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Malaria
Organic Compounds to Combat Neglected Tropical Diseases 191
Scheme 14: General procedure for the preparation of the 2-substituted isoquinolin-3-ones [33].
3.5. Thiosemicarbazones
The antimalarial activity of thiosemicarbazones is known since 1979 when Klayma n
et al. prepared and tested a series of compounds against P. berghei in mice [34].
Chiyanzu and co-workers reported the activity of thiosemicarbazones containing
an isatin moiety as inhibitors of falcipain-2 (IC
50
4.4-43.9 µM) (Fig. 13). When
tested without any modification, commercial isatins displayed no activity,
demonstrating the importance of the thiosemicarbazone moiety [11, 14].
N
N
CH
3
N
H
N
H
S
79
N
H
R
1
R
2
O
N
NH
NH
2
S
80
Figure 13: Chemical structure of a thiosemicarbazone 79 synthesized by Klayman [34] and
general structure of isatin-thiosemicarbazones 80.
The synthesis of isatin-thiosemicarbazones is straightforward, as previously
shown in this chapter (section 2.2, Scheme 5).
NaH
R
1
R
2
CONHNHBoc
O
OCH
3
N
R
1
R
2
O
NHBoc
OCH
3
BocNHNH
2
R
1
R
2
COOH
O
OCH
3
TFA
LiOH
N
R
1
R
2
O
NH
2
OCH
3
R
1
R
2
COOCH
3
O
OCH
3
HOOC OCH
3
N
R
1
R
2
O
N
H
OCH
3
O
R
3
COOCH
3
R
2
R
1
72
Reagents and conditions: (i) P
2
O
5
, (CH
2
)
2
Cl
2
, rt, 16 h; (ii) THF/methanol, rt, 4 h; (iii) EDC, CH
2
Cl
2
/DMF, rt, 12 h; (iv)
THF, rt, 2 h; (v) CH
2
Cl
2
, rt, 5 h; (vi) CH
2
Cl
2
, rt, 3-6 h.
(i)
(ii) (iii)
(iv)
(v)
(vi)
ethyl chloroformate
or
aryl isocyanate
73, 62-64% 74, 87-96% 75, 82-89%
76, 88-91%77, 87%78, 68-73%
R
1
= R
2
= OCH
3
or
R
1
R
2
= OCH
2
O
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192 Organic Compounds to Combat Neglected Tropical Diseases de Oliveira et al.
Fujii et al. also reported the synthesis and evaluation of a series of
thiosemicarbazones as potential inhibitors of the cysteine proteases: rhodesain,
cruzain and falcipain-2. Among the thiosemicarbazone tested, 81 (Fig. 14) was the
most active against falcipain-2, with IC
50
375 nM. General procedure for
synthesis of 81 is highlighted in Scheme 15. Synthesis of the thiosemicarbazones
involves the reaction between a ketone with thiosemicarbazide. A variety of
ketones can be prepared via palladium-catalyzed coupling of acid chlorides with
organoboronic acid (Scheme 15) [35].
Figure 14: Chemical structure of thiosemicarbazone 81.
Scheme 15: General procedure for synthesis of thiosemicarbazones [35].
Based on the foregoing, the synthesis of potential antimalarial drug candidates is
feasible and may represent an important therapeutic innovation and to become a
reality in the near future.
AKNOWLEDGEMENTS
The authors are grateful to Federal University of Minas Gerais (UFMG) for all the
support.
CONFLICT OF INTEREST
The authors confirm that this chapter contents have no conflict of interest.
B
OH
OH
Cl
Cl
R
O
Cl
Cl
N
R
H
NNH
2
S
Cl
Cl
RCl
O
H
2
NNH
NH
2
S
82
Reagen ts and condi t i ons: (i) Pd Cl
2
(PPh
3
)
2
, K
3
PO
4
-monohydrate, toluene, 80 ºC; (ii) EtOH, AcOH,
70 ºC, 3 days.
