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Fernandes, Guilherme F. dos Santos
Faculty of Pharmaceutical Sciences, Paulista State University- UNESP,
Araraquara-SP, Brazil
Ito, Felicia Megumi
Federal Institute of Mato Grosso do Sul. Rua Tanure Salime, s/n, 79400-000,
Coxim-MS, Brazil
Leite, Clarice Q. F.
Laboratory of Mycobacteriology “Prof. Dr. Hugo David”, Department of
Biological Science, Faculty of Pharmaceutical Sicences, Paulista State University
- UNESP, Jaú-SP, Brazil
Lopes, Marcela Silva
Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, Federal
University of Minas Gerais, Belo Horizonte-MG, Brazil
Marino, Leonardo B.
Laboratory of Mycobacteriology “Prof. Dr. Hugo David”, Department of
Biological Science, Faculty of Pharmaceutical Sicences, Paulista State University
- UNESP, Jaú-SP, Brazil
Micheletti, Ana Camila
Institute of Chemistry, Federal University of Mato Grosso do Sul, Campo
Grande-MS, Brazil
Natsui, Ana Patricia Yatsuda
Department of Clinical, Toxicological and Bromatological Analyses, Faculty of
Pharmaceutical Sciences of Ribeirao Preto, São Paulo University - USP, Ribeirão
Preto-SP, Brazil
Neves Filho, Ricardo A.W.
Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry,
Weinberg, Germany
v
Oliveira, Renata Barbosa de
Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, Federal
University of Minas Gerais, Belo Horizonte-MG, Brazil
Oliveira, Ronaldo Nascimento de
Laboratory of Synthesis of Bioactive Compounds, Department of Molecular
Sciences, Federal Rural University of Pernambuco, Recife-PE, Brazil
Pavan, Fernando Rogério
Laboratory of Mycobacteriology “Prof. Dr. Hugo David”, Department of
Biological Science, Faculty of Pharmaceutical Sicences, Paulista State University
- UNESP, Jaú-SP, Brazil
Pinheiro, Luiz Carlos da Silva
Department of Organic Synthesis, Institute of Drug Technology - Farmanguinhos,
Oswaldo Cruz Foundation - Fiocruz, Rio de Janeiro-RJ, Brazil
Rezende, Lucas Cunha Dias
Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences of
Riberão Preto – FCFRP, University of São Paulo - USP, Ribeirao Preto – SP,
Brazil
Santos, Edson dos Anjos dos
Federal Technological University of Paraná, Apucarana-PR, Brazil
Santos, Gabriela Bianchi dos
Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences of
Ribeirão Preto - FCFRP, São Paulo University - USP, Ribeirão Preto-SP, Brazil
Santos, Jean Leandro
Faculty of Pharmaceutical Sciences, Paulista State University- UNESP,
Araraquara-SP, Brazil
Organic Compounds to Combat Neglected Tropical Diseases, 2014, 3-31 3
CHAPTER 1
CHAGAS DISEASE
An Overview of Recent Advances in the Search for Synthetic
Organic Compounds with Trypanocidal Activity
Ana Camila Micheletti
1,*
, Edson dos Anjos dos Santos
2
and Felicia Megumi Ito
3
1
Federal University of Mato Grosso do Sul, Institute of Chemistry, Av. Senador
Filinto Muller, 1555, 79074-460, Campo Grande-MS, Brazil;
2
Federal
Technological University of Paraná, Campus Apucarana, Rua Marcílio Dias,
635, CEP 86812-460, Apucarana-PR, Brazil and
3
Federal Institute of Mato
Grosso do Sul. Rua Tanure Salime, s/n, 79400-000, Coxim-MS, Brazil
Abstract: Chagas disease was discovered over 100 years ago, and continues to be a
major public health problem, with 16 to 18 million people infected with Trypanososma
cruzi, its causative agent, and 21,000 deaths associated with this disease every year.
