Design, synthesis, and biological evaluation of new growth inhibitors of Trypanosoma cruzi (epimastigotes)

Article abstract of DOI:10.1021/jm9607616

As a continuation of our project aimed at the search for new chemotherapeutic agents against Chagas' disease, several drugs structurally related to the insect growth regulator Fenoxycarb and the naturally occurring juvenfie hormone of insects were designed, synthesized, and evaluated as antiproliferative agents against the parasite responsible of this disease. Isoprenoid derivatives (compounds 33, 34, 36, and 37) were potent growth inhibitors of Trypanosoma cruzi epimastigotes. In addition, taking into account the high activity observed for compound 30 and the inhibitory action of related compounds, the allyl ether moiety bonded at the polar extreme of these inhibitors proved to be a promising group for the design of new drugs.

Full text of DOI:10.1021/jm9607616

2
314
J . Med. Chem. 1997, 40, 2314-2322
Design , Syn th esis, a n d Biologica l Eva lu a tion of New Gr ow th In h ibitor s of
Tr ypa n osom a cr u zi (Ep im a stigotes)
†
‡
‡
,†
†
Andrea J . Schvartzapel, Li Zhong, Roberto Docampo, J uan B. Rodriguez,* and Eduardo G. Gros
Departamento de Qu ´ı mica Org a´ nica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires,
Pabell o´ 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,
2
001 South Lincoln Avenue, Urbana, Illinois 61801
X
Received November 1, 1996
As a continuation of our project aimed at the search for new chemotherapeutic agents against
Chagas’ disease, several drugs structurally related to the insect growth regulator Fenoxycarb
and the naturally occurring juvenile hormone of insects were designed, synthesized, and
evaluated as antiproliferative agents against the parasite responsible of this disease. Isoprenoid
derivatives (compounds 33, 34, 36, and 37) were potent growth inhibitors of Trypanosoma
cruzi epimastigotes. In addition, taking into account the high activity observed for compound
3
0 and the inhibitory action of related compounds, the allyl ether moiety bonded at the polar
extreme of these inhibitors proved to be a promising group for the design of new drugs.
In tr od u ction
that replicate within the crop and midgut of Chagas’
disease vectors, the nondividing highly infective meta-
cyclic and bloodstream trypomastigotes, and, finally, the
clinically more relevant form, amastigotes which are
Chagas’ disease, or American trypanosomiasis, is still
a major health problem that affects millions of people
in Mexico and Central and South America. The
1
8
etiologic agent of this illness is the hemoflagellate
protozoan Trypanosoma (Schizotrypanum) cruzi which
is transmitted in rural areas to humans and other
mammals by Reduviid bugs of different species such as
Rhodnius and Triatoma and in large urban centers by
transfusion of infected blood, even in countries where
Chagas’ disease is not endemic.2 The number of infected
people is estimated to be about 15-20 million, and close
to 50 000 deaths attributed to Chagas’ disease occur
each year. As this serious health problem is closely
related to poverty, there is a lack of interest from
pharmaceutical companies to carry out a research and
developmental program because it is not commercially
attractive.
found within the cells in host tissues.
Our lead structures were discovered while working
on the design and preparation of juvenile hormone
9
analogues (J HAs) of insects (hormones crucial for
maintaining larval stages and maturation of the repro-
ductive system in the female) to be evaluated against
the Chagas’ disease vector, i.e., Triatoma infestans. The
synthetic compounds presented a variable degree of
activity against this insect, and some of them were more
active than the naturally occurring juvenile hor-
1
0,11
mones.
Taking into account that these insects, after
treatment with J HAs, were less susceptible to natural
infections with the parasite T. cruzi than normal
1
2
New chemotherapeutic agents are needed because the
trypanocidal drugs presently in use, Nifurtimox (4-[(5-
nitrofurfurylidene)amino]-3-(methylthio)morpholine 1,1-
dioxide) and Benznidazole (N-benzyl-2-nitro-1-imida-
zoleacetamide), cause severe side effects in patients and
nontreated vectors, the designed J HAs were tested
against T. cruzi (epimastigotes). Surprisingly, they
showed a variable degree of activity, some of them being
very active in inhibiting cell proliferation of this
13-15
parasite.
These compounds, formerly juvenile hor-
3
-5
lack specificity against the chronic stage of the disease.
mone analogues of insects, became cell growth inhibi-
tors. At the beginning, the well-known insect growth
regulator Fenoxycarb (N-{2-[(4-phenoxyphenoxy)ethyl]-
The urgency for more selective and less toxic drugs has
led to evaluation of chemical therapy based on the
knowledge of T. cruzi biochemistry and the mode of
action of these compounds.6 In addition, due to the risk
that T. cruzi may be transmitted by blood transfusions,
it is very important to have new compounds to eliminate
this parasite in blood to be transfused. At the present
time, the drug in use for this action is Gentian Violet
1
6
ethyl}carbamate) was employed as standard control
because it behaved as a highly active agent against egg
eclosion and nymphal stages of T. infestans. However,
some modified structures having the 4-phenoxyphenoxy
moiety were found to be more active than Fenoxycarb
in experiments involving T. cruzi cells. We have studied
the mode of action of these drugs, and there is evidence
(N-{4-bis[[4-(dimethylamino)phenyl]methylene]-2,5-cy-
clohexadien-1-ylidene}-N-methylammonium chloride), a
that they inhibit sterol biosynthesis within the cells as
dye discovered to be effective for this purpose many
7
17-19
years ago which suffers from some limitations regard-
it was observed in Leydig tumor cells.
Tumor and
4
ing its safety.
T. cruzi cells have many similarities due, mainly, to
their rapid replication, and in fact, some antitumor
agents have shown effects as trypanocidal drugs.2
The parasite occurs in three main morphological
forms: the epimastigotes that are the dividing forms
0-22
Compounds 1 and 2, two representative members of
our designed drugs, the former structurally related to
Fenoxycarb and the latter structurally related to natu-
ral juvenile hormones of insects, proved to be very active
*
Corresponding author. Phone: 54-1-782-0529. Fax: 54-1-788-6915/
5
4-1-787-2696. E-mail: J BR@quimor.qo.fcen.uba.ar.
†
Universidad de Buenos Aires.
University of Illinois at Urbana-Champaign.
Abstract published in Advance ACS Abstracts, J une 15, 1997.
‡
X
S0022-2623(96)00761-3 CCC: $14.00 © 1997 American Chemical Society

New Growth Inhibitors of T. cruzi
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15 2315
Ch a r t 1. Chemical Structures of Five Representative
Members of Antireplicative Agents for T. cruzi
Sch em e 1a
a
Reagents: (a) allyl bromide, KOH/DMSO, rt (80%), m-CPBA,
Cl2CH2, rt (61%); (b) HClO4, THF-H2O, 48 h (90%); (c) DHP,
Cl2CH2, PPTs, rt (52%); (d) EtNCO/py, rt (39%).
Sch em e 2
against the intracellular form of the parasite,23 and as
occurs with other sterol biosynthesis inhibitors, they
were inactive agents against trypomastigotes.24 As part
of our efforts to improve the antireplicative activity of
these sterol biosynthesis inhibitors against this parasite
and in order to investigate their structure-activity
relationship, we prepared a series of new derivatives
structurally related to our lead drugs (compounds 1-5)
and evaluated their biological activity (Chart 1).
carbonate polar end, were easily prepared by treating
15
28
alcohols 11 and 12 with vinyl chloroformate (Scheme
).
In order to study the influence of the terminal phenyl
2
nonpolar moiety in the aromatic series, this portion of
the framework was replaced by a methyl group keeping
the selected polar substructures. 4-Methoxyphenol (15)
was used as starting material. This compound was
transformed into the tetrahydropyranyl ether derivative
16 by treatment of 2-bromoethyl tetrahydro-2H-pyran-
2-yl ether with a suspension of potassium hydroxide in
dimethyl sulfoxide, employing a modified Williamson
Ra tion a le
The preparation of the new compounds in this study
1
3-15
was motivated by the good antitrypanostatic activity
of the lead compounds 1-5. These antiparasitic agents
can be divided into two different families: one having
an isoprenic nonpolar chain and the other possessing
an aromatic hydrocarbon-like skeleton, specifically, a
2
9
procedure. Removal of the tetrahydropyranyl group
of 16 with pyridinium p-toluenesulfonate gave alcohol
17, which after treatment with ethyl isocyanate afforded
the carbamate 18 in good yield. Phenol 15 reacted with
allyl bromide to give the allylic derivative 19 in excellent
4
-phenoxyphenoxy moiety. Among the end polar groups,
the best results were obtained when allylic ethers,
tetrahydro-2H-pyran-2-yl ethers, and N-ethylcarbam-
ates were employed.1
3-15
In the last case, the positions
3
0-32
of both nitrogen and oxygen atoms are inverted com-
pared with Fenoxycarb. In addition, previous results
had indicated that vinylic carbonates could also have
yield. On reaction with diborane
followed by oxida-
tion with hydrogen peroxide, 19 was converted into the
alcohol 20 with high regioselectivity. Transformation
of 20 into inhibitors 21 and 22 was achieved by
treatment with dihydropyran and ethyl isocyanate,
respectively. Epoxidation of allyl ether 19 with m-
chloroperbenzoic acid gave epoxide 23 that, after re-
giospecific ring opening with lithium aluminum hy-
1
5
potential utility as a polar extreme in our inhibitors.
