Effect of complexation of 3-aminoquinoxaline-2-carbonitrile 1,4-dioxides with palladium and copper on their anti-T. cruzi activity

Article abstract of DOI:10.1007/s00044-011-9660-y

Pd(II) and Cu(II) complexes of 3-aminoquinoxaline-2-carbonitrile 1,4-dioxides were prepared in order to improve the anti-Trypanosoma cruzi activity of these ligands. The in vitro evaluations demonstrated that the metal complexation modified the activity of the ligands in different manners. Except for one compound, complexation with palladium increased the trypanosomicidal activity 20-80-times. Besides, copper also modified favorably the activity, however, the copper compounds resulted less active than the palladium ones, at the studied doses. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9660-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1439–1444
DOI 10.1007/s00044-011-9660-y
ORIGINAL RESEARCH
Effect of complexation of 3-aminoquinoxaline-2-carbonitrile
1,4-dioxides with palladium and copper on their anti-T. cruzi
activity
Diego Ben ´ı tez
•
Mar ´ı a L. Lavaggi
Hugo Cerecetto
•
•
Dinorah Gambino
Mercedes Gonz a´ lez
•
Mar ´ı a H. Torre
•
Received: 8 May 2010 / Accepted: 4 May 2011 / Published online: 20 May 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Pd(II) and Cu(II) complexes of 3-aminoqui-
noxaline-2-carbonitrile 1,4-dioxides were prepared in order
to improve the anti-Trypanosoma cruzi activity of these
ligands. The in vitro evaluations demonstrated that the
metal complexation modified the activity of the ligands in
different manners. Except for one compound, complexa-
tion with palladium increased the trypanosomicidal activity
(T. cruzi), with symptoms progressing from mild swelling
to intestinal disease and ultimately heart failure. The cur-
rent drugs for this disease are two nitroaromatic com-
Ò
pounds, Nifurtimox (Nfx, Lampit ) and Benznidazole
Ò
(Bnz, Rochagan ) (Rodrigues Coura and Castro 2002;
Schofield et al., 2006). This chemotherapy is insufficient,
as it exhibits unacceptable side effects and often do not
completely eliminate the parasite despite chronic admin-
istration (Cerecetto and Gonz a´ lez, 2007, 2010; Castro
et al., 2006). Moreover, resistance to these agents has
emerged (http://www.who.int/tdr/diseases/chagas/direction.
htm). For these reasons the development of more safe and
efficient drugs against Chagas’ disease is urgent (Nwaka
and Ridley, 2003). Several types of compounds have been
described as anti-T. cruzi agents acting on different bio-
logical targets (Rivera et al., 2009). Some quinoxaline
derivatives were carefully selected from Dr. Antonio
Monge chemical-library in order to evaluate them against
T. cruzi being 3-aminosubstituted-2-carbonitrile deriva-
tives (i.e., 1 and 2, Fig. 1) good in vitro T. cruzi growth
inhibitors (Aguirre et al., 2004; Ancizu et al., 2009)
while the 3-amino-2-carbonitrile derivatives were inactive
(i.e. 3–7, Fig. 1). However, QSAR study predicts deriva-
tives 3–7 to be more active than experimentally found,
i.e., percentage of growth inhibition for derivative 7 at
2
0–80-times. Besides, copper also modified favorably the
activity, however, the copper compounds resulted less
active than the palladium ones, at the studied doses.