Nifurtimox (Nfx) and benznidazole (Bnz) are even today the only clinically available
drugs for the chemotherapy of Chagas disease, but they show significant side effects,
involve long-term treatment and there are other problems, like emergence of resistant
strains. This chapter aims to highlight recent contributions from the organic synthesis
field on developing new compounds with trypanocidal activity, including discussion on
important structural features and molecular targets.
Keywords: Chagas disease, antichagasic activity, organic synthesis, trypanocidal
activity.
1. INTRODUCTION
The year 2009 was 100 years since the discovery of Chagas disease, but it
continues to be a serious public health problem almost completely ignored by the
pharmaceutical market, and is therefore, classified as a neglected disease.
Neglected diseases, such as Chagas disease, leishmaniasis, schistosomiasis,
malaria, filariosis and sleeping sickness affect a quarter of the world and are
prevalent throughout the tropics and subtropics, representing a major public health
problem in regions least able to deal with the economic burden. Millions of people
*Address correspondence to Ana Camila Micheletti: Federal University of Mato Grosso do Sul, Institute
of Chemistry, Av. Senador Filinto Muller, 1555, 79074-460, Campo Grande-MS, Brazil; Tel/Fax: +55 67
3345 3558; E-mail: anamicheletti@gmail.com
Send Orders for Reprints to reprints@benthamscience.net
4 Organic Compounds to Combat Neglected Tropical Diseases Micheletti et al.
worldwide still die of diseases that can be prevented and treated. Daily, over
35,000 people die from infectious and neglected diseases. Very little investment is
devoted to research and development of drugs to treat diseases affecting poor
populations. The lack of interest from pharmaceutical companies searching for
new drugs for certain diseases is directly connected to the low purchasing power
of these populations [1, 2]. Moreover, parasitic protozoa are eukaryotic; so they
share many common features with their mammalian host, making the
development of effective and selective drugs a hard task [3].
Most of the drugs used in therapies were discovered at least five decades ago.
They are difficult to administer, have high toxicity, and the treatments are time-
consuming and costly. The urgency in finding new medicines for neglected
diseases has motivated research and development in various countries around the
world [1, 2].
Chagas disease, also known as American trypanosomiasis, is caused by the
flagellate protozoan parasite Trypanosoma cruzi, and is responsible for a
considerable human mortality and morbidity, especially in Latin America, where
it is endemic. An estimated 16 to 18 million people are infected with T. cruzi
worldwide and more than 100 million people are at risk of acquiring the disease.
Recent surveys indicate that about 200,000 new cases and 21,000 deaths are
associated with this disease every year [2, 4]. The easy migration of infected
individuals due to globalization is of great concern since the disease is being
spread to non-endemic regions [5].
T. cruzi presents three main morphological forms in a complex life cycle, which
necessarily involves crossing a vertebrate host (mammals, including man) and
invertebrate host (hematophagous insects of the subfamily Triatominae): the
epimastigote and metacyclic trypomastigote forms found in insects, besides the
amastigote and trypomastigote blood forms responsible for the multiplication and
spread of infection in man, respectively [2]. The vectors are bugs (family
Reduviidae), hematophagous insects, popularly known as kissing bugs or weevils.
Any mammal can harbor the parasite, while birds and reptiles are refractory to
infection. The main reservoirs in the sylvatic cycle are opossums, armadillos,
dogs, cats, rats etc. In the domestic cycle, due to the proximity of the dwellings of
Chagas Disease
Organic Compounds to Combat Neglected Tropical Diseases 5
man with the wild environment, the reservoirs are humans and domestic or
synanthropic mammals such as dogs, cats, rats and pigs [6].
Chagas disease is transmitted by triatomine feces (90%), through contact with
broken skin or mucous membranes of the eye, blood transfusion, organ
transplantation, laboratory accidents, and oral or congenital contamination.
Vectorial and transfusional transmission have steadily declined through
multinational initiatives focused on vector control (Triatoma infestans) and blood
donor screening [5], but the sanitary problems associated with those already
infected still remains a challenge [7].
