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Lymphatic Filariasis
Organic Compounds to Combat Neglected Tropical Diseases 161
Recent studies have also shown that a much higher, 1000 mg dose of albendazole,
is well tolerated in cancer patients [15]. Despite its widespread application and
inclusion into the Global Programme to Eliminate Lymphatic Filariasis, the effect
of albendazole against adult and larval filarial parasites deserves further rigorous
research [26, 37].
S
H
N
NH
N
O
O
NO
2
NH
2
NO
2
NH
2
NCS
S
NH
2
NH
2
Albendazole
Br
2
, NH
4
SCN
1) OH
-
2) Br(CH
2
)
2
CH
3
3) [H]
NCNHCO
2
Me or
ClCO
2
Me
Scheme 8: Synthesis of albendazole.
4.4. Anti-Wolbachia Antibiotics
Use of the antibiotic doxycycline combined in combination with ivermectin has
demonstrated a high degree of effectiveness against the filarial worm. This new
approach for LF treatment takes advantage of the mutualistic relationship between
Wolbachia bacteria and the parasite. This symbiotic relationship is essential for
larval development, fertility and survival [34]. Doxycycline, which is effective at
eliminating the symbiont from the host nematode, is an alternative treatment
option for areas where lymphatic filariasis is co-endemic with L. loa. As L. loa is
free of Wolbachia symbiosis, it is not affected by anti-Wolbachia treatments, and
avoids the risk of serious adverse events caused by rapid killing of microfilariae.
Doxycycline is directly obtained by a Wilkinson-type catalyzed reduction of
methacycline, which is semisynthesized from oxytetracycline by hemiacetali-
zation, and an exo-double bond formation followed by reduction [40] (Scheme 9).
Starting from a biocatalyzed reduction of benzoic acid, the total synthesis of
doxycycline [41], is an elaborated convergent strategy driven by consecutive ring
construction. The key features of this approach are as follows: epoxide
isomerization; ring A closure; diastereoselective sulfoxidation and Mislow-Evans
rearrangement; and Michael-Dieckmann reaction toward the C-ring (Scheme 9).
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162 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
CO
2
H
OH
OH
CO
2
H
OH
OH
CO
2
H
O
TBSO
OTBS
O
CO
2
CH
3
TBSO
O
O
N
O
N
BnO
TBSO
N
O
N
O
OBn
OH
TBSO
HO
H
B
N
O
N
BnO
Li
N
O
N
O
OH
TBSO
H
OH
CO
2
H
OBoc
D
B
A
N
OO
OH
OOH
OH
OH
NH
2
OH
HH
A
B
C
D
OH
OH
H
OH O
N
O
H
OH
OH
HO
NH
2
O
OH
OH OH
OH
N
O
H
OH
OH
NH
2
O
O
Cl
OH
OH OH OH
N
O
H
OH
OH
NH
2
O
Cl
HF
N
O
O
OH
OOH
OH
OH
NH
2
OH
H
H
B
A
A. euthropus B9
1) TMSCH
2
N
2
2) TBSOTf, Et
3
N
N-chlorosuccinimide
1) LiOTf,
2) TFA
1) CBr
4
/PPh
3
, PhSh
2) chiral oxidant, P(OMe)
3
Doxycycline
Zn/HCl
Wilkinson-type
RhCl(PPh
3
)
3
Total synthesis:
Semisynthesis:
Methacycline
oxytetracycline
Scheme 9: Schematic representation of synthesis and semi-synthesis of doxycycline.
4.5. Suramin
Suramin is a symmetrical polysulfonated naphthylurea that has been used in the
treatment of trypanosomiasis since the early 1920s [42]. Responding to a military
request for an effective treatment for an epidemic of equine trypanosomiasis
during the World War I, suramin was developed by the Bayer company in 1916
[43], based on earlier observations that dyes such as trypan blue and trypan red
were effective in eliminating trypanosome infections in mice [44] (Fig. 3).
The synthesis of suramin is based on an ‘outside-in’ approach, starting from the
amidation of the terminal sulfonated naphthyl amine, followed by a sequence of
nitro reduction and amide-forming reactions, to end with the internal urea
generated by reacting the product with phosgene (Scheme 10) [45]. An ‘inside-
out’ strategy was developed by starting with the symmetric urea [46].
