
21.5 ( 1.5
22.0 ( 2.0
18.3 ( 4.8
19.3 ( 4.8
27.5 ( 0.5
15.5 ( 0.5
12.5 ( 0.5
15.0 ( 3.0
38.0 ( 2.0
31.5 ( 1.5
20.5 ( 0.5
20.3 ( 1.3
19.8 ( 2.8
24.8 ( 4.8
16.3 ( 0.8
17.0 ( 0.0
8.3 ( 2.3
91.8 ( 8.25
239.5 ( 32.5
218.0 ( 42.0 (9)
98.0 ( 25.0 (59)
69.3 ( 25.0 (71)
578.5 ( 7.5
The replacement of the oxygen atom between the
phenyl groups by a sulfur (compound 48) produced a
dramatic reduction in biological activity as well as the
isomerization of the allyl ether function (drug 52). It
is worthy to point out the inhibitory action shown when
the terminal phenyl group was replaced by a chlorine
atom in the case of drug 51 which was more active than
the analogues 6 and 20. In contrast, drug 50 was only
moderately active.
238.0 ( 59.0 (59)
124.5 ( 29.3 (79)
63.5 ( 10.5 (89)
85.0 ( 3.0
270.5 ( 6.8
59.3 ( 4.3 (78)
57.0 ( 2.0 (78)
48.0 ( 3.5 (82)
733.5 ( 15.5
Of the designed drugs, thiocyanate 56 was the most
potent drug among the tested compounds. At concen-
trations as low as 37 µM, almost complete growth arrest
took place. The biological activity exhibited for drug 56
was extremely high, with an IC50 of 2.2 µM, 4 times
more active than Nifurtimox, which showed an IC50 of
8.6 µM under similar assay conditions. In addition,
compound 56 was very active to control proliferation of
amastigotes grown on L6E9 myoblasts. At concentra-
tions as low as 0.37 µM, compound 56 was able to inhibit
50% of growth and to reduce the percentage of myo-
blasts containing amastigotes to one-half, while at a
concentration of 18 µM, almost complete eradication of
the parasites took place. In the range of concentrations
used, this compound was not toxic to myoblasts and no
changes in their normal morphology were determined
(Table 2). Nifurtimox was also used as positive control
in the amastigote form of the parasite. This drug
exhibited a similar effect as 56 as a growth inhibitor of
intracellular T. cruzi (Table 3).
85.5 ( 10.0 (88)
76.3 ( 0.8 (90)
28.0 ( 1.0 (96)
a
% R, percent reduction compared to control.
Ta ble 3. Growth Inhibition of Intracellular T. cruzi by
Nifurtimox
% myoblasts
with parasites
no. of parasites/
myoblasts (%R)a
1, nifurtimox
none (24 h)
none (48 h)
1.0 (µg/mL)
2.5 (µg/mL)
5.0 (µg/mL)
none (72 h)
1.0 (µg/mL)
2.5 (µg/mL)
5.0 (µg/mL)
34.50 ( 2.50
16.25 ( 3.75
14.00 ( 0.01
13.50 ( 0.01
13.50 ( 3.00
20.00 ( 0.01
12.50 ( 0.5
7.00 ( 0.01
6.75 ( 0.25
80.25 ( 1.25
155.0 ( 2.5
64.50 ( 1.00 (58)
34.75 ( 1.75 (78)
27.00 ( 9.00 (83)
321.0 ( 21.5
70.50 ( 15.75 (78)
20.25 ( 2.25 (94)
9.25 ( 1.25 (97)
a
% R, percent reduction compared to control.
A minimum of 200 cells were screened in each culture.
The results are presented in Tables 2 and 3.
The rest of the tested compounds presented remark-
able action in inhibiting the proliferation of this para-
site. Consequently, thiolcarbamate 59 and thiolcarbon-
ate 60 were also very active compounds demonstrating
similar inhibition values, with IC50 values of 17.0 and
15.1 µM, respectively. Isobutyl thiolcarbonate 61 even
proved to be a very potent antiproliferative agent
against this parasite and was slightly less active than
59 and 60. The presence of two sulfur atoms, each one
bonded to the carbonyl group, did not result in an
increase of the biological activity, taking dithiolcarbon-
ate 62 as an example. On the contrary, compound 60
was 3 times more active than 62. It is worth pointing
out the activity observed for thiolcarbonates 60 and 61
as compared with carbonates 7 and 8, which had
previously presented IC50 values close to 100 and 25 µM,
respectively.16 The growth inhibitory effect was more
dramatic with the pair of drugs 7 and 60 than with the
pair 8 and 61. In the former case, the activity was
increased by more than 6 times, while in the latter case,
the activity was also increased but to a lesser extent.
Resu lts a n d Discu ssion
Biological assays on the proliferation of the epimas-
tigote form of T. cruzi of this family of compounds were
very promising. Nifurtimox (compound 1) and lead drug
5 were employed as positive controls.
Replacement of the hydrogen atoms at the ortho
position of 4-phenoxyphenol by different functions pro-
duced a slight improvement on the biological activity.
On the other hand, when the substitution was made at
the C-4′ position an important impairing on the inhibi-
tory action was observed, making an exception for drug
16. Contrary to this, as was previously noticed,30 in this
study the tetrahydropyranyl ether was more active than
the allyl ether compared with the same nonpolar
residue. For example, the pairs of drugs 12 and 13, 16
and 17, 19 and 20 exhibited a variable degree of
activities favoring the tetrahydropyranyl ethers. Com-
pounds 12 and 16 proved to be very active compounds
(IC50 of 67 and 85 µM, respectively) and more active
than lead drug 6 (IC50 138 µM).30 From the analysis of
Table 1, it can be deduced that increments in the atomic
size of the substituent provoked improvements on
biological activity. Thus, allyl ether 36 was found to
be more active than 13, and this compound was more
active than 20 (IC50 of 91, 182, and >250 µM, respec-
tively). Compound 20 exhibited almost the same inhibi-
tory action as 5 (IC50 221 µM). The acetamido derivative
30 was also a very active compound with an IC50 of 97
Although xanthates 63 and 64 were not so active as
the rest of this family of compounds, it is interesting to
point out that the biological activity exhibited for
O-ethyl xanthate 63, in which the sulfur atom is at
carbon-1, compared with the activity observed for its
analogue 64. Compound 63 is 2-fold more active than
64. Thus, replacement of the carbonyl group by a
thiocarbonyl unit did not produce any improvement in
the biological activity, but when the sulfur atom is not

1546 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9
Cinque et al.
visualized by 254-nm UV or by immersion into an ethanolic
solution of 5% H2SO4.
Elemental analyses were performed by UMYMFOR (Fac-
ultad de Ciencias Exactas y Naturales, CONICET). The
results were within (0.4% of the theoretical values except
where otherwise stated.
at carbon-1, the biological activity substantially de-
creased. The increment of chain length in 67 did not
improve the biological activity. Although 67 was ex-
tremely active with an IC50 of 3.5 µM, it was less active
than its analogue 56. The presence of an episulfide at
the polar extreme also produced a very active compound,
as was the case of 69 with an IC50 of 3.9 µM. Com-
pounds 74 and 79 were very active drugs, and the
presence of the thiocyante group certainly improved the
biological activity compared with their precursor tet-
rahydropyranyl ethers 71 and 76, which were moder-
ately active compounds.
The results presented in this work indicate the strong
influence of the sulfur atom on the biological activity.
The biological activity exhibited for thiocyanate 56 is
quite encouraging. This drug was almost 4 times more
active than the well-known trypanocidal agent Nifur-
timox. Moreover, the presence of the thiocyanate moiety
itself does not ensure ultrapotent inhibitory action;
contrarily, the nonpolar residue bonded to this unit has
a strong influence on biological activity.
In conclusion, compound 56 and closely related com-
pounds in which the thiocyanate or episulfide group is
present as polar ends represent an interesting example
of a new class of drugs to control proliferation of T. cruzi
cells that were rationally designed and prepared. Stud-
ies on the mechanism of action of this drug, as well as
modifications in the skeleton of compound 56, keeping
the thiocyanate moiety, are currently being pursued in
our laboratory.
2-Br om o-4-p h en oxyp h en ol (10) a n d 2,6-Dibr om o-4-
p h en oxyp h en ol (11). To a solution of 98% tert-butylamine
(240 mg, 3.3 mmol) in anhydrous toluene (25 mL) cooled to
-30 °C and under nitrogen atmosphere was added bromine
(80 µL, 1.54 mmol) dropwise, and the mixture was stirred for
10 min. The mixture was cooled to -70 °C, and a solution of
4-phenoxyphenol (9) (611 mg, 3.3 mmol) in methylene chloride
(10 mL) was carefully added. The reaction mixture was stirred
for 2 h and then was allowed to warm to room temperature.
The organic layer was washed with a saturated solution of
sodium chloride (3 × 30 mL) and dried (MgSO4), and the
solvent was evaporated. The residue was purified by column
chromatography (silica gel) employing hexane-CH2Cl2 (97:3)
as eluent to afford 396 mg (45% yield) of pure compound 10
and 142 mg of the side product 11 as colorless oils. Compound
10: Rf 0.37 (hexane-CH2Cl2, 7:3); 1H NMR (CDCl3) δ 5.51 (s,
1 H, OH), 6.93-7.28 (m, 7 H, aromatic protons); 13C NMR
(CDCl3) δ 109.96 (C-2), 116.48 (C-2′), 117.96 (C-6), 120.36 (C-
5), 122.86 (C-4′), 123.05 (C-3), 129.69 (C-3′), 148.58 (C-4),
150.44 (C-1), 157.67 (C-1′); MS (m/z, relative intensity) 266
(M+, 75), 264 (M+, 80), 189 (9), 187 (9), 157 (34), 128 (21), 77
(64), 51 (100). Compound 11: Rf 0.54 (hexane-CH2Cl2, 7:3);
MS (m/z, relative intensity) 346 (M+, 0.8), 344 (M+, 1.5), 342
(M+, 0.8), 266 (92), 264 (100), 157 (30), 128 (17), 109 (18), 84
(19), 76 (19), 49 (37), 43 (92).
2-(2-Br om o-4-p h en oxyp h en oxy)eth yl Tetr a h yd r o-2H-
p yr a n -2-yl Eth er (12). A solution of 10 (115.6 mg, 0.44
mmol) in dimethyl sulfoxide (3 mL) was treated with potas-
sium hydroxide (100 mg, 1.79 mmol). The mixture was stirred
at room temperature for 5 min. Then, bromoethyl tetrahy-
dropyranyl ether (180 mg, 0.86 mmol) was added, and the
reaction mixture was stirred at room temperature overnight.
The mixture was partitioned between water (50 mL) and
methylene chloride (50 mL). The aqueous phase was extracted
with methylene chloride (2 × 30 mL). The combined organic
layers were washed with a saturated solution of sodium
chloride (5 × 50 mL) and dried (MgSO4). The residue was
purified by column chromatography (silica gel) eluting with
hexane-CH2Cl2 (95:5) to give 58 mg (33% yield) of pure
compound 12 as a colorless oil: Rf 0.55 (hexanes-EtOAc, 7:3);
IR (film, cm-1) 3067, 3040, 2941, 2872, 1589, 1485, 1454, 1265,
1217, 1126, 1078, 1036, 987, 901, 872, 816, 750, 692; 1H NMR
(CDCl3) δ 1.53-1.91 (m, 6 H, H-3′′′, H-4′′′, H-5′′′), 3.56 (m, 1
H, H-6′′′a), 3.81-4.08 (m, 3 H, H-1, H-2, H-6′′′b), 4.19 (m, 2
H, H-2), 4.78 (m, 1 H, H-2′′′), 6.95-7.35 (m, 8 H, aromatic
protons); 13C NMR (CDCl3) δ 19.26 (C-4′′′), 25.41 (C-5′′′), 30.50
(C-3′′′), 62.05 (C-6′′′), 65.58 (C-1), 69.55 (C-2), 99.00 (C-2′′′),
112.87 (C-2′), 114.70 (C-2′′), 118.07 (C-5′), 119.10 (C-6′), 123.08
(C-4′′), 124.43 (C-3′), 129.72 (C-3′′), 150.95 (C-4′), 151.82 (C-
1′), 157.70 (C-1′′); MS (m/z, relative intensity) 394 (M+, 7), 392
(M+, 7), 266 (20), 264 (20), 129 (100), 85 (58). Anal. (C19H21O4-
Br) C, H.
Exp er im en ta l Section
The glassware used in air- and/or moisture-sensitive reac-
tions was flame-dried, and reactions were carried out under a
dry nitrogen atmosphere. Unless otherwise noted, chemicals
were commercially available and used without further puri-
fication. Solvents were distilled before use. Toluene and
tetrahydrofuran were distilled from sodium/benzophenone
ketyl, pyridine was distilled from calcium hydride and stored
over potassium hydroxide pellets, dimethyl sulfoxide was
distilled from calcium hydride and stored over freshly activated
3-Å molecular sieves, and methanol was distilled from mag-
nesium methoxide and stored over 3-Å molecular sieves.
Anhydrous N,N-dimethylformamide was used as supplied from
Aldrich.