Therefore, a new set of related compounds possessing
these polar moieties was designed, prepared, and evalu-
ated against the epimastigote forms of T. cruzi which
is, by far, the preferred target for new drugs.
3
3
The preparation of analogues of compound 3 with an
increment of hydrophilicity at the polar extreme by
adding a hydroxyl group was the first modification
considered. The designed compounds 9 and 10 were
straightforwardly prepared from acid hydrolysis (per-
chloric acid) of epoxide 715 followed by careful addition
dride, afforded the secondary alcohol 24 in very good
yield. Alcohol 24 reacted with ethyl isocyanate to yield
the carbamate derivative 25 (Scheme 3).
In order to study the influence of planarity on the
biological activity, it was of interest to replace the
2
oxygen atom between the phenyl groups by an sp unit
2
5,26
of 1 equiv of either dihydropyran
or ethyl isocyan-
ate to give these compounds with reasonable yields
Scheme 1). HPLC analyses showed the presence of a
as a linker giving rise to a potentially planar nonpolar
framework. It was decided that the carbonyl group
would be suitable for this transformation. Therefore,
4-benzoylphenol (26) was used as starting material
which, following a similar protocol to obtain 16-19,
afforded compounds 27-30 with comparable yields.
2
7
(
single isomer in both cases.
As a second variation, compounds 13 and 14, which
retain the 4-phenoxyphenoxy skeleton but with a vinyl

2
316 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15
Schvartzapel et al.
Sch em e 3a
a
Reagents: (a) BrCH2CH2OTHP, KOH/DMSO, rt (68%); (b) MeOH, PPTs, rt overnight (80%); (c) EtNCO/py, rt (64%); (d) allyl bromide,
KOH/DMSO, rt (93%); (e) i. BH3-THF, rt 30 min, ii. H2O2/NaOH, 40 °C (42%); (f) DHP, PPTs, Cl2CH2, rt (80%); (g) EtNCO/py, rt (37%);
(h) m-CPBA, Cl2CH2, rt (77%); (i) LiAlH4, THF, rt 3 h (87%); (j) EtNCO/py, rt (30%).
Sch em e 4a
a
Reagents: (a) BrCH2CH2OTHP, KOH/DMSO, rt (26%); (b) MeOH, PPTs, rt overnight (73%); (c) EtNCO/py, rt (98%); (d) allyl bromide,
KOH/DMSO, rt (66%); (e) LiAlH4, reflux (63%).
Sch em e 5a
Compound 31 was easily formed from 27 by treatment
with lithium aluminum hydride in tetrahydrofuran
(Scheme 4).
Since one of our more potent drugs (compound 2),
which had been previously designed,13 has an isoprenoid
skeleton, it was decided to bond the selected polar
groups to isoprenoid units. Therefore, geraniol (32) was
transformed into its tetrahydropyranyl ether (33) and
N-ethylcarbamate (34) derivatives by similar procedures
as indicated above. Following the standard procedure
derivatives of trans,trans-farnesol (35) were also pre-
pared yielding tetrahydropyranyl, N-ethylcarbamate,
and vinyl carbonate derivatives, compounds 36-38,
respectively (Scheme 5).
a
Reagents: (a) DHP, Cl2CH2, PPTs, rt overnight (81% for 33);
EtNCO/py, rt (84% for 34); (b) DHP, Cl CH , PPTs, rt overnight
(97% for 36); EtNCO/py, rt (99% for 37); ClC(O)OCHdCH2/py, rt
77% for 38).
2
2
(
Dr u g Scr een in g
6
2
-3 × 10 cells/mL (as determined by counting in a
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% triethanolamine), and 10%
newborn calf serum. The initial inoculum contained
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

New Growth Inhibitors of T. cruzi
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15 2317
Ta ble 1
Ch a r t 2. Ajoene, a Bioactive Compound Isolated from
Garlic
compd
IC50 (µM)
compd
IC50 (µM)
1
2
8
9
0
3
4
6
7
8
9
1
2
138
210
270
142
233
260
>240
218
>500
>300
209
>300
>350
24
25
27
28
29
30
31
33
34
36
37
38
>500
>350
268
>400
>300
129
1
1
1
1
1
1
1
2
2
example, vinyl carbonate 13 was much less active than
closely related carbonate derivatives: methyl, ethyl, and
isobutyl carbonates bonded to the same nonpolar frame-
>500
68
176
78
147
>500
1
5
work (4-phenoxyphenoxypropyl moiety).
Replacing the phenyl group by a methyl group did not
result in a greater inhibitory action; in fact, the inhibi-
tion values decreased in such a way that the presence
of the phenyl group seems to be important for the
inhibitory effect. For example, compound 16 is only
moderately active, while its analogue, compound 1, that
contains the 4-phenoxyphenoxy skeleton is a good
growth inhibitor of the parasite. In addition, a similar
behavior on the inhibition action was observed when the
oxygen atom between the phenyl groups has been
replaced by a carbonyl group which potentially contains
a planar aromatic skeleton. In this case, the IC50 for
compound 27 was almost 2 times the concentration
required for compound 1. Remarkably, when the allyl
ether moiety was present in either framework, these
drugs became potent antiproliferative agents (com-
pounds 19 and 30), although both of these drugs were
not so active as the allylic ether derivative bearing the
(
5, 10, 50, and 100 µg/mL), each one in quadruplicate.
Drugs were dissolved in ethanol. A control without drug
was done with each group that was tested.
To calculate percent inhibition, the following formula
was used:
(
∆A × 100)
d
1
00 -
) percent inhibition
∆
A
c
where ∆Ac and ∆Ad are the differences in the absorbance
of control cultures and drug-treated cultures, respec-
tively, at the beginning and end of the experiment. The
maximum amount of solvent used (1% ethanol) did not
have any significant effect on the epimastigotes growth.
The values of IC50 were estimated by linear and
polynomial regression. The results are presented in
Table 1.
4
-phenoxyphenoxy moiety as nonpolar skeleton. This
drug has potent action against T. cruzi proliferation and
requires a concentration of around 50 µM to inhibit 50%
1
3,15
of growth.
Moreover, substituted allyl ethers and
Resu lts a n d Discu ssion
propargyl ether derivatives structurally related to Fen-
oxycarb have previously been shown to possess good
Compounds 1 and 2 were used as positive controls.
Of the designed drugs, compounds 33 and 36 were
shown to be potent inhibitors of T. cruzi replication. The
geranyl derivative 33 was the most potent drug among
the assayed compounds. At 210 µΜ complete growth
arrest took place, and it even showed activity at
concentrations as low as 42 µM (40% inhibition). Iso-
prenoid carbamate derivatives 34 and 37 were also very
active inhibitors but to a lesser extent than tetrahydro-
pyranyl ethers. In this case, contrary to what was
observed for the isoprenoid tetrahydropyranyl ethers,
the drug derived from farnesol (37) was slightly more
potent than its analogue derived from geraniol (34).
These four drugs are more active than the thiolcarbon-
ate 2 which previously was the most potent isoprenoid
1
5
activity.
It is worthy to point out the high inhibitory values
shown when the allyl ether moiety was selected as the
polar end of the drug. This group is often found among
drugs that have potent biological action against prolif-
eration of the epimastigote forms of T. cruzi. In addi-
tion, ajoene (39), a natural product isolated from
3
4
garlic, is a growth inhibitor of T. cruzi cells (epimas-
3
5,36
tigotes)
and contains an allyl thioether moiety
(Chart 2). The rest of the assayed compounds had small
to vanishing inhibitory action.
As a result of the above observations, the allyl ether
group seems to be a promising and attractive polar end
group for the design of new compounds. Work aimed
at exploiting the potential biological activity of allyl
ethers bonded to an aromatic or isoprenoid skeleton is
currently being pursued in our laboratory.
1
3,14
derivative assayed against growth of T. cruzi cells.
Careful analyses of the biological activity showed that
tetrahydropyranyl ether derivatives also were more
active than N-ethyl carbamates if compared with the
same nonpolar residues. For example, the pairs of
drugs 9 and 10, 16 and 18, 27 and 29 presented a
moderate degree of activity favoring the tetrahydropy-
ranyl ethers. The presence of a hydroxyl group at the
C-2 position in compounds 9 and 10 resulted in a
dramatic impairing of the biological activity compared
with closely related structures in which this functional-
ity was not present (compounds 3 and 4). We have
previously found that these latter compounds exhibited
potent action as antitrypanostatic agents with an IC50
Exp er im en ta l Section
Unless otherwise noted, chemicals were commercially avail-
able and used without further purification. Air and/or mois-
ture sensitive reactions were carried out under a dry nitrogen
atmosphere in flame-dried glassware. Solvents were distilled
before use. Pyridine was distilled from calcium hydride and
stored over KOH pellets; dimethyl sulfoxide was distilled from
calcium hydride and stored over freshly activated 3 Å molec-
ular sieves; ether and tetrahydrofuran were distilled from
sodium benzophenone.
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.
1
5
of 50 µM for both drugs (Chart 1).
The use of vinylic carbonates as polar end group did
not result in an increase in biological activity. For
1
The H-NMR spectra are referenced with respect to the
residual CHCl proton of the solvent CDCl at 7.26 ppm.