Suramin acts on the folate metabolism of the macrofilarias [47]. Additionally, this
drug destabilizes filarial DNA and adversely affects the protein kinases and
enzymes associated with glucose catabolism [26].
Lymphatic Filariasis
Organic Compounds to Combat Neglected Tropical Diseases 163
HO
N
H
2
N
N
S
O
-
OO
S
O
-
O
O
N
N
S
OH
O
-
O
O
NH
2
S
-
O
O
O
Na
+
Na
+
Na
+
Na
+
HO
N
H
2
N
N
S
O
-
OO
S
O
-
O
O
N
N
S
OH
O
-
O
O
NH
2
S
-
O
O
O
Na
+
Na
+
Na
+
Na
+
OO
OO
O
N
H
H
N
H
N
N
H
N
H
SO
3
-
SO
3
--
O
3
S
-
O
3
S
SO
3
-
SO
3
-
N
OH
S
NH
2
S
N
H
N
H
N
O
N
N
OH NH
2
SS
O
O
O
O
O
O
O
O
OO OO
Na
+
Na
+
Na
+
Na
+
Trypan red
Trypan blue
Suramin
Afridol violet
Anionic naphthyl ending group
spacer group
(rigidity/planarity)
spacer group
(size)
Figure 3: Suramin structural similarity to dyes.
NH
2
SO
3
HHO
3
S
HO
3
S
OCl
NO
2
N
H
SO
3
HHO
3
S
HO
3
S
O
NH
2
OCl
NO
2
1)
2) [H]
1)
2) 1/2 COCl
2
Suramin
"Outside-in approach"
Scheme 10: Suramin synthesis using the ‘outside-in’ approach.
4.6. Other Filaricidal Agents
As the mainstream drugs for LF act mainly in the microfilaria nematode with little
activity against the adult worm, the mature filaria survive even after the treatment,
leading to the reappearance of the infection in the host. Hence, there is an urgent
need for new active compounds with structural diversity that are able to kill the
macrofilaria as well. Thus, a new class of compounds has emerged to overcome
the lack of structural diversity and the emergence of drug resistance to the current
filaricidal treatments. Some of the new active molecules are show below (Fig. 4).
Various types of heterocycles have been described to have potent antifilarial
activity. The pyrimidine derivatives have shown promising activity against adult
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164 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
O
O
O
N
H
N
S
O
O
N
+
O
O
-
NN
NH
2
N
S
N
OO
N
H
N
S
N
H
O
N
H
O
N
O
O
O
N
O
N
OO
N
O
O
O
N
O
NO
O
O
O
O
O
OH
OH
OH
O
ON
N
O
O
O
O
1-(thiophen-2-yl)-9H-pyrido[3,4-b]indole:
Unknown
Nitazoxanide:
Macro and microfilaricidal
Undefined mechanis of action
Benzopyrone:
Reduces lymphodema
Emodepside:
Effective against larvae and preadult worm
2,3,8-trihydroxy-1-methylanthracene-9,
10(4aH,9aH)-dione:
Effective against microfilariae and adults worm s
Macro and microfilaricidal
Undefined activity
Goniothalamin A
Targets filariasis vector
3,6 epoxy-1,5 dioxocines
Activity on adult worms
Thiazoles
Pyrimidines
Chalcones
Quinolones
Cyclooctadepsipeptide
Coumarins
Figure 4: Recent examples of new structural motifs in anfiliarial research.
worms, with inhibition of adult worm motility as well as sterilization of female
nematodes [48]. However, the mechanism of action of this class of compounds is
still unclear, although some findings suggest a potential inhibition of DNA
topoisomerase II. Thiazole derivatives exhibit broad activity against anaerobic
bacteria and a variety of helminthes, and have also been tested against the
different stages of filaria, resulting in high effectiveness. For instance, the
commercially available nitazoxanide (Alinia
TM
) blocks the worms´
embryogenesis, being active against the both larvae and adult worms [49]. The
coumarin [50] and quinolones [51] groups of antibiotics commonly act by
inhibiting DNA gyrase leading to the blockage of the ATPase activity, or by
inhibiting the DNA topoisomerase II, rerulting in reduction of lymphoedema and
inflammation in filarial patients. Futhermore, the quinolones inhibit the
microfilariasis and cause the death of adult male and B. malayi female worms
[51]. Styryl lactones, a class of secondary metabolites ubiquitous in the genus
Lymphatic Filariasis
Organic Compounds to Combat Neglected Tropical Diseases 165
Goniothalamus, showed interesting activity against larval Culex quinquefascitus,
the vector of LF. The mechanism of action of this effect is not entirely clear, and
the activity of the Goniothalamin A depends on the larval development stage.