Nuclear magnetic resonance spectra were recorded using a
Bruker AC-200 MHz spectrometer. Chemical shifts are re-
ported in parts per million (δ) relative to tetramethylsilane.
The 1H NMR spectra are referenced with respect to the
residual CHCl3 proton of the solvent CDCl3 at 7.26 ppm.
Coupling constants are reported in hertz. 13C NMR spectra
were fully decoupled and are referenced to the middle peak of
the solvent CDCl3 at 77.0 ppm. Splitting patterns are desig-
nated as s, singlet; d, doublet; t, triplet; q, quartet.
Melting points were determined using a Fisher-J ohns
apparatus and are uncorrected. IR spectra were recorded
using a Nicolet Magna 550 spectrometer.
Low-resolution mass spectra were obtained on a VG TRIO
2 instrument at 70 eV (direct inlet). Positive ion fast atom
bombardment mass spectra (FABMS) were obtained on a VG
ZAB BEqQ spectrometer at an accelerating voltage of 8 kV
and a resolution of 500. Thioglycerol was used as the sample
matrix, and ionization was effected by a beam of cesium atoms.
2-Br om o-4-p h en oxyp h en yl P r op -2-en -1-yl Eth er (13).
A solution of compound 10 (117 mg, 0,44 mmol) in dimethyl
sulfoxide (5 mL) was treated with potassium hydroxide (100
mg, 1.8 mmol), and the mixture was stirred for 5 min. Then,
allyl bromide (0.1 mL, 1.16 mmol) was added, and the mixture
was stirred at room temperature for 5 h. The reaction was
worked up as described for the preparation of compound 7.
The residue was purified by column chromatography (silica
gel) using toluene-MeOH (0.1%) as eluent to obtain 118 mg
(88% yield) of pure ether 13 as a colorless oil: Rf 0.88 (toluene-
MeOH, 99:1); IR (film, cm-1) 3070, 2922, 2868, 1589, 1483,
1284, 1265, 1215, 1188, 1040, 1016, 997, 928, 906, 752, 692;
1H NMR (CDCl3) δ 4.57 (dt, J ) 5.0, 1.2 Hz, 2 H, H-1), 5.30
Flash chromatography was performed according to the Still
methodology50 with E. Merck silica gel (Kieselgel 60, 230-400
mesh). Analytical thin-layer chromatography was performed
employing 0.2-mm coated commercial silica gel plates (E.
Merck, DC-aluminum sheets, Kieselgel 60 F254) and was
(dd, J ) 10.5, 1.4 Hz, 1 H, H-3cis 2), 5.46 (dd, J ) 17.2, 1.6
to
Hz, 1 H, H-3trans 2), 6.05 (ddt, J ) 17.2, 10.1, 5.3 Hz, 1 H,
to
H-2), 6,83-7.35 (m, 8 H, aromatic protons); 13C NMR (CDCl3)

SAR of New Growth Inhibitors of T. cruzi
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9 1547
δ 70.40 (C-1), 112.79 (C-2′), 114.50 (C-2′′), 117.75 (C-3), 118.10
(C-5′), 119.00 (C-6′), 123.09 (C-4′′), 124.43 (C-3′), 129.72 (C-
3′′), 132.69 (C-2), 150.95 (C-4′), 151.34 (C-1′), 157.62 (C-1′′);
MS (m/z, relative intensity) 306 (M+, 51), 304 (M+, 52), 265
(100), 263 (91), 219 (15), 156 (20), 128 (95), 77 (90). Anal.
(C15H13O2Br) C, H.
4-P h en oxyp h en yl Aceta te (14). A solution of 4-phenox-
yphenol (1.69 g, 9.1 mmol) in pyridine (5 mL) was treated with
acetic anhydride (0.9 mL). The reaction mixture was stirred
at room temperature for 16 h. The mixture was partitioned
between methylene chloride (30 mL) and 10% HCl solution
(20 mL), and the mixture was stirred for 1 h. The organic
phase was washed with 10% HCl (3 × 30 mL) and water to
pH ) 7 and dried (MgSO4), and the solvent was evaporated to
afford 1.80 g (87% yield) of pure acetate 14 as a colorless oil
that was used in the next step without further purification:
Rf 0.52 (CH2Cl2-hexane, 7:3); MS (m/z, relative intensity) 228
(M+, 8), 186 (100), 157 (10), 129 (12), 109 (15).
4-(4-Br om op h en oxy)p h en yl Aceta te (15). A suspension
of acetate 14 (666 mg, 2.9 mmol) in water (10 mL) was treated
with bromine (0.19 mL, 3.7 mmol). The reaction mixture was
stirred at room temperature for 2 h. Then, the reaction was
quenched with a 1.0 M aqueous solution of sodium bisulfite
(4 mL), and the mixture was extracted with methylene chloride
(3 × 20 mL). The combined organic layers were washed with
brine (2 × 15 mL) and dried (MgSO4), and the solvent was
evaporated. The residue was purified by column chromatog-
raphy (silica gel) employing toluene-MeOH (0.1%) as eluent
to afford 577 mg (58% yield) of pure compound 15 as a colorless
oil: Rf 0.47 (toluene-MeOH, 9:1); IR (film, cm-1) 3075, 1772,
1585, 1500, 1488, 1373, 1253, 1186, 1078, 1017, 909, 830; MS
(m/z, relative intensity) 308 (M+, 6), 306 (M+, 6), 266 (52), 264
(57), 157 (23), 128 (12), 41 (100).
6.91 (m AB, 4 H, H-2′, H-3′, H-5′, H-6′), 7.37 (d, J ) 8.9 Hz, 2
H, H-3“, H-5”); 13C NMR (CDCl3) δ 69.30 (C-1), 114.74 (C-4′′),
115.90 (C-2′), 117.68 (C-3), 119.25 (C-3′), 120.76 (C-2′′), 132.47
(C-3′′), 133.23 (C-2), 149.78 (C-4′), 155.17 (C-1′), 157.70 (C-
1′′); MS (m/z, relative intensity) 306 (M+, 27), 304 (M+, 29),
265 (57), 263 (59), 185 (29), 157 (34), 155 (39), 128 (100). Anal.
(C15H13O2Br) C, H.
2-Ch lor o-4-p h en oxyp h en ol (18). A solution of 4-phenox-
yphenol (910 mg, 4.9 mmol) in benzene (20 mL) was treated
with N-chlorosuccinimide (570 mg, 4.3 mmol). The reaction
mixture was refluxed for 48 h. Then, the mixture was allowed
to cool to room temperature and was partitioned between
water (100 mL) and methylene chloride (100 mL). The
aqueous phase was extracted with methylene chloride (2 ×
70 mL). The combined organic layers were washed with a
saturated solution of sodium chloride (2 × 100 mL) and dried
(MgSO4), and the solvent was evaporated. The residue was
purified by column chromatography (silica gel) eluting with
hexane-CH2Cl2 (2:1) to give 493 mg (46% yield) of pure
compound 18 as a colorless oil: Rf 0.48 (hexane-CH2Cl2, 1:1);
MS (m/z, relative intensity) 222 (M+, 26), 220 (M+, 67), 186
(100), 157 (40), 129 (30), 109 (46).
2-(2-Ch lor o-4-p h en oxyp h en oxy)eth yl Tetr a h yd r o-2H-
p yr a n -2-yl Eth er (19). Phenol 18 (235 mg, 1.06 mmol) in
dimethyl sulfoxide (5 mL) was treated with potassium hydrox-
ide (250 mg, 4.5 mmol). The suspension was stirred for 5 min.
Then, bromoethyl tetrahydropyranyl ether (440 mg, 2.1 mmol)
was stirred at room temperature overnight. The reaction
mixture was worked up as described for compound 12. The
residue was purified by column chromatography (silica gel)
employing hexane-CH2Cl2 (7:3) as eluent to afford 272 mg
(74% yield) of pure compound 19 as a colorless oil: Rf 0.48
(hexanes-EtOAc, 1:1); IR (film, cm-1) 3067, 3042, 2943, 2874,
1589, 1487, 1454, 1263, 1217, 1140, 1126, 1078, 1036, 912, 872,
2-[4-(4-Br om op h en oxy)p h en oxy]eth yl Tetr a h yd r o-2H-
p yr a n -2-yl Eth er (16). Compound 15 (98 mg, 0.32 mmol) in
dimethyl sulfoxide (5 mL) was treated with potassium hydrox-
ide (1.3 mmol). The suspension was stirred for 30 min at room
temperature. Then, bromoethyl tetrahydropyranyl ether (130
mg, 0.6 mmol) was added; the reaction mixture was stirred at
room temperature overnight. The reaction was worked up as
described for the preparation of compound 12. The residue
was purified by column chromatography (silica gel) eluting
with hexane-CH2Cl2 (3:2) to afford 75 mg (60% yield) of pure
compound 16 as a colorless oil: Rf 0.37 (hexanes-EtOAc, 2:3);
IR (film, cm-1) 3073, 3045, 2941, 2872, 1639, 1608, 1580, 1504,
1481, 1456, 1352, 1279, 1227, 1163, 1140, 1126, 1068, 1034,
1
816, 752, 692; H NMR (CDCl3) δ 1.50-1.82 (m, 6 H, H-3′′′,
H-4′′′, H-5′′′), 3.54 (m, 1 H, H-6′′′a), 3.80-4.15 (m, 3 H, H-1,
H-6′′′b), 4.20 (t, J ) 5.0 Hz, 2 H, H-2), 4.76 (t, J ) 3.2 Hz, 1 H,
H-2′′′), 6.90-7.36 (m, 8 H, aromatic protons); 13C NMR (CDCl3)
δ 19.27 (C-4′′′), 25.41 (C-5′′′), 30.40 (C-3′′′), 62.07 (C-6′′′), 65.61
(C-1), 69.51 (C-2), 98.99 (C-2′′′), 115.14 (C-2′′), 118.12 (C-5′),*
118.33 (C-6′),* 121.46 (C-3′), 123.10 (C-4′′), 124.00 (C-2′),
129.72 (C-3′′), 150.81 (C-4′), 150.90 (C-1′), 157.61 (C-1′′); MS
(m/z, relative intensity) 350 (M+, 7), 348 (M+, 21), 222 (12),
220 (41), 209 (29), 207 (27), 129 (95), 127 (13), 109 (39), 107
(48), 85 (100), 83 (54), 73 (63). Anal. (C19H21O4Cl) C, H.
2-Ch lor o-4-p h en oxyp h en yl P r op -2-en -1-yl Eth er (20).
A solution of compound 18 (135 mg, 0.69 mmol) in dimethyl
sulfoxide (5 mL) was treated with potassium hydroxide (130
mg, 2.3 mmol). The mixture was stirred for 5 min at room
temperature. Then, allyl bromide (100 µL, 1.2 mmol) was
added, and the reaction mixture was stirred for 5 h. The
reaction mixture was treated according to the general proce-
dure described for the preparation of 12. The product was
purified by column chromatography eluting with toluene-
MeOH (0.02%) to give 135 mg (75% yield) of pure ether 20 as
1
928, 908, 872, 824, 758, 714, 569, 517, 500; H NMR (CDCl3)
δ 1.55-1.90 (m, 6 H, H-3′′′, H-4′′′, H-5′′′), 3.56 (m, 1 H, H-6′′′a),
3.78-4.08 (m, 3 H, H-1, H-6′′′b), 4.10-4.17 (m, 2 H, H-2), 4.71
(distorted t, J ) 3.4 Hz, 1 H, H-2′′′), 6.81 (d, J ) 8.9 Hz, 2 H,
H-2′′, H-6′′), 6.93 (m AB, 4 H, H-2′, H-3′, H-5′, H-6′), 7.37 (d,
J ) 8.9 Hz, 2 H, H-3′′, H-5′′); 13C NMR (CDCl3) δ 19.35 (C-
4′′′), 25.39 (C-5′′′), 30.49 (C-3′′′), 62.17 (C-6′′′), 65.84 (C-1), 67.97
(C-2), 98.99 (C-2′′′), 114.71 (C-4′′), 115.89 (C-2′), 119.20 (C-3′),
120.76 (C-2′′), 132.44 (C-3′′), 149.77 (C-4′), 155.51 (C-1′), 157.72
(C-1′′); MS (m/z, relative intensity) 394 (M+, 9), 392 (M+, 9),
266 (16), 264 (16), 157 (12), 155 (10), 129 (100). Anal.
(C19H21O4Br) C, H.
a colorless oil: Rf 0.88 (toluene-MeOH, 99:1); IR (film, cm-1
)
3072, 3042, 2986, 2918, 2877, 1589, 1485, 1269, 1215, 1053,
1
1020, 997, 922, 754, 690; H NMR (CDCl3) δ 4.58 (d, J ) 5.0
Hz, 2 H, H-1), 5.31 (d, J ) 10.5 Hz, 1 H, H-3cis to 2), 5.46 (d, J
) 17.2 Hz, 1 H, H-3trans to 2), 6.07 (ddt, J ) 17.2, 10.2, 5.2 Hz,
1 H, H-2), 6.85-7.36 (m, 8 H, aromatic protons); 13C NMR
(CDCl3) δ 70.35 (C-1), 114.85 (C-2′′), 117.80 (C-3), 118.15 (C-
6′),* 118.22 (C-5′),* 121.44 (C-3′), 123.11 (C-4′′), 123.82 (C-2′),
129.72 (C-3′′), 132.74 (C-2), 150.41 (C-4′), 150.72 (C-1′), 157.55
(C-1′′); MS (m/z, relative intensity) 262 (M+, 28), 260 (M+, 79),
221 (56), 219 (100). Anal. (C15H13O2Cl) C, H.