3
3

2
318 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15
Schvartzapel et al.
Coupling constants are reported in hertz. 13C-NMR spectra
were fully decoupled and are referenced to the middle peak of
intensity) 344 (M , 6), 186 (43), 159 (9), 85 (100), 69 (25), 57
(31), 41 (48). Anal. (C20 ) C, H.
+
24 5
H O
the solvent CDCl
nated as s, singlet; d, doublet; t, triplet; q, quartet; p, pentet;
br, broad.
Melting points were determined using a Fisher-J ohns
apparatus and are uncorrected. IR spectra were recorded
using a Nicolet Magna 550 spectrometer.
3
at 77.0 ppm. Splitting patterns are desig-
(()-2-Hyd r oxy-3-(4-p h en oxyp h en oxy)p r op -1-yl Eth yl-
ca r ba m a te (10). Diol 8 (74 mg, 0.3 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
3 h. The mixture was partitioned between methylene chloride
(50 mL) and HCl 10% (50 mL). The organic phase was washed
with 10% HCl (3 × 50 mL) and water (3 × 50 mL). Then, the
Low-resolution mass spectra were obtained on a VG TRIO
4
organic layers were dried (MgSO ) and evaporated. The
2
instrument at 70 eV (direct inlet). Positive ion fast atom
residue was purified by column chromatography using hex-
ane-ethyl acetate (7:3) as eluent to give 37 mg (39% yield) of
pure carbamate 10 as a white solid. HPLC analysis revealed
the presence of a single isomer employing methanol-water
bombardment mass spectra (FABMS) were obtained on a VG
ZAB BEqQ spectrometer at an accelerating voltage of 30 kV
and a resolution of 2000. Thioglycerol was used as the sample
matrix, and ionization was effected by a beam of cesium atoms.
(
4:1) at a flow rate of 3.00 mL/min: R 0.47 (hexane-AcOEt,
f
Flash chromatography was run according to the Still
-
1
2
2
7
-
(
:3); mp 82-83 °C (MeOH-H
2
O); IR (film, cm ) 3339, 3067,
3
7
protocol 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-Plaskitkfolien, Kieselgel 60 F254) and was visualized
by 254 nm UV or immersion into an ethanolic solution of 5%
974, 2932, 1699, 1522, 1489, 1221, 1163, 1103, 1034, 872, 843,
1
98, 692, 511; H NMR (CDCl
CH ), 3.07 (s, 1 H, -OH), 3.25 (m, 2 H, -NCH
m, 2 H, H-3), 4.23 (m, 1 H, H-2), 4.31 (m, 2 H, H-1), 4.80 (s,
3
) δ 1.16 (t, J ) 7.2 Hz, 3 H,
NCH
2
3
2
CH ), 4.02
3
1
3
1
H, -NH), 6.88-7.35 (m, 9 H, aromatic protons); C NMR
H
2
SO
4
.
(CDCl
3
) δ 15.3 (MeCH
2
), 35.6 (MeCH NH), 63.2 (C-3), 69.7 (C-
2
Preparative high-performance liquid chromatography was
2
4
), 70.3 (C-1), 115.2 (C-2′′), 117.3 (C-2′), 120.5 (C-3′), 122.5 (C-
performed on a Micromeritics chromatograph with a solvent
delivery system Model 750 and a variable wavelength detector
Model 787 using a Beckmann Ultrasphere ODS-2 column (250
′′), 129.7 (C-3′′), 154.6 (C-4′), 158.4 (C-1′′); MS (m/ z, relative
+
intensity) 331 (M , 26), 186 (36), 146 (100). Anal. (C18
C, H, N.
21 5
H O N)
×
10 mm, 5 µm) at a flow rate of 3.0 mL/min. Solvents HPLC
4
-P h en oxyp h en oxyp r op yl Eth en yl Ca r bon a te (13). A
grade were employed.
solution of alcohol 11 (54 mg, 0.22 mmol) in pyridine (2 mL)
in the presence of 4-(dimethylamino)pyridine (5 mg) was
treated with vinyl chloroformate (0.1 mL). The mixture was
stirred overnight. The reaction mixture was partitioned
between methylene chloride (50 mL) and 10% HCl (50 mL).
The organic phase was washed with 10% HCl (3 × 50 mL)
and water (3 × 50 mL). The organic layers were dried
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.
(
()-4-P h en oxyp h en oxy 3-(1,2-Dih yd r oxyp r op yl) Eth er
8). A solution of epoxide 7 (1.80 g, 6.9 mmol) in 160 mL of
tetrahydrofuran-water (13:3) was treated with 70% HClO
100 µL). The reaction mixture was stirred at room temper-
ature for 48 h. The mixture was partitioned between a
saturated aqueous solution of NaHCO (100 mL) and CH Cl
100 mL). The aqueous phase was extracted with CH Cl (2
70 mL). The combined organic layers were dried (MgSO ),
(
4
(MgSO ), and the solvent was evaporated. The residue was
4
(
purified by column chromatography eluting with hexane-ethyl
acetate (9:1) to yield 47 mg (68% yield) of pure carbonate 13
-
1
3
2
2
as a colorless oil: R 0.50 (hexane-AcOEt, 4:1); IR (film, cm )
f
(
2
2
3042, 2986, 2943, 2879, 1765, 1652, 1595, 1488, 1410, 1269,
1
×
4
1226, 1169, 1084, 1049, 942, 878, 701, 509; H NMR (CDCl )
3
and the solvent was evaporated. The residue was purified by
column chromatography (silica gel) employing hexane-ethyl
acetate (1:1) as eluent to afford 1.610 g (90% yield) of pure
δ 2.20 (q, J ) 6.1 Hz, 2 H, H-2), 4.08 (t, J ) 6.0 Hz, 2 H, H-1),
4.44 (t, J ) 6.3 Hz, 2 H, H-3), 4.60 (dd, J ) 6.2, 2.0 Hz, 1 H,
H-2′′′ ), 4.94 (dd, J ) 13.8, 2.0 Hz, 1 H, H-2′′′
cis
trans
), 6.85-7.10
diol 8 as a white solid: R
f
0.20 (hexane-EtOAc, 1:1); mp 73-
(m, 6 H, aromatic protons), 7.10 (dd, J ) 13.8, 6.2 Hz, 1 H,
4 °C (water); IR (KBr, cm-1) 3406, 2926, 2872, 1591, 1508,
13
7
1
H-1′′′), 7.25-7.35 (m, 4 H, aromatic protons); C NMR (CDCl )
3
1
491, 1456, 1244, 1120, 1038, 874, 839, 771, 690; H NMR
) δ 3.50-3.90 (m, 2 H, H-1), 4.01-4.20 (m, 3 H, H-2,
δ 31.6 (C-2), 64.4 (C-3), 65.4 (C-1), 97.7 (C-2′′′), 115.6 (C-2′′),
117.7 (C-2′), 120.8 (C-3′), 122.5 (C-4′′), 129.6 (C-3′′), 142.7 (C-
1′′′), 152.7 (C-4′), 155.0 (C-1′), 158.5 (C-1′′); MS (m/ z, relative
(CDCl
3
1
3
H-3), 6.88-7.35 (m, 9 aromatic protons); C NMR (CDCl
3
) δ
3.7 (C-1), 69.7 (C-2), 70.5 (C-3), 115.7 (C-2′′), 117.7 (C-2′),
+
6
1
1
intensity) 314 (M , 7), 227 (3), 199 (6), 185 (10), 129 (71), 85
20.7 (C-3′), 122.6 (C-4′′), 129.6 (C-3′′), 150.7 (C-1′), 154.7 (C-
), 158.2 (C-1′′); MS (m/ z, relative intensity) 260 (M , 68), 186
(72), 41 (100). Anal. (C H O ) C, H.
1
8
18
5
+
(()-4-P h en oxyp h en oxyp r op a n -2-yl Eth en yl Ca r bon a te
(14). To alcohol 12 (78 mg, 0.3 mmol) in pyridine (3 mL) was
added vinyl chloroformate (0.1 mL), and the reaction mixture
was stirred at room temperature overnight. The reaction
mixture was worked up as described for compound 13 and
purified by column chromatography eluting with hexane-ethyl
acetate (4:1) to afford 70 mg (69% yield) of pure compound 14
(100), 158 (17), 129 (23), 109 (22), 77 (68), 57 (26), 51 (51).
1
Anal. (C15
()-2-H yd r oxy-3-(4-p h en oxyp h en oxy)p r op -1-yl Tet -
r a h yd r o-2H-p yr a n -2-yl Eth er (9). To a solution of diol 8
182 mg, 0.7 mmol) in methylene chloride (20 mL) were added
H
16
O
4
‚ /
3 2
H O) C, H.
