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Lymphatic Filariasis
Organic Compounds to Combat Neglected Tropical Diseases 171
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172 Organic Compounds to Combat Neglected Tropical Diseases, 2014, 172-19 5
CHAPTER 6
MALARIA
Synthesis of Hybrid Molecules and Inhibitors of Falcipain for Use
as Therapeutic Agents in Treatment of Malaria
Renata Barbosa de Oliveira
*
, Marcela Silva Lopes and Saulo Fehelberg Pinto
Braga
Federal University of Minas Gerais, Laboratory of Pharmaceutical Chemistry,
Faculty of Pharmacy, Av. Antônio Carlos 6627 – Belo Horizonte – MG - Brazil
Abstract: Malaria is a tropical disease caused by infectious species of Plasmodium that
are transmitted to people through the bites of infected mosquitoes. Malaria kills more
than 650,000 people worldwide each year. Plasmodium resistance to antimalarial
medicines, toxicity and high cost are the major obstacles in the fight against this
disease. Therefore, there is an urgent need for the development of new more effective
and less toxic antimalarials, especially compounds that act against novel molecular
targets in order to circumvent the problem of increasing resistance. This chapter is
focused on recent advances in the field of synthesis of compounds having antimalarial
activity based on two strategies: synthesis of hybrid molecules and synthesis of
inhibitors of a cysteine protease (falcipain) that plays a key role in malaria parasites.
Keywords: Malaria, antimalarial drug, hybrid molecules, falcipain inhibitors.
1. INTRODUCTION
Malaria is currently endemic in 106 countries, affecting especially the poorest
segments of the population of Africa, Asia and Latin America. It is responsible for
high mortality and morbidity in these regions, being especially lethal to children
and pregnant women because their anti-malarial immunity level is low.
Furthermore, malaria is a risk for travelers and immigrants, with imported cases
increasing in non-endemic areas. According to estimates by World Health
Organization, in 2010 there were 655,000 malaria deaths, of which 91% were in
Africa [1, 2].
*Address correspondence to Renata Barbosa de Oliveira: Federal University of Minas Gerais, Laboratory
of Pharmaceutical Chemistry, Faculty of Pharmacy. Av. Antônio Carlos 6627 – Belo Horizonte – MG -
Brazil; Tel: +55-31-34096365; Fax: +55-31-34096935; E-mail: renatabo@farmacia.ufmg.br
Send Orders for Reprints to reprints@benthamscience.net
Malaria
Organic Compounds to Combat Neglected Tropical Diseases 173
Malaria is transmitted to humans by the bite of the female Anopheles mosquito
that carries the infectious species of Plasmodium. Human malaria is caused by
five different species of Plasmodium: P. falciparum, P. vivax, P. ovale,
P. malariae and P. knowlesi. P. falciparum causes the most severe form of
malaria and P. vivax is more widespread. The other three species are found much
less frequently [1, 2].
Regarding the treatment, a range of drugs is currently available for the treatment
of malaria patients. However, Plasmodium resistance to antimalarial medicines,
their toxicity and their high cost are the major obstacles in the fight against
malaria [1, 2]. The search for new antimalarials more effective and less toxic is
therefore mandatory, especially compounds that act against novel molecular
targets in order to circumvent the problem of increasing resistance. The main
drugs available for the treatment of malaria and their classification according to
the chemical family are shown in Fig. 1.
In view of the risks for treatment failure due to the emergence of drug resistance,
monotherapies for the treatment of uncomplicated malaria are no longer
recommended. Artemisinin-based combination therapies (ACT) had been adopted as
first-line treatment, using a combination of drugs with different mechanisms of
action. The ACTs currently recommended by WHO are: artemether plus
lumefantrine, artesunate plus amodiaquine, artesunate plus mefloquine, artesunate
plus sulfadoxine-pyrimethamine, and dihydroartemisinin plus piperaquine.
Chloroquine is still being used as first-line treatment in some countries [1, 2].
Many approaches to antimalarial drug discovery are available as, for example, the
development of hybrid molecules having different biological functions and dual
mode of action and the search for new therapeutic targets.
2. SYNTHESIS OF HYBRID MOLECULES WITH A DUAL MODE OF
ACTION
A recent rational approach of antimalarial drug development consists in designing
hybrid drugs by covalently linking two distinct chemical moieties containing
different pharmacophores with a different mechanism of a ction. The ma in advantage
of these hybrid molecules is the capacity to target the parasite by two independent
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174 Organic Compounds to Combat Neglected Tropical Diseases de Oliveira et al.
mechanisms of action, thus avoiding development of resistance [3]. There are many
forms in which the hybrid molecule may be designed and a general representati on of
one of the most common approach is illustrated in Fig. 2.
Figure 1: Chemical structure of the antimalarial drugs.
Malaria
Organic Compounds to Combat Neglected Tropical Diseases 175
Figure 2: General representation of hybridization approach.
Here we review the synthesis of some hybrid molecules that have been developed
for the treatment of malaria, with particular emphasis on those deemed promising
for development of clinical application.