4-(4-Ch lor op h en oxy)p h en yl Aceta te (21). A solution of
14 (264 mg, 1.15 mmol) in methylene chloride (10 mL) was
treated with 1-chlorobenzotriazole (180 mg, 1.15 mmol). The
reaction mixture was stirred at room temperature for 6 days.
The solvent was evaporated, and the residue was purified by
column chromatography (silica gel) using toluene-MeOH
(0.1%) as eluent to yield 148 mg (49% yield) of pure compound
21 as a colorless oil: Rf 0.92 (hexanes-EtOAc, 7:3); IR (film,
4-(4-Br om op h en oxy)p h en yl P r op -2-en -1-yl Eth er (17).
Compound 15 (156 mg, 0.51 mmol) in dimethyl sulfoxide (5
mL) was treated with potassium hydroxide (100 mg, 1.8 mmol),
and the mixture was stirred for 30 min. Then, allyl bromide
(0.1 mL) was added, and the reaction mixture was stirred at
room temperature for 5 h. The reaction was quenched as
depicted for the preparation of compound 12. The residue was
purified by column chromatography (silica gel) using toluene-
MeOH (0.1%) as eluent to obtain 126 mg (81% yield) of pure
compound 17 as a colorless oil: Rf 0.93 (toluene-MeOH, 9:1);
IR (film, cm-1) 3058, 3086, 2916, 2866, 1884, 1647, 1578, 1504,
1483, 1427, 1404, 1300, 1290, 1244, 1219, 1194, 1097, 1016,
1
997, 935, 843, 825, 814; H NMR (CDCl3) δ 4.51 (dt, J ) 5.2,
1.5 Hz, 2 H, H-1), 5.29 (dq, J ) 10.4, 1.3 Hz, 1 H, H-3cis 2),
to
5.41 (dq, J ) 17.2, 1.3 Hz, 1 H, H-3trans to 2), 6.05 (ddt, J ) 17.2,
10.4, 5.2 Hz, 1 H, H-2), 6.81 (d, J ) 8.9 Hz, 2 H, H-2“, H-6”),

1548 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9
Cinque et al.
cm-1) 3099, 3069, 3045, 1759, 1591, 1482, 1350, 1253, 1210,
1186, 1090, 1011, 836, 770; MS (m/z, relative intensity) 264
(M+, 8), 262 (M+, 22), 228 (38), 222 (51), 220 (81), 186 (100),
157 (31), 129 (23), 109 (33).
was used in the next step without further purification: Rf 0.37
(hexanes-EtOAc, 3:2); mp 107-108 °C; IR (KBr, cm-1) 3383,
3314, 1597, 1539, 1489, 1223, 1080, 876, 844, 781; MS (m/z,
relative intensity) 201 (M+, 100), 183 (10), 172 (11), 156 (10),
144 (13), 128 (18), 96 (24).
4-(4-Ch lor op h en oxy)p h en yl P r op -2-en -1-yl Eth er (22).
To a solution of 21 (90 mg, 0.34 mmol) in dimethyl sulfoxide
(5 mL) was added potassium hydroxide (100 mg, 1.8 mmol).
The mixture was stirred for 20 min. Then, allyl bromide (100
µL, 1.2 mmol) was added, and the reaction mixture was stirred
at room temperature for 3 h. The reaction was quenched as
depicted for compound 12. The residue was purified by column
chromatography (silica gel) eluting with hexanes-EtOAc
(0.5%) to give 61 mg (68% yield) of pure ether 22 as a colorless
oil: Rf 0.47 (hexanes-EtOAc, 49:1); IR (film, cm-1) 3078, 2856,
1755, 1591, 1504, 1485, 1425, 1227, 1090, 1009, 926, 874, 845,
2-Am in o-4-p h en oxyp h en yl P r op -2-en -1-yl Eth er (27),
2-(P r op -2-en -1-yla m in o-4-p h en oxyp h en yl P r op -2-en -1-yl
Eth er (28), a n d 2-(Dip r op -2-en -1-yla m in o-4-p h en oxyp h e-
n yl P r op -2-en -1-yl Eth er (29). Compound 26 (760 mg, 3.8
mmol) was treated with potassium hydroxide (425 mg, 7.6
mmol) and allyl bromide (320 µL, 3.8 mmol) following the
method of preparation described for 13. After the usual
workup, the residue was purified by column chromatography
(silica gel) eluting with hexanes-EtOAc (99:1) to yield 600 mg
(65% yield) of pure 27, 350 mg of compound 28, and 100 mg of
29 as colorless oils. Compound 27: Rf 0.84 (hexanes-EtOAc,
7:3); IR (film, cm-1) 3477, 3391, 3078, 3038, 2925, 2859, 1622,
1589, 1516, 1496, 1303, 1217, 1024, 971, 931, 865, 752, 698;
MS (m/z, relative intensity) 241 (M+, 13), 200 (100). Com-
pound 28: Rf 0.75 (hexanes-EtOAc, 7:3); IR (film, cm-1) 3430,
3087, 2966, 2931, 2859, 1610, 1600, 1516, 1489, 1454, 1230,
1222, 1173, 1018, 1000, 929, 858, 760, 693. MS (m/z, relative
intensity) 281 (M+, 17), 240 (100), 162 (14), 146 (87). Com-
pound 29: Rf 0.60 (hexanes-EtOAc, 7:3); IR (film, cm-1) 3084,
3071, 3018, 2978, 2932, 2852, 1642, 1591, 1501, 1489, 1457,
1217, 1171, 1115, 1171, 994, 966, 921, 757, 693; MS (m/z,
relative intensity) 321 (M+, 12), 280 (100), 238 (12), 212 (24),
186 (11), 146 (24).
2-Acet a m id o-4-p h en oxyp h en yl P r op -2-en -1-yl E t h er
(30). To a solution of 27 (116 mg, 0.48 mmol) in pyridine (3
mL) was added acetic anhydride (1.0 mL). The reaction
mixture was stirred at room temperature overnight. The
reaction was quenched as depicted for compound 14. The
residue was purified by column chromatography (silica gel)
employing hexanes-EtOAc (7:3) as eluent to give 85 mg (63%
yield) of pure compound 30 as a white solid: Rf 0.47 (hexanes-
EtOAc, 7:3); mp 79-80 °C; IR (KBr, cm-1) 3310, 1666, 1589,
1599, 1537, 1491, 1429, 1376, 1261, 1217, 1175, 1122, 1076,
1024, 995, 924, 889, 814; 1H NMR (CDCl3) δ 2.12 (s, 3 H, CH3C-
(O)NH), 4.43 (dt, J ) 5.4, 1.2 Hz, 2 H, H-1), 5.28 (dq, J ) 10.5,
1.3 Hz, 1 H, H-3cis to 2), 5.35 (dq, J ) 17.4, 1.5 Hz, 1 H, H-3trans
to 2), 6.02 (ddt, J ) 17.4, 10.5, 5.4 Hz, 1 H, H-2), 6.61 (dd, J )
8.8, 2.8 Hz, 1 H, H-5′), 6.77 (d, J ) 8.9 Hz, 1 H, H-6′), 6.90 (m,
2 H, H-2′′, H-6”), 6.99 (dt, J ) 7.03, 1.2 Hz, 1 H, H-4′′), 7.23
(m, 2 H, H-3′′, H-5′′), 7.74 (s broad, 1 H, NH), 8.12 (d, J ) 2.5
Hz, 1 H, H-3′); 13C NMR (CDCl3) δ 25.00 (CH3C(O)NH), 70.20
(C-1), 110.55 (C-3′), 112.14 (C-5′), 113.97 (C-6′), 117.98 (C-3),
118.41 (C-2′′), 122.65 (C-4′′), 129.04 (C-2′), 129.63 (C-3′′), 132.93
(C-2), 142.97 (C-1′), 150.68 (C-4′), 158.20 (C-1′′), 168.13 (CdO);
MS (m/z, relative intensity) 283 (M+, 20), 242 (40), 200 (100),
85 (42), 83 (60). Anal. (C17H17O3N): C, H.
1
825; H NMR (CDCl3) δ 4.52 (dt, J ) 5.3, 1.4 Hz, 2 H, H-1),
5.29 (dq, J ) 10.5, 1.4 Hz, 1 H, H-3cis to 2), 5.41 (dq, J ) 17.2,
1.4 Hz, 1 H, H-3trans to 2), 6.06 (ddt, J ) 17.2, 5.3, 1.4 Hz, 1 H,
H-2), 6.86 (d, J ) 8.9 Hz, 2 H, H-2“, H-6”), 6,93 (m AB, 4 H,
H-2′, H-3′, H-5′, H-6′), 7.24 (d, J ) 8.9 Hz, 2 H, H-3“, H-5”);
13C NMR (CDCl3) δ 69.33 (C-1), 115.91 (C-2′), 117.69 (C-3),
118.85 (C-3′), 120.69 (C-2′′), 129.53 (C-3′′), 133.25 (C-2), 149.96
(C-4′), 155.14 (C-1′), 157.13 (C-1′′); MS (m/z, relative intensity)
262 (M+, 28), 260 (M+, 79), 221 (56), 219 (100), 128 (24), 127
(27). Anal. (C15H13O2Cl) C, H.
2-Nitr o-4-p h en oxyp h en ol (23) a n d 2,4-Din itr o-4-p h e-
n oxyp h en ol (24). To a solution of 4-phenoxyphenol (541 mg,
2.9 mmol) in glacial acetic acid (15 mL) was added dropwise
70% nitric acid (180 mg, 2.9 mmol) with vigorous stirring. The
mixture was stirred at room temperature for 15 min. The
reaction mixture was poured into an aqueous saturated
solution of sodium bicarbonate (40 mL). The mixture was
extracted with methylene chloride (3 × 30 mL), the combined
organic layers were washed with water (2 × 20 mL) and dried
(MgSO4), the solvent was evaporated. The residue was puri-
fied by column chromatography (silica gel) using hexanes-
EtOAc (9:1) as eluent to afford 471 mg (70% yield) of pure
mononitro derivative 23 and 64 mg of dinitro derivative 24 as
yellow solids. Compound 23: Rf 0.62 (hexanes-EtOAc, 7:3);
mp 54-55 °C; IR (KBr, cm-1) 3343, 3092, 3079, 3059, 1630,
1591, 1544, 1472, 1432, 1313, 1240, 1161, 949, 791, 850; MS
(m/z, relative intensity) 231 (M+, 100), 196 (8), 128 (25), 77
(70), 51 (72). Compound 24: Rf 0.03 (hexanes-EtOAc, 7:3);
mp 129-130 °C; IR (KBr, cm-1) 3093, 1645, 1591, 1548, 1494,
1422, 1349, 1313, 1253, 1192, 1084, 993, 927, 842; MS (m/z,
relative intensity) 276 (M+, 17), 197 (3), 183 (3), 172 (5), 91
(15), 63 (19), 51 (100).
2-Nitr o-4-p h en oxyp h en yl P r op -2-en -1-yl Eth er (25). To
a solution of compound 23 (114 mg, 0.5 mmol) in dimethyl
sulfoxide (3 mL) was added potassium hydroxide (100 mg, 1.8
mmol). The mixture was stirred at room temperature for 5
min. Then, allyl bromide (100 µL, 1.2 mmol) was added, and
the reaction mixture was stirred overnight. After the usual
workup, the residue was purified by column chromatography
(silica gel) eluting with hexanes-EtOAc (3:2) to afford 23 mg
(17% yield) of pure compound 25 as a yellow oil: Rf 0.62
(hexane-CH2Cl2, 2:3); IR (film, cm-1) 3080, 2924, 2870, 1591,
1529, 1500, 1423, 1356, 1271, 1217, 1153, 993, 949, 841, 756,
4-(4-Nitr op h en oxy)p h en yl Meth yl Eth er (32). A solu-
tion of 4-methoxyphenol (31) (2.160 g, 17 mmol) in dimethyl
sulfoxide (5 mL) was treated with potassium hydroxide (960
mg, 17 mmol). The reaction mixture was stirred for 5 min.
