Terpenoid Derivatives as Potential Trypanocidal Agents
Lozano E1, Barrera P1,2, Spina R1 and Sosa MA1,2*
1Instituto de Histología y Embriología, Facultad de Ciencias Médicas, UNCuyo, Mendoza, Argentina
2Facultad de Ciencias Exactas y Naturales, UNCuyo, Mendoza, Argentina
- *Corresponding Author:
- Miguel A. Sosa
Instituto de Histología y Embriología, FCMUNCuyo
E-mail: [email protected]
Received date: April 28, 2016; Accepted date: May 05, 2016; Published date: May 10, 2016
Citation: Lozano E, Barrera P, Spina R, Sosa MA (2016) Terpenoid Derivatives as Potential Trypanocidal Agents. Med chem (Los Angeles) 6:319-321.
Copyright: © 2016 Lozano E, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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In this review we refer to a promising family of molecules in the fight against Chagas disease. Terpene derivatives are abundant in the plant Kingdom and in the last years many compounds have shown important biological activities. Diterpenes and sesquiterpene lactones have shown in vitro and in vivo trypanocidal activity and they emerge as potential antichagasic drugs. These molecules may act on these parasites by multiple mechanisms, as it has been reported. Moreover, given the chemical structure of these compounds it is feasible to modify these molecules by chemical substitution in order to optimize their action against parasites.
Chagas disease; Trypanosoma cruzi; Mammalian cells;
Chagas disease or American trypanosomiasis is a disease caused by
the kinetoplastid protozoan Trypanosoma cruzi. This parasitic disease
affects millions of people in Latin America and is still expanding
worldwide due to migration phenomena. Chagas is one of the most
devastating diseases caused by parasites of the Trypanosomatidae
family. Trypanosoma cruzi is transmitted through the bite of triatiomine
haematophage insects such as Triatoma infestans. However, congenital
and transfusion (iatrogenic) transmission are also relevant in the
transmission cycle, since they are responsible for the expansion of this
disease in non-endemic areas . After an acute phase and subsequent
state of latency, the disease commonly progresses to a chronic phase, with
clinical manifestations in various organs. The chronic manifestations
of the disease are sometimes life-threatening [2-4]. Although advances
have been made in the field of molecular biology and pathophysiology
of Chagas disease, the search for an effective treatment has yet been
unsuccessful due to several reasons; a) the existence of a wide variety
of strains, with different virulence and drug resistance profile, b) the
fact that the acute phase is often asymptomatic, c) the difficulty to find
a drug with suitable selectivity for the parasite, and d) most funds are
intended for the development of diagnostic tests and prevention.
For decades, the search for drugs to treat Chagas disease has been a
constant challenge. Nowadays, the treatments of Chagas’ disease entail
the election between either one of two nitroheterocyclic compounds,
that is, benznidazole or nifurtimox [5-7]. Both drugs are effective
when administered at the onset of the acute phase. Conversely, their
effectiveness is limited during the chronic stage, there are regional
degrees of effectiveness due to drug resistance; and they present severe
side effects that lead to the immediate interruption of treatment in a
high percentage of the patients. Most of the knowledge that currently
exists about the biology of the parasite and the identification of
potential molecular targets, together with the wide range of natural
molecules, mainly in the plant kingdom, has encouraged researchers
to continue the intense search for new drugs against T. cruzi [8-10].
The main vulnerability of parasites is related to the high sensitivity
to oxidative stress due to the rudimentary defense system they have
[11,12]. Natural compounds are an attractive source of new drugs,
because they can be subjected to synthetic modifications to optimize
their bioactivity. Thus, families of natural compounds have been tested
as potential trypanocidal agents in in vitro and in vivo assays [13,14].
Although many compounds that have been tested have shown strong
trypanocidal activity in vitro, few of them have been tested in clinical
trials for the treatment of Chagas disease [15,16]. More recently,
terpenes and sesquiterpene lactones obtained from the plant leaves have shown high toxicity on the different stages of parasites and with
low toxicity on mammalian cells [17,18]. Terpene derivatives are very
abundant in nature, therefore, they are an attractive compounds family
to be assayed for biological activity. Over the past ten years, hundreds
of new terpene-derived molecules exhibiting trypanocidal activity have
been described [19-27] and some of them have already been tested
against T. cruzi both in vitro and in vivo [28,29]. Interestingly, some of
these molecules are feasible to modify chemically in order to optimize
their action on parasites. For example, an increase of lipophilicity
by chemical modifications has proved to be an adequate strategy for
improving the trypanocidal activity of diterpenes (Figure 1) [23,30,31].
Figure 1: Structures of Abietane (1), and three derivatives (2-4). R1: COCH3, R2: Si (CH3)3 and R3: CH2-CH=CH2 (30).
Other terpenoid derivatives such as sesquiterpene lactones
are known to have a wide spectrum of biological activities, mostly
mediated through α,β-unsaturated carbonyl groups [32,33]. Many
sesquiterpene lactones with high activity against T. cruzi have been
isolated from the aerial parts of plants [34-36]. The mechanism of
action of some sesquiterpene lactones is currently under study. In
some cases, it has been reported that these compounds can generate
free radicals within trypanosomes [37,38]. Accordingly, ultrastructural
studies have demonstrated that most of these compounds may affect
mitochondrial function [39,40]. It is known that de α-methylene-γ-
lactone of sesquiterpene lactones is responsible for most of the biological properties of these compounds . Some authors have suggested that
the cytotoxicity of these compounds is mediated by an interaction of
the α-methylene with sulphydryl groups of enzymes that are crucial
for parasite life survival . It is also possible that these compounds
may affect calcium metabolism, given their similarity to thapsigargin,
a potent inhibitor of this ion (Figure 2). The latter hypothesis has not
yet been tested.
Figure 2: Structure Dehydroleucodine and Thapsigargin.
All these studies along with others that have been carried out since
the 50s [43,44] have contributed to the understanding of the life cycle
of parasites and to clarify some molecular targets that could be used
for the development of drugs against T. cruzi.
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