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Lymphatic Filariasis
Organic Compounds to Combat Neglected Tropical Diseases 151
by three nematodes known as filariae, namely Wuchereria bancrofti, Brugia
malayi and Brugia timori, all belonging to the superfamily Filarioidea, family
Onchocercidae. W. bancrofti is responsible for 90% of the 120 million infected
people, whereas most of the remainder, 10%, is caused by Brugia malayi in the
southeast Asia, with a very small percentage due to Brugia timori [3]. The filariae
are heteroxenic parasites, with a life cycle occurring in the definite host
(mammalian) and the intermediate host (mosquitos from the genera Aedes, Culex,
Anopheles, Mansonia, and Ochlerotatus). The cycle starts (Fig. 2) when a
mosquito bites an infected host (humans) that has larval stages in the blood
(microfilariae). In the intermediate host there are two molts, generating the
infective larvae (L3) that is deposited on the skin of the definite host during its
blood meal. The L3 reach the circulation through the bite wound migrating to the
lymphatics, where they turn into adults (females 70 to 100 mm length, 0.30 mm
diameter, males 35 to 40 mm, 0.1 mm) that mate and the females release
microfilariae (250–300 mm long, 8 mm wide) after a period of 6 to 12 months.
The adults are able to live for many years in the human host, releasing millions of
sheated microfilariae, which are very active during the night (except in the South
Pacific) and migrate towards the peripheral circulation, where it will be ingested
during the bite of another mosquito, establishing the life cycle [4].
LF is characterized to be a chronic infection, usually asymptomatic, but
nevertheless 40 million individuals exhibit clinical symptoms [5]. People living in
the risk areas are usually infected during their childhood, but the disfiguring
clinical manifestations will appear years after, mostly in the adulthood [5]. The
appearance of clinical symptoms is related to the host inflammatory response
against dead or dying adult worms, since when the worms are alive there is very
little inflammatory response [3, 6]. The worms, upon death, release antigenic
elements that provoke lymphangitis and lymphadenitis with pain and swelling,
and chronically the ultimate effects are lymphatic vessels with problems in the
circulation of the lymph, culminating with extravasation of fluid and damage of
the lymph vessels [6]. Due to the localization of the adults in the lymphatic
vessels and lymph nodes of the pelvic region (genitals and legs), but also
mammary glands and arms, the morbidity of LF is very high [3]. The most known
form of LF is elephantiasis, which is the result of the lymphedema combined with
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152 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
lymphangitis, lymphadenitis and in males hydrocele. In these conditions patients
have swelling, pain and the affected organs exhibit malfunctioning, leading not
only to permanent disability but also psychosocial damages [4, 7]. The evolution
of clinical symptoms is a combination of immune response of the host against
antigens released by the adult worms, secondary bacterial infections and also the
symbiotic bacteria Wolbachia [6].
Figure 2: Life cycle of Wuchereria bancrofti (based on http://www.dpd.cdc.gov/dpdx). Mosquito
bite an infected person ingesting the microfilariae present at human peripheral circulation (1).
Inside the mosquito, the microfilariae exsheat and migrate to the thoracic muscles, where will
grow and molt from L1 to L3, the infective stage (2). The L3s migrate to the proboscis and during
the blood meal of the mosquito the L3s penetrate the human skin at the puncture site (3). The L3
migrate towards the lymphatic system, developing to adults (4), which mate and produce
microfilariae (5). The microfilariae migrate to the blood stream, during the day the microfilariae
tend to stay in the deep blood vessels, and during the night they migrate to the peripheral
circulation. Figures of adults and microfilariae are from [4].
3. LF AS AN ERADICABLE DISEASE
The International Task Force for Disease Eradication (ITFDE) was formed at the
Carter Center in 1988 and was composed by scientists and international health
Lymphatic Filariasis
Organic Compounds to Combat Neglected Tropical Diseases 153
organizations with the purpose to establish criteria to be applied systematically to
evaluate potential eliminable diseases. For eradication, the ITFDE defined as
‘reduction of the worldwide incidence of a disease to zero as a result of deliberate
efforts, obviating the necessity for further control measures’. As a result of several
years of study, in 1993 the ITFDE launched a historical list of the six diseases
candidates for global eradication where LF was among these candidates [8].