Keywords Palladium complexes ꢀ Copper complexes ꢀ
Chagas disease ꢀ 3-Aminoquinoxaline-2-carbonitrile 1 ꢀ
4
-dioxide ꢀ Trypanosoma cruzi
Introduction
Chagas’ disease is the third largest neglected disease in
Latin America after malaria and schistosomiasis, affecting
at least 15 million people with more than 25 million at the
risk of infection (http://www.who.int/tdr.). Its infectious
agent is the protozoan parasite Trypanosoma cruzi
25 lM would be 60% but experimentally this compound
inhibited 25% at this concentration. The low activities
displayed by these derivatives could be the result of their
low solubilities in the physiological media (Zamalloa et al.,
D. Ben ´ı tez ꢀ M. L. Lavaggi ꢀ H. Cerecetto ꢀ M. Gonz a´ lez (&)
Laboratorio de Qu ´ı mica Org a´ nica, Facultad de Ciencias-
Facultad de Qu ´ı mica, Universidad de la Rep u´ blica,
Montevideo, Uruguay
1997a, b). Another possibility, which was not identified in
e-mail: megonzal@fq.edu.uy
the previous QSAR studies (Aguirre et al., 2004), is that
anti-T. cruzi agents must comply with specific structural
requirements, i.e., volume, in the 3-amino moiety like
derivatives 1 and 2 (Fig. 1). Recently, the authors have
reported the biological characterization as anti-T. cruzi
D. Gambino ꢀ M. H. Torre (&)
Department of Inorganic Chemistry, Facultad de Qu ´ı mica,
Universidad de la Rep u´ blica, Montevideo, Uruguay
e-mail: mtorre@fq.edu.uy
123

1
440
Med Chem Res (2012) 21:1439–1444
agents of a series of vanadyl complexes of the type
IV
Materials and methods
[
V O(L) ] where L are the bidentate 3-aminoquinoxa-
2
line-2-carbonitrile 1,4-dioxides ligands (Urquiola et al.,
006) (8–11, Fig. 1). Complexation to vanadium of the
Chemistry
2
quinoxaline ligands led to excellent antiprotozoal activity
similar to that of the reference drugs Nfx and Bnz and
All common laboratory chemicals were purchased from
commercial sources and used without further purification.
The ligands, 3-aminoquinoxaline-2-carbonitrile 1,4-diox-
ides, were synthesized by reaction of the corresponding
benzofuroxan and malonitrile as previously described
(Gonz a´ lez et al., 2007). The benzo-substituted quinoxa-
lines were obtained as mixtures of 6- and 7-substituted
isomers (Gonz a´ lez et al., 2007). The palladium complexes,
12–15, and the copper complexes, 16–21 (Scheme 1) were
synthesized and characterized following previously estab-
lished methodologies (Urquiola et al., 2009, 2008). In
particular, palladium complexes 12ꢀH O, 13ꢀH O,
higher than that of the corresponding free ligands. The
IV
anti-trypanosomal activity of [V O(L) ] complexes could
2
be explained on the basis of their lipophilicities and the
electronic characteristics of the quinoxaline substituents
(
Urquiola et al., 2006). On the other hand, the use of
multitarget-directed drugs (MTDDs) emerges as a new
strategy for the development of new Chagas’ disease
agents (Cavalli and Bolognesi, 2009). This approach,
based in the combination of two or more pharmacophores
into a new chemical entity, defined as hybrid-drugs, is
still in its early stage for this illness. One of the recent
focuses has been the development of MTDDs as anti-
T. cruzi agents using DNA-interacting moieties linked to
free-radical releasing- or fumarate reductase inhibitor-
pharmacophores where the first one was represented by
palladium, platinum or gold metals and the second one by
the 5-nitrofuryl scaffold (Vietes et al., 2008a, b, 2009;
Otero et al., 2006a).
2
2
14ꢀ3H O, and 15ꢀ2CH OH were synthesized by ligand
2
3
-
2
substitution onto [PdCl ]
4
under reflux in methanol.
1
Thermogravimetric, FAB-MS and H-NMR results were
exhaustively discussed and were in agreement with the
proposed analytical and structural formula (Urquiola et al.,
2009).
On the other hand, copper complexes 16–21 were syn-
thesised sonicating each ligand in dried ethanol until total
dissolution. To the resulting solution 20.0 mL of an etha-
nolic solution of CuSO ꢀ5H O (0.075 mmol) were added.
Having this in mind, the authors have studied the bio-
logical behavior, against T. cruzi, of new hybrid-drugs
obtained by the complexation of 3-amino-2-carbonitrile-
quinoxaline 1,4-dioxides with palladium and copper as an
effort to develop novel MTDD trypanosomicidal agents by
changing the volume at the 3-amino level and by improv-
ing bioavailability of the organic ligands. To the best of the
knowledge, this report constitutes the first of its kind in
using Pd and Cu complexes of quinoxaline 1,4-dioxides in
the design of targeted antitrypanosomal agents.
4
2
After stirring for half an hour, a purple precipitate was
formed, then filtered, washed with small portions of etha-
nol, and dried at room temperature.