Then, 1-chloro-4-nitrobenzene (2.741 g, 17 mmol) and cuprous
chloride (10 mg) were added, and the reaction mixture was
stirred at 70 °C for 16 h. The mixture was poured into water
(50 mL) and was extracted with methylene chloride (3 × 30
mL). The combined organic layers were washed with brine
(5 × 70 mL) and dried (MgSO4), and the solvent was evapo-
rated. The residue was purified by column chromatography
(silica gel) using hexane-CH2Cl2 (7:3) as eluent to give 1.942
g (45% yield) of pure compound 32 as a green solid: Rf 0.44
(hexane-CH2Cl2, 1:1); mp 111-112 °C; IR (KBr, cm-1) 3112,
3016, 2850, 1610, 1585, 1507, 1487, 1455, 1343, 1298, 1239,
1198, 1186, 1163, 1110, 1102, 1031, 879, 843, 748, 712, 689,
652, 536; MS (m/z, relative intensity) 245 (M+, 100), 230 (36),
156 (10), 128 (33).
1
692; H NMR (CDCl3) δ 4.66 (dt, J ) 5.0, 1.5 Hz, 2 H, H-3),
5.35 (dq, J ) 10.5, 1.4 Hz, 1 H, Hcis to 2), 5.47 (dq, J ) 17.1, 1.5
Hz, 1 H, H-3trans 2), 6.04 (ddt, J ) 17.3, 10.3, 5.0 Hz, 1 H,
to
H-2), 6.98-7.40 (m, 7 H, aromatic protons), 7.48 (d, J ) 2.9
Hz, 1 H, H-3′); 13C NMR (CDCl3) δ 70.83 (C-1), 115.76 (C-3′),
116.63 (C-6′), 118.42 (C-3), 118.70 (C-2′′), 123.99 (C-4′′), 124.43
(C-5′), 130.04 (C-3′′), 131.90 (C-2′), 137.02 (C-2), 147.80 (C-1′),
156.69 (C-4′), 159.26 (C-1′′); MS (m/z, relative intensity) 271
(M+, 62), 230 (43), 171 (12), 144 (18), 131 (25), 77 (100). Anal.
(C15H13O4N) C, H, N.
2-Am in o-4-p h en oxyp h en ol (26). A solution of 23 (1.212
g, 5.2 mmol) in ethyl acetate (50 mL) in the presence of 10%
palladium on charcoal (50 mg) was treated with hydrogen
under 3 atm at room temperature for 1 h. Then the reaction
mixture was filtered, and the solvent was evaporated to afford
973 mg (92% yield) of compound 26 as a brown crystal that
4-(4-Nitr op h en oxy)p h en ol (33). To a mixture of alumi-
num chloride (1.101 g) in mercaptoethanol (7.5 mL) was added
dropwise 32 (305 mg, 1.24 mmol) in mercaptoethanol (3 mL)
keeping the reaction temperature below 0 °C. The reaction
mixture was stirred at 0 °C for 3 h. The mixture was poured

SAR of New Growth Inhibitors of T. cruzi
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9 1549
into 10% hydrochloric acid (30 mL) and was extracted with
methylene chloride (3 × 30 mL). The combined organic layers
were washed with brine (3 × 50 mL) and dried (MgSO4), and
the solvent was evaporated. The residue was purified by
column chromatography eluting with Cl2CH2-hexane (4:1) to
give 260 mg (91% yield) of pure phenol 33 as a yellow solid:
Rf 0.14 (CH2Cl2-hexane, 3:2); mp 175-176 °C; MS (m/z, relative
intensity) 231 (M+, 100), 185 (8), 157 (28), 128 (25).
(5 mL) was added. The resulting mixture was extracted with
methylene chloride (3 × 20 mL). The combined organic layers
were washed with water (3 × 50 mL) and dried (MgSO4), and
the solvent was evaporated. The residue was purified by
column chromatography (silica gel) eluting with hexanes-
EtOAc (9:1) to afford 257 mg (26% yield) of pure compound
37 and 553 mg of undesired 4-phenoxyphenyl acetate (14): Rf
0.21 (hexanes-EtOAc, 4:1); IR (film, cm-1) 3350, 3072, 3006,
1756, 1683, 1611, 1525, 1504, 1366, 1254, 1181, 1009, 916, 850,
830, 592; MS (m/z, relative intensity) 270 (M+, 11), 228 (75),
213 (100), 186 (30), 157 (10).
4-(4-Nitr op h en oxy)p h en yl P r op -2-en -1-yl Eth er (34). A
solution of phenol 33 (121 mg, 0.52 mmol) in dimethyl sulfoxide
(3 mL) was treated as depicted for 13. After the usual workup,
the product was purified by column chromatography (silica gel)
eluting with hexane-CH2Cl2 (9:1) to afford 113 mg (80% yield)
of pure 34 as a yellow oil: Rf 0.5 (hexanes-EtOAc, 8:2); IR
(film, cm-1) 3110, 3089, 2931, 2869, 1610, 1591, 1507, 1493,
1424, 1342, 1255, 1232, 1192, 1168, 1111, 1024, 1011, 998, 933,
4-(4-Acetylp h en oxy)p h en yl P r op -2-en -1-yl Eth er (38).
A solution of 37 (158 mg, 0.58 mmol) in dimethyl sulfoxide (3
mL) was treated with potassium hydroxide and allyl bromide
according to the protocol described for compound 13. After
the usual workup, the residue was purified by column chro-
matography (silica gel) eluting with hexanes-EtOAc (19:1) to
afford 60 mg (38% yield) of pure compound 38 as a white
1
879, 840, 752, 692; H NMR (CDCl3) δ 4.58 (dt, J ) 5.2, 1.5
Hz, 2 H, H-1), 5.32 (dq, J ) 10.5, 1.4 Hz, H-3cis to 2), 5.44 (dq,
J ) 17.2, 1.4 Hz, H-3trans to 2), 6.08 (ddt, J ) 17.2, 10.5, 5.3 Hz,
1 H, H-2), 6.97 (d, J ) 9.2 Hz, 2 H, H-2′, H-6′), 7.03 (m AB, 4
H, H-2, H-3, H-5, H-6), 8.18 (d, J ) 9.3 Hz, 2 H, H-3“, H-5”);
13C NMR (CDCl3) δ 69.31 (C-1), 116.20 (C-2′), 116.42 (C-2′′),
117.85 (C-3), 121.72 (C-3′), 125.86 (C-3′′), 133.04 (C-2), 147.97
(C-4′), 156.19 (C-1′), 164.06 (C-1′′); MS (m/z, relative intensity)
271 (M+, 5), 264 (18), 230 (100), 184 (10), 128 (37). Anal.
(C15H13O4N‚1/2H2O) C, H, N.
1
solid: Rf 0.77 (hexanes-EtOAc, 7:3); mp 54-55 °C; H NMR
(CDCl3) δ 2.55 (s, 3 H, -C(O)CH3), 4.54 (d, J ) 5.3 Hz, 2 H,
H-1), 5.30 (dd, J ) 10.5, 1.3 Hz, 1 H, H-3cis to 2), 5.42 (dd, J )
17.2, 1.4 Hz, 1 H, H-3trans to 2), 6.08 (ddt, J ) 17.2, 10.5, 5.3 Hz,
1 H, H-2), 6.94 (d, J ) 8.7 Hz, 2 H, H-2′, H-6′), 6,95 (m AB, 4
H, H-2, H-3, H-5, H-6), 7.91 (d, J ) 8.7, 1.9 Hz, 2 H, H-3′,
H-5′); 13C NMR (CDCl3) δ 26.34 (CH3C(O)), 69.27 (C-1), 115.98
(C-2′), 116.40 (C-2′′), 117.74 (C-3), 121.55 (C-3′), 130.51 (C-
3′′), 131.45 (C-4′′), 133.14 (C-2), 148.65 (C-1′), 155.69 (C-4′),
162.82 (C-1′′); MS (m/z, relative intensity) 268 (M+, 54), 227
(68), 157 (14), 91 (17), 76 (14), 43 (100). Anal. (C16H16O3) C,
H.
2-Iod o-4-p h en oxyp h en ol (35). To a suspension of ami-
nophenol 26 (312 mg, 1.35 mmol), water (1.4 mL), and
concentrated sulfuric acid (90 µL) cooled to 0 °C was added
dropwise sodium nitrite (97 mg, 1.35 mmol) in water (1.0 mL).
The reaction mixture was stirred for 20 min at 0 °C. Then,
concentrated sulfuric acid (30 µL) was added. The mixture
was poured into an aqueous solution of sodium iodide (6.0 M,
0.3 mL), and the mixture was stirred for 10 min at 0 °C. Then,
cuprous chloride (10 mg) was added, and the reaction mixture
was heated at 75-80 °C until evolution of nitrogen ceased.
The mixture was allowed to cool to room temperature and was
extracted with methylene chloride (3 × 20 mL). The combined
organic layers were washed with a saturated solution of
sodium bisulfite (2 × 30 mL) and dried (MgSO4), and the
solvent was evaporated. The residue was purified by column
chromatography (silica gel) using hexane-CH2Cl2 (3:2) as
eluent to afford 128 mg (30% yield) of pure iodophenol 35 as
4-(4-Ben zoylp h en oxy)p h en yl Ben zoa te (39) a n d 4-P h e-
n oxyp h en yl Ben zoa te (40). To a mixture of anhydrous
aluminum chloride (690 mg, 4.9 mmol) in carbon disulfide (10
mL) was added 4-phenoxyphenol (890 g, 4.8 mmol) at -5 °C.
Then, benzoyl chloride (0.6 mL, 5.1 mmol) was added. The
reaction mixture was stirred for 2 h at -5 °C, and the reaction
was quenched as depicted for 37. The residue was purified
by column chromatography (silica gel) using hexanes-EtOAc
(19:1) as eluent to afford 283 mg (15% yield) of pure benzoyl
derivative 39 and 1.050 g of benzoate 40 as white solids.
Compound 39: Rf 0.47 (hexanes-EtOAc, 4:1); mp 130-131
°C; IR (KBr, cm-1) 3098, 3072, 3045, 3012, 1743, 1644, 1604,
1505, 1452, 1439, 1320, 1273, 1187, 1068, 942, 705; MS (m/z,
relative intensity) 394 (M+, 13), 106 (13), 105 (100). Compound
40: Rf 0.67 (hexanes-EtOAc, 4:1); mp 99-100 °C; IR (KBr,
cm-1) 5065, 3038, 1737, 1590, 1488, 1454, 1318, 1267, 1246,
1190, 1069, 1029, 870, 791, 711.
a colorless oil: Rf 0.53 (hexane-CH2Cl2, 1:1); IR (film, cm-1
)
3501, 3073, 3052, 2924, 2852, 1505, 1588, 1476, 1405, 1255,
1218, 1034, 896, 749, 691; MS (m/z, relative intensity) 312 (M+,
13), 157 (6), 128 (11), 92 (11), 77 (100).
2-Iod o-4-p h en oxyp h en yl P r op -2-en -1-yl E t h er (36).
Compound 35 (125 mg, 0.4 mmol) in dimethyl sulfoxide (5 mL)
was treated with potassium hydroxide and allyl bromide as
depicted for compound 13. After the usual workup, the residue
was purified by column chromatography (silica gel) eluting
with hexane-CH2Cl2 (3:2) to give 76 mg (54% yield) of pure
compound 36 as a colorless oil: Rf 0.75 (hexane-CH2Cl2, 1:1);
IR (film, cm-1) 3065, 2924, 2854, 1587, 1479, 1423, 1265, 1215,
4-(4-Ben zoylp h en oxy)p h en yl P r op -2-en -1-yl Eth er (41).
A solution of 39 (149 mg, 0.37 mmol) in dimethyl sulfoxide
(3.0 mL) was treated with potassium hydroxide and allyl
following the methodology described for 13. After the usual
workup, the product was purified by column chromatography
(silica gel) eluting with CH2Cl2-hexane (3:2) to afford 99 mg
(79% yield) of pure 41 as a white solid: Rf 0.67 (hexanes-
EtOAc, 4:1); mp 95-96 °C; IR (KBr, cm-1) 3063, 2914, 2866,
1644, 1600, 1508, 1444, 1291, 1244, 1146, 1113, 1021, 931, 842,
1
1034, 995, 928, 895, 750, 692; H NMR (CDCl3) δ 4.57 (dd, J
1
) 4.9, 1.2 Hz, 2 H, H-1), 5.31 (dt, J ) 10.5, 1.4 Hz, 1 H, H-3cis
to 2), 5.51 (dt, J ) 17.2, 1.5 Hz, 1 H, H-3trans to 2), 6.07 (ddt, J )
17.2, 10.5, 4.9 Hz, 1 H, H-2), 6.77 (d, J ) 8.9 Hz, 1 H, H-6′),
6.93-7.11 (m, 4 H, aromatic protons), 7.26-7.35 (m, 2 H,
aromatic protons), 7.47 (d, J ) 2.9 Hz, 1 H, H-3′); 13C NMR
(CDCl3) δ 70.44 (C-1), 86.73 (C-2′), 113.09 (C-3), 117.68 (C-6′),
117.99 (C-2′′), 120.12 (C-5′), 123.01 (C-4′′), 129.72 (C-3′), 130.40
(C-3′′), 132.65 (C-2), 151.06 (C-4′), 153.69 (C-1′′), 157.77 (C-
1′); MS (m/z, relative intensity) 352 (M+, 43), 311 (16), 156
(7), 128 (33), 77 (100). Anal. (C15H13O2I) C, H.