Following this list (which later became 7 diseases), another important landmark in
LF happened at the 1997 World Health Assembly, with the Resolution 50.29
(WHA 50.29) recommending that global elimination of LF should be considered a
public health problem by the member states of WHO. At the same year the WHO
commenced the Global Programme to Eliminate Lymphatic Filariasis (GPELF)
and at 2000 the Global Alliance to Eliminate Lymphatic Filariasis (GAELF-
www.filariasis.org) was established as a broad, global partnership of more than 40
public and private-sector partners, and Ministries of Health in LF endemic
countries [9]. The strategy of GPELF has two components: (i) stopping the spread
of infection (interrupting transmission) and (ii) alleviating the suffering of
affected populations (controlling morbidity) (http://www.who.int/ lymphatic
_filariasis/disease/en/). The goal to eliminate the disease by 2020 relies on the
fact that the reservoir is essentially the man, except for B. malayi that has minor
nonhuman primates as reservoir [8]. In that sense, the central idea of the GPELF
was based on the fact that transmission could be interrupted by Mass Drug
Administration (MDA), as there are very effective drugs against microfilariae, in
Africa (where onchocerciasis is also endemic) it is used albendazole + ivermectin
and in the rest of the countries the combination albendazole + diethylcarbamazine
(DEC) or only DEC is used [2]. Albendazole is donated by GlaxoSmithKline and
ivermectin by Merck and Co. Inc. In 2008 the MDA reached nearly 700 million of
the 1.33 billion at risk population and the drug administration was implemented in
51 of the 71 countries where MDA is actually required [2].
In earlier studies on economic benefits and on health impact derived from the 1.9
billion treatments done by the GPELF from 2000 to 2007, several significant
findings were taken:
i). Prevention of LF infection in 6.6 million newborns [10]
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154 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
ii). Prevention of 6 million cases of hydrocele and 3.5 million lymphedema in
individuals previously infected but without manifestations [10]
iii). US$ 21.8 billion of direct and indirect economic benefits over the lifetime
of 31.4 million people treated during the analyzed period [11]
iv). An associated US$19.5 billion lifetime benefit from individuals previously
infected with LF [11]
The MDA has not reached national scale in many countries and some have major
problems in sustaining yearly MDA [12]. There are modeling calculations
indicating that it would be necessary more than 8 rounds of MDA
(diethylcarbamazine + albendazole) in countries with 70% treatment coverage,
but with the addition of vector control six rounds would be needed [3, 13]. The
drugs utilized at the GPELF (albendazole with ivermectin or DEC) have major
results on microfilariae but limited effects on the adult forms of W. bancrofti [14].
Therefore ideally it would be necessary a drug without adverse reactions and
positive effect on the lymphatic disease, and in this aspect anti-Wolbachial
chemotherapy (antibiotics) is appearing as an alternative for treatment of
individuals who require adult worms targeting [12].
Although the great advances accomplished by the GPELF, there are many
challenges on the way for the 2020 LF elimination. It is clear that the control of
LF will improve economical development, but current research allied to search for
new options of treatment should be performed.
4. CHEMICAL ASPECTS OF LF PHARMACOTHERAPY
The limited number of programs of drug development for LF, including both
compound design and biological assays, is to some extent regarding research into
human nematode diseases due to limited interest by a group of pharmaceutical
companies. As there are no obvious economic advantages in pursuing this
research, the active molecules are randomly discovered, during screening studies,
or generated by punctual modification of well-known drugs. Today, the few drugs
adopted to treat LF contribute to an increase in the resistance of the parasites, and
Lymphatic Filariasis
Organic Compounds to Combat Neglected Tropical Diseases 155
recent studies have shown that the pro-poor strategy adopted by the WHO varies
among countries since the drugs used target the same biochemical pathways [15].
Although the available pharmacotherapy is considered insufficient to achieve the
eradication, and the primary research efforts are focusing on finding new drugs,
current rationale behind the chemistry of therapeutic alternatives is crucial for the
rational advancement of new chemical entities. This will be necessary to go
beyond the well-known macrolactones, piperazines, imidazoles and dye
derivatives. In parallel with drug development, it should be considered to attempt
to enhance the availability of new drugs attempting the ultimate goal of
eradicating LF, combining synthetic, semi-synthetic, and biotechnological
strategies to produce more economically viable pharmaceutical final products and
intermediates.
4.1. Macrolides
4.1.1. Avermectins
Avermectins were first isolated from the fermentation broth of cultures of
Streptomyces avermectinius (former S. avermitillis) in 1975, and structurally
characterized as a 16-membered macrolactone [16] containing a spiroketal
fragment [16-18]. Ivermectin [19, 20] is the successfully marketed representative
di-hydro semisynthetic derivative obtained from the catalytic reduction of the 22-
23-double-bond of avermectin B1a [21] and also from deoxygenation of
avermectin B2a by a Barton-McCombie-like procedure (Scheme 1) [21, 22].
Despite the fact that fermentative methodology from S. avermectinus remains the
most viable method for producing avermectins [17], some synthetic methods
towards class B avermectins (the most active antifilarial) have been developed.