(
(
dihydropyran (1 mL) and PPTs (20 mg). The reaction mixture
was stirred at room temperature overnight. The mixture was
washed with water (3 × 20 mL) and dried, and the solvent
was evaporated. The residue was purified by column chro-
matography (silica gel) eluting with hexane-ethyl acetate (7:
-1
as a colorless oil: R 0.50 (hexane-AcOEt, 4:1); IR (film, cm )
f
3094, 3043, 2986, 2937, 2876, 1767, 1647, 1589, 1504, 1492,
1396, 1356, 1263, 1220, 1088, 1045, 945, 845, 783, 697, 521;
1
H NMR (CDCl ) δ 1.47 (d, J ) 6.4 Hz, 3 H, H-3), 4.06 (m AB,
3
3
) to afford 125 mg (52% yield) of a (1:1) diastereomeric
2 H, H-1), 4.61 (dd, J ) 6.2, 1.9 Hz, 1 H, H-2′′′cis), 4.95 (dd, J
) 13.9, 1.9 Hz, 1 H, H-2′′′trans), 5.20 (m, 1 H, H-2), 6.85-7.10
(m, 6 H, aromatic protons), 7.12 (dd, J ) 13.9, 6.2 Hz, 1 H,
mixture of compound 9 as a colorless oil. HPLC analysis
revealed the presence of a single peak which corresponded to
the terminal tetrahydropyranyl ether. A mixture of methanol-
water (4:1) was used as eluent at a flow rate of 3.00 mL/min:
H-1′′′), 7.25-7.35 (m, 4 H, aromatic protons); 13C NMR (CDCl
)
3
δ 16.5 (C-3), 70.4 (C-1), 73.7 (C-2), 97.9 (C-2′′′), 115.8 (C-2′′),
117.8 (C-2′), 120.7 (C-3′), 122.6 (C-4′′), 129.6 (C-3′′), 142.6 (C-
1′′′), 152.2 (C-4′), 154.7 (C-1′), 158.3 (C-1′′); MS (m/ z, relative
-1
R
f
0.61 (hexane-AcOEt, 1:1); IR (film, cm ) 3435, 3065, 3042,
2
1
941, 2872, 1724, 1589, 1504, 1489, 1223, 1161, 1122, 1074,
1
+
034, 906, 845, 750, 692, 511; H NMR (CDCl
3
) δ 1.50-1.85
intensity) 314 (M , 12), 227 (13), 185 (22), 129 (100), 59 (93).
(
4
7
m, 6 H, H-3′′′, H-4′′′, H-5′′′), 3.56-3.61 (m, 2 H, H-6′′′), 3.71-
18 5
Anal. (C18H O ) C, H.
.14 (m, 5 H, H-1, H-2, H-3), 4.58-4.69 (m, 1 H, H-2′′′), 6.87-
4-Met h oxyp h en oxyet h yl Tet r a h yd r o-2H -p yr a n -2-yl
Eth er (16). 4-Methoxyphenol (15) (1.110 g, 8.9 mmol) in
dimethyl sulfoxide (10 mL) was treated with potassium
hydroxide (36 mmol). The suspension was stirred for 5 min.
Then, bromoethyl tetrahydropyranyl ether (3.730 g, 17.0
mmol) was added, and the reaction mixture was stirred at
.35 (m, 9 H, aromatic protons); 13C NMR (CDCl
) δ 19.8, 20.1
3
(C-4′′′), 25.2, 25.7 (C-5′′′), 30.7, 31.3 (C-3′′′), 63.2, 63.4 (C-6′′′),
6
2
1
8.4, 68.6 (C-1), 69.1 (C-2), 69.4 (C-3), 100.2 (C-2′′′), 115.7 (C-
′′), 117.7 (C-2′), 120.7 (C-3′), 122.5 (C-4′′), 129.6 (C-C-3′′),
50.5 (C-4′), 156.0 (C-1′), 158.4 (C-1′′); MS (m/ z, relative

New Growth Inhibitors of T. cruzi
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15 2319
room temperature overnight. The mixture was partitioned
between water (50 mL) and methylene chloride (50 mL). The
aqueous layer was extracted with methylene chloride (2 × 50
mL). The combined organic layers were washed with brine
cooled to 0 °C under a nitrogen atmosphere was added
dropwise 0.85 M diborane in tetrahydrofuran (1.5 mL), and
the mixture was stirred at room temperature for 1 h. The
excess of the reagent was decomposed by careful addition of
water. The reaction mixture was warmed to 50 °C, and NaOH
1.0 M (2.0 mL) was added followed by slow addition of a 30%
solution of hydrogen peroxide (0.32 mL). The mixture was
(
5 × 100 mL) and dried (MgSO
4
), and the solvent was
evaporated. The residue was purified by column chromatog-
raphy eluting with hexane-ethyl acetate (7:3) to afford 1.532
g of compound 16 (68% yield) as a colorless oil:
R
f
0.28
stirred for 1 h at room temperature. Solid K
2 3
CO (2 g) was
added and the organic layer separated. The aqueous phase
-
1
(
hexane-AcOEt, 7:3); IR (film, cm ) 3057, 2943, 2872, 1587,
1
5
3
510, 1460, 1354, 1290, 1247, 1134, 1084, 992, 935, 836, 744,
was extracted with methylene chloride (2 × 20 mL). The
1
31; H NMR (CDCl
.52 (m, 1 H, H-6′′a), 3.75 (s, 3 H, OCMe), 3.76-4.20 (m, 5 H,
3
) δ 1.50-1.90 (m, 6 H, H-3′′, H-4′′, H-5′′),
4
combined organic layers were dried (MgSO ), and the solvent
was evaporated. The residue was purified by column chro-
matography employing hexane-EtOAc (4:1) as eluent to give
f
199 mg (42% yield) of alcohol 20 as a white solid: R 0.34
H-1, H-2, H-6′′b), 4.70 (distorted t, J ) 3.2 Hz, 1 H, H-2′′),
.84 (m AB, 4 H, aromatic protons); 13C NMR (CDCl
) δ 19.1
C-4′′), 25.2 (C-3′′), 30.3 (C-5′′), 55.3 (OCH ), 61.8 (C-1), 65.7
6
3
-
1
(
(
(
3
(hexane-AcOEt, 1:1); mp 65-66 °C (H
2
O); IR (KBr, cm )
C-2′′), 67.9 (C-2), 98.6 (C-6′′), 114.3 (C-3′), 115.5 (C-2′), 152.8
C-1′), 153.7 (C-4′); MS (m/ z, relative intensity) 252 (M , 24),
3277, 2953, 2934, 2837, 2870, 1682, 1512, 1471, 1392, 1292,
+
1
3
1244, 1115, 1061, 1034, 947; H NMR (CDCl ) δ 1.86 (s, 1 H,
1
29 (88), 109 (20), 85 (100), 73 (75). Anal. (C14
H
20
O
4
) C, H.
OH), 2.03 (p, J ) 5.9 Hz, 2 H, H-2), 3.77 (s, 3 H, OCMe), 3.86
4
-Meth oxyp h en oxyeth a n ol (17). To a solution of com-
(t, J ) 5.8 Hz, 2 H, H-1), 4.08 (t, J ) 5.9 Hz, 2 H, H-3), 6.84
(m A
2), 55.7 (OCH
2′), 152.9 (C-1′), 153.9 (C-4′); MS (m/ z, relative intensity) 182
2
B
2
, 4 H, aromatic protons); 13C NMR (CDCl
3
) δ 32.1 (C-
pound 16 (145 mg, 0.57 mmol) in methanol (5 mL) was added
PPTs (10 mg), and the reaction mixture was stirred for 48 h
at room temperature. The mixture was partitioned between
methylene chloride (50 mL) and water (50 mL). The aqueous
layer was extracted with water (2 × 50 mL), and the combined
organic layers were washed with brine (3 × 70 mL), dried,
and evaporated. The residue was purified by column chro-
matography (silica gel) employing hexane-ethyl acetate (7:3)
as eluent to yield 77 mg of pure alcohol 17 (80% yield) as a
3
), 60.5 (C-1), 66.5 (C-3), 114.7 (C-3′), 115.5 (C-
+
(M , 48), 124 (100), 109 (79). Anal. (C10
14 3
H O ) C, H.
4-Met h oxyp h en ylp r op yl Tet r a h yd r o-2H -p yr a n -2-yl
Eth er (21). Alcohol 20 (60 mg, 0.33 mmol) was treated with
DHP according to the protocol depicted for 8. The product was
purified by column chromatography (silica gel) eluting with
hexane-EtOAc (4:1) to afford 70 mg (80% yield) of pure
white solid: R
f
0.35 (hexane-AcOEt, 1:1); mp 68-69 °C (H
2
O);
tetrahydropyranyl ether derivative 21 as a colorless oil: R
f
-1
-1
IR (KBr, cm ) 3302, 2955, 2390, 2870, 2837, 1890, 1869, 1637,
0.64 (hexane-AcOEt, 7:3); IR (film, cm ) 3054, 2947, 1591,
1
5
512, 1443, 1398, 1294, 1244, 1178, 1053, 932, 827, 729, 689,
1509, 1468, 1387, 1352, 1288, 1234, 1182, 1138, 1122, 1066,
1
1
32; H NMR (CDCl
3
) δ 3.76 (s, 3 H, OCMe), 3.93 (m, 2 H,
1036, 985, 868, 825, 741, 523; H NMR (CDCl
3
) δ 1.45-1.95
H-1), 4.01 (m, 2 H, H-2), 6.84 (m AB, 4 H, aromatic protons);
(m, 6 H, H-3′′, H-4′′, H-5′′), 2.05 (p, J ) 6.3 Hz, 2 H, H-2),
3.43-3.98 (m, 4 H, H-1, H-6′′), 3.76 (s, 3 H, OCMe), 4.02 (t, J
1
3
C NMR (CDCl
3
) δ 55.7 (OCH
3
), 61.5 (C-1), 70.0 (C-2), 114.7
(C-3′), 115.6 (C-2′), 152.8 (C-1′), 154.1 (C-4′); MS (m/ z, relative
) 6.3 Hz, 2 H, H-3), 4.59 (dd, J ) 4.0, 2.7 Hz, 1 H, H-2′′), 6.83
+
13
intensity) 168 (M , 66), 124 (94), 109 (100), 81 (39). Anal.