(i)
(ii)
83
84
R = alkyl, aryl, alkylaryl
Malaria
Organic Compounds to Combat Neglected Tropical Diseases 193
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196 Organic Compounds to Combat Neglected Tropical Diseases, 2014, 196-23 0
CHAPTER 7
SCHISTOSOMIASIS
Recent Progresses in Synthesis and Evaluation of Bioactive
Compounds with Molluscicidal Activity - Molluscicidal Activity of
Synthetic and Natural Products
Ronaldo Nascimento de Oliveira
1,*
and Ricardo A. W. Neves Filho
2
1
Federal Rural University of Pernambuco, Department of Molecular Sciences,
Laboratory of Synthesis of Bioactive Compounds - LSCB,, Rua Dom Manoel de
Medeiros S/N, Dois Irmãos, 52171-900, Recife, PE, Brazil;
2
Department of
Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120
Halle (Saale), Germany
Abstract: Parasitic infections affect a vast number of people around the world.
Schistosomiasis is a known example of tropical parasitic disease. Since the past decade,
an increasing effort has been made towards its control. There are two main chemical
interventions employed to cut off the schistosomiasis life-cycle. The first one consists of
therapy, to treat infected individuals. The second uses molluscicidal compounds to
control the population of the vector snails. This latter strategy has been considered as
one of the best preventive actions, since it eliminates the parasites before they can reach
human hosts. Towards this end, synthetic molluscicide, niclosamide, has proved to have
efficient activity against schistosomiasis. Nevertheless, undesirable side effects
associated with this compound, such as toxicity to non-target organisms in the aquatic
environment, encouraged the search for new molluscicidal compounds. Although
synthetic drugs often display higher molluscicidal activity than natural products, their
lack of selectivity towards nocive snails, as well as difficult biodegradation, cause
severe burdens on the environment. This problem has caused criticism on the use of the
currently available synthetic molluscicides and turned the interest of a part of the
scientific community to the investigation of new compounds, including natural
substances. In fact, the dilemma between synthetic and natural products is not yet
settled, and it still remains a challenge to find an effective and eco-friendly substance to
combat the snails selectively. The focus of this chapter is to present an overview of
recent studies on synthetic compounds and natural products with molluscicidal activity.
Keywords: Schistosomiasis, snail control, molluscicidal activity, synthetic
compounds, natural products.
*Address correspondence to Ronaldo Nascimento de-Oliveira: Federal Rural University of Pernambuco,
Department of Molecular Sciences, Laboratory of Synthesis of Bioactive Compounds - LSCB, Rua Dom
Manoel de Medeiros S/N, Dois Irmãos, 52171-900, Recife, PE, Brazil; Tel/Fax: +55 81 33206382/+55 81
33206374; E-mail: ronaldonoliveira@dcm.ufrpe.br
Send Orders for Reprints to reprints@benthamscience.net
Schistosomiasis
Organic Compounds to Combat Neglected Tropical Diseases 197
1. INTRODUCTION
Parasitic infections affect a vast number of people around the world; epidemiologists
suggest that almost one-half of the planet’s human population might be infected [1].
Schistosomiasis is a well-known example of a tropical parasitic disease. It is caused
by an intravascular trematode infection caused by blood-dwelling fluke worms of the
genus Schistosoma [2, 3]. The World Health Organization has estimated that 200-
209 million people are infected by this parasite, what makes it the second most
devastating parasitic disease after malaria [4].
Figure 1: a) Total Published Papers - Items in Each Year; b) Citations in Each Year. Source: Web
of Knowledge (Topic Schistosomiasis) accessed 05-06-2014.
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198 Organic Compounds to Combat Neglected Tropical Diseases de Oliveira and Neves-Filho
Fig. 1 illustrates the related papers about schistosomiasis, indicating that the interest
in this subject has increased since the 1970s. Citations of the subject have reached
10000 (Fig. 1b). Despite the growing numbers of papers and their citations, an
effective development of new drugs for schistosomiasis control has not yet been
achieved.