The complex 22, [Cu(3-H)(ala-H)], where 3-H and ala-H
are the deprotonated quinoxaline 3 (Fig. 1) and alanine,
was synthesized through a solid state technique by mixing
CuCO Cu(OH) (11 mg), alanine (9 mg), and 3 (20.0 mg),
3
2
adding some drops of water and heating the mixture at
Fig. 1 Trypanosomicidal
-aminoquinoxaline-2-
carbonitrile 1,4-dioxides, 1 and
, inactive ones, 3–7, and their
corresponding vanadium
complexes, 8–11
O
N
O
N
O
N
3
Cl
CN
F
F
CN
R1
R2
CN
2
H
H
N
O
N
N
O
N
N
O
NH2
S
O
1
2
-R = -R = -H,
R = -H, -R = -CH ,
R = -H, -R = -Cl,
R = -H, -R = -Br,
3
1
2
-
-
-
-
4
5
6
7
1
2
3
1
2
1
2
R = -R = -Cl,
1
2
O
N
CN
NH
R3
N
O
-
R = -H,
= -CH
8
9
3
VO
O
-R
-R
-R
3
3
1
3
,
HN
NC
N
= -Cl, 10
= -Br, 11
R3
N
O
1
23

Med Chem Res (2012) 21:1439–1444
1441
Scheme 1 Synthetic
O
N
O
O
procedures for the preparation
of ligands, palladium, and
cooper complexes
R1
R2
NO2
NH2
R1
R2
NC
CN
R1
R2
CN
NaClO
N
N
NaOH / MeOH
Et N / DMF
3
N
O
NH2
O
N
O
N
R1
R2
CN
R1
R2
CN
NH
Na [PdCl ]
2
4
N
O
NH2
N
O
MeOH or MeOH-DMF (1:1)
reflux, 24 h
Pd
O
HN
NC
N
R2
-
R = -R = -H,
12
1
2
N
O
R1
-
-
-
R = -H, -R = -CH , 13
1
2
3
R = -H, -R = -Cl, 14
1
2
R = -R = -Cl,
15
1
2
O
N
O
R1
R2
CN
R1
R2
N
CN
NH
CuII. (H
O)
2 X
.
CuSO4 5H O
2
N
O
NH2
N
O
EtOH, r.t., 30 min
2
-
-
-
-
-
-
R = -R = -H, x= 0,
16
1
2
R = -H, -R = -CH , x= 2, 17
1
2
3
R = -H, -R = -Cl, x= 1,
18
19
1
2
R = -H, -R = -Br, x= 0,
1
2
R = -Cl, -R = -OCH , x= 1, 20
1
2
3
R = -Cl, -R = -F, x= 0,
21
1
2
O
N
O
N
CN
NH2
CN
NH
Ala CuII.
CuCO Cu(OH)2
3
N
O
N
O
o
H
O (cat), 80 C, 6h
2
3
22
8
0°C during 6 h (Tarallo et al., 2009). A red complex was
obtained.
14, Found/Calc.(%): C, 34.36/34.23; H, 2.20/2.23; N,
-
1
17.65/17.74. Yield: 45%. IR (KBr) (m/cm ): 3396 (N–H),
1614 and 1664 (C=N?O), 2242 (C:N).
15, Found/Calc.(%): C, 33.75/33.80; H, 2.06/1.99; N,
The results of the elemental analysis (%) obtained with a
Carlo Erba EA 1108 analyzer, the yields and the IR spectra
performed with a Bomen M102 instrument (4000–400
-
1
15.67/15.77. Yield: 67%. IR (KBr) (m/cm ): 3347 (N–H),
1561 and 1579 (C=N?O), 2232 (C:N).
16, Found/Calc.(%): C, 46.17/46.41; N, 23.94/24.05; H,
-
1
cm ) were:
2, Found/Calc.(%): C, 41.41/41.20; H, 2.52/2.30; N,
1
-
1
-1
2
1.34/21.35. Yield: 52%. IR (KBr) (m/cm ): 3400 (N–H),
561 and 1618 (C=N?O), 2235 (C:N).
2.49/2.16. Yield: 53%. IR (KBr) (m/cm ): 3386 (N–H),
1
1575 and 1593 (C=N?O), 2221 (C:N).
17, Found/Calc.(%): C 45.47/45.47; N 21.17/21.17; H
1
3, Found/Calc.(%): C, 43.23/43.30; H, 2.95/2.91; N,
-
1
-1
2
0.04/20.20. Yield: 61%. IR (KBr) (m/cm ): 3406 (N–H),
561 and 1618 (C=N?O), 2230 (C:N).
