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Schistosomiasis
Organic Compounds to Combat Neglected Tropical Diseases 201
Figure 5: Schistosoma species parasitizing in humans and their main vector.
Figure 6: Examples of synthetic molluscicides.
Table 1 presents the main compounds that are used in schistosomiasis control, as
well as the action and treatment of infection of each.
Table 1: Compounds used in schistosomiasis control
Compounds Effective Treatment/Action
Mechanism
(a)
Metrifonate (1)
Organophosphate compound
S. hematobium: the drug appears to alter cholinesterase activity in
the nematode, paralyzing the adult worm and causing its death.
Oxamniquine (2)
Semi-synthetic tetrahydroqu inoline
S. mansoni: mechanism unknown, but appears to entail binding of
the drug to the nematode’s DNA.
Praziquantel (3)
Synthetic isoquinoline-pyrazine
derivative
All Schistosoma infections: increases membrane permeability to
Ca
++
in the nematode, causing paralysis and death of the worm.
Niclosamide (4)
Salicylamide derivative
Total snail control: inhibiting oxidative phosphorylation within the
parasite, causing the cestode to be rapidly killed.
(a) Containing concept adapted from ref. [1].
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202 Organic Compounds to Combat Neglected Tropical Diseases de Oliveira and Neves-Filho
The synthetic molluscicide niclosamide (4) has proved to be efficient (LD
50
< 0.5
ppm) against the schistosomiasis vectors [11]. Nevertheless, undesirable effects
such as toxicity to non-target organisms in the same environment have
encouraged the search for alternatives to control the aquatic snails.
The following sections provide an overview on the latest results in the field of
bioactive compounds with molluscicidal activity. They comprise recent studies on
synthetic compounds and substances isolated from natural sources (plants and
marine organisms).
2. STRATEGIES TO COMBAT SCHISTOSOMIASIS BASED UPON
MOLLUSCICIDAL COMPOUNDS
The molluscicidal strategy has been considered the most effective means to break
the transmission cycle of the schistosoma [6]. The compound niclosamide (4) is
the most widely used molluscicide available, because it is lethal to the snails at all
stages of their life-cycle.
Although synthetic drugs are in general more effective for snail control than
compounds from natural origins, there are many criticisms on their damage to the
environment caused by the inherent lack of selectivity and biodegradation. Thus,
natural products have gained interest in the scientific community [12]. The
reasons justifying research on natural products include the high cost of synthetic
mollusicides, their toxicity, and rise of resistant species. In fact, main drawbacks
related to niclosamide (4) appears to be its high cost of production and the fact
that its formulation causes broad fish mortality due to the high concentration
necessary to control snails [6]. Nevertheless, in spite of this fact no other
molluscicide (synthetic or natural) has displayed a performance significant
enough to replace niclosamide (4) [13].
Fig. 7 shows an organogram that we adopted to explain the strategies for combatting
snails using bioactive compounds. Two main categories, natural products (NP) and
synthetic were chosen. We focused initially on molluscicidal activity using NP
isolated from plants and marine sources. The semi-synthetic compounds and total
synthesis based on NP will be presented below. Finally, the protocols for preparing
effective synthetic molluscicidal compounds will be discussed.
Schistosomiasis
Organic Compounds to Combat Neglected Tropical Diseases 203
2.1. Natural Products
The research on natural products represents a major strategy for discovering and
developing new drugs. In 1996, Perrett and Whitfield [6] in the review “Current
Available Molluscicides” presented the importance and the role of molluscicides in
the integrated control of human schistosomiasis. Their review cited that that
triterpenoid saponins are the active components from extracts of Swartzin
madagascarensis and Phytolacca dodecandra (endod.). The structure of the
molluscicide saponin lemmatoxin (7) is depicted in Fig. 8. This compound has
displayed significant activity in concentrations lower than 1.5 mg/L (1.9 µM) [14].
Figure 7: Strategy adopted to explain the bioactive molluscicidal compounds.
Figure 8: Structure of lemmatoxin (7).
Perrett and Whitfield [6] also described some molluscicide isoflavanoids (8-10) as
potential new biocide agents (Fig. 9). They discussed about the combined use of
synthetic and plant-origin molluscicides, but obstacles in large-scale attainment of
intermediates and products from plant material limited considerably the use of
these substances. The research group concluded that the identification of
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204 Organic Compounds to Combat Neglected Tropical Diseases de Oliveira and Neves-Filho
molluscicidal molecules from plant sources would inspire the design of libraries
of a new compound for synthetic development [6].