The main limitation in exploring schistosomiasis infection is to know more about the
complex life-cycle of the worm (digenetic and dioecious) [5]. Thus, it is opportune
to understand the Schistosome life-cycle as shown Fig. 2. The parasites require three
environmental niches, freshwater, an aquatic snails host and a mammalian host to
complete their reproductive cycle [5, 6]. The life-cycle consists mainly of six stages:
A,B,C- paired adult Schistosomes; 1- excreted Schistosome egg (from feces or
urine); 2- miracidium larva in aquatic environment; 3- mollusks as intermediate
hosts; 4- generations of sporocysts; 5- cercaria: infective larval stage; 6- penetration
through skin and developing stages in human host (Fig. 2).
Figure 2: Schistosomiasis Life-Cycle from Center of Disease Control and Prevention.
(http://www.cdc.gov/dpdx/schistosomiasis/index.html).
Schistosomiasis
Organic Compounds to Combat Neglected Tropical Diseases 199
Thus, the main preventive strategy to break up the life-cycle of the parasite at stage 3
(Fig. 2) is the employment of molluscicidal compounds to eliminate the snails,
which serve as temporary hosts for the parasites before they are transmitted to
humans.
1.1. Drugs to Control Schistosomiasis
Since the past decade an increasing effort has been made to control schistosomiasis.
There are two interventions based on bioactive compounds to control the
schistosomiasis life-cycle. The first consists of chemotherapy with the infected
individuals. The second is based on the use of molluscicidal compounds to control
the population of the vector snails. In endemic disease control, there are four major
types of biocidal compounds that exhibit activity against schistosomiasis:
metrifonate (1), oxamniquine (2), praziquantel (3) and niclosamide (4) (see Fig. 3).
Figure 3: Compounds that exhibit activity against schistosomiasis.
Since the development of praziquantel (3), its use has been preferred rather than
other various previously used anti-schistosomal agents, because it is effective in the
combat of all forms of schistosomiasis and particularly well tolerated by the human
organism. Thus, substance (3) has become the main drug against the major species
of schistosome [7]. Wu and co-workers [7] reported that praziquantel (3) can kill
adult worms effectively, but it has little effect on the eggs and is ineffective against
sporocysts in the host snails (Fig. 4). Fig. 4 presents the main drugs used against
schistosomiasis and highlights the most effective compounds for its control:
praziquantel (3), employed in chemotherapy of the infected human host; and
niclosamide (4), used as a molluscicidal agent for killing the snail host. The strategy
for eliminating the parasites from the human host may not be considered as
preventive, but snail control has been regarded as one of the best preventive actions.
Thus, the use and development of molluscicides are highly supported actions in
integrated schistosomiasis control programs [8].
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200 Organic Compounds to Combat Neglected Tropical Diseases de Oliveira and Neves-Filho
There are five Schistosoma species parasitizing in humans, their main vectors are
depicted in Fig. 5. S. japonicum is more frequently found in the small intestine,
while S. mansoni occurs more often in the large intestine [9]. S. haematobium is
found in most of the clinical cases in the bladder. Katayama fever, hepatic
perisinusoidal egg granulomas, Symmers’ pipe stem periportal fibrosis and portal
hypertension, are pathologies caused by S. mansoni and S. japonicum
schistosomiasis [9]. The genus Oncomelania and Bulinus is found in China, the
Philippines, Indonesia, Africa and Arabia. Biomphalaria glabrata is the main
intermediate host for Schistosoma mansoni in South America [10].
Figure 4: Effective compounds in schistosomiasis life-cycle.
Synthetic molluscicides are considered as the most efficient way to control
schistosomiasis. In this class of compounds, some highly active substances are
copper sulfate, niclosamide (4), trifenmorph (5) and sodium pentachlorophenate -
NaPCP (6) (Fig. 6).
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