818, 801, 732, 692, 682; H NMR (CDCl3) δ 4.53 (dt, J ) 5.2,
1.2 Hz, 2 H, H-3), 5.29 (dd, J ) 10.5, 1.3 Hz, 1 H, H-3cis 2),
to
5.42 (dd, J ) 17.2, 1.2 Hz, 1 H, H-3trans to 2), 6.07 (ddt, J ) 17.2,
10.5, 5.3 Hz, 1 H, H-2), 6.91-7.05 (m, 6 H, aromatic protons),
7.41 (m, 3 H, aromatic protons), 7.73-7.83 (m, 4 H, aromatic
protons); 13C NMR (CDCl3) δ 69.26 (C-1), 115.99 (C-2′), 116.26
(C-2′′), 117.67 (C-3), 121.54 (C-3′), 128.16 (C-3′′′), 129.70 (C-
3′′), 131.43 (C-4′′), 131.96 (C-2′′′), 132.39 (C-4′′′), 133.14 (C-2),
138.04 (C-1′′′), 148.74 (C-1′), 155.67 (C-4′), 162.47 (C-1′′), 195.30
(CdO); MS (m/z, relative intensity) 330 (M+, 51), 289 (76), 152
(15), 105 (100). Anal. (C22H18O3) C, H.
4-(4-Acetoxyp h en oxy)p h en yl Aceta te (37). A suspen-
sion of anhydrous aluminum chloride (660 mg) in carbon
disulfide (5 mL) was cooled to -5 °C under nitrogen atmo-
sphere. Then, 4-phenoxyphenol (810 mg, 4.34 mmol) was
added followed by careful addition of acetyl chloride (0.33 mL,
4.7 mmol), keeping the reaction temperature below -5 °C. The
mixture was stirred for 2 h at room temperature. The mixture
was poured into ice (5 g), and concentrated hydrochloric acid
S-Eth yl 3,7-Dim eth ylocta -2,6-d ien -1-yl Th iolca r bon a te
(43). A solution of geraniol (42) (1.540 g, 10 mmol) was treated
with ethyl chlorothiolformate (1.25 mL, 12 mmol). The reac-
tion mixture was stirred at room temperature overnight. The
reaction was quenched as depicted for compound 14. The
product was purified by column chromatography (silica gel)
eluting with hexanes-EtOAc (19:1) to afford 2.254 g (93%

1550 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9
Cinque et al.
yield) of pure thiolcarbonate 43 as a colorless oil: Rf 0.68
(hexanes-EtOAc, 4:1); IR (film, cm-1) 2968, 2932, 1709, 1449,
1377, 1271, 1136, 972, 924, 677; 1H NMR (CDCl3) δ 1.31 (t, J
) 7.4 Hz, 3 H, SCH2CH3), 1.59 (s, 3 H, Me at C-7), 1.67 (s, 3
H, H-8), 1.71 (s, 3 H, Me at C-3), 1.99-2.14 (m, 4 H, H-4, H-5),
2.86 (q, J ) 7.4 Hz, 2 H, SCH2CH3), 4.71 (d, J ) 7.2 Hz, 2 H,
H-1), 5.07 (m, 1 H, H-6), 5.35 (dt, J ) 7.3, 1.1 Hz, 1 H, H-2);
13C NMR (CDCl3) δ 15.00, 16.45, 17.65, 25.30, 25.61 (C-8),
26.21, 39.48, 63.96, 117.76, 123.63, 131.84, 143.20, 171.00; MS
(m/z, relative intensity) 136 (35), 95 (11), 93 (27), 81 (43), 69
(100). Anal. (C13H22O2S) C, H.
colorless oil: Rf 0.63 (hexanes-EtOAc, 9:1); IR (film, cm-1
)
3084, 2922, 2870, 2540, 1572, 1483, 1288, 1253, 1105, 1016,
1
802, 754, 660, 559; H NMR (CDCl3) δ 4.58 (d, J ) 5.1 Hz, 2
H, H-1), 5.32 (dd, J ) 10.5, 1.2 Hz, 1 H, H-3cis), 5.45 (dd, J )
17.3, 1.5 Hz, 1 H, H-3trans), 6.03 (ddt, J ) 17.2, 10.5, 1.5 Hz, 1
H, H-2), 6.83 (d, J ) 8.8 Hz, 1 H, H-5′), 7.15 (dd, J ) 8.8, 2.5
Hz, 1 H, H-4′), 7.36 (d, J ) 2.5 Hz, 1 H, H-3′); 13C NMR (CDCl3)
δ 70.02 (C-1), 114.59 (C-6′), 118.08 (C-3), 123.98 (C-2′), 125.91
(C-4′), 127.46 (C-5′), 130.02 (C-3′), 132.30 (C-2), 152.97 (C-1′);
MS (m/z, relative intensity) 202, 204, 206 (M+, 37, 23, 4), 169
(6), 167 (18), 166 (3), 164 (15), 162 (24), 137 (4), 135 (23), 133
(39), 41 (100). Anal. (C9H8OCl2) C, H.
S-Eth yl 3,7-Dim eth yl-6,7-ep oxyoct-2-en -1-yl Th iolca r -
bon a te (44). To a solution of thiolcarbonate 43 (900 mg, 3.71
mmol) in methylene chloride (30 mL) was added dropwise
m-chloroperoxybenzoic acid (900 mg) in methylene chloride (20
mL) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h.
The mixture was allowed to room temperature, the organic
phase was extracted with an aqueous saturated solution of
sodium bicarbonate (3 × 50 mL) and water (2 × 50 mL) and
dried (MgSO4), and the solvent was evaporated. The residue
was purified by column chromatography (silica gel) eluting
with hexanes-EtOAc (4:1) to give 887 mg (93% yield) of pure
epoxide 44 as a colorless oil: Rf 0.30 (hexanes-EtOAc, 4:1);
IR (film, cm-1) 2963, 2930, 1709, 1456, 1377, 1271, 1138, 972,
924, 874, 818, 679; 1H NMR (CDCl3) δ 1.25 (s, 3 H, H-8), 1.29
(s, 3 H, Me at C-7), 1.30 (t, J ) 7.4 Hz, 3 H, SCH2CH3), 1.73
(s, 3 H, Me at 3), 2.20 (m, 2 H, H-4), 2.68 (t, J ) 6.2 Hz, 1 H,
H-6), 2.85 (q, J ) 7.4 Hz, 2 H, SCH2CH3), 4.72 (d, J ) 7.2 Hz,
2 H, H-1), 5.40 (dt, J ) 7.3, 1.1 Hz, 1 H, H-2); 13C NMR (CDCl3)
δ 14.99, 16.44, 18.71, 24.78, 25.31, 27.01, 36.17, 58.33, 63.76,
63.84, 118.40, 142.28, 171.03; MS (m/z, relative intensity) 172
(4), 153 (12), 135 (16), 109 (17), 95 (35), 81 (76), 71 (82), 49
(83), 43 (100). Anal. (C13H22O3S) C, H.
4-Hyd r oxyp h en yl P h en yl Su lfid e (47). A mixture of
phenol (45; 600 mg, 6.4 mmol) and benzensulfinic acid (46;
1.605 g, 11.3 mmol) was heated to 60 °C, and the reaction
mixture was stirred at this temperature for 1 h. The mixture
was partitioned between an aqueous saturated solution of
potassium carbonate (100 mL) and methylene chloride (100
mL). The organic layer was washed with water (3 × 70 mL)
and dried (MgSO4), and the solvent was evaporated. The
residue was purified by column chromatography (silica gel)
eluting with toluene-EtOAc (49:1). The more polar residue
was repurified by column chromatography eluting with hex-
anes-EtOAc (4:1) to give 250 mg (19% yield) of pure compound
47 as a colorless oil: Rf 0.45 (toluene-EtOAc, 9:1); IR (film,
cm-1) 3370, 3059, 1701, 1599, 1492, 1448, 1362, 1261, 1177,
1106, 1027, 835, 740, 692, 535; MS (m/z, relative intensity)
202 (M+, 100), 183, 173, 141. Anal. (C12H10OS‚1/3EtOAc) C,
H.
2,4-Dich lor op h en oxyeth yl Tetr a h yd r o-2H-p yr a n -2-yl
Eth er (51). To a suspension of 2,4-dichlorophenol (820 mg, 5
mmol) and potassium hydroxide (1.100 g, 20 mmol) in dimethyl
sulfoxide (3 mL) was added bromoethyl tetrahydropyranyl
ether (2.090 g, 10 mmol) following the method described for
13. After the usual treatment the product was purified by
column chromatography (silica gel) employing hexanes-EtOAc
(9:1) as eluent to give 407 mg (28% yield) of pure compound
51 as a colorless oil: Rf 0.43 (hexanes-EtOAc, 4:1); IR (film,
cm-1) 2943, 2871, 1585, 1480, 1292, 1265, 1080, 1015, 802, 739;
1H NMR (CDCl3) δ 1.52-1.84 (m, 6 H, H-3′′, H-4′′, H-5′′), 3.51
(m, 1 H, H-6′′a), 3.85 (m, 2 H, H-1), 4.04 (m, 1 H, H-6′′b), 4.17
(distorted t, J ) 4.7 Hz, 2 H, H-2), 4.72 (m, 1 H, H-2′′), 6.87
(d, J ) 8.8 Hz, 1 H, H-5′), 7.14 (dd, J ) 8.8, 2.5 Hz, 1 H, H-4′),
7.34 (d, J ) 2.5 Hz, 1 H, H-3′); 13C NMR (CDCl3) δ 19.19 (C-
4′′), 25.33 (C-3′′), 30.40 (C-5′′), 61.98 (C-1), 65.39 (C-2′′), 69.07
(C-2), 98.94 (C-6′′), 114.61 (C-6′), 123.92 (C-2′), 125.84 (C-4′),
127.40 (C-5′), 129.85 (C-3′), 153.36 (C-1′); MS (m/z, relative
intensity) 290, 292, 294 (M+, 13, 9, 1), 129 (79), 85 (100). Anal.
(C13H16O3Cl2) C, H.
4-P h en oxyp h en yl P r op -1-en -1-yl Eth er (52). To a solu-
tion of compound 6 (326 mg, 1.4 mmol) in anhydrous tetrahy-
drofuran (7 mL) was added dropwise a 2.0 M solution of
n-butyllithium (1.12 mL) at 0 °C under nitrogen atmosphere.
The mixture was stirred at room temperature for 1 h. Then,
a saturated solution of ammonium chloride (20 mL) was added.
The mixture was extracted with methylene chloride (3 × 15
mL). The combined layers were washed with water (2 × 20
mL) and dried (MgSO4), and the solvent was evaporated. The
residue was purified by column chromatography (silica gel)
eluting with hexane-CH2Cl2 (9:1) to afford 63 mg (20% yield)
of pure compound 52 as a colorless oil: Rf 0.5 (hexane-CH2-
Cl2, 4:1); IR (film, cm-1) 3043, 2922, 2865, 1700, 1588, 1504,
1
1219, 1110, 1021, 843, 751, 691; H NMR (CDCl3) δ 1.72 (dd,
J ) 6.7, 1.7 Hz, 3 H, H-3), 4.85 (m, 1 H, H-2), 6.33 (dd, J )
6.4, 1.7 Hz, 1 H, H-1), 6.93-7.34 (m, 9 H, aromatic protons);
13C NMR (CDCl3) δ 9.33 (C-3), 107.21 (C-2), 117.36 (C-2′′),
117.96 (C-2′), 120.56 (C-3′), 122.73 (C-4′′), 129.66 (C-3′′), 141.33
(C-1), 153.70 (C-1′), 158.15 (C-1′′); MS (m/z, relative intensity)
226 (M+, 100), 197 (23), 186 (55), 170 (10), 157 (14), 141 (6),
129 (18), 115 (13), 109 (17), 91 (6), 77 (37), 63 (8), 51 (25). Anal.
(C15H14O2) C, H.
4-(P h en ylth io)p h en yl P r op -2-en -1-yl Eth er (48).
A
solution of compound 47 (100 mg, 0.5 mmol) in dimethyl
sulfoxide (3 mL) was treated with allyl bromide following the
general procedure. The residue was purified by column
chromatography (silica gel) employing hexanes-EtOAc (19:
1) as eluent to afford 119 mg (96% yield) of pure allyl ether
48 as a colorless oil: Rf 0.63 (hexanes-EtOAc, 4:1); IR (film,
cm-1) 3073, 3019, 2916, 2868, 2541, 1891, 1593, 1493, 1285,
1242, 1173, 1024, 928, 739, 691, 532; 1H NMR (CDCl3) δ 4.55
(d, J ) 5.2 Hz, 2 H, H-1), 5.30 (d, J ) 10.5 Hz, 1 H, H-3cis),
5.42 (d, J ) 17.2 Hz, 1 H, H-3trans), 6.06 (ddt, J ) 17.2, 10.4,
5.1 Hz, 1 H, H-2), 6.91 (d, J ) 8.8 Hz, 2 H, H-2′, H-6′), 7.19
(m, 5 H, aromatic protons), 7.40 (d, J ) 8.7 Hz, 2 H, H-3′, H-5′);
13C NMR (CDCl3) δ 68.86 (C-1), 115.79 (C-2′), 117.81 (C-3),
124.73 (C-4′), 125.77 (C-4′′), 128.32 (C-3′′), 128.87 (C-2′′), 132.93
(C-2), 135.13 (C-3′), 138.42 (C-1′′), 158.77 (C-1′); MS (m/z,
relative intensity) 242 (M+, 38), 201 (100), 171 (8), 129 (17).
