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Chagas Disease
Organic Compounds to Combat Neglected Tropical Diseases 21
possess a wide range of biological activities and some derivatives are considered
as promising anti-trypanosomal agents, especially as inhibitors of T. cruzi
dihydrofolate reductase (DHFR). Based on this information, Palma et al. [39]
have synthesized a series of 2-exo-aryl-1,4-epoxytetrahydronaphtho[1,2-
b]azepines and cis-2-aryl-4-hydroxytetrahydronaphtho[1,2- b]azepines that
showed activity against free epimatigotes of T. cruzi (IC
50
values ranging from
0.50 to 38.77 μM). Some of the compounds were also active on amastigotes, and
the most active compound (39, Fig. 13) had an IC
50
value of 9.9 μM on this
intracellular form of the parasite, with a good selectivity index with respect to
activity on mammalian cells. Gómez-Ayala et al. [40], encouraged by such
positive results, focused on the replacement of the naphthalene ring of the series
by an isostere benzene ring with the aim of synthesizing new analogues with
comparable or better antiparasitic activity. The purpose of their paper is to report
the synthesis, the spectroscopic characterization, and the antiparasitic activity of
two new series of 1,4-epoxy-2-exo-aryl- and cis-2-aryl-4-hydroxytetrahydro-1-
benzazepines. Many 1,4-epoxy-cycloadducts and amino-alcohols were active,
with IC
50
values of 6.10–35.39 μM against the epimastigote form of T. cruzi. In
this case, derivatives had only moderate activity against the amastigote form of
the parasite, with an IC
50
of 40.16 μM for the most active one (40, Fig. 13).
N
H
OH
Br
N
O
Cl
F
(39)
(40)
Figure 13: Trypanocidal benzazepine derivatives.
Other cyclic amines were prepared by Germain et al. [41], after evaluating over
300,000 compounds of the NIH-MLPCN collection to identify compounds
capable of inhibiting T. cruzi replication. Two scaffolds (41 and 42, Fig. 14) were
identified and selected for further SAR investigation and optimization efforts.
Many derivatives showed good activities together with high selectivity indexes,
compound 43 (Fig. 14) being the most active, with an IC
50
value of 35 nM, and
displaying no toxicity to the host cells up to 19.5 μM.
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22 Organic Compounds to Combat Neglected Tropical Diseases Micheletti et al.
Other classes of nitrogenated heterocycles appear in literature showing antichagasic
activity, such as phenoxazines, triazoles and thiadiazoles. Benzo[a]phenoxazines
were synthesized by Shi et al. [42], with a number of substituted phenyl groups on
the sp
2
nitrogen but, according to the authors, the compounds showed insufficient
activities against T. cruzi. IC
50
values ranged from >229 μM to 11 μM (44, Fig. 15),
and a selectivity index < 2 in almost all cases.
Figure 14: Cyclic amines 41 to 43.
Megazol (45) is a nitro 1,3,4-thiadiazole that has been shown to be highly active
against T. cruzi, including strains resistant to benznidazole, in vitro and in vivo
and has become a core structure for the design of new leads for the treatment of
Chagas disease. It has been described as a scavenger of trypanothione, the
cofactor for trypanothione reductase, but despite its noteworthy trypanocidal
activity, megazol (45) development was discontinued due to reports of in vitro
mutagenic and genotoxic effects. Salomão et al. [43] synthesized 1,3,4-
thiadiazole-2-arylhydrazone derivatives of megazol (45) in order to find potential
trypanocidal agents, exploring the hypothesis that the introduction of a radical
N
O
N
CH
3
CH
3
N
O
N
N
CH
3
CH
3
OCH
3
CH
3
N
O
N
N
CH
3
OCH
3
CH
3
CH
3
(41)
(42)
(43)
Chagas Disease
Organic Compounds to Combat Neglected Tropical Diseases 23
scavenger arylhydrazone moiety in the heterocyclic framework of megazol (45)
could modulate the production of toxic nitro anion radical species, thus avoiding
potentially mutagenic properties. The study identified new possible prototypes;
IC
50
/2 day values for the active compounds were 2.9 ± 0.6, and 1.6 ± 1.0 μM (46,
Fig. 15) on intracellular amastigotes, with good selectivity indexes.
Figure 15: Active nitrogen heterocycles 44 to 48.