The use of plant products has gained interest all over the world. Recently Braz-
Filho published a review featuring natural compounds isolated from plants along
with their properties in many fields [15]. A family of saponins glycoside-
triterpenics (11) isolated from Sapindus rarak showed biocidal activity between
6.25 and 12.5 mg/L (Fig. 10). The triterpenoid saponin (12) isolated from the fruit
of Sapindus saponaria was the most active compound (LC
100/24 h
= 3.0 mg/L or
3.7 µM) against B. glabrata. The diglycosides (13) isolated from the fruit of
Tetrapleura tetraptera Taub. are cited as highly active (LC not shown). It was
observed that the presence of the NHAc group might not be essential for the
molluscicidal activity of the compound (13) in comparison with triterpenoid
saponins from Phytolacca dodecandra (endod.).
Figure 9: Structure of some molluscicide isoflavanoids.
OH
O
O
HO
O
CO
2
H
H
H
H
OH
O
HO
OH
O
O
R
OH
R
R
HO
O
O
HO
O
CO
2
H
H
H
H
OH
O
HO
OH
HO
CO
2
H
RO
O
O
HO
NHAc
CO
2
H
H
H
H
OH
OR
(11) R = H; OH; OAc
(12)
(13) R = H; galactopyranosil
Figure 10: Some molluscicidal saponins isolated from plants.
Socolsky and co-workers [11] isolated two new bicyclic phloroglucinols (14a)
and (14b) from diethyl ether extract of an Argentine collection of the fern
Schistosomiasis
Organic Compounds to Combat Neglected Tropical Diseases 205
Elaphoglossum piloselloides (Fig. 11). The compounds showed activity against
the snail Biomphalaria peregrine (a Schistosomiasis vector in South America).
The acute molluscicidal activity (LC
50
) for compound (14a) was 2.9 ppm (5.8 µM),
while the compound (14b) presented a value of 9.4 ppm (1.8 µM). Based on a
strategy of acetylation for structural identification, the compounds (14a,b) were
protected to furnish the acylphloroglucinols (15a) and (15b). After molluscicidal
activity trials, the potencies of the tested compounds were compared. It was
observed that the snails were less sensitive to the acetylated phloroglucinols, which
presented 14.9 µM and 40.6 µM LC
50
values for (15a) and (15b), respectively.
O
HO
O
O
R
OH
OCH
3
HO
HO
O
AcO
AcO
AcO
O
R
OAc
H
3
CO
OAc
(14a) R= H
(14b) R= Et
(15a) R= H
(15b) R= Et
Figure 11: Phloroglucinols against Biomphalaria pereg ri n e snails.
Ten naturally occurring compounds were tested by Radwan and El-Zemity [16]
for molluscicidal activity against the fresh water snail Biomphalaria alexandrina,
a snail-vector of Schistosoma mansoni (Fig. 12). The results showed that thymol
(16) was the most effective compound, followed by trans-anethole (17) and
pulegone (18). The use of PBO (piperonyl butoxide) mixed with (16) enhanced
the molluscicidal activity to 5.9 µg/mL. The same group, in 2008, [17] described
some monoterpenoids, and their corresponding new synthesized N-methyl
carbamate derivatives, as potential molluscicidal compounds against
Biomphalaria alexandrina. After the screening they noted that the carbamate β-
citronellol (19) is the most active compound (Fig. 12). When the authors mixed
this compound with PBO, they also observed a synergic effect.
Phenolic compounds constitute one of the main classes of secondary metabolites
in plants. In 2004, Lahlou [18] studied the structures of 14 phenolic compounds
and their molluscicidal activities against Bulinus truncatus snails (Fig. 12). It was
found that flavone (20, LC
50
24.4 µM) and phenolic acid (21, LC
50
26.3 µM) were
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206 Organic Compounds to Combat Neglected Tropical Diseases de Oliveira and Neves-Filho
the most active, while niclosamide (4) exhibited LC
50
values of 2.20 ppm (6.7
µM) in a comparative assay.
OH
O
O
N
H
O
O
OH
OH
OH
HO
2
C
OMe
O
LC
50
= 13.9 g/mL (92 M)
(16)
(19)
LC
50
= 5.4 g/mL (25 M)
LC
50
(16) + PBO = 5.9 g/mL
LC
50
(19) + PBO = 2.7 g/mL
(20)
(21)
LC
50
= 5.47 ppm (24.4 M)
LC
50
= 4.47 ppm (26.3 M)
(17)
(18)
LC
50
= 28.1 g/mL (189.6 M)
LC
50
= 49.9 g/mL (327.8 M)
Figure 12: Molluscicidal compounds against the Biomphalaria alexandrina snail.