Indeed, a large body of evidence suggests that this class may act in the induction
of apoptosis [52]. Neoeudistomin derivatives are a class of heterocycles that are
based on the structure-activity on eudistomin [53], and show promising activity in
rodents against L. sigmodontis and A. viteae, through the inhibition of both macro
and microfilariae, however, the mechanism of action is still unclear [26, 54, 55].
Natural cyclooctadepsipeptides and semisynthetic derivatives have received
attention for their ability to overcome the drug resistance that has emerged from
the commonly used classes of anthelmintics [56]. Emodepside (V) is a
semisynthetic derivative from this class that affects larvae and preadult stages of
filariae. Additionally, it demonstrates a completely new mode of action,
interacting with the latrotoxin – induced Ca
2+
and also causing relaxation of
nematodes via Ca
2+
-activated potassium channels [26, 54].
Other non-heterocyclic natural products have also been described as antifilarial.
Some examples include the chalcones, which exhibit a wide spectrum of
biological functions such as antibacterial and antimalarial activities. Preliminary
studies shows that their inhibitory effect on filaria occurs by depleting the cellular
level of GSH or electrophilic attack by an α,β- unsaturated carbonyl moiety on the
thiol group of GSH by a Michael-type addition reaction, which might induce
oxidative stress in the parasitic cell. However, to understand the mode of action of
chalcones on filarial parasites, additional work is needed [57]. Among the
antharaquinones, the most active antifilarial is the 1-methyl-2,3,8-trihydroxy-
anthraquinone, which was shown to produce 100% mortality of adult B. malayi
within 1–5 days of treatment at a concentration of 5 ppm. Most of the
anthraquinones are reported to have marked effects on intrauterine embryos of
filarial [58].
Another recently synthetized group of compounds, characterized by a [1,5]-
dioxocines have been tested against the B. malayi. These previous reports have
demonstrated complete inhibition of motility in macrofilarias, both in vitro and
in vivo with, no apparent signs of toxicity in normal animals [59].
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166 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
The diversity scaffold presented above (Fig. 4), may lead to the development of new
antifilarial agents, after optimization and elucidation of their precise mechanism of
action. The chart (Fig. 5) summarizes the target, the consequence for the filarial
pathogen, and the drugs/class of compounds that act through the indicated mechanism.
Figure 5: A functional relationship between antifilarial drugs, biochemical targets and
physiological consequences.
On the primary level, it shows the identified biochemical targets on the filarial
nematode. Then, on the second level, it shows the consequences that lead to the
parasites’ death. On the last level, there is a list of drugs and other active
compounds that can act through the indicated biochemical pathway.
5. CONCLUDING REMARKS
The recent development in antifilarial drugs is based on bioprospective studies of
existing libraries of synthetic and natural products, from which findings occur at
random. This is mainly a consequence of the lack of collaborative programs for
rapid and efficient drug discovery program for LF treatments, including the
development of a robust in vitro biological assays and associated high-throughput
system, integrated with a complete knowledge of the biochemistry and genome of
the worm combined with dedicated medicinal-chemistry investigation [60].
Recent efforts (e.g. the WHO´s Helmint Drug Initiative) reinforce this integrated
framework and provide opportunities to greatly enhance the drug discovery
paradigm [60].
Lymphatic Filariasis
Organic Compounds to Combat Neglected Tropical Diseases 167
Although widely adopted throughout the world, the available therapeutic arsenal
for LF consists of an inefficient single therapy of LF. Furthermore, there is an
urgent need for a macrofilaricidal compound [61]. The recent structural findings
in studies of antifilarial compounds could help establish useful structure-activity
relationships, thus leading to innovative and synthetically viable structures.
ACKNOWLEDGEMENTS
We acknowledge Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
(CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico
(CNPq) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
for the financial support to the authors.
CONFLICT OF INTEREST
The authors confirm that this chapter contents have no conflict of interest.
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