2.1. Endoperoxide-Quinoline Based Hybrids
Trioxaquines are synthetic hybrid molecules obtained by the covalent attachment,
via a linker, of a trioxane and an aminoquinoline motifs (Fig. 3).
The synthesis of first generation trioxaquines developed by Meunier and co-
workers [4] is illustrated in Scheme 1. Nucleophilic substitution at the C-4
chlorine of the 4,7-dichloroquinoline 1 with 1,2-diaminoethane afforded the
aminoquinoline derivative 2. The trioxane moiety 5 was synthesized in two steps:
photo-oxygenation of 1,4-diphenylcyclopenta-1,3-diene 3 followed by reaction
with 1,4-cyclohexanedione. Coupling of amine 2 with ketone 5, via reductive
amination, yielded 87% of the trioxaquine 6.
Figure 3: Example of structure for a classical trioxaquine.
Three trioxaquines were synthesized as depicted in Scheme 1 by varying the
length of chain (2-4 carbons) connecting the two active moieties (Fig. 4).
Araújo et al. have also synthesized a series of quinoline/acridine endoperoxide
hybrids based on 1,2,4-trioxalaquines heterocycle according to synthetic pathway
shown in Scheme 2 [5].
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176 Organic Compounds to Combat Neglected Tropical Diseases de Oliveira et al.
Scheme 1: Route of synthesis of first generation trioxaquines [4].
Figure 4: Chemical structures of trioxaquines synthesized by Meunier and co-workers [4].
The synthesis of 1,2,4-trioxolane hybrid molecules began with the formation of
the O-methyl oxime 9 from O-methyl hydroxylamine hydrochloride and the
adamant-2-one in molar ratio of 1:1 [5, 6]. Ozonolysis reaction of O-methyl
oxime 9 in presence of 1,4-cyclohexadione furnished the corresponding ozonide
10. Subsequently, reductive amination of 10 and aminoquinoline/acridine
derivatives was carried out using sodium triacetoxyborohydride in methylene
chloride at room temperature to produce trioxolaquines 11-14 (Scheme 2). All
products were obtained as a 1:1 mixture of diastereomers (Fig. 5) [5].
Coslédan et al. have prepared and evaluated the antiplasmodial activity of 120
trioxaquines and trioxalaquines (IC
50
values ranged from 5 to 74 nM). Among
these 120 compounds, 72 were selected for evaluation on mice infected by the
CSR strain of Plasmodium vinckei petteri, and 25 of the 72 molecules were
chosen for further studies of absorption, distribution, metabolism, excretion and
toxicity (ADMET). From these studies, the trioxaquine PA1103/SAR116242 (Fig.
6) was selected for preclinical development as a drug candidate [7].
Malaria
Organic Compounds to Combat Neglected Tropical Diseases 177
N
O
CH
3
O
O
O
O
N Cl
HN
N Cl
N
H
N
N Cl
MeO
N
H
N
H
N
O
O
O
O
O
O
N N N
Cl
O
O
O
N N N
Cl
MeO
NH
2
n
N Cl
HN NH
2
n
MeO
H
N
N
Cl
n
H
N
O
O
O
H
N
N
Cl
n
OMe
11a, n=2, 44%
11b, n=3, 49%
12, 70%
13a, n=2, 44%
13b, n=3, 49%
14, 70%
(i)
(ii)
(ii)
(ii)
(ii)
Reagents and conditions: (i) O
3
, -78ºC, 1,4-cyclohexadione, pentane/CH
2
Cl
2
, 0 ºC, 1-2 h; (ii) NaHB(OAc)
3
, CH
2
Cl
2
, rt.
10, 75%
O
NH
3
+
Cl
-
H
3
CO
8
9
Scheme 2: Quinoline /acridine endoperoxide hybrids synthesized by Araújo et al. [5].
Figure 5: Mixture of diastereomers obtained by Araújo et al. [5].
Figure 6: Chemical structure of PA1103/SAR116242.
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178 Organic Compounds to Combat Neglected Tropical Diseases de Oliveira et al.
Scheme 3: Route of synthesis of PA1103/SAR116242 [7]
The synthesis of PA1103/SAR116242 is shown in Scheme 3. Treatment of the
allylic alcohol 15 with molecular oxygen and triethylsilane (Mukaiyama’s
peroxysilylation) provided peroxysilyl alcohol 16 in 46% yield. Cyclization using
the alcohol 16 and 1,4-cyclohexanedione in CHCl
3
afforded the target keto-
trioxane intermediate 19. Alternatively, the trioxane intermediate 19 could also be
synthesized by opening of the epoxide 17 using molybdenum catalysts in
combination with hydrogen peroxide, followed by reaction of the resultant alcohol
18 with 1,4-cyclohexanedione. Reaction of the 4,7-dichloroquinoline with the
trans-1,4-diaminocyclohexane produced the aminoquinoline PA1019/
SSR132244, which was coupled to 19 to give PA1103/SAR116242 as a mixture
of two diastereoisomers [7].