Wanyonyi and co-workers [19] tested bioactive steroid alkaloid glycosides from
Salanum aculeastrum against Biomphalaria pfeifferi (Fig. 13). They isolated
solaculine A (26) from methanol extracts of the root bark, solamargine (27) and β-
solamarine (28) from the berries. Solaculine A (26) did not show molluscicidal
activity, but the compounds (27) and (28) killed 100% of the tested snails at 12.5
ppm. The mixture (1:1) of 27 and 28 exhibited a LC
100
value of 8.0 ppm. The
authors observed that the molluscicidal activity is related to the number and type of
sugar present in the structure as well as inter-glycosidic linkage, but not to the type
of aglycone moiety.
Silva and co-workers [20] reported a new glycoalkaloid solanandaine (29) from
fractionation of the alkaloid extract of the fruit of Solanum asperum (Fig. 13).
They tested the crude extracts as well as the isolated pure alkaloid Solanandaine
(29). The compound (29) presented a LC
90
value of 112.8 nM against
Biomphalaria glabrata after 24 h of exposition.
Schistosomiasis
Organic Compounds to Combat Neglected Tropical Diseases 207
In 2002, Lima and co-workers [21] evaluated the toxicity of soluble derivatives
(K
+
salts) of the natural product lapachol (30) and isolapachol (32) at different
stages of the cycle of S. mansoni (Fig. 14). The comparative results shown that
potassium salts (31) and (33) are more active against B. glabrata.
O
NH
RO
O
NH
RO
HO
O
O
NH
O
OH
O
O
OH
O
HO
OH
OH
OH
HO
HO
H
H
H
H
H
(26) R = -gal-rham-xyl
rham
(27) R = -glu-rham
rham
(28) R = -glu-rham
rham
(29)
Figure 13: Steroid alkaloid glycoside s from Salanum aculeastrum against Biomphalaria pfeiff eri snails.
Figure 14: Natural products lapachol and isolapachol against S. mansoni.
In 2009, Baloch [22] isolated from Euphorbia conigera Boiss a library of
diterpene ester derivative compounds that were tested against B. glabrata snails.
The best results were found for compounds (34) and (35), which displayed an
excellent molluscicidal activity (LC
50
< 30 nM) (Fig. 15).
Recently, Mata and co-workers [23] described the molluscicidal activity of
compounds isolated from Euphorbia conspicua N. E. Br. The compound (36)
appeared to be totally inactive against the egg masses of Biomphalaria glabrata, but
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208 Organic Compounds to Combat Neglected Tropical Diseases de Oliveira and Neves-Filho
presented LC
100
value of 1 µg/mL (2.2 µM) against B. glabrata snail, while
niclosamide (4) showed LC
100
value of 1.5 µg/mL (4.6 µM) in comparative assays
(Fig. 15).
R
R
1
O
OR
2
OR
3
O
O
NH
O
H
2
N
O
(34) R = anthranyloil; R
1
= H; R
2
= Ac; R
3
= angeloyl
(35) R = anthranyloil; R
1
= H; R
2
=angeloyl; R
3
= Ac
(36) R= angeloyl A; R
1
= H; R
2
= H; R
3
= Ac
Anthranyloil
Angeloyl
Figure 15: Molluscicidal compounds isolated from Euphorbia conspicua N. E. Br.
In 2010, Mendonça’s group [24] isolated 8,15-epoxy-labdane and norlabdan
triterpenoids from hexane extract of the aerial parts of the grass Eragrostis viscosa
(Fig. 16). The hexane extract presented moderate activities against the snail B.
glabrata (ca. 52 % of mortality at 100 µg/mL), the main compound was (37a).
The composition of the extract from 0.92 Kg of dried aerial parts of plant was: 2g
of (37a), 261 mg of (37b), 8 mg of (37c), 537 mg of (37d) and 12 mg of (38).
Four compounds (39a,b) and (40a,b) were isolated from the root bark of
Caryopteris x clandonensis (Fig. 17). These compounds were tested against the
snail Bilinus truncatus and showed strong molluscicidal activity with LC
100
< 4
ppm [25]. The most active compound was α-caryopterone (39a) with LC
100
value
of 2 ppm (7.8 µM) after 24 h. The crude chloroform extract also exhibited
excellent biocidal activity (< 5 ppm).