) C, H.
-(4-Meth oxyp h en oxy)eth yl Eth ylca r ba m a te (18). Al-
(m AB, 4 H, aromatic protons); C NMR (CDCl
3
) δ 19.5 (C-
(C
9
H
12
O
3
4′′), 25.4 (C-5′′), 29.8 (C-2), 30.7 (C-3′′), 55.7 (OCH ), 62.2 (C-
3
2
6′′), 64.0 (C-1), 65.6 (C-3), 98.9 (C-2′′), 114.6 (C-3′), 115.5 (C-
2′), 151.2 (C-1′), 153.7 (C-4′); MS (m/ z, relative intensity) 266
cohol 17 (74 mg, 0.44 mmol) in pyridine (3 mL) was treated
with ethyl isocyanate (0.1 mL) in the presence of 4-(dimethyl-
amino)pyridine. The reaction mixture was worked up as
described for compound 10 and the residue purified by column
chromatography eluting with hexane-ethyl acetate (3:2) to
+
(M , 23), 165 (8), 143 (76), 124 (80), 109 (33), 95 (11), 85 (100).
Anal. (C15
22 4
H O ) C, H.
3-(4-Meth oxyp h en oxy)p r op yl Eth ylca r ba m a te (22). A
solution of compound 20 (68 mg, 0.38 mmol) in pyridine (3
mL) was treated with ethyl isocyanate (0.1 mL) and 4-(di-
methylamino)pyridine (10 mg), and the mixture was stirred
at room temperature overnight. The reaction mixture was
worked up as depicted for compound 10. The residue was
purified by column chromatography eluting with hexane-
EtOAc (4:1) to give 35 mg (37% yield) of pure 22 as a white
afford 66 mg of carbamate 18 as a white solid:
f
R 0.47
-
1
(
3
1
hexane-AcOEt, 1:1); mp 86-87 °C (H
2
O); IR (KBr, cm
)
337, 3053, 2978, 2935, 1690, 1537, 1508, 1460, 1356, 1294,
1
261, 1178, 1076, 1034, 825, 733, 646, 521; H NMR (CDCl
CH ), 3.23 (m, 2 H, -NCH
3
2
)
-
δ 1.14 (t, J ) 7.3 Hz, 3 H, -NCH
CH
2
3
3
), 3.77 (s, 3 H, OCMe), 4.11 (m, 2 H, H-2), 4.39 (m, 2 H,
H-1), 4.74 (s, 1 H, NH), 6.84 (m AB, 4 H, aromatic protons);
solid: R
f
2
0.41 (hexane-AcOEt, 1:1); mp 63-64 °C (H O); IR
1
3
-1
C NMR (CDCl
OCH ), 63.2 (C-1), 67.2 (C-2), 114.7 (C-3′), 115.7 (C-2′), 152.7
C-1′), 154.1 (C-4′), 156.2 (CdO); MS (m/ z, relative intensity)
3
) δ 15.1 (MeCH
2
NH), 35.9 (MeCH
2
NH), 55.7
(KBr, cm ) 3344, 2976, 2961, 2930, 2870, 2833, 1681, 1537,
1510, 1468, 1437, 1387, 1358, 1293, 1259, 1225, 1117, 1065,
1034, 947, 831, 723, 638, 530; H NMR (CDCl
7.2 Hz, 3 H, -NCH
(m, 2 H, -NCH CH
(
(
3
1
3
) δ 1.13 (t, J )
+
2
39 (M , 5), 151 (4), 124 (12), 116 (100), 72 (66), 44 (70). Anal.
N) C, H, N.
-Meth oxyp h en yl P r op -2-en -1-yl Eth er (19). 4-Meth-
2
CH
3
), 2.07 (p, J ) 6.3 Hz, 2 H, H-2), 3.20
), 3.76 (s, 3 H, OCMe), 3.98 (t, J ) 6.2 Hz,
(C
12
H
17
O
4
2
3
4
2 H, H-3), 4.24 (t, J ) 6.3 Hz, 2 H, H-1), 4.64 (s, 1 H, NH),
6.83 (m AB, 4 H, aromatic protons); 13C NMR (CDCl
) δ 15.3
(MeCH NH), 29.2 (C-2), 35.8 (MeCH NH), 55.7 (OCH ), 61.6
oxyphenol (3.332 g, 2.7 mmol) in dimethyl sulfoxide (10 mL)
was treated with potassium hydroxide (10 mmol), and the
mixture was stirred for 5 min. Then, allyl bromide (3.8 mL,
3
2
2
3
(C-1), 65.2 (C-3), 114.7 (C-3′), 115.5 (C-2′), 153.0 (C-1′), 153.9
(C-4′); MS (m/ z, relative intensity) 253 (M , 12), 182 (11), 165
+
4
.3 mmol) was added, and the reaction mixture was stirred at
room temperature for 3 h. The reaction mixture was worked
up as depicted for compound 16. The residue was purified by
column chromatography employing hexane-ethyl acetate (19:
(5), 149 (10), 130 (100), 124 (66), 109 (75). Anal. (C13
C, H, N.
19 4
H O N)
(()-Oxir a n ylm eth yl 4-Meth oxyp h en yl Eth er (23). To
a solution of allyl ether 19 (564 mg, 3.4 mmol) in methylene
chloride (20 mL) was added 80% 3-(chloroperoxy)benzoic acid
(710 mg) in methylene chloride (10 mL) dropwise at 0 °C. The
reaction mixture was stirred at room temperature for 20 h.
The organic layer was washed with a saturated solution of
1
) as eluent to obtain 4.071 g of pure ether 19 (93% yield) as
-
1
a colorless oil: R
f
0.83 (hexane-AcOEt, 7:3); IR (film, cm
)
3
9
080, 2997, 2951, 2908, 2833, 1508, 1464, 1231, 1107, 1039,
28, 754, 523; H NMR (CDCl ) δ 3.77 (s, 3 H, OCMe), 4.49
1
3
(
dt, J ) 5.3, 1.5 Hz, 2 H, H-1), 5.28 (dq, J ) 10.5, 1.5 Hz, 1 H,
), 5.40 (dq, J ) 17.3, 1.6 Hz, 1 H, H-3trans to ), 6.06
ddt, J ) 17.2, 10.5, 5.3 Hz, 1 H, H-2), 6.85 (m A , 4 H,
), 69.5 (C-
), 114.6 (C-3′), 115.7 (C-2′), 117.3 (C-3), 133.6 (C-2), 152.7 (C-
′), 153.9 (C-4′); MS (m/ z, relative intensity) 164 (M , 29), 123
) C, H.
-(4-Meth oxyp h en yl)p r op a n ol (20). To a solution of 19
423 mg, 2.6 mmol) in anhydrous tetrahydrofuran (5 mL)
H-3cis to
2
2
NaHCO
3
(2 × 30 mL) and water (2 × 30 mL), dried (MgSO
4
),
(
2
B
2
and evaporated. The residue was purified by column chro-
1
3
aromatic protons); C NMR (CDCl
1
1
3
) δ 55.7 (OCH
3
matography employing hexane-EtOAc (9:1) as eluent to afford
471 mg (77% yield) of pure epoxide 23 as a colorless oil: R
f
+
1
0.52 (hexane-AcOEt, 7:3); H NMR (CDCl ) δ 2.74 (dd, J )
3
(100), 95 (44), 69 (34), 41 (81). Anal. (C10
H
12
O
2
4.9, 2.7 Hz, 1 H, H-3a), 2.89 (distorted t, J ) 4.5 Hz, 1 H, H-3b),
3.33 (m, 1 H, H-2), 3.77 (s, 3 H, OCMe), 3.92 (dd, J ) 11.1, 5.6
Hz, 1 H, H-1a), 4.17 (dd, J ) 11.1, 3.3 Hz, 1 H, H-1b), 6.85 (m
3
(

2
320 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15
Schvartzapel et al.
AB, 4 H, aromatic protons); 13C NMR (CDCl
) δ 44.7 (C-3),
), 69.6 (C-1), 114.7 (C-3′), 115.8 (C-2′),
pure alcohol 28 as a white solid: R
mp 84-85 °C; IR (film, cm ) 3275, 2951, 2930, 2878, 1639,
1603, 1576, 1504, 1445, 1418, 1379, 1308, 1290, 1256, 1176,
0.22 (hexane-AcOEt, 3:2);
3
f
-
1
5
1
5
0.2 (C-2), 55.7 (OCH
52.7 (C-1′), 154.3 (C-4′); MS (m/ z, relative intensity) 180 (M ,
1), 124 (100), 109 (92), 95 (42).