Anal. (C15H14OS) C, H.
4-P h en oxyp h en oxyeth yl 4-Tolu en esu lfon a te (54) a n d
4-P h en oxyp h en oxyeth yl Ch lor id e (55). A solution of
alcohol 53 (960 mg, 4.17 mmol) in pyridine (5 mL) was treated
with p-toluenesulfonyl chloride (954 mg, 5.0 mmol), and the
mixture was stirred at room temperature for 4 h. Then, 5%
HCl (50 mL) was added, and the reaction mixture was stirred
for an additional hour. The mixture was extracted with
methylene chloride (50 mL), and the organic layer was washed
with 5% HCl (3 × 50 mL) and H2O (3 × 50 mL). The organic
phase was dried (MgSO4), and the solvent was evaporated. The
residue was purified by column chromatography (silica gel)
employing hexanes-EtOAc (9:1) as eluent to afford 1.068 mg
of tosylate 54 (70% yield) and 210 mg of chloride 55 (17% yield)
as colorless oils. Compound 54: Rf 0.16 (hexanes-EtOAc, 4:1);
IR (film, cm-1) 3070, 2955, 2926, 1589, 1504, 1360, 1223, 1190,
932, 777, 553; MS (m/z, relative intensity) 384 (M+, 10), 248
(7), 199 (53), 185 (15), 155 (28), 91 (56), 49 (100). Compound
55: Rf 0.59 (hexanes-EtOAc, 4:1); IR (film, cm-1) 3064, 2962,
2927, 2866, 1589, 1504, 1220, 1039, 841, 756, 513; MS (m/z,
2,4-Dich lor op h en yl P r op -2-en -1-yl Eth er (50). Com-
pound 50 was obtained as described for compound 13 from
2,4-dichlorophenol (compound 49; 1.635 g, 10 mmol). After
the usual treatment the residue was purified by column
chromatography (silica gel) eluting with hexanes-EtOAc (19:
1) to afford 1.502 g (74% yield) of pure allyl ether 50 as a

SAR of New Growth Inhibitors of T. cruzi
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9 1551
relative intensity) 250 (23), 248 (M+, 64), 185 (61), 129 (34),
84 (62), 79 (68), 49 (100).
relative intensity) 317 (M+, 10), 186 (100), 132 (86). Anal.
(C17H19O3NS) C, H, N, S.
S-(4-P h en oxyph en oxyeth yl) Eth yl Th iolcar bon ate (60).
Mercaptane 58 (72 mg, 0.29 mmol) in pyridine (3 mL) was
treated with ethyl chloroformate (0.1 mL). The reaction
mixture was stirred at room temperature overnight. The
mixture was partitioned between methylene chloride (50 mL)
and 10% HCl (50 mL). The organic phase was washed with
10% HCl (4 × 50 mL) and water (3 × 50 mL). The organic
layers were dried (MgSO4), and the solvent was evaporated.
The residue was purified by column chromatography (silica
gel) eluting with toluene-ethyl acetate (99:1) to afford 51 mg
(55% yield) of pure thiolcarbonate 60 as a colorless oil: Rf 0.52
(hexanes-EtOAc, 4:1); IR (film, cm-1) 3038, 2984, 2930, 1719,
4-P h en oxyp h en oxyeth yl Th iocya n a te (56). A solution
of tosylate 54 (1.068 mg, 2.89 mmol) in anhydrous dimethyl-
formamide (5 mL) was treated with potassium thiocyanate
(1.966 mg, 20.23 mmol). The reaction mixture was heated at
100 °C for 3 h. The mixture was allowed to cool to room
temperature, and water (70 mL) was added. The aqueous
phase was extracted with methylene chloride (2 × 50 mL), and
the combined organic layers were washed with brine (5 × 50
mL) and water (2 × 50 mL). The solvent was dried (MgSO4)
and evaporated. The residue was purified by column chro-
matography (silica gel) eluting with hexanes-EtOAc (4:1) to
give 573 mg (73% yield) of pure compound 56 as a white
solid: Rf 0.27 (hexanes-EtOAc, 4:1); mp 52 °C (EtOH-H2O);
1
1604, 1146, 864; H NMR (CDCl3) δ 1.31 (t, J ) 7.0 Hz, 3 H,
1
IR (film, cm-1) 3051, 2936, 2869, 2156, 1504, 1228; H NMR
-CH2CH3), 3.22 (t, J ) 6.6 Hz, 2 H, H-1), 4.15 (t, J ) 6.6 Hz,
2 H, H-2), 4.29 (q, J ) 7.0 Hz, 2 H, -CH2CH3), 6.86-7.07 (m,
7 H, aromatic protons), 7.25-7.33 (m, 2 H, aromatic protons);
13C NMR (CDCl3) δ 14.24 (CH2CH3), 30.08 (C-1), 63.77 (CH2-
CH3), 67.20 (C-2), 115.74 (C-2′′), 117.69 (C-2′), 120.69 (C-3′),
122.48 (C-4′′), 129.56 (C-3′′), 150.58 (C-4′),154.56 (C-1′), 158.32
(C-1′′), 170.52 (CdO); MS (m/z, relative intensity) 318 (M+,
6), 186 (18), 133 (28), 84 (50), 49 (100). Anal. (C17H18O4S) C,
H.
(CDCl3) δ 3.33 (t, J ) 5.8 Hz, 2 H, H-1), 4.30 (t, J ) 5.8 Hz, 2
H, H-2), 6.87-7.09 (m, 7 H, aromatic protons), 7.25-7.34 (m,
2 H, aromatic protons); 13C NMR (CDCl3) δ 33.23 (C-1), 66.37
(C-2), 113.47 (SCN), 115.86 (C-2′′), 117.78 (C-2′), 120.63 (C-
3′), 122.65 (C-4′′), 129.58 (C-3′′), 151.16 (C-4′),153.89 (C-1′),
158.01 (C-1′′); MS (m/z, relative intensity) 271 (M+, 100), 185
(86). Anal. (C15H13O2NS) C, H, N, S.
4-P h en oxyp h en oxyet h yl Disu lfid e (57) a n d 4-P h en -
oxyp h en oxyeth yl Mer ca p ta n e (58). Thiocyanate 56 (297
mg, 1.1 mmol) was treated with a 1.0 M solution of sodium
methoxide in anhydrous methanol (5 mL). The reaction
mixture was stirred at room temperature for 2 h. The mixture
was partitioned between water (70 mL) and methylene chloride
(70 mL). The organic layer was washed with water (5 × 50
mL) and dried (MgSO4), and the solvent was evaporated to
afford 265 mg of a 2:1 mixture of 57 and 58 favoring the
disulfide. The residue was dissolved in glacial acetic acid, and
zinc (642 mg, 9.8 mmol) was added. The reaction mixture was
refluxed for 1 h. The mixture was allowed to cooled to room
temperature and was partitioned between water (50 mL) and
methylene chloride (70 mL). The organic phase was washed
with water (2 × 50 mL) and dried (MgSO4), and the solvent
was evaporated to yield 245 mg (91% yield) of pure sulfide 58
as a white solid. This compound was used without further
purification. To characterize both components, 100 mg of the
mixture 57/58, in an independent experiment, could be re-
solved by column chromatography (silica gel) eluting with
hexane-i-PrOH (1%) to afford 61 mg of disulfide 57 as a white
solid and 30 mg of pure compound 58. Compound 57: Rf 0.58
(hexanes-EtOAc, 4:1); mp 68-69 °C (MeOH-EtOAc); IR (film,
cm-1) 3042, 2922, 2868, 1589, 1504, 1487, 1215, 1020, 841, 752,
528; MS (m/z, relative intensity) 279 (1), 260 (11), 246 (20),
186 (100), 75 (80); FABMS (m/z, relative intensity) 490 (53),
503 (100). Anal. (C28H26O4S2‚EtOAc) C, H. Compound 58:
Rf 0.64 (hexanes-EtOAc, 4:1); mp 45 °C (MeOH); IR (film,
cm-1) 3041, 2931, 2868, 1589, 1504, 1490, 1220, 843; MS (m/
z, relative intensity) 246 (M+, 30), 185 (100).
S-(4-P h en oxyp h en oxyeth yl) Isobu tyl Th iolca r bon a te
(61). A solution of mercaptane 58 (30 mg, 0.12 mmol) in
pyridine (2 mL) was treated with isobutyl chloroformate (0.1
mL), and the reaction mixture was stirred at room tempera-
ture overnight. The reaction mixture was worked up as
described for compound 60 and purified by column chroma-
tography (silica gel) eluting with toluene-hexanes-ethyl
acetate (50:50:0.75) to give 14 mg (40% yield) of isobutyl
thiolcarbonate 61 as a colorless oil: Rf 0.43 (hexanes-EtOAc,
19:1); IR (film, cm-1) 2962, 1717, 1506, 1223, 1142, 841, 754;
1H NMR (CDCl3) δ 0.94 (d, J ) 6.8 Hz, 6 H, -CH(CH3)2), 1.98
(m, 1 H, -CH(CH3)2), 3.23 (t, J ) 6.5 Hz, 2 H, H-1), 4.02 (d, J
) 6.6 Hz, 2 H, -CH2CH), 4.15 (t, J ) 6.5 Hz, 2 H, H-2), 6.86-
7.11 (m, 7 H, aromatic protons), 7.25-7.33 (m, 2 H, aromatic
protons); 13C NMR (CDCl3) δ 18.90 (-CH(CH3)2), 27.87 (-CH-
(CH3)2), 30.14 (C-1), 67.29 (C-2), 73.72 (-CH2CH), 115.79 (C-
2′′), 117.73 (C-2′), 120.72 (C-3′), 122.52 (C-4′′), 129.59 (C-3′′),
150.63 (C-4′), 154.61 (C-1′), 158.34 (C-1′′), 170.71 (CdO); MS
(m/z, relative intensity) 346 (M+, 12), 186 (75), 149 (21), 105
(29), 57 (100). Anal. (C19H22O4S) C, H.
4-P h en oxyp h en oxyeth yl Eth yl Dith iolca r bon a te (62).
To a solution of mercaptane 58 (66 mg, 0.27 mmol) in pyridine
(3 mL) was added ethyl chlorothiolformate (0.1 mL), and the
reaction mixture was stirred at room temperature for 16 h.
The reaction mixture was worked up as described for 60 and
purified by column chromatography using hexanes-ethyl
acetate (97:3) as eluent to afford 40 mg (44% yield) of
dithiolcarbonate 62 as a pale yellow oil: Rf 0.42 (hexanes-
EtOAc, 19:1); IR (film, cm-1) 3044, 2972, 2932, 2874, 1747,
1647, 1506, 1244, 872, 739; 1H NMR (CDCl3) δ 1.31 (t, J ) 7.4
Hz, 3 H, -CH2CH3), 2.99 (q, J ) 7.4 Hz, 2 H, -CH2CH3), 3.35
(t, J ) 6.4 Hz, 2 H, H-1), 4.11 (t, J ) 6.5 Hz, 2 H, H-2), 6.84-
7.04 (m, 7 H, aromatic protons), 7.25-7.32 (m, 2 H, aromatic
protons); 13C NMR (CDCl3) δ 14.89 (CH2CH3), 25.30 (CH2CH3),
29.56 (C-1), 67.18 (C-2), 115.78 (C-2′′), 117.72 (C-2′), 120.71
(C-3′), 122.53 (C-4′′), 129.58 (C-3′′), 150.66 (C-4′), 154.51 (C-
1′), 158.31 (C-1′′), 189.20 (CdO); MS (m/z, relative intensity)
334 (M+, 16), 260 (7), 246 (18), 186 (39), 149 (67), 89 (54), 75
(100). Anal. (C17H18O3S2) C, H.
S-(4-P h en oxyp h en oxyet h yl) N-E t h ylt h iolca r b a m a t e
(59). Compound 58 (70 mg, 0.28 mmol) in pyridine (3 mL)
was treated with ethyl isocyanate (0.1 mL) and 4-(dimethyl-
amino)pyridine (10 mg). The reaction mixture was stirred for
4 h. The mixture was partitioned between methylene chloride
(50 mL) and 10% HCl (50 mL). The organic phase was washed
with 10% HCl (4 × 50 mL) and water (3 × 50 mL). Then, the
organic layers were dried (MgSO4) and evaporated. The
residue was purified by column chromatography employing
hexanes-ethyl acetate (4:1) as eluent to give 50 mg (56% yield)
of pure thiolcarbamate 59 as a white solid: Rf 0.21 (hexanes-
EtOAc, 4:1); mp 86-87 °C; IR (film, cm-1) 2978, 2935, 2874,
1655, 1589, 1507, 1489, 1221, 845; 1H NMR (CDCl3) δ 1.17 (t,
J ) 7.2 Hz, 3 H, -CH2CH3), 3.28 (t, J ) 6.5 Hz, 2 H, H-1),
3.34 (m, 2 H, -CH2CH3), 4.13 (t, J ) 6.5 Hz, 2 H, H-2), 5.47
(broad s, 1 H, -NH), 6.87-7.07 (m, 7 H, aromatic protons),
7.29 (m, 2 H, aromatic protons); 13C NMR (CDCl3) δ 14.87
(CH2CH3), 29.05 (C-1), 36.48 (CH2CH3), 67.93 (C-2), 115.73 (C-
2′′), 117.66 (C-2′), 120.68 (C-3′), 122.44 (C-4′′), 129.54 (C-3′′),
150.46 (C-4′), 154.69 (C-1′), 158.34 (C-1′′); MS (m/z,
4-P h en oxyp h en oxyeth yl O-Eth yl Xa n th a te (63).