The disease is characterized by three clinical phases named acute, indeterminate
and chronic, that differ in symptoms and morbidity. The acute phase can be
identified or not (acute Chagas disease - ACD) shows a tendency to progression to
chronic forms if not treated early with specific drug. In humans, in the absence of
treatment, the symptoms persist for about two months, with a mortality of 2% to
8%, especially among children. After the acute phase, approximately 60% - 70%
of the infected patients will progress to an indeterminate form, without any
clinical manifestation. The remaining 30% to 40% develop chronic clinical forms,
divided into three types according to the presented complications: cardiac,
digestive or mixed (with cardiac and digestive) [2, 6].
The old and quite unspecific drugs nifurtimox (Nfx, 1), a nitrofuran derivative,
and benznidazole (Bnz, 2) (Fig. 1), a nitroimidazole derivative, are even today the
only clinically available drugs for the chemotherapy of Chagas disease. Both
drugs act via the reduction of the nitro group. Nfx and Bnz show trypanocidal
effects on all forms of the parasite, curing around 80% of acute cases. However,
patients should undergo long-term treatment, about 60 days, with 2-3 doses per
day; the drugs are not accessible for patients, in some cases being restricted to
specialized clinics when medical monitoring during the course of treatment is
required. There are also other problems, for example, some strains of T. cruzi are
resistant to treatment, low antiparasitic activity of these drugs in chronic disease,
besides significant side effects that both drugs induce, like include anorexia,
nausea, vomiting, headache, central nervous system depression, maniacal
symptoms, seizures, vertigo, peripheral polyneuropathies and dermatitis, probably
6 Organic Compounds to Combat Neglected Tropical Diseases Micheletti et al.
because of non-selective bioreduction, affecting the parasite and the mammalian
host [2, 7-10].
Figure 1: Current drugs for the chemotherapy of Chagas disease.
Because of the urgent need for new therapies for Chagas disease, many research
groups around the world are focusing on developing molecules with antiparasitic
potential with more appropriate treatment regimens. In this chapter we gather
information published since 2009 on the advances of organic synthesis in creating
new molecules with antichagasic activity.
2. NEW SYNTHETIC MOLECULES
2.1. Naphthoquinones
Quinones are widely distributed in nature and naphthoquinone derivatives are
considered privileged structures in medicinal chemistry on the basis of their
biological activities and structural properties. In folk medicine, plants containing
naphthoquinones are usually employed for the treatment of different diseases [11,
12]. Their fundamental feature is their easy reduction and, therefore, the ability to
act as an oxidizing or dehydrogenating agent, and their biological activity is
related to the acceptance of 1 and/or 2 electrons to form the corresponding radical
anion or dianion species [11, 13]. The redox-cycling of quinones may be initiated
by either one- or two-electron reduction. The one-electron reduction of quinones
is catalyzed by NADPH–cytochrome P450 reductase, generating unstable
semiquinones. These transfer electrons to molecular oxygen and return to their
original quinoidal form, thus generating superoxide anion radical (•O
2−
) that can
form other highly reactive oxygen species (ROS) (H
2
O
2
, •HO). These ROS may
react directly with DNA or other cellular macromolecules, such as lipids and
proteins, leading to cell damage [11].
SNN
O
NO
2
CH
3
O
O
nifurtimox
(1)
NH
O
N
N
NO
2
benznidazole
(2)
Chagas Disease
Organic Compounds to Combat Neglected Tropical Diseases 7
Many groups have been synthesizing molecules with a quinone scaffold with the
aim to produce new trypanocidal agents. Ramos et al. [13] synthesized 2,3-
diphenyl-1,4-naphthoquinone (3, Fig. 2) that proved to be active against
trypomastigotes of T. cruzi in an in vitro assay, with an LD
50
of 2.5 μM. The
compound was studied in vivo as well, in the murine model, showing activity with
low toxicity. The study revealed that 3 acts by producing oxidative radicals, but
caused no genomic DNA fragmentation, also being a competitive inhibitor of
lipoamide dehydrogenase of the parasite (TcLipDH). During evolution, these
parasites developed a specific thiol redox metabolism based on the trypanothione
system. In addition, they possess LipDH, an enzyme that is structurally and
mechanistically closely related to trypanothione reductase (TR).