3.13/3.17. Yield 55%. IR (KBr) (m/cm ): 3356 (N–H),
1
1610, 1592 and 1593 (C=N?O), 2225 (C:N).
123

1
442
Med Chem Res (2012) 21:1439–1444
1
8, Found/Calc. (%): C 39.78/39.09; N 20.49/20.27; H
solution in DMSO. The final concentration of DMSO in the
culture media never exceeded 1% and the control was run
in the presence of 1% DMSO and in the absence of any
compound. No effect on epimastigotes growth was
observed by the presence of up to 1% DMSO in the culture
media. Nfx was used as the reference trypanosomicidal
drugs. The percentage of growth inhibition was calculated
as follows {1-[(Ap-A0p)/(Ac-A0c)]} 9 100, where
Ap = A590 of the culture containing the studied compound
at day 5; A0p = A590 of the culture containing the studied
compound right after addition of the inocula (day 0);
Ac = A590 of the culture in the absence of any compound
(control) at day 5; A0c = A590 in the absence of the
compound at day 0.
-
1
2
.31/1.81. Yield 48%. IR (KBr) (m/cm ): 3358 (N–H),
589 and 1561 (C=N?O), 2225 (C:N).
9, Found/Calc. (%): C 34.15/34.54; N 17.25/17.91; H
1
1
-
1
2
.17/1.26. Yield 54%. IR (KBr) (m/cm ): 3364 (N–H),
586 and 1561 (C=N?O), 2221 (C:N).
1
2
0, Found/Calc.(%): C, 39.62/39.18; N, 17.92/18.28; H,
-
1
1
.96/2.29. Yield 39%. IR (KBr) (m/cm ): 3386 (N–H),
562 and 1584 (C=N?O), 2228 (C:N), 1340 (N?O).
1
2
1, Found/Calc.(%): C, 37.98/37.88; N, 19.35/19.63; H,
-
1
1
.08/1.06. Yield 41%. IR (KBr) (m/cm ): 3362 (N–H),
573 and 1595 (C=N?O), 2231 (C:N).
1
2
2, Found/Calc. (%): C, 40.97/40.48; N, 19.91/;19.74,
-
1
H, 3.15/3.05. Yield: 95%. IR (KBr) (m/cm ): 3385 (NH);
-
2
226 (C:N), 1395 (COO ).
The electronic spectra recorded on a Shimadzu UV-
1
603 spectrophotometer in DMF solution of all the copper
Results and discussion
complexes show a d-d broad band in the 500–594 nm range
characteristic of Cu(II) in a distorted octahedral geometry
The synthesis of the quinoxaline ligands (Scheme 1) were
achieved using previously described methods yielding the
desired intermediates in excellent yields and high purities.
The previously described synthetic approaches for the
palladium, 12–15, and the copper complexes, 16–21
(Scheme 1), were performed with excellent yields and high
purities. Complex 22 was designed as analog of copper
complex 16 in order to evaluate the effect of the inclusion
of a hydrosoluble co-ligand, alanine, in the anti-T. cruzi
activity. Cooper complex 22 was prepared using a novel
methodology in solvent-free conditions using as cooper
reagent CuCO ꢀCu(OH) . Analytical data and conducto-
(
Lever, 1984).
Conductometric measurements of complexes were per-
-4
-
3
formed at 25°C in 10 –10 M DMF and DMSO solu-
tions using a Conductivity Meter 4310 Jenway (Geary,
1
971). The measurements showed no significant change in
the conductivity in comparison with that of the pure sol-
vents. This behavior is in agreement with the neutrality of
the complexes, according to the assigned formula. In
addition, the stability of the complexes in DMSO solutions
during the time involved in the biological tests was stated
by this technique.
3
2
Low-temperature (120 K) EPR experiments of DMSO
solution of complexes 16–21 were performed using a
Varian E109 spectrometer equipped with a rectangular
cavity and 100 kHz field modulation. The g-values were
obtained by means of spectral simulation using the soft-
ware package EasySpin (Stoll and Schweiger, 2006). An
exhaustive EPR spectrum analysis of these copper
compounds was previously reported (Torre et al., 2005;
Urquiola et al., 2008).