A
solution of tosylate 54 (38 mg, 0.105 mmol) in dimethyl
sulfoxide (2 mL) was treated with potassium O-ethyl xanthate
(87 mg, 0.52 mmol). The reaction mixture was stirred at 90
°C for 2 h. Then, the mixture was allowed to cool to room
temperature and was partitioned between water (50 mL) and
methylene chloride (50 mL). The aqueous phase was extracted
with methylene chloride (3 × 40 mL). The combined organic
layers were washed with brine (5 × 50 mL) and water (2 × 50
mL) and dried (MgSO4), and the solvent was evaporated. The
residue was purified by column chromatography (silica gel)

1552 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9
Cinque et al.
using hexanes-EtOAc (9:1) as eluent to give 30 mg (86% yield)
of pure xanthate 63 as a colorless oil: Rf 0.56 (hexanes-EtOAc,
9:1); IR (film, cm-1) 2994, 2933, 1589, 1504, 1489, 1221, 1111,
60 °C; IR (KBr, cm-1) 3070, 2872, 1593, 1508, 1302, 1244, 1105,
1034, 839, 773, 743, 613; 1H NMR (CDCl3) δ 2.33 (dd, J ) 5.2,
1.4 Hz, 1 H, H-3a), 2.62 (d, J ) 6.2 Hz, 1 H, H-3b), 3.28 (m, 1
H, H-2), 3.92 (dd, J ) 10.2, 6.9 Hz, 1 H, H-1a), 4.19 (dd, J )
10.2, 5.4 Hz, 1 H, H-1b), 6.867.36 (m, 9 H, aromatic protons);
13C NMR (CDCl3) δ 23.92 (C-3), 31.44 (C-2), 73.31 (C-1), 115.98
(C-2′′), 117.83 (C-2′), 120.78 (C-3′), 122.63 (C-4′′), 129.69 (C-
3′′), 150.85 (C-4′), 154.73 (C-1′), 158.37 (C-1′′); MS (m/z, relative
intensity) 258 (M+, 35), 185 (19), 129 (18), 83 (20), 73 (100).
Anal. (C15H14O2S) C, H.
2-[4-(Ben zyloxy)p h en oxy]eth yl Tetr a h yd r o-2H-p yr a n -
2-yl Eth er (71). A solution of 4-(benzyloxy)phenol (70; 2.00
g, 9.9 mmol) in dimethyl sulfoxide (5 mL) was treated with
bromoethyl tetrahydropyranyl ether as depicted for 13. After
the usual workup, the product was purified by column chro-
matography eluting with hexanes-EtOAc (4:1) to yield 1.786
g (55% yield) of pure compound 71 as a colorless oil: Rf 0.39
(hexanes-EtOAc, 4:1); IR (film, cm-1) 3051, 2943, 2872, 1508,
1454, 1231, 1034, 826, 737, 525; 1H NMR (CDCl3) δ 1.53-1.87
(m, 6 H, H-3′′′, H-4′′′, H-5′′′), 3.51 (m, 1 H, H-6′′′a), 3.46-4.00
(m, 3 H), 4.03-4.12 (m, 2 H), 4.67 (distorted t, J ) 3.3 Hz, 1
H, H-2′′′), 5.00 (s, 2 H, PhCH2O), 6.87 (m AB, 4 H, H), 7.24-
7.42 (m, 5 H, aromatic protons); 13C NMR (CDCl3) δ 19.32 (C-
4′′′), 25.39 (C-5′′′), 30.48 (C-3′′′), 62.11 (C-6′′′), 65.89 (C-1), 68.08
(C-2), 70.65 (PhCH2), 98.91 (C-2′′′), 115.76 (C-2′, C-3′), 127.39
(C-4′′),* 127.78 (C-2′′),* 128.46 (C-3′′), 137.29 (C-1′′), 153.07
(C-1′); MS (m/z, relative intensity) 328 (M+, 20), 129 (77), 91
(99), 85 (100). Anal. (C20H24O4) C, H.
2-[4-(Ben zyloxy)p h en yl]eth a n ol (72). A solution of com-
pound 71 (1.496 g, 4.6 mmol) in methanol (30 mL) was treated
with pyridinium 4-toluenesulfonate (30 mg). The reaction
mixture was stirred at room temperature overnight. Then,
water (50 mL) was added, and the mixture was extracted with
methylene chloride (3 × 50 mL). The combined organic layers
were washed with brine (3 × 50 mL) and dried (MgSO4), and
the solvent was evaporated. The residue was purified by
column chromatography eluting with hexanes-EtOAc (7:3) to
give 919 mg (82% yield) of pure alcohol 72 as a white solid:
Rf 0.10 (hexanes-EtOAc, 4:1); mp 103 °C; IR (KBr, cm-1) 3491,
2961, 2914, 1612, 1512, 1454, 1250, 1055, 903, 802, 729, 698,
604; MS (m/z, relative intensity) 244 (M+, 55), 153 (21), 109
(63), 91 (100). Anal. (C15H16O3) C, H.
2-[4-(Ben zyloxy)p h en yl]eth yl 4-Tolu en esu lfon a te (73).
A solution of alcohol 72 (909 mg, 3.72 mmol) in anhydrous
pyridine (3 mL) was treated with tosyl chloride (850 mg, 4.46
mmol) at 0 °C. The mixture was stirred at room temperature
for 5 h. The reaction mixture was worked up as described for
54. The residue was purified by column chromatography
(silica gel) eluting with hexanes-EtOAc (19:1) to afford 1.217
g (82% yield) of pure tosylate 73 as a white solid: Rf 0.74
(hexane-EtOAc); mp 90-92 °C; MS (m/z, relative intensity)
398 (M+, 14), 199 (41), 155 (16), 91 (100). Anal. (C22H22O5S)
C, H.
1
1051, 842, 756, 692; H NMR (CDCl3) δ 1.42 (t, J ) 7.0 Hz, 3
H, -CH2CH3), 3.53 (t, J ) 6.5 Hz, 2 H, H-1), 4.20 (t, J ) 6.5
Hz, 2 H, H-2), 4.67 (q, J ) 7.0 Hz, 2 H, -CH2CH3), 6.85-7.07
(m, 7 H, aromatic protons), 7.25-7.33 (m, 2 H, aromatic
protons); 13C NMR (CDCl3) δ 13.78 (-CH2CH3), 34.98 (C-1),
66.30 (C-2), 70.25 (-CH2CH3), 115.81 (C-2′′), 117.71 (C-2′),
120.70 (C-3′), 122.52 (C-4′′), 129.58 (C-3′′), 150.63 (C-4′), 154.56
(C-1′), 158.31 (C-1′′), 214.27 (CdS); MS (m/z, relative intensity)
334 (M+, 1), 248 (70), 185 (79), 149 (43), 129 (50), 77 (100).
Anal. (C17H18O3S2) C, H.
P r op -2-en -1-yl O-(4-P h en oxyp h en oxyeth yl) Xa n th a te
(64). A solution of alcohol 53 (70 mg, 0.28 mmol) in anhydrous
dimethylformamide (2 mL) was treated with carbon disulfide
(1 mL) and DBU (20 mg). The mixture was stirred at room
temperature for 20 min, and allyl bromide (100 µL) was added.
The reaction mixture was stirred for 30 min. The mixture was
partitioned between water (50 mL) and methylene chloride (50
mL). The aqueous phase was extracted with methylene
chloride (2 × 30 mL). The combined organic layers were
washed with brine (5 × 50 mL) and water (2 × 50 mL) and
dried (MgSO4), and the solvent was evaporated. The residue
was purified by column chromatography employing hexanes-
EtOAc (19:1) as eluent to give 40 mg (39% yield) of pure
xanthate 64 as a yellow oil: Rf 0.51 (hexanes-EtOAc, 9:1);
IR (film, cm-1) 2994, 2933, 1589, 1504, 1489, 1221, 1111, 1051,
842, 756, 692; 1H NMR (CDCl3) δ 3.78 (dt, J ) 7.0, 1.0 Hz,
SCH2CHdCH2), 4.30 (t, J ) 4.6 Hz, 2 H, H-2), 4.92 (t, J ) 4.6
Hz, 2 H, H-1), 5.16 (dd, J ) 10.1, 1.1 Hz, H-3′′′cis), 5.33 (dq, J
) 17.0, 1.2 Hz, 1 H, H-3′′′trans), 5.93 (ddt, J ) 17.0, 7 Hz, 1 H,
H-2′′′), 6.87-7.08 (m, 7 H, aromatic protons), 7.24-7.33 (m, 2
H, aromatic protons); 13C NMR (CDCl3) δ 38.90 (C-1), 65.92
(C-2), 71.51 (-OCH2CHdCH2), 115.85 (C-2′′), 117.77 (C-2′),
119.05 (-OCH2CHdCH2), 120.73 (C-3′), 122.58 (C-4′′), 129.61
(C-3′′), 131.55 (-OCH2CHdCH2), 150.80 (C-4′), 154.57 (C-1′),
156.24 (C-1′′); MS (m/z, relative intensity) 346 (M+, 1), 248
(12), 185 (20), 161 (63), 77 (70), 41 (100). Anal. (C18H18O3S2)
C, H.
3-(4-P h en oxyp h en oxy)p r op yl 4-Tolu en esu lfon a te (66).
A solution of alcohol 65 (570 mg, 0.23 mmol) in anhydrous
pyridine (5 mL) was treated with tosyl chloride (530 mg) at 0
°C. The mixture was stirred at room temperature overnight.
The reaction was quenched as described for 54. The residue
was purified by column chromatography (silica gel) eluting
with hexanes-EtOAc (4:1) as eluent to yield 550 mg (60%
yield) of pure tosylate 66 as a colorless oil: Rf 0.27 (hexanes-
EtOAc, 4:1).
3-(4-P h en oxyp h en oxy)p r op yl Th iocya n a te (67). To a
solution of tosylate 66 (158 mg, 0.4 mmol) in anhydrous N,N-
dimethylformamide (3 mL) was added potassium thiocyanate
(400 mg, 4.1 mmol). The reaction mixture was treated as
described for 56. After the usual workup, the product was
purified by column chromatography (silica gel) employing
hexanes-EtOAc as eluent to afford 100 mg (87% yield) of pure
compound 67 as a colorless oil: Rf 0.46 (hexanes-EtOAc, 4:1);
IR (film, cm-1) 2924, 2871, 2154, 1589, 1504, 1489, 1219, 1043,
2-[4-(Ben zyloxy)p h en yl]eth yl Th iocya n a te (74). A so-
lution of compound 73 in N,N-dimethylformamide (5 mL) was
treated with potassium thiocyanate (610 mg). The reaction
mixture was stirred at 100 °C for 3 h. The reaction was
quenched as depicted for 56. The residue was purified by
column chromatography (silica gel) using hexane-CH2Cl2 (7:
3) as eluent to afford a 70% yield of pure thiocyanate 74 as a
white solid: Rf 0.33 (hexanes-EtOAc, 1:1); mp 78 °C; IR (KBr,
cm-1) 2928, 2882, 2156, 1516, 1464, 1402, 1296, 1242, 1045,
833, 737, 694; 1H NMR (CDCl3) δ 3.30 (t, J ) 5.9 Hz, 2 H,
H-1), 4.26 (t, J ) 5.9 Hz, 2 H, H-2), 5.02 (s, 2 H, PhCH2O),
6.89 (m AB, 4 H, H-2′, H-3′), 7.31-7.44 (m, 5 H, aromatic
protons); 13C NMR (CDCl3) δ 33.26 (C-1), 66.55 (C-2), 70.57
(PhCH2O), 115.51 (C-2′),* 115.89 (C-3′),* 127.34 (C-2′′), 127.82
(C-4′′), 128.45 (C-3′′), 137.03 (C-1′′), 152.04 (C-4′), 153.69 (C-
1′); MS (m/z, relative intensity) 285 (M+, 70), 186 (64), 185
(48), 129 (25), 77 (100). Anal. (C16H15O2NS): C, H, N.