The first total synthesis of avermectin B1a was described by Hanessian et al. [23],
which considered the macrolactone as a ‘two-part’ structure. This process begins
by synthesis of the ‘northern’ spiroacetal subunit from a sequence of C-C
coupling and chain-elongation, followed by a coupling with the “southern”
aldehyde subunit toward the direct intermediate for DCC-DMAP
macrolactonization. A final silver triflate-mediated glycosylation yields
avermectin B1a (Scheme 2).
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156 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
O
O
H
HO
O
O
O
O
H
O
OO
O
H
OH
H
H
OH
O
HH
O
O
H
HO
O
O
O
O
H
O
OO
O
H
OH
H
H
OH
O
HH
O
O
H
HO
O
O
O
O
H
O
OO
O
H
OH
H
H
OH
O
HH
OH
O
O
H
TBDMSOH
2
C(O)CO
O
O
O
O
H
O
OO
O
H
OC(O)CH
2
OTBDMS
H
H
OH
O
HH
Avermectin B1a
Wilkinson's catalyst
Ivermectin
Avermectin B2a
deprotection
Barton-McCombie deoxygenation
sequence of protection,
thiocarbonati o n an d radical reducti on
Scheme 1: Schematic representation of different pathways for semi-synthesis of ivermectin.
Alternative synthesis adopting the ‘northern + southern’ approach was described
by Ley et al. 1991(Scheme 3) [24]. In general, the key features of this convergent
strategy include the epoxide ring opening toward the saturated pyran ring,
followed by camphorsulfonic catalyzed spirocyclization and Davis oxizaridine
oxidation of the unsaturated 1,7-dioxaspiro-[5,5]-undec-4-ene-type subunit to
form the ‘northern’ fragment. The ‘southern’ furan subunit was achieved by a
sequence of steps, starting from a lithiated alkene addition to the epoxide
cyclohexanone, and a sequence of oxidation, protection, hydroboration and
heterocyclization toward the heterocyclic ring. The final ‘northern-southern’
coupling and double-bond introduction using selenenyl/Davis oxaziridine work-
up leads to the aglycon avermectin B1a.
Using a different strategy, White et al. [25], separate avermectin B2a into 3
different building blocks for the construction of the macrolactone. In this
approach, the authors adopted a convergent synthesis considering a first coupling
between fragment B and C into D, which was then used for a second coupling to
A, followed by the macrolactonization step (Scheme 4).
Lymphatic Filariasis
Organic Compounds to Combat Neglected Tropical Diseases 157
RO
OSiub-tPh
2
OO
OBn
O
O
RO
R'
O
CO
2
Me
OR
O
H
OR'
O
O
OH
H
O
O
OH
H
HO
OMe
RO
+
coupling and chain
elongation condition
"northern"
"southern"
Macrolactonization and
glycosylation
Avermectin B1a
coupling conditions
Scheme 2: Hanessian’s ‘Northern + Southern’ total synthesis of avermectin B1a.
TBDPSO OTBDMS
O
O
TBDPSO
O
O
TBDMS
OH
O
TBDPSO
O
O
OR
2
O
PhO
2
S
O
O
OTBDPS
Li S
Ph
O
OTBDPS
OH
SO
2
Ph
HO
OTBDPS
OH
SO
2
Ph
OH
OTBDMS
OTBDPS
HO
PhO
2
S
O
OTBDMS
"northern"
"southern"
+
Avermectin B1a
Scheme 3: Ley’s total synthesis of aglycon avermectin B1a.
O
O
OH
H
O
O
OH
H
HO
OMe
RO
O
O
HO
2
C
HO
H
OH
A
O
O
O
H
OH
B
O
OH
OH
O
O
OH
HO
CH
2
SO
2
Ph
D
C
+
Scheme 4: White’s synthetic planning for the total synthesis of avermectin B1a.
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158 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
Ivermectin was discovered during a screening program at Merck in the mid-1970s
[20, 26], and was shown to kill microfilaria directly by binding to and opening
glutamate-gated chloride ion channels in the nerve and muscle cells of parasitic
worms [20]. This causes the cells to hyperpolarize and leads to paralysis and death
of the microfilaria. Additionally, ivermectin may cause enhance the effect of the
inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which also
contributes to microfilarial paralysis [20]. Although there is no available data
demonstrating the effectiveness of ivermectin on macrofilaria, it may sterilize
them, further reducing microfilaraemia [15].