Da Silva Jr. et al. [14] synthesized and evaluated the trypanocidal activity of β-
lapachone -based 1,2,3-triazoles, 3-arylamino-nor-β-lapachones, 3-alkoxy-nor-β-
lapachones and imidazole anthraquinones. 2,2-Dimethyl-3-(2,4-dibromophenyl-
amino)-2,3-dihydronaphtho[1,2-b]furan-4,5-dione (IC
50
/24 h 24.9 ± 7.4) and 4-
azido-3-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (4, Fig.
2) with 23.4 ± 3.8 μM showed a trypanocidal activity higher than benznidazole,
against bloodstream trypomastigote forms of the parasite. The group continued the
work and prepared other quinoidal compounds [5]. Based on a nor--lapachone
1,2,3-triazole phenyl-substituted derivative as a prototype, novel triazolic
naphthofuranoquinones with different electron donating or withdrawing groups in
the phenyl ring were synthesized and evaluated for anti-T. cruzi activity. Also,
lapachol was used as starting material for the synthesis, by structural modifications .
The insertion of a 1,2,3-triazole group into the 1,4-naphthoquinoidal structure
efficiently enhanced its pharmacological activity, and five substances were identified
as potent trypanocidal compounds, with derivatives more active than benznidazol
(IC
50
/24 h, from 10 to 80 μM) (5, Fig. 2).
Ferreira et al. [12] also have prepared 16 derivatives based on β-lapachone. The
compounds presented a broad spectrum of lytic effects upon bloodstream
trypomastigotes of T. cruzi, with five derivatives having IC
50
/24 h in the range of
20 (6, Fig. 2) to higher than 4000 M.
Ubiquinone (coenzyme Q - CoQ) is a quinoidal compound that occurs in the lipid
core of mitochondrial membranes and functions in the electron transport chain as
8 Organic Compounds to Combat Neglected Tropical Diseases Micheletti et al.
a carrier. A structural feature common to CoQ mimics is a lipophilic side chain,
which increases permeability in the inner phospholipid bilayers of mitochondria,
where electron transport complexes are embedded. Phosphonium cations are used
extensively as molecular probes for studying mitochondrial function and have
demonstrated utility as mediators of transport into mitochondria. The attachment
of a triphenylphosphonium group to an alkyl or alkenyl side chain can guide the
lipocation into energized mitochondria by electrostatic attraction and leads to
increased drug concentrations in the mitochondrial matrix. Long et al. [15]
hypothesized that if a phosphonium moiety were bound to the lipid substituent in
antagonists of the Plasmodium and Trypanosoma electron transport chains, higher
drug concentrations would be achieved inside the mitochondrion and would lead
to increased antiparasitic effects. With this aim, they examined the effects on
antiparasitic activity of phosphonium group attachment to structural analogs of
CoQ containing phthalimide and 1,4-naphthoquinone platforms. The compounds
were assessed for efficacy against Vero cell-infected T. cruzi amastigotes. The
IC
50
values for inhibition of parasite development ranged from 1.6 (7, Fig. 2) to
5.4 μM and variable degrees of Vero cell toxicity was observed.
Figure 2: Active quinoidal compounds.
O
O
O
O
O
CH
3
CH
3
Br
N
N
+
N
-
O
O
O
Br
Cl
O
O
N
N
N
O
O
CH
3
P
+
9
(3)
(4)
(5)
(6)
(7)
Chagas Disease
Organic Compounds to Combat Neglected Tropical Diseases 9
2.2. Nitrofuranes and Nitrothiophenes
5-Nitrofuryl derivatives possess high and selective anti-T. cruzi activity in vitro
and in vivo, and one of the mechanisms of action of this family of compounds is
the induction of oxidative stress in the parasite [16]. Gerpe et al. [16] have
synthesized 5-nitrofuran and 5-nitrothiophene -derivatives with allylamide and (3-
phenyl)allylamine moieties, using connection via thiosemicarbazone,
semicarbazone, or amide linkers. Allylamine derivatives potently inhibit squalene
epoxidase (SE), a microsomal mono-oxygenase that catalyzes the conversion of
squalene to 2,3-oxidosqualene using molecular oxygen. SE is essential for the
synthesis of cholesterol in mammals and ergosterol in fungi, and some allylamines
have also shown to be potent in vitro and in vivo T. cruzi growth inhibitors, acting
by selective reduction of the parasite’s endogenous membrane sterol levels.