2.2. Quinoline-Novel Target Based Hybrid
Historically, chloroquine has been one of the most successful and widely used
antimalarial drugs. Unfortunately, its extensive use over many years led to
chloroquine resistance in Plasmodium falciparum and Plasmodium vivax, the
HO
Et
3
SiH
O
2
HO
O
O
SiEt
3
HO
O
HO
O
OO
O
OO
O
NCl
HN
NH
2
H
N
N
Cl
N
H
O
O
O
N
Cl
Cl
NH
2
NH
2
16, 46%
19, 30% from 16
28% from 18
or
MoO
2
(acac)
2
50% H
2
O
2
PA1103/SAR116242
58%
PA1019/SSR132244
91%
15
18, 50%
17
(i) (ii)
(iii)
(iv)
(v)
Reagents and conditions: (i) EtOH anhyd r ous, rt, 4 h; (ii) Et
2
O, MgSO
4
; (iii) TsOH, CHCl
3
, 0.5 h; (iv) 190 ºC, 45 min.;
(v) NaBH
3
CN, MeOH, HCl, iPrOH.
1
Malaria
Organic Compounds to Combat Neglected Tropical Diseases 179
parasite species responsible for most human malaria cases. The mechanism of
resistance is related to mutations in the gene PfCRT, which is believed to be a
transporter located in the digestive vacuole membrane and may be involved in the
reduction of the concentrations of chloroquine at its site of action (increased
chloroquine efflux mechanism) [8]. An alternative to overcome chloroquine
resistance would be to develop a hybrid molecule by linking chloroquine moiety
to resistance reversing agents such as verapamil or imipramine. These resistance
reversing agents are believed to act by inhibiting the protein PfCRT activity,
promoting drug accumulation in the digestive vacuole [9]. Based on this
approach, Burgess et al. synthesized a chloroquine-imipramine hydrid 22, in 3
steps, as shown in Scheme 4 [10]. The synthesis consisted on the selective
displacement of the C-4 chlorine on 4,7-dichloroquinoline 1 by reaction with 3-
aminopropanol, followed by activation of the alcohol through mesylation with
methanesulfonyl chloride in THF in presence of triethylamine, and finally a
second nucleophilic displacement with desimipramine free base provided the
hybrid 22 in 84% yield.
The hybrid 22 displayed remarkable antiplasmodial activity at low nanomolar
concentrations against both chloroquine-susceptible and resistant strains. In mice,
it demonstrated high oral efficacy (> 99% suppression of P. chabaudi growth) at
dose of 64 mg/kg/day [10].
Aminoquinoline-isatin hybrids represent another class of hybrid molecules based
on multiple target sites. Isatins (also known as 2,3-dioxindoles) and their
thiosemicarbazone derivatives are known to inhibit Plasmodium falciparum
cysteine protease (falcipain-2) [11, 12]. Falcipain-2 is a papain family cysteine
protease that plays a key role in the parasite life cycle by degrading erythrocyte
proteins, most notably hemoglobin. Inhibition of falcipain-2 prevents parasite
maturation and, therefore, this enzyme represents a potential target for the
development of novel antimalarial drugs [13]. Thus, the combination of
aminoquinoline (inhibits the formation of -haematin) to a number of structures
based on isatin (falcipain-2 inhibitor) appears to be a promising approach for the
design of hybrid antimalarial agents (Fig. 7).
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180 Organic Compounds to Combat Neglected Tropical Diseases de Oliveira et al.
N
Cl
Cl
H
2
NOH
N
HN
Cl
OH
MsCl
N
HN
Cl
OMs
N
HN
N
HN
Cl
N
CH
3
N
(i) (ii)
(iii)
20, 90%
21, 63%
22, 84%
Reagents and conditions: (i) 140 ºC, rt, 24 h; (ii) THF , Et
3
N, 0 ºC, 45 min.; (iii) THF, Et
3
N, 50-60 ºC, 72 h.
1
Scheme 4: Route of synthesis of chloroquine-imipramine hydrid 22 [10].
Figure 7: General structure of aminoquinoline-isatin hybrids [14].
Chiyanzu et al. synthesized a series of 4-aminoquinoline-based isatin derivatives
that was effective against three strains of P. falciparum and with potential to
inhibit falcipain-2. The quinoline–ethylene isatin derivatives 23 were prepared
using a route very similar to that shown in Scheme 4: reaction of ethanolamine
and 4,7-dichloroquinoline 1, followed by O-mesylation and subsequent reaction
of mesylate formed with commercially available isatins and sodium hydride in
N,N-dimethylformamide (DMF). The substituted isatins 23 were converted to
their corresponding thiosemicarbazones by treatment with thiosemicarbazide in
ethanol. The hybrid molecules 26 and 27 with a protonatable piperazinemethyl
linker were obtained via Mannich reaction of paraformaldehyde with the chloro-4-
piperazin-1-yl-quinoline 25. The iminium ion formed in situ was then reacted with
different isatins and isatin-3-thiosemicarbazones to provide the desired N-
Mannich isatin derivatives 26 and 27 (Scheme 5) [14].
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