3
+
1
1149, 1094, 1053, 922, 797, 739, 692, 636, 511; H NMR
(
3
CDCl ) δ 2.13 (s, 1 H, -OH), 4.00 (m, 2 H, H-1), 4.17 (distorted
(
()-1-(4-Meth oxyp h en oxy)p r op a n -2-ol (24). To a 1.0 M
t, J ) 4.5 Hz, 2 H, H-2), 6.95-7.86 (m, 9 H, aromatic protons);
solution of LiAlH in tetrahydrofuran (20 mL) was added
4
1
3
C NMR (CDCl
C-3′′), 129.6 (C-2′′), 130.3 (C-3′), 131.9 (C-4′), 132.5 (C-4′′),
38.1 (C-1′′), 162.3 (C-1′), 195.5 (CdO); MS (m/ z, relative
3
) δ 61.1 (C-1), 69.4 (C-2), 114.1 (C-2′), 128.1
dropwise epoxide 23 (378 mg, 2.1 mmol) in anhydrous tet-
rahydrofuran (5 mL) under a nitrogen atmosphere. The
reaction mixture was stirred for 5 h at room temperature. The
reaction was quenched by addition of ethyl acetate (1.0 mL),
and the mixture was partitioned between a saturated solution
of sodium potassium tartrate (100 mL) and methylene chloride
(
1
+
intensity) 242 (M , 43), 198 (11), 121 (100), 105 (48). Anal.
) C, H.
-(4-Ben zoylp h en oxy)eth yl Eth ylca r ba m a te (29).
14 14 3
(C H O
2
A
solution of alcohol 28 (77 mg, 0.32 mmol) in pyridine (3 mL)
was treated with ethyl isocyanate (0.1 mL) and 4-(dimethyl-
amino)pyridine (10 mg), and the mixture was stirred at room
temperature overnight. The reaction mixture was worked up
as described for 10. The residue was purified by column
chromatography eluting with hexane-EtOAc (3:2) to yield 98
(
100 mL). The aqueous phase was extracted with methylene
choride (2 × 50 mL). The combined organic layers were
washed with the tartrate solution (2 × 100 mL) and water (2
×
4
70 mL), dried (MgSO ), and evaporated. The residue was
purified by flash chromatography eluting with hexane-AcOEt
9:1) to afford 332 mg (87% yield) of pure alcohol 24 as a white
solid: R 0.43 (hexane-AcOEt, 7:3); mp 62-63 °C (H O); IR
KBr, cm ) 3412, 2924, 2835, 1869, 1637, 1514, 1456, 1369,
(
mg (98% yield) of pure 29 as a white solid: R 0.34 (hexane-
f
f
2
-
1
-
1
AcOEt, 3:2); mp 89-90 °C (H
2
O); IR (KBr, cm ) 3342, 3065,
(
2
976, 2937, 2878, 1705, 1647, 1603, 1541, 1446, 1250, 1148,
1
337, 1292, 1242, 1178, 1161, 1111, 1084, 1043, 866, 744, 532;
1
1
999, 918, 847, 791, 708, 638, 625; H NMR (CDCl
J ) 7.3 Hz, 3 H, -NCH CH ), 3.24 (m, 2 H, -NCH
3
2
) δ 1.15 (t,
CH ), 4.24
H NMR (CDCl
3
) δ 1.27 (d, J ) 6.5 Hz, 3 H, H-3), 2.38 (s, 1 H,
2
3
3
-
3
OH), 3.74 (dd, J ) 9.3, 7.7 Hz, 1 H, H-1a), 3.77 (s, 3 H, OCMe),
(
distorted t, J ) 5.0 Hz, 2 H, H-2), 4.46 (distorted t, J ) 4.3
Hz, 2 H, H-1), 4.72 (s, 1 H, NH), 6.96-7.85 (m, 9 H, aromatic
protons); 13C NMR (CDCl
) δ 15.1 (MeCH NH), 35.8 (MeCH
NH), 62.7 (C-1), 66.6 (C-2), 114.0 (C-2′), 128.1 (C-3′′), 129.6
C-2′′), 130.4 (C-3′), 131.8 (C-4′), 132.4 (C-4′′), 138.1 (C-1′′),
62.1 (C-1′), 195.4 (CdO); MS (m/ z, relative intensity) 313
.90 (dd, J ) 9.3, 3.2 Hz, 1 H, H-1b), 4.17 (m, 1 H, H-2), 6.83
13
(
m AB, 4 H, aromatic protons); C NMR (CDCl
3
) δ 18.7 (C-3),
3
2
2
-
5
1
4
5.7 (OCH
52.8 (C-1′), 154.1 (C-4′); MS (m/ z, relative intensity) 182 (M ,
2), 137 (3), 124 (100), 109 (75). Anal. (C10 ) C, H.
()-1-(4-Meth oxyp h en oxy)p r op a n -2-yl Eth ylca r ba m -
3
), 66.3 (C-1), 74.2 (C-2), 114.7 (C-3′), 115.6 (C-2′),
+
(
14 3
H O
1
(
(
+
M , 1), 147 (9), 116 (100). Anal. (C18
-Ben zoylp h en yl P r op -2-en -1-yl Eth er (30). Compound
0 was obtained as described for 19 from 4-benzoylphenol (26)
19 4
H O N) C, H.
a te (25). A solution of alcohol 24 (80 mg, 0.44 mmol) in
pyridine (3 mL) was treated with ethyl isocyanate (0.1 mL)
and 4-(dimethylamino)pyridine (10 mg), and the mixture was
stirred at room temperature overnight. The reaction mixture
was worked up as described for compound 10. The residue
was purified by column chromatography eluting with hexane-
EtOAc (4:1) to give 33 mg (30% yield) of pure 25 as a white
solid: R
(
1
4
3
(2.116 g, 10 mmol). After the usual workup the residue was
purified by column chromatography (silica gel) eluting with
hexane-ethyl acetate (9:1) to obtain 1.587 g of pure ether 30
(
f
66% yield) as a white solid: R 0.47 (hexane-AcOEt, 4:1); mp
-
1
7
1
1
9
7-78 °C; IR (KBr, cm ) 3080, 3059, 3022, 2939, 2868, 1639,
f
0.54 (hexane-AcOEt, 7:3); mp 44-45 °C (H
2
O); IR
603, 1574, 1506, 1445, 1418, 1364, 1306, 1284, 1252, 1175,
-
1
KBr, cm ) 3342, 2978, 2935, 2876, 2876, 1703, 1508, 1460,
148, 1364, 1306, 1284, 1252, 1175, 1148, 1113, 1076, 1011,
1
230, 1086, 1045, 997, 825, 746; H NMR (CDCl
7.2 Hz, 3 H, -NCH CH ), 1.34 (d, J ) 6.5 Hz, 3 H, H-3), 3.20
m, 2 H, -NCH CH ), 3.76 (s, 3 H, OCMe), 3.94 (dd, J ) 5.3,
.5 Hz, 2 H, H-1), 4.24 (t, J ) 6.3 Hz, 2 H, H-1), 4.65 (s, 1 H,
3
) δ 1.13 (t, J
1
35, 920, 849, 795, 744, 700, 640, 600; H NMR (CDCl
3
) δ 4.63
)
(
1
2
3
(
ddd, J ) 5.2, 1.5, 1.3 Hz, 2 H, H-1), 5.33 (ddt, J ) 17.2, 1.5,
2
3
1
1
6
.2, 1.5 Hz, 1 H, H-3trans to 2), 5.44 (ddt, J ) 10.4, 1.4, 1.2 Hz,
), 6.07 (ddt, J ) 17.2, 10.4, 5.2 Hz, 1 H, H-2),
H, H-3cis to
2
NH), 5.12 (m, 1 H, H-2), 6.83 (m AB, 4 H, aromatic protons);
1
3
.94-7.86 (m, 9 H, aromatic protons); C NMR (CDCl ) δ 68.9
3
1
3
C NMR (CDCl
NH), 55.7 (OCH
C-2′), 153.0 (C-1′), 154.1 (C-4′); MS (m/ z, relative intensity)
3
) δ 15.2 (MeCH
3
2 2
NH), 17.0 (C-3), 35.4 (MeCH -
), 69.2 (C-1), 71.2 (C-2), 114.7 (C-3′), 115.8
(C-1), 114.2 (C-3), 118.1 (C-2′), 128.1 (C-3′′), 129.6 (C-2′′), 130.2
(
1
1
C-3′), 131.8 (C-4′), 132.4 (C-2, C-4′′), 138.2 (C-1′′), 162.2 (C-
′), 195.4 (CdO); MS (m/ z, relative intensity) 238 (M , 44),
97 (18), 161 (44), 141 (21), 105 (59), 77 (68), 41 (100). Anal.
(
+
+
2
53 (M , 16), 182 (8), 165 (12), 137 (5), 130 (100), 109 (34).
Anal. (C13 N) C, H, N.
-(4-Ben zoylp h en oxy)eth yl Tetr a h yd r o-2H-p yr a n -2-yl
19 4
H O
(C
16
H
14
O
2
) C, H.