1,2,3-Triazole-based tetrafluorophenoxymethyl ketones were prepared by Brak
et al. [32] with the aim to obtain cruzain inhibitors. Because of the ability of
1,2,3-triazoles to function as rigid linking units that mimic the atom placement
and electronic properties of a peptide bond without the susceptibility to
N
ON
Cl
NO
2
CH
3
CH
3
N
N
S
N
H
N
CH
3
N
N
CH
3
O
2
N
OH
N
N
S
NH
2
N
N
CH
3
O
2
N
N
NH
N
N
N
CH
3
CH
3
CH
3
n-Bu
O
O
F
F
F
F
N
O
Cl
O
OAc
AcO
OAc
AcO
O
(44)
(45)
(46)
(47)
(48)
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24 Organic Compounds to Combat Neglected Tropical Diseases Micheletti et al.
hydrolysis, many known 1,2,3-triazoles possess biological activity. The
compounds differ in the number of carbon atoms (1 to 6) and type (straight,
branched and/or cyclic) of side chains linked to the same scaffold, and many of
them proved to be cruzain inhibitors, as well as being active against intracellular
parasites. Derivatives with an n-butyl chain attached to an α-carbonyl position
near the triazolic moiety (47, Fig. 15) have the best interaction with the enzyme,
and the more potent inhibitors all had improved activity in cell culture (IC
50
= 3.1
- 4.2 μM).
Bouchikhi et al. [44] have synthesized isoindigo derivatives, simpler nitrogen
heterocycles, bearing an acetyl-sugar residue attached to one of the indolin-2-one
nitrogens and diversely substituted on the aromatic rings. The best activities
against T. cruzi (TulahuenC2C4) were found for compounds with IC
50
values in
the range of 10–30 M, with 48 (Fig. 15) being the most active. The study
suggests that these scaffolds could be of value for the discovery of new molecules
useful as lead compounds for tropical diseases.
2.5. Nitrogenated Open Chain Compounds
Classes of nitrogenated open chain compounds like hydrazides, hydrazones,
amidines, diamines and others, some of them containing sulfur, also play
important roles in the search for novel trypanocidal agents.
Borchhardt et al. [45] reported the synthesis of 3,4,5-trimethoxybenzohydrazides
containing different aromatic substituents such as nitro-, bromo-, methoxyphenyl,
naphthyl etc., as cruzain inhibitors. These derivatives inhibited the activity of the
enzyme at a range of concentration from 40 μM (49, Fig. 16) to 60 μM.
Arylimidamides, diamidines and a guanylhydrazones with trypanocidal activity
are described by Pacheco et al. [46], all containing aromatic moieties and/or O
and S heterocycles. The arylamidine 50 (Fig. 16) showed striking anti-parasitic
activity (IC
50
= 4.05 μM against bloodstream trypomastigotes and IC
50
= 0.76 μM
against intracellular forms) and low toxicity (selectivity index near 100).
Putrescine and 1,3-propanediamine are reported to show activities against
P. falciparum, L. donovani and T. cruzi, probably interfering with polyamine
metabolism, validating diamines derivatives as an attractive scaffold for the
Chagas Disease
Organic Compounds to Combat Neglected Tropical Diseases 25
development of new anti-parasitic drugs. Caminos et al. [1] synthesized a series of
N,N-substituted diamines, covering different chain lengths (between the two
nitrogen atoms) and degrees of substitution in the aromatic moiety. Compounds
were assayed on epimastigotes of T. cruzi, and many derivatives showed activity
below 10 μM (some of them showed submicromolar activities). The best
trypanocidal agents, such as derivative 51 (Fig. 16) with IC
50
= 0.73 μM and a
good selectivity index, regarding cytotoxicity on Vero cells, have a bulky group
para to the nitrogenated chain (O-benzyl). When the substituent is smaller (OMe),
the compounds are inactive.
Figure 16: Nitrogenated open chain trypanocidal compounds.
Thiosemicarbazones have been described as having parasitocidal action against
T. cruzi. This class of small molecules has been evaluated over the last 50 years as
antiviral, antibacterial and anticancer compounds. Thiosemicarbazone s derived fr om
1-indanones were synthesized by Caputto et al. [47], based on data from the
literature, that exhibited, in some cases, relevant anti-T. cruzi activities (epimastigote
form), the most active being the 4,5-dimethoxy-substituted derivative 52 (Fig. 16)
(IC
50
= 1.8 μM, SI= 989.0). It is interesting to note that, for this group, chloro and
nitro derivatives were not active against T. cruzi in culture. Compound 52 inhibited
cruzipain, the major cysteine protease expressed in all the life cycle stages of the
parasite, pointing to this as the target of action. This endoproteinase is the most
O
O
O
CH
3
CH
3
CH
3
N
H
O
N
O
NH
NH
HN
HN
H
N
N
H
O
O
O
CH
3
O
CH
3
N
H
N
S
NH
2
O
CH
3
O
CH
3
(49)
(50)
(51)
(52)
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26 Organic Compounds to Combat Neglected Tropical Diseases Micheletti et al.
abundant member among the cysteine-, serine-, threonine-, and metallo-proteinases,
and it is essential for infection of host cells, replication and metabolism of the
parasite and it plays multiple roles in disease pathogenesis.