metric, thermogravimetric and FAB-MS results were in
agreement with the proposed analytical and structural for-
mula. Conductometric measurements showed that the
complexes behave as non electrolytes, in agreement with
the non charged formula proposed. In addition, it was
demonstrated by conductometry that the compounds are
Table 1 Percentage of Trypanosoma cruzi growth inhibitions (PGI,
%
) for the studied compounds
Ligand PGI V-
complex
PGI Pd-
complex
PGI Cu-
complex
PGI
Biology
3
4
5
6
7
25.0
5.0
8
59.5 12
47.5 13
95.0 14
91.5
40.8 16
53.9 17
78.1 18
19
62.7
14.0
4.0
Trypanosoma cruzi epimastigotes (Tulahuen 2 strain) were
grown at 28°C in an axenic medium (BHI-Tryptose) as
previously described (Urquiola et al., 2006; Otero et al.,
9
0.0 10
31.5 11
25.0
2
006a, b), complemented with 5% foetal calf serum. Cells
0.0
were harvested in the late log phase, re-suspended in fresh
15
4.8 21
22
0.0
medium, counted in Neubauer’s chamber and placed in
6
4-well plates (2 9 10 /ml). Cell growth was measured as
3.9
2
23
35.0
the absorbance of the culture at 590 nm, which was proved
to be proportional to the number of cells present. Before
inoculation, the media were supplemented with the indi-
cated amount of the studied compound from a stock
Nfx
100.0
PGI percentage of growth inhibition (%) of Tulahuen 2 epimastigotes
at 25 lM. The results are the mean values of three different experi-
ments with a SD less than 10% in all cases
1
23

Med Chem Res (2012) 21:1439–1444
1443
Fig. 2 Comparative
trypanosomicidal activities
(
PGI T. cruzi percentages of
growth inhibition at 25.0 lM)
stable in DMF solution for at least 6 days at 30°C and in
DMSO for at least 24 h. Thermogravimetic measurements
showed the presence of crystallization water molecules in
the cases of palladium complexes and coordinated
water molecules for the copper ones. Electronic, IR,
the activities of the methyl-substituted-, 17, or the chloro-
substituted derivative, 18 (Table 1).
In general, the derivatization of 3-aminoquinoxaline-2-
carbonitrile 1,4-dioxides with palladium and copper
produced improvement of the ligands activity, compare
anti-T. cruzi activities of ligands 3, 4, and 5 and the cor-
responding activities of Pd (II) complexes 12, 13, and 14,
or the corresponding of Cu (II) complexes 16, or the mix-
complex 22, 17, and 18 (Table 1). The inclusion of alanine
as co-ligand in the mix-Cu (II) complex 22 conducted to a
decrease in the anti-T. cruzi activity indicating, like the
vanadium-complex parent compounds (Urquiola et al.,
2006), that a more lipophilic entity, as result of a second
quinoxaline 1,4-dioxide ligand, produces more trypanoso-
micidal agents.
1
H NMR (for Pd complexes), and ESR (for Cu com-
plexes) spectroscopies allow us to complete the structural
characterizations.
The results of anti-T. cruzi behavior of the studied
complexes, together with the ligands and vanadium parent
complexes activities, are given in Table 1 and Fig. 2.
Except for one complex, 15, the palladium derivatization
modified positively the trypanosomicidal activities
increasing the ligands behaviors from 20- to 80-times. On
the other hand, the copper derivatization also modified
positively the studied activity, however, more poorly active
complexes, at the studied doses, with this metal were
obtained. From the Pd (II)-complexes series the most rel-
evant derivative was the chloro-derivative 14 while in the
case of Cu (II)-complexes series was the un-substituted-
derivative 16 (Table 1). No clear structure-activity rela-
tionship was observed when the authors analyzed together
both series of complexes. However, when it was analyzed
each series independently some facts could be achieved.
For the palladium-derivatized quinoxaline 1,4-dioxides,
like the vanadium-complex parent compounds (Urquiola
et al., 2006), the electronic effect of the substituent seem to
be playing a role in the anti-T. cruzi behaviors, i.e., the
inductive electron-withdrawing substituent capability
increase the activity of the studied compound (compare
activities of 12 and 14, Table 1). Derivative 15 ruled out
from this proposal, maybe the inadequate solubility of this
compound in the biological milieu could uncover the actual
result. On the other hand, for the copper-derivatized
quinoxaline 1,4-dioxides the steric effect of the substituent
seem to be playing in the anti-T. cruzi behaviors and the
substituents electronic effect seem to be the opposite of the
Pd (II) series, compare the activity of the unsubstituted
derivative, 16, the most active derivative of this series, and
Conclusion
The results show that the antitrypanosomal activity of the
quinoxalines is clearly modified after derivatization. The
parent ligands having poor trypanosomicidal activity
became, in the majority of the cases, active on complexa-
tion with palladium and, in some cases, with copper. These
observations suggest that these metal-based active agents
possess a great potential as therapeutic agents.