-[4-(r-Hyd r oxy-r-p h en ylm eth yl)p h en oxy]eth yl Tet-
r a h yd r o-2H-p yr a n -2-yl Eth er (31). To a 1.0 M solution of
LiAlH in tetrahydrofuran (30 mL) was added dropwise
compound 27 (772 g, 2.4 mmol) in anhydrous tetrahydrofuran
10 mL) under a nitrogen atmosphere. The reaction mixture
2
2
Eth er (27). 4-Benzoylphenol (26) (1.420 g, 7.2 mmol) in
dimethyl sulfoxide (10 mL) was treated with potassium
hydroxide (28 mmol). The suspension was stirred for 5 min.
Then, bromoethyl tetrahydropyranyl ether (3.160 g, 14.4
mmol) was added, and the reaction mixture was stirred at
room temperature overnight. The mixture was treated as
described for compound 16. The residue was purified by
column chromatography eluting with hexane-ethyl acetate (7:
4
(
was refluxed for 7 h. The mixture was allowed to cooled to
room temperature, and the reaction was quenched as described
for 24. The residue was purified by flash chromatography
eluting with hexane-EtOAc (7:3) to give 510 mg (63% yield)
3
) to obtain 587 mg (26% yield) of compound 27 as a colorless
of pure 31 as a colorless oil: R
f
0.48 (hexane-AcOEt, 3:2); IR
0.51 (hexane-AcOEt, 3:2); IR (film, cm- ) 3061, 2943,
872, 1733, 1655, 1601, 1508, 1446, 1419, 1256, 1078, 1034,
43, 700, 638, 627; 1H NMR (CDCl
) δ 1.51-1.82 (m, 6 H,
1
oil: R
2
7
f
-1
(film, cm ) 3427, 3061, 3030, 2941, 2872, 1653, 1610, 1601,
1
1
510, 1454, 1418, 1387, 1352, 1250, 1202, 1173, 1139, 1124,
080, 1034, 987, 924, 872, 812, 742, 700, 627; H NMR (CDCl )
3
1
3
H-3′′′, H-4′′′, H-5′′′), 3.56 (m, 1 H, H-6′′′a), 3.75-4.05 (m, 3 H,
H-1, H-6′′′b), 4.25 (m, 2 H, H-2), 4.71 (t, J ) 3.3 Hz, 1 H, H-2′′′),
6
δ 1.51-1.78 (m, 6 H, H-3′′′, H-4′′′, H-5′′′), 2.38 (s, 1H, OH),
3
4
.54 (m, 1 H, H-6′′′a), 3.76-4.16 (m, 5 H, H-1, H-2, H-6′′′b),
.98-7.84 (m, 9 H, aromatic protons); 13C NMR (CDCl
) δ 19.3
3
.25 (m, 2 H, H-2), 4.69 (t, J ) 3.3 Hz, 1 H, H-2′′′), 5.79 (s, 1
(
(
(
C-4′′′), 25.3 (C-5′′′), 30.4 (C-3′′′), 62.1 (C-6′′′), 65.6 (C-1), 67.6
13
H, PhCH(OH)), 6.86-7.39 (m, 9 H, aromatic protons); C NMR
C-2), 99.0 (C-2′′′), 114.1 (C-2′), 128.1 (C-3′′), 129.6 (C-2′′), 130.2
(CDCl
3
) δ 19.1 (C-4′′′), 25.3 (C-5′′′), 30.3 (C-3′′′), 62.0 (C-6′′′),
5.7 (C-1), 67.3 (C-2), 75.5 (PhCOH), 98.8 (C-2′′′), 114.5 (C-
′), 126.3 (C-4′′), 127.2 (C-2′′), 127.7 (C-3′), 128.2 (C-3′′), 136.4
C-3′), 131.8 (C-4′), 132.4 (C-4′′), 138.2 (C-1′′), 162.5 (C-1′),
6
2
+
1
(
95.4 (CdO); MS (m/ z, relative intensity) 326 (M , 67), 242
22 4
11), 198 (12), 121 (25), 105 (33), 85 (100). Anal. (C20H O )
(
3
C-4′), 144.1 (C-1′′), 158.2 (C-1′); MS (m/ z, relative intensity)
28 (M , 5), 182 (3), 129 (25), 105 (8), 85 (100). Anal.
C, H.
+
4
-Ben zoylp h en oxyeth a n ol (28). Compound 27 (316 mg,
(C20H O ) C, H.
24 4
1
.0 mmol) dissolved in methanol (20 mL) was treated with
(()-3,7-Dim eth ylocta -2,6-d ien -1-yl Tetr a h yd r o-2H-p y-
r a n -2-yl Eth er (33). A solution of geraniol (32) (131 mg, 0.85
mmol) in methylene chloride (30 mL) was treated with
dihydropyran (0.1 mL) as described for 9. Purification by flash
pyridinium p-toluenesulfonate (20 mg) following the procedure
for compound 17. Purification by flash chromatography elut-
ing with hexane-EtOAc (3:3) afforded 172 mg (73% yield) of

New Growth Inhibitors of T. cruzi
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15 2321
afforded 175 mg (77% yield) of pure carbonate 38 as a colorless
chromatography employing hexane-EtOAc (19:1) as eluent
afforded 163 mg (81% yield) of pure 33 as a colorless oil: R
-1
f
oil: R
f
0.40 (hexane-AcOEt, 19:1); IR (film, cm ) 2966, 2924,
-
1
0
1
.55 (hexane-AcOEt, 9:1); IR (film, cm ) 2926, 2872, 1464,
1
2856, 1761, 1664, 1456, 1387, 1244, 1157, 945, 920, 899, 783;
1
377, 1261, 1117, 1076, 1024, 906, 869, 816; H NMR (CDCl
3
)
3
H NMR (CDCl ) δ 1.60 (s, 6 H, Me at C-7, Me at C-11), 1.68
δ 1.60 (s, 3 H, Me at C-7), 1.68 (s, 6 H, Me at C-3, H-8), 1.42-
(s, 3 H, H-12), 1.74 (s, 3 H, Me at C-3), 1.90-2.15 (m, 8 H,
H-4, H-5, H-8, H-9), 4.55 (dd, J ) 6.2, 1.3 Hz, 1 H, H-2′cis to
H-1′), 4.71 (d, J ) 7.2 Hz, 2 H, H-1), 4.90 (d, J ) 13.8 Hz, 1 H,
H-2′atrans to H-1′), 5.09 (m, 2 H, H-6, H-10), 5.40 (t, J ) 7.1 Hz,
1
3
7
.80 (m, 6 H, H-3′, H-4′, H-5′), 2.00-2.20 (m, 4 H, H-4, H-5),
.51 (m, 1 H, H-6′a), 3.89 (m, 1 H, H-6′b), 4.03 (dd, J ) 11.9,
.5 Hz, 1 H, H-1a), 4.23 (dd, J ) 11.9, 6.3 Hz, 1 H, H-1b), 4.63
1
3
(
t, J ) 3.3 Hz, 1 H, H-2′), 5.09 (m, 1 H, H-6), 5.36 (m, 1 H,
1 H, H-1′), 7.08 (dd, J ) 13.8, 6.1 Hz, 1 H, H-1′); C NMR
(CDCl ) δ 16.0 (Me at C-3), 16.5 (Me at C-7), 17.6 (Me at C-11),
1
3
H-2); C NMR (CDCl
3
) δ 16.3 (Me at C-3), 17.6 (Me at C-7),
9.6 (C-4′), 25.5 (C-5, C-5′), 26.3 (C-8), 30.7 (C-3′), 39.6 (C-4),
2.2 (C-6′), 63.6 (C-1), 97.7 (C-2′), 120.6 (C-2), 124.0 (C-6), 131.5
3
1
6
25.6 (C-9), 26.1 (C-5), 26.7 (C-8), 39.5 (C-4), 39.7 (C-8), 65.2
(C-1), 97.5 (C-2′), 117.2 (C-2), 123.5 (C-10), 124.3 (C-6), 131.3
(C-11), 135.6 (C-7), 142.7 (C-3), 144.0 (C-1′), 156.5 (CdO); MS
+
(
1
C-7), 140.1 (C-3); MS (m/ z, relative intensity) 238 (M , 1),
37 (19), 85 (100), 69 (75). Anal. (C15 ) C, H.
,7-Dim eth ylocta -2,6-d ien -1-yl Eth ylca r ba m a te (34). A
+
H
26
O
2
(m/ z, relative intensity) 292 (M , 5), 204 (8), 189 (11), 161 (13),
3
147 (12), 136 (69), 121 (46), 93 (54), 81 (100). Anal. (C18
C, H.
28 3
H O )
solution geraniol (128 mg, 0.32 mmol) in pyridine (3.0 mL) was
treated as described for 10. The residue was purified by
column chromatography eluting with hexane-EtOAc (19:1) to
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 and UMYMFOR for spectra
and NIH Grant AI23259 to R.D.
give 158 mg (84% yield) of pure 34 as a colorless oil: R
f
0.43
-
1
(
hexane-AcOEt, 4:1); IR (film, cm ) 3333, 2971, 2922, 1694,
1
1
531, 1460, 1382, 1262, 1141, 1020,907, 779; H NMR (CDCl
δ 1.11 (t, J ) 7.2 Hz, 3 H, -NCH CH ), 1.58 (s, 3 H, Me at
C-7), 1.66 (s, 3 H, H-8), 1.68 (s, 3 H, Me at C-3), 1.95-2.15 (m,
H, H-4, H-5), 3.19 (dt, J ) 7.1, 6.0 Hz, 2 H, -NCH CH ), 4.56
d, J ) 7.0 Hz, 2 H, H-1), 5.06 (m, 1 H, H-6), 5.32 (t, J ) 7.0
3
)
2
3
4
(
2
3
Su ppor tin g In for m ation Available: Table of data needed
to calculate percent inhibition (5 pages). Ordering information
is given on any current masthead page.