Among synthesized derivatives, many have activity against T. cruzi (like 8, with
IC
50
of 1.9 μM), and also the ability to accumulate squalene, a property favored
by the presence of the 5-nitro moiety.
Herrera et al. [10] prepared, based on the cytotoxic characteristics and potential
pharmacophoric effect of the class, thienyl-2-nitropropene compounds that proved
to be trypanocidal. The IC
50
of the most active compound (9, Fig. 3) on
epimastigotes and amastigotas in vitro ranged from 0.6 to 1.3 μM.
O
N
N
H
N
H
O
2
N
CH
2
CH
2
S
NO
2
CH
3
(8)
(9)
Figure 3: Active nitrofurans and nitrothiop h enes.
2.3. Metal Complexes
The many activities of metal ions in biology have stimulated the development of
metal-based chemotherapeutics in different fields of medicine. Although emphasis
has been placed mainly on cancer treatment as a result of the great success of
cisplatin, recent studies have also included parasitic diseases. A significant
number of studies have provided evidence of the usefulness of applying the
10 Organic Compounds to Combat Neglected Tropical Diseases Micheletti et al.
complexation of transition metals with antitrypanosomal ligands as a strategy for
enhancing pharmacological properties (efficacy, bioavailability) or the desired
chemical properties (such as lipophilicity and reactivity). This approach takes
advantage of the emerging medicinal chemistry paradigm on drug discovery to
develop agents that could modulate multiple targets simultaneously with the aim
of enhancing efficacy relative to drugs that address only a single target. It is useful
to modify the ligand’s pharmacological profile and/or obtain compounds that
could act through a dual mechanism of action combining the pharmacological
properties of the metal and ligand in a cooperative effect. Biological properties of
the metal-ligand species will depend not only on the nature of the ligand and the
metal but also on the co-ligands and especially on the structural and
physicochemical characteristics of the complex [7, 17, 18].
Ruthenium and vanadium seem to be privileged among metals to construct
complexes as anti-protozoal agents. Ruthenium has proved to be an excellent
choice for the development of anti-T. cruzi metal complexes, because of their
redox stability, excited state lifetime and rate of ligand exchange [18]. Pagano
et al. [7] have synthesized ruthenium complexes containing thiosemicarbazones
with a 5-nitrofuryl moiety, which is considered to be a pharmacophore for
trypanocidal activity. They have synthesized three series of mixed-ligand
ruthenium complexes of the formula [RuCl
2
(HL)
2
], [RuCl
3
(DMSO)(HL)] and
[RuCl(PPh
3
)(L)
2
] (where L means ligand) with bioactive 5-nitrofuryl-containing
thiosemicarbazones (10, Fig. 4), and although coordination to ruthenium seems to
decrease the anti-T. cruzi activity of the ligand, the effect of the presence of
different co-ligands on the activity and related physicochemical properties was
evident. In the light of this, while a high lipophilicity seems to favor the
trypanocidal effect, the free radical scavenger capacity of the complexes could be
correlated to a lower biological activity. The most active compound showed 80%
of growth inhibition of T. cruzi epimastigote cells at 25 μM (growth inhibition of
the parasite under treatment with nifurtimox was taken as 100%). It had been
stated that the mechanism of action of the complexes is the same as that of the
ligands, i.e. bioreduction and redox cycling. Donnici et al. [18] described the
preparation and biological characterization of eight new ruthenium complexes
[Ru-Cl
2
(ATZ)(COD)], where COD represents 1,5-cyclooctadiene, with aryl-4-
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