2.6. Sugars, Phosphorus Compounds, Phenolic Derivatives
T. cruzi trans-sialidase (TcTS) is involved in the transfer of sialic acid from host
glycoconjugates to mucins of the parasite. Scavenging sialic acid from the host
glycoconjugates aids the recognition and attachme nt of the par asite to host cells, and
allows its evasion from the host’s immune response, resulting in host cells invasion
where the parasite can complete its life cycle [48, 49]. Campo et al. [49] have
synthesized 1,2,3-triazole sialic acid-based neoglycoconjugates to evaluate their
activity in inhibition of TcTS, by mimicking of the terminal sugars of
T. cruzi mucins. The target sialylmimetic neoglycoconjugates are represented by 1,4-
disubstituted 1,2,3-triazole-sialic acid derivatives containing a galactose modified at
either the C-1 or C-6 positions, glucose or gulose at the C-3 positions, and by the
amino acid derivative 1,2,3-triazole fused threonine-3-O-galactose. The study
concludes that sialic acid and galactosyl units are relevant for TcTS inhibition, and
the best trypanocidal agent showed had IC
50
= 260 M (53, Fig. 17).
O
HO
CH
3
HO
OH
HO
COOH
O
N
N
N
O
OH
OH
H
H
OH
H
H
HO
H
N
H
CH
3
P
O
HO
OH
P
O
OH
HO
N
N
H
P
l-Oytubosi
O
l-Oytubosi
CN
O
O
O
Cl
Cl
8
(53)
(54)
(55)
(56)
Figure 17: Antichagasic compounds 53 to 56.
Chagas Disease
Organic Compounds to Combat Neglected Tropical Diseases 27
Rosso et al. [50] have prepared 1-[2-(alkylamino)ethyl] bisphosphonates with
alkyl groups having 9, 10, 11, 12, 14, or 18 carbon atoms and one with a benzyl
moiety, which were designed on the basis of literature data about antichagasic
activity of aminobisphosphonates. The compounds were tested for inhibition of
farnesyl diphosphate synthase of T. cruzi (Tc FPPS), which has been
demonstrated to be the target of bisphosphonates that have activity in vitro and
in vivo against T. cruzi, and solanesyl diphosphate synthase, another important
prenyltransferase in T. cruzi (Tc SPPS), which is involved in the synthesis of
ubiquinone. Compound 54 (Fig. 17) proved to be an extremely potent growth
inhibitor against the clinically more relevant form of T. cruzi exhibiting an IC
50
value of 0.67 M, significantly more potent than benznidazole. This cellular
activity was associated with the inhibition of enzymatic activity towards the target
enzyme Tc FPPS with an IC
50
value of 0.81 M. Nogueira et al. [51] synthesized
a new series of dialkylphosphorylhydrazones, designed according to the concepts
of molecular hybridization of the functional hydrazonic groups of nifurtimox (1)
and miltefosine phosphate, an anticancer drug, active against Leishmania. Butyl
and isobutyl substituents were linked to the phosphoryl group, whereas nitro,
cyano, carboxy, chloro groups substituted the aromatic moieties. The activity of
these compounds was just moderate against epimastigotes of T. cruzi, with IC
50
values ranging from 8.3 (55, Fig. 17) to 83.5 M.
Besides the synthesis of 3,4,5-trimethoxybenzohydrazides, Borchhardt et al. [45]
have prepared chalcones to evaluate their activity as cruzain inhibitors, as the
class is described in the literature as inhibitors of malarial cysteine proteases. The
most potent compounds had IC
50
values between 20 (56, Fig. 17) and 25 μM and
represent a new class of lead candidates for further development. Furthermore,
almost all active chalcone derivatives possess the methylenedioxyphenyl (1,3-
benzodioxole) moiety, which suggests a significant contribution of this group to
the observed activity.
ACKNOWLEDGEMENTS
The authors are indebted to Professor Derrick L. J. Clive (University of Alberta,
Canada) for the great assistance with English review of this book chapter.
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28 Organic Compounds to Combat Neglected Tropical Diseases Micheletti et al.
CONFLICT OF INTEREST
The authors confirm that this chapter contents have no conflict of interest.
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