Figure 16: Molluscicidal triterpenoids isolated from Eragrostis viscose.
Schistosomiasis
Organic Compounds to Combat Neglected Tropical Diseases 209
O
O
R
O
O
R
HO
(39) a R= OH
b R= H
(40) a R= H
b R= OH
Figure 17: Molluscicidal compounds isolated from Caryopteris x clandonensis.
Two compounds, sanguinarine (41) and chelerythrine (42) were obtained from
fruits of Macleaya cordada (Will) (Fig. 18). They were evaluated as molluscicidal
agents against snail of Oncomlania hupensis and exhibited significant LC
50
value
of 0.59 ppm (1.8 µM) at 48 h for ( 41) and LC
50/48 h
value of 2.70 ppm (8.5 µM).
The total alkaloids showed LC
50/48 h
= 0.69 ppm. The compounds (41, 42) were
considered as plant-origin products of low-cost [26].
N
+
O
O
O
O
N
+
O
O
(41)(42)
Figure 18: Molluscicidal compounds isolated from Macleaya cordada (Will).
Song and co-workers [27] describe the dimeric triterpenoid dibelamcandal A (43)
with a structure containing a six-member ring linked to spiro-iridal-type
triterpenoid scaffold (Fig. 19). This compound was isolated from the rhizome of
Belamcanda chinensis and demonstrated significant molluscicidal activity against
Pomacea canallculata with a LC
50
value of 1.26 µg/mL (0.9 µM).
Several academic groups are engaged in the screening of marine-derived small
molecules (MDSMs) for antiparasitic substances and encouraging results have
emerged in the past decade [28]. In 1995, the Gerwick group isolated a Barbamide
(44) from marine Cyanobacterium lingbeja majuscule that presented toxicity to the
mollusk Biomphalaria glabrata (LC
100
values of 10 µg/mL) [29] (Fig. 20). Four
years later the same group obtained 70 mg of Tanikolide (45) from 860 mg of a
crude extract from the same marine-cyanobacteria. It showed a LC
50
of 9.0 µg/mL or
31.6 µM against the same snail specie [30]. Recently, the Germick group isolated the
metabolites Thiopalmyrone (46) and Palmirrolinone (47) from an assemblage of
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210 Organic Compounds to Combat Neglected Tropical Diseases de Oliveira and Neves-Filho
Palmyra Atoll Cyanobacteria [31]. The compounds (46) and (47) showed
molluscicidal activity with LC
50
values of 8.3 µM and 6.0 µM, respectively.
Furthermore, the researchers observed a slight enhancement in molluscicidal effect
(LC
50
= 5 µM) when an equimolar mixture between (46) and (47) was used.
OH
CHO
O
O
R
HO
O
O
R
CHO
HO
OH
OH
OH
Dibelamcandal A
(43)
R = -(CH
2
)
12
CH
3
Figure 19: Molluscicidal triterpenoid isolated from Belamcanda chinensis.
In 2010, Gerwick and co-workers isolated a new molluscicidal compound from a
Papua New Guinea collection of Lyngbya bouilonii [13]. The structure of this
compound was elucidated as dimeric macrolide containing two xylose residues
(see Fig. 20), and compound (48). The substance was named cyanolide A (48) and
displayed highly potent molluscicidal activity (LC
50
= 1.2 μM) against B.
glabrata. Given the promising biological profile of cyanolide A (48) and its
scarcity in natural sources (isolation yield 0.1%), research groups around the
world have investigated this molecule and designed several total syntheses of it.
The first total synthesis of cyanolide A (48) was published by Hong and Kim few
months after the publication of its isolation [32]. The key steps of their strategy
involved: first, the preparation of the cyanolide A aglicone via a sequence
involving a tandem oxidation/Michael addition; asymmetric ethylation; and
dimerization. The last step was the installation of the xylose moieties via
glycosilation reaction (Scheme 1). Using the intermediate compounds (I) and (II),
it was possible obtain cyanolide (48) in 10 steps with a 22% overall yield.
She and co-workers reported a slightly different approach to the cyanolide A (48)
(Scheme 2) [33]
.
The synthesis began with the addition of the 1,3-dithiane (2’) to the
(S)-2-ethyloxirane (1’), followed by deprotection of the thioacetal moiety to afford
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