Acknowledgments DB wishes to thank ANII for scholarships.
Financial support from RIDIMEDCHAG-CYTED is acknowledged.
References
Aguirre G, Cerecetto H, Di Maio R, Gonz a´ lez M, Montoya Alfaro
ME, Jaso A, Zarranz B, Ortega MA, Aldana I, Monge-Vega A
0
(2004) Quinoxaline N, N -dioxide derivatives and related
compounds as growth inhibitors of Trypanosoma cruzi struc-
ture-activity relationships. Bioorg Med Chem Lett 14:
3
835–3839
Ancizu S, Moreno E, Torres E, Burguete A, P e´ rez-Silanes S, Ben ´ı tez
D, Villar R, Solano B, Mar ´ı n A, Aldana I, Cerecetto H, Gonz a´ lez
123

1
444
Med Chem Res (2012) 21:1439–1444
M, Monge A (2009) Heterocyclic-2-carboxylic acid (3-cyano-1,
-di-N-oxidequinoxalin-2-yl)amide derivatives as hits for the
development of neglected disease drugs. Molecules 14:2256–
272
Tarallo MB, Costa-Filho AJ, Vieira ED, Monge A, Leite CQ, Pavan
FR, Borthagaray G, Gambino D, Torre MH (2009) Research of
new mixed-chelate copper complexes with quinoxaline N1, N4-
dioxide derivatives and alanine as ligands, potential antimyco-
bacterial agents. J Argentine Chem Soc 97:80–89
Torre MH, Gambino D, Araujo J, Cerecetto H, Gonz a´ lez M, Lavaggi
ML, Azqueta A, L o´ pez de Cerain A, Monge Vega A, Abram U,
Costa-Filho AJ (2005) Novel Cu(II) Quinoxaline N1, N4–
dioxide complexes as selective hypoxic cytotoxins. Eur J Med
Chem 40(5):473–480
4
2
Castro JA, de Meca MM, Bartel LC (2006) Toxic side effects of drugs
used to treat Chagas’ disease (American trypanosomiasis). Hum
Exp Toxicol 25:471–479
Cavalli A, Bolognesi ML (2009) Neglected tropical diseases: multi-
target-directed ligands in the search for novel lead candidates
against Trypanosoma and Leishmania. J Med Chem 52:
7
339–7359
Urquiola C, Vieites M, Aguirre G, Mar ´ı n A, Solano B, Arrambide G,
Nobl ´ı a P, Lavaggi ML, Torre MH, Gonz a´ lez M, Monge A,
Gambino D, Cerecetto H (2006) Improving anti-trypanosomal
activity of 3-aminoquinoxaline-2-carbonitrile N1, N4-dioxide
derivatives by complexation with vanadium. Bioorg Med Chem
15:5503–5509
Urquiola C, Gambino D, Cabrera M, Lavaggi ML, Cerecetto H,
Gonz a´ lez M, L o´ pez de Cer a´ in A, Monge A, Costa-Filho AJ,
Torre MH (2008) New copper-based complexes with quinoxa-
line N(1), N(4)-dioxide derivatives, potential antitumoral agents.
J Inorg Biochem 102:119–126
Cerecetto H, Gonz a´ lez M (2007) Benzofuroxan and Furoxan.
Chemistry and biology. In: Khan MTH (ed) Topics in hetero-
cyclic chemistry. Bioactive heterocycles V, vol 10. Springer,
Berlin
Cerecetto H, Gonz a´ lez M (2010) Synthetic medicinal chemistry in
Chagas’ disease: compounds at the final stage of ‘‘Hit-to-Lead’’
phase. Pharmaceuticals 2. doi:10.3390/ph20x000x
Geary WJ (1971) The use of conductivity measurements in organic
solvents for the characterisation of coordination compounds.