1
3
Hz, 1 H, H-2); C NMR (CDCl
at C-3), 17.6 (Me at C-7), 25.6 (C-5), 26.3 (C-8), 35.9 (MeCH
NH), 39.5 (C-4), 61.5 (C-1), 119.0 (C-2), 123.8 (C-6) 131.7 (C-
), 141.5 (C-3), 156.6 (CdO); MS (m/ z, relative intensity) 225
3
) δ 15.2 (MeCH
2
NH), 16.4 (Me
2
-
Refer en ces
7
(
+
(1) Kirchhoff, L. V. American Trypanosomiasis (Chagas’ Disease)-A
M , 1), 161 (7), 137 (100) 121 (29). Anal. (C13
H
23
O
2
N) C, H,
Tropical Disease now in the United States. N. Engl. J . Med.
N.
1
993, 329, 639-644.
(
()-3,7,11-Tr im eth yld od eca -2,6,10-tr ien -1-yl Tetr a h y-
(
(
(
2) Galel, S. A.; Kirchhoff, L. V. Risk factors for Trypanosoma cruzi
infection in California blood donors. Transfusion 1996, 36, 227-
231.
3) 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.
4) Docampo, R.; Moreno, S. N. J . Biochemical Toxicology of Anti-
parasitic Compounds Used in the Chemotherapy and Chemo-
prophilaxis of American Trypanosomiaisis (Chagas’ Disease).
Rev. Biochem. Toxicol. 1985, 7, 159-204.
5) Gutteridge, W. E. Existing Chemotherapy and its Limitations.
Br. Med. Bull. 1985, 41, 162-168.
6) 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.
d r o-2H-p yr a n -2-yl Eth er (36). The procedure for the prepa-
ration of 9 was followed, using trans,trans-farnesol (35) (134
mg, 6.0 mmol) and dihydropyran (0.1 mL) in methylene
chloride (20 mL). Purification by flash chromatography eluting
with hexane-EtOAc (19:1) yielded 176 mg (97% yield) of pure
compound 36 as a colorless oil: R
f
0.50 (hexane-AcOEt, 4:1);
-
1
IR (film, cm ) 2939, 2872, 1681, 1452, 1383, 1200, 1024, 870,
1
8
1
26; H NMR (CDCl
3
) δ 1.42-1.80 (m, 6 H, H-3′, H-4′, H-5′),
(
.56 (s, 6 H, Me at C-7, Me at C-11), 1.66 (s, 6 H, H-12, Me at
C-3), 1.90-2.20 (m, 8 H, H-4, H-5, H-8, H-9), 3.51 (m, 1 H,
H-6′a), 3.87 (m, 1 H, H-6′b), 4.00 (dd, J ) 11.8, 7.4 Hz, 1 H,
H-1a), 4.21 (dd, J ) 11.8, 6.3 Hz, 1 H, H-1b), 4.61 (distorted t,
(
1
H, H-2′), 5.09 (m, 2 H, H-6, H-10), 5.34 (t, J ) 7.0 Hz, 1 H,
(7) Nussenzweig, V.; Sonntag, R.; Biancalana, A.; Pedreira de
Fleitas, J . L.; Amato Neto, V.; Kloetzel, J . Ac a˜ o de Corantes
Trifenil-metanicos sobre o Trypanosoma cruzi “in vitro.” Em-
pr eˆ go de Violeta de Genciana na Profilaxia da Transmiss a˜ o da
Mol e´ stia de Chagas por Transfus a˜ o de Sangue. Hospital (Rio
de J aneiro) 1953, 44, 731-744.
1
3
H-2); C NMR (CDCl
7.6 (Me at C-11), 19.6 (C-4′), 25.5 (C-9, C-5′), 26.3 (C-5)*, 26.7
C-8)*, 30.7 (C-3′), 39.6 (C-4), 39.6 (C-8), 62.1 (C-6′)*, 63.6 (C-
)*, 99.7 (C-2′), 120.7 (C-2), 123.9 (C-10), 124.3 (C-6), 131.1
C-11), 135.1 (C-7), 140.0 (C-3); FABMS (m/ z, relative inten-
3
) δ 15.9 (Me at C-3), 16.3 (Me at C-7),
1
(
1
(
(8) De Souza, W. Cell Biology of Trypanosoma cruzi. Int. Rev. Cytol.
1984, 86, 197-283.
+
sity) 306 (M , 45), 305 (100). Anal. (C20
34 2
H O ) C, H.
(
9) For a review of the 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.
3
,7,11-Tr im eth yld od eca -2,6,10-tr ien -1-yl Eth ylca r ba m -
a te (37). The procedure for the synthesis of 10 was followed,
employing farnesol (172 mg, 0.77 mmol), ethyl isocyanate (0.1
mL), and 4-(dimethylamino)pyridine (10 mg) in pyridine (3
mL). Purification by column chromatography eluting with
hexane-EtOAc (9:1) afforded 227 mg (99% yield) of pure 37
(
(
(
10) 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.
11) Rodriguez, J . B.; Gros, E. G.; Stoka, A. M. Synthesis and Activity
of J uvenile Hormone Analogues (J HA). Part II. Z. Naturforsch.
-1
as a colorless oil: R
f
0.38 (hexane-AcOEt, 4:1); IR (film, cm
)
1
989, 44b, 983-987.
3
7
1
355, 2978, 2936, 2865, 1694, 1531, 1389, 1262, 1148, 1084,
86; H NMR (CDCl
.59 (s, 6 H, Me at C-7, Me at C-11), 1.67 (s, 3 H, H-12), 1.70
12) 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.
1
3
) δ 1.12 (t, J ) 7.2 Hz, 3 H, -NCH
2 3
CH ),
(
s, 3 H, Me at C-3), 1.90-2.15 (m, 8 H, H-4, H-5, H-8, H-9),
.20 (q, J ) 7.1 Hz, 2 H, -NCH CH ), 4.57 (d, J ) 7.0 Hz, 2 H,
H-1), 5.09 (m, 2 H, H-6), 5.33 (t, J ) 7.0 Hz, 1 H, H-2);
NMR (CDCl ) δ 15.2 (MeCH NH), 15.9 (Me at C-3), 16.3 (Me
at C-7), 17.5 (Me at C-11), 25.5 (C-9), 26.1 (C-5), 26.7 (C-8),
3
2
3
1
3
C
3
2
(13) Rodriguez, J . B.; Gros, E. G.; Stoka, A. M. Synthesis and Activity
of J uvenile Hormone Analogues (J HA) for Trypanosoma cruzi.
BioMed. Chem. Lett. 1991, 1, 679-682.
3
2
5.8 (MeCH
2
NH), 39.5 (C-4), 39.6 (C-8), 61.5 (C-1), 119.0 (C-
(
14) 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.
), 123.6 (C-10), 124.3 (C-6), 131.1 (C-11), 135.3 (C-7), 141.4
+
(
2
C-3), 156.5 (CdO); MS (m/ z, relative intensity) 293 (M , 5),
21 (46), 204 (20), 177 (54), 162 (100), 147 (81), 138 (78). Anal.
N) C, H.
,7,11-Tr im eth yld od eca -2,6,10-tr ien -1-yl Eth en yl Ca r -
(
15) Schvartzapel, A. J .; Fichera, L.; Esteva, M.; Rodriguez, J . B.;
Gros, E. G. Design, Synthesis, and anti-Trypanosoma cruzi
Evaluation of a New Class of Cell Growth Inhibitors Structurally
Related to Fenoxycarb. Helv. Chim. Acta 1995, 78, 1207-1214.
16) 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.
18 31 2
(C H O
3
bon a te (38). The procedure for the preparation of 13 was
followed, employing farnesol (172 mg, 0.77 mmol) and vinyl
chloroformate (0.1 mL) in pyridine (3.0 mL). Purification by
flash chromatography eluting with hexane-EtOAc (49:1)
(

2
322 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15
Schvartzapel et al.
(
17) 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.
(26) Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. Pyridinium p-
Toluensulfonate. A Mild and Efficient Catalyst for the Tetrahy-
dropyranylation of Alcohols. J . Org. Chem. 1977, 42, 3772-3774.
(27) Agarwal, K. L.; Khorana, H. G. Studies on Polynucleotides. CII.
The Use of Aromatic Isocyanates for Selective Blocking of the
Terminal 3′-Hydroxyl Group in Protected Deoxyribooligonucle-
otides. J . Am. Chem. Soc. 1972, 94, 3578-3585.
(
18) 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.
(28) Fieser, L. F.; Herz, J . E.; Klohs, M. W.; Romero, M. A.; Utne, T.
Cathylation (Carbethoxylation) of Steroid Alcohols. J . Am. Chem.
Soc. 1952, 74, 3309-3313.
(
19) Very recently, an interesting paper has been published in which
the authors report a cure on experimental Chagas’ disease
employing a bis-triazole derivative as the chemotherapeutic
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