4.1.2. Moxidectin
Moxidectin is a semisynthetic macrolactone derived from nemadectin A [27], a
16-member macrolactone structurally related to the avermectins, which is isolated
from the actinomycete Streptomyces cyanogriseus subsp. noncyanogenus (Singh
et al., 2010) [26, 28, 29]. Moxidectin differs structurally from ivermectin by
lacking a dissacharide in the structure at C-13 and by an olefinic substitution at C-
25. Moxidectin also has an unique methoxime appended to its structure [29].
The key feature of the semisynthesis of moxidectin is the selective oxidation of
the ketone at C-23, which is directly used in methoximation [28, 30]. Although
some attempts at oxidation involving biocatalysis have been described, the most
commonly used approach for obtaining the desired ketone still involves the
protection-oxidation-deprotection sequence of reactions (Scheme 5).
O
O
O
O
O
OH
H
H
OH
H
OH
H
1. PNBCl
2. PDC
O
O
O
O
O
O
H
H
OH
H
O
H
O
NO
2
NH
2
OCH
3
deprotection
O
O
O
O
O
N
H
H
OH
H
OH
H
OCH
3
Nemadectin
Moxidectin
Scheme 5: Semi-synthesis of Moxidectin.
Lymphatic Filariasis
Organic Compounds to Combat Neglected Tropical Diseases 159
The primary mode of action of moxidectin is similar to ivermectin, whereby it
causes paralysis and death of parasites due to interaction with the subunit of the
Glu-Cl channels [31]. After exposure to moxidectin, microfilaricidal effects alter
embryo morphology which include cuticular and structural damage and reduction
of motility [32]. Compared to ivermectin, moxidectin has a considerably longer
plasma half-life and thus may either need less frequent dosing or provide higher
efficacy [26, 32].
4.2. Diethylcarbamazine (DEC)
Diethylcarbamazine citrate (DEC) has been used in the treatment and control of
LF since 1947 and it continues to play an important role, as it is the primary drug
used in the Global Programme for the Elimination of Lymphatic Filariasis [33].
DEC is a synthetic organic compound that inhibits the arachidonic acid
metabolism in microfilariae, making them more susceptible to attack by the host
immune system. Thus, DEC unmasks the surface of microfilaria, exposing
antigenic determinants that facilitate the attachment and killing of parasites by
Kupffer cells [26]. Adult worms may be resistant in up to 50% of the patients [34]
and this compound has no activity in vitro since its mechanism of action involves
the activation of the immune system of the host. In addition, fortifying salt (0.1%–
0.6%) with DEC is a safe and cost effective method for controlling LF
transmission and has been used in pilot projects in several countries in an attempt
to eliminate the disease [26].
DEC can be prepared from N-methylpiperazine, either by acylation with phosgene
or ethyl chloroformate producing carbamoyl chloride or carbamate, respectively,
both used for condensation with diethylamine (Scheme 6). Alternatively,
piperazine itself can be attached to N,N-diethylcarbamoyl chloride, followed by
an Eschweiler-Clarke reaction to produce DEC. Direct of N-methylpiperazine to
the appropriate acyl chloride also produces DEC [35].
An important feature in the synthesis of DEC and other antifilarial piperazines
described in the literature is a high yield production of a piperazine ring. Classic
synthetic methodologies for the production of the fundamental piperazine are usually
carried out from 2-aminoethanol, in the presence of ammonia, or from
ethylenediamine with oxirane, in both cases involving a dehydration step (Scheme 7).
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160 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
N
N
H
3
C
N
O
HN
N
O
N
N
N
O
R
N
NH
Cl
O
N
H
N
Cl
O
R
DEC
HCOOH, HCHO
R= Cl, OEt
R= Cl, OEt
Scheme 6: Commercial synthetic procedures for production of DEC.
OH
NH
2
NH
3
-H
2
O
N
H
H
N
-H
2
O
NH
2
NH
2
O
2x
+
+
Classic methods
Scheme 7: Classic methodologies for obtaining piperazine rings.
4.3. Albendazole
Albendazole is a broad-spectrum anti-helmintic generally used to treat intestinal
helminthes such as nematodes [36]. Originally developed for veterinary use in
1982, it was ultimately approved for humans to treat intestinal helminthes
infections, although this was followed by continued efforts to establish
albendazole efficacy in the treatment of systemic infectious [37]. The first
description of albendazole´s potential use in treating LF was reported in Sri Lanka
in 1993 and the ongoing studies described that when given in combination with
DEC or ivermectin, it reduced microfilaria loads in peripheral vasculature for
longer time periods than treatment with either drug alone [37].
The various processes for the synthesis of albendazole are generally very similar and
involve the thiocyanation of 2-nitroaniline, followed by base-catalyzed alkylation
and reduction of the phenylenediamine derivative used for heterocyclization of the
imidazole carbamoyl-substituted drug (Scheme 8) [38, 39].
Albendazole acts by inhibiting the polymerization of b-tubulin and microtubule
formation; and is unlikely to have a detrimental effect on the adult parasites. The
drug also inhibits the enzyme fumarate reductase, which is helminth specific [34].
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