1
872, 843, 752, 692; H NMR (CDCl3) δ 2.30 (p, J ) 6.6 Hz, 2
H, H-2), 3.19 (t, J ) 6.9 Hz, 2 H, H-1), 4.10 (t, J ) 5.7 Hz, 2
H, H-3), 6.82-7.33 (m, 9 H, aromatic protons); 13C NMR
(CDCl3) δ 31.37 (C-1), 36.39 (C-2), 65.18 (C-3), 115.52 (C-2′′),
117.73 (C-2′), 120.71 (C-3′), 122.55 (C-4′′), 129.58 (C-3′′), 154.57
(C-1′), 158.26 (C-1′′); MS (m/z, relative intensity) 285 (M+, 47),
197 (6), 186 (50), 129 (33), 85 (51), 77 (83), 41 (100). Anal.
(C16H15O2NS) C, H, N.
4-P h en oxyp h en yl 2,3-Ep isu lfop r op -1-yl Eth er (69). A
solution of epoxide 68 (186 mg, 0.77 mmol) in N,N-dimethyl-
formamide (3 mL) was treated with potassium thiocyanate
(500 mg), and the mixture was stirred at 100 °C for 3 h. The
mixture was worked up as depicted for 56, and the residue
was purified by column chromatography eluting with hex-
anes-EtOAc (9:1) to afford 93 mg (47% yield) of pure com-
pound 69 as a white solid: Rf 0.38 (hexanes-EtOAc, 9:1); mp
2-(4-Ben zylp h en oxy)et h yl Tet r a h yd r o-2H -p yr a n -2-yl
Eth er (76). 4-Benzylphenol (75; 867 mg, 4.7 mmol) was
treated with potassium hydroxide (655 mg, 11.7 mmol) and
bromoethyl tetrahydropyranyl ether (1.360 g, 6.5 mmol) as

SAR of New Growth Inhibitors of T. cruzi
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9 1553
(3) Brener, Z. Biology of Trypanosoma cruzi. Annu. Rev. Microbiol.
1973, 27, 347-382.
(4) Kirchhoff, L. V. American Trypanosomiasis (Chagas’ Disease)-A
Tropical Disease now in the United States. N. Engl. J . Med.
1993, 329, 639-644.
(5) Galel, S. A.; Kirchhoff, L. V. Risk factors for Trypanosoma cruzi
infection in California blood donors. Transfusion 1996, 36, 227-
231.
(6) Canc¸ado, J . R.; Brener, Z. In Trypanosoma cruzi e Doenc¸a de
Chagas; Brener, Z., Andrade, Z., Eds.; Guanabara Koogan: Sao
Paulo, 1979; pp 362-424.
(7) Brener, Z. Present Status of the Chemotherapy and Chemopro-
phylaxis of Human Trypanosomiasis in the Western Hemi-
sphere. Pharmacol. Ther. 1979, 7, 71-90.
(8) Schmun˜is, G. A.; Szarfman, A.; Coarasa, L.; Guilleron, C.;
Peralta, J . M. Anti-Trypanosoma cruzi Agglutinins in Acute
Human Chagas’ Disease. Am. J . Trop. Med. Hyg. 1980, 29, 170-
178.
(9) Marr, J . J .; Docampo, R. Chemotherapy for Chagas’ Disease: a
Perspective of Current Therapy and Considerations for Future
Research. Rev. Infect. Dis. 1986, 8, 884-903.
(10) Ferreira, A. O. Tratamento da Forma Indeterminada da Doenc¸a
de Chagas com Nifurtimox e Benznidazol. Rev. Soc. Bras. Med.
Trop. 1990, 23, 209-211.
(11) Nussenzweig, V.; Sonntag, R.; Biancalana, A.; Pedreira de
Fleitas, J . L.; Amato Neto, V.; Kloetzel, J . Aca˜o de Corantes
Trifenil-metanicos sobre o Trypanosoma cruzi “in vitro.” Em-
preˆgo de Violeta de Genciana na Profilaxia da Transmissa˜o da
Mole´stia de Chagas por Transfusa˜o de Sangue. Hospital (Rio
de J aneiro) 1953, 44, 731-744.
(12) Docampo, R.; Moreno, S. N. J . Biochemical Toxicology of Anti-
parasitic Compounds Used in the Chemotherapy and Chemo-
prophylaxis of American Trypanosomiaisis (Chagas’ Disease).
Rev. Biochem. Toxicol. 1985, 7, 159-204.
described for 13. After the usual workup, the product was
purified by column chromatography eluting with hexanes-
EtOAc (19:1) to afford 966 mg (65% yield) of pure compound
76 as a colorless oil: Rf 0.24 (hexanes-EtOAc, 19:1); IR (film,
cm-1) 3028, 2941, 2872, 1612, 1510, 1454, 1246, 1126, 1034,
729, 698; 1H NMR (CDCl3) δ 1.54-1.80 (m, 6 H), 3.54 (m, 1 H,
H-6′′′a), 3.77-4.02 (m, 3 H), 3.91 (s, 2 H, PhCH2), 4.04-4.15
(m, 2 H), 4.69 (distorted t, J ) 3.3 Hz, 1 H, H-2′′′), 6.85 (d, J
) 8.6 Hz, 2 H, H-2′), 7.08 (d, J ) 8.6 Hz, 2 H, H-3′), 7.14-7.25
(m, 5 H, aromatic protons); 13C NMR (CDCl3) δ 19.30 (C-4′′′),
25.39 (C-5′′′), 30.46 (C-3′′′), 40.99 (PhCH2), 62.07 (C-6′′′), 65.80
(C-1), 67.42 (C-2), 98.88 (C-2′′′), 114.69 (C-2′), 125.89 (C-4′′),
128.34 (C-2′′), 128.75 (C-3′′), 129.75 (C-3′), 133.36 (C-4′), 141.51
(C-1′′), 157.28 (C-1′); MS (m/z, relative intensity) 318 (M+, 18),
184 (23), 129 (81), 85 (100). Anal. (C20H24O3) C, H.
2-(4-Ben zylp h en oxy)eth a n ol (77). To a solution of com-
pound 76 (966 mg, 3.04 mmol) in methanol (30 mL) was added
pyridinium p-toluenesulfonate (50 mg). The reaction mixture
was stirred at room temperature overnight. The mixture was
partitioned between water (50 mL), methylene chloride (50
mL). The aqueous phase was extracted with methylene
chloride (2 × 30 mL), the combined organic layers were washed
with brine (2 × 50 mL) and dried (MgSO4), and the solvent
was evaporated to afford 536 mg (77% yield) of pure alcohol
77 as a white solid. This alcohol was used in the next step
without further purification: Rf 0.11 (hexanes-EtOAc, 4:1);
mp 64-65 °C; IR (KBr, cm-1) 3491, 2961, 2914, 1612, 1512,
1454, 1250, 1055, 903, 802, 729, 698, 604; MS (m/z, relative
intensity) 228 (M+, 100), 184 (76), 183 (74), 165 (32), 106 (39),
91 (49).
(13) Rodriguez, J . B.; Gros, E. G. Recent Developments in the Control
of Trypanosoma cruzi, the Causative Agent for Chagas’ Disease.
Curr. Med. Chem. 1995, 2, 723-742.
(14) Rodriguez, J . B.; Gros, E. G.; Stoka, A. M. Synthesis and Activity
of J uvenile Hormone Analogues (J HA). Z. Naturforsch. 1988,
43B, 1038-1042.
(15) Rodriguez, J . B.; Gros, E. G.; Stoka, A. M. Synthesis and Activity
of J uvenile Hormone Analogues (J HA). Part II. Z. Naturforsch.
1989, 44B, 983-987.
(16) Stoka, A. M.; Rivas, C.; Segura, E.; Rodriguez, J . B.; Gros, E. G.
Biological Activity of Synthetic J uvenile Hormone Analogues for
Trypanosoma cruzi. Z. Naturforsch. 1990, 45B, 96-98.
(17) For a review of action of juvenile hormones of insects, see:
Kramer, S. J .; Law, J . H. Synthesis and Transport of J uvenile
Hormones in Insects. Acc. Chem. Res. 1980, 13, 297-303.
(18) Masner, P.; Dorn, S.; Vogel, W.; Kaelin, M.; Graf, O.; Guenthart,
E. Types of Response of Insects to a New Insect Growth
Regulators and to a Proven Standards. Pr. Nauk. Inst. Chem.
Org. Fiz. Politech. Wroclaw 1981, 22, 809-818.
(19) Perlawagora-Szumlewicz, A.; Petana W. P.; Figueiredo, M. J .
The Evaluation of Host Efficiency and Vector Potential of
Laboratory J uvenilized Vector of Chagas’ Disease. I - Effects
of Developmental Changes Induced by J uvenile Hormone Ana-
logues in Pantrongylus megistus (Hemiptera-Reduviidae) on the
Susceptibility of Insects to gut Infection with Trypanosoma cruzi.
Rev. Inst. Med. Trop. 1975, 17, 97-102.
2-(4-Ben zylp h en oxy)eth yl 4-Tolu en esu lfon a te (78). Al-
cohol 77 (500 mg, 2.19 mmol) in pyridine (5 mL) was treated
with tosyl chloride (500 mg, mmol) as depicted for 54. The
residue was purified by column chromatography (silica gel)
eluting with hexanes-EtOAc (85:15) to afford 528 mg (63%
yield) of pure tosylate 78 as a white solid: Rf 0.27 (hexanes-
EtOAc, 4:1); mp 49-51 °C; IR (KBr, cm-1) 3028, 3924, 1610,
1599, 1510, 1494, 1454, 1358, 1073, 1020, 922, 813, 781, 734.
Anal. (C22H22O4S) C, H.
2-(4-Ben zylp h en oxy)eth yl Th iocya n a te (79). To a solu-
tion of tosylate 78 (286 mg, 0.74 mmol) was added potassium
thiocyanate (363 mg, mmol). The solution was stirred at 100
°C for 3 h. After the usual workup, the product was purified
by column chromatography employing hexanes-EtOAc (19:
1) as eluent to give 104 mg (52% yield) of pure thiocyanate 79
as a colorless oil: Rf 0.36 (hexanes-EtOAc, 4:1); IR (film, cm-1
)
3028, 2918, 2872, 2154, 1611, 1508, 1242, 1177, 1030, 729, 698,
602; 1H NMR (CDCl3) δ 3.25 (t, J ) 5.9 Hz, 2 H, H-1), 3.91 (s,
2 H, PhCH2), 4.24 (t, J ) 5.9 Hz, 2 H, H-2), 6.83 (d, J ) 8.6
Hz, 2 H, H-2′), 7.11 (d, J ) 8.6 Hz, 2 H, H-3′), 7.17-7.30 (m,
5 H, aromatic); 13C NMR (CDCl3) δ 33.28 (C-1), 40.99 (PhCH2),
65.89 (C-1), 114.72 (C-2′), 126.02 (C-4′′), 128.41 (C-2′′), 128.75
(C-3′′), 130.01 (C-3′), 132.52 (C-4′), 141.25 (C-1′′), 156.18 (C-
1′); MS (m/z, relative intensity) 269 (M+, 50), 242 (19), 182
(64), 91 (100). Anal. (C16H15NOS) C, H, N.
(20) Vladusic, E. A.; Bussmann, L. E.; Visconti, P. E.; Stoka, A. M.;
Rodriguez, J . B.; Gros, E. G.; Charreau, E. H. Effect of J uvenile
Hormone on Mammalian Steroidogenesis. J . Steroid. Biochem.
Mol. Biol. 1994, 50, 181-187.
Ack n ow led gm en t. The authors would like to thank
the National Research Council of Argentina (CONICET)
and the University of Buenos Aires (Grant EX-017) for
partial financial support, UMYMFOR for spectra, and
NIH Grant AI23259 to R.D.
(21) Vladusic, E. A.; Pignataro, O. P.; Bussmann, L. E.; Charreau,
E. H. Regulation of the Cholesterol Ester Cycle and Progesterone
Synthesis by J uvenile Hormone in MA-10 Leydig Tumor Cells.
J . Steroid. Biochem. Mol. Biol. 1995, 52, 83-90.
(22) Unpublished results.
(23) Docampo, R.; Schmun˜is, G. A. Sterol Biosynthesis Inhibitors:
Potential Chemotherapeutics Against Chagas Disease. Parasitol.
Today 1997, 13, 129-130.
(24) Docampo, R.; Moreno, S. N. J .; Turrens, J . F.; Katzin, A. M.;
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Ultrastructural Alterations Produced by Miconazole and Econa-
zole in Trypanosoma cruzi. Mol. Biochem. Parasitol. 1981, 3,
169-180.
Su p p or tin g In for m a tion Ava ila ble: NMR spectral data
for compounds 11, 14, 15, 18, 21, 23, 24, 26-29, 32, 33, 35,
37, 39, 40, 47, 54, 55, 58, 66, 72, 73, 77, and 78 and a table of
data needed to calculate percent inhibition (11 pages). Order-
ing information is given on any current masthead page.
(25) Urbina, J . A.; Payares, G.; Molina, J .; Sanoja, C.; Liendo, A.;
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Evaluation of Two Potent Inhibitors of Trypanosoma cruzi
epimastigotes against the Intracellular Form of the Parasite.
BioMed. Chem. Lett. 1996, 6, 2783-2786.
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