Coord Chem Rev 7:81–122
Gonz a´ lez M, Cerecetto H, Monge A (2007) Quinoxaline 1,4-dioxide
and phenazine 5,10-dioxide. Chemistry and biology. In: Khan
MTH (ed) Topics in Heterocyclic Chemistry. Bioactive hetero-
ccyles V, vol.11 Springer, Berlin
Lever ABP (1984) Inorganic electronic spectroscopy. Elsevier,
Amsterdam
Nwaka S, Ridley RG (2003) Virtual drug discovery and development
for neglected diseases through public-private partnerships. Nat
Rev Drug Disc 2:919–928
Otero L, Vieites M, Boiani L, Denicola A, Rigol C, Opazo L, Olea-
Azar C, Maya JD, Morello A, Krauth-Siegel RL, Piro OE,
Castellano E, Gonz a´ lez M, Gambino D, Cerecetto H (2006a)
Novel antitrypanosomal agents based on palladium nitrofur-
ylthiosemicarbazone complexes: DNA and redox metabolism as
potential therapeutic targets. J Med Chem 49:3322–3331
Otero L, Aguirre G, Boiani L, Denicola A, Rigol C, Olea-Azar C,
Maya JD, Morello A, Gonz a´ lez M, Gambino D, Cerecetto H
Urquiola C, Vieites M, Torre MH, Cabrera M, Lavaggi L, Cerecetto
H, Gonz a´ lez M, L o´ pez de Cer a´ in A, Monge A, Smircich P, Garat
B, Gambino D (2009) Cytotoxic palladium complexes of
bioreductive quinoxaline N1, N4-dioxide prodrugs. Bioorg
Med Chem 17:1623–1629
Vieites M, Otero L, Santos D, Toloza J, Figueroa R, Norambuena E,
Olea-Azar C, Aguirre G, Cerecetto H, Gonz a´ lez M, Morello A,
Maya JD, Garat B, Gambino D (2008a) Platinum(II) metal
complexes as potential anti-Trypanosoma cruzi agents. J Inorg
Biochem 102:1033–1043
Vieites M, Smircich P, Parajon-Costa B, Rodr ´ı guez J, Galaz V, Olea-
Azar C, Otero L, Aguirre G, Cerecetto H, Gonz a´ lez M, G o´ mez-
Barrio A, Garat B, Gambino D (2008b) Potent in vitro anti-
Trypanosoma cruzi activity of pyridine-2-thiol N-oxide metal
complexes having an inhibitory effect on parasite-specific
fumarate reductase. J Biol Inorg Chem 13:723–735
Vieites M, Otero L, Santos D, Olea-Azar C, Norambuena E, Aguirre
G, Cerecetto H, Gonz a´ lez M, Kemmerling U, Morello A, Maya
DJ, Gambino D (2009) Platinum-based complexes of bioactive
3-(5-nitrofuryl)acroleine thiosemicarbazones showing anti-Try-
panosoma cruzi activity. J Inorg Biochem 103:411–418
Zamalloa E, Aldana I, Bachiller CM, Monge A (1997a) Physico-
chemical properties and stability of the new hypoxia-selective
(
2006b) Nitrofurylsemicarbazone rhenium and ruthenium com-
plexes as anti-trypanosomal agents. Eur Med Chem
1:1231–1239
J
4
Rivera G, Bocanegra-Garc ´ı a V, Ordaz-Pichardo C, Nogueda-Torres
B, Monge A (2009) New therapeutic targets for drug design
against Trypanosoma cruzi, advances and perspectives. Curr
Med Chem 16:3286–3293
agent
7-chloro-3-[[N,N-dimethylamino)propyl]amino]-2-qui-
Rodrigues Coura J, Castro SL (2002) A critical review on Chagas
disease chemotherapy. Mem Inst Oswaldo Cruz 97:3–24
Schofield CJ, Jannin J, Salvatella R (2006) The future of Chagas
disease control. Trends Parasitol 22:583–588
Stoll S, Schweiger A (2006) EasySpin, a comprehensive software
package for spectral simulation and analysis in EPR. J Magn
Reson 178:42–55
noxalinecarbonitrile 1,4-di-N-oxide hydrochloride. Arzneimit-
telforsch 47:873–878
Zamalloa E, Dios-Vi e´ itez C, Gonz a´ lez-Pe n˜ a E, Monge A (1997b)
Determination of a new hypoxia selective agent from 2-quinox-
alinecarbonitrile 1,4-di-N-oxides in plasma by high performance
liquid chromatography. Arzneimittelforsch 47:1044–1046
1
23