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Chagas Disease
Organic Compounds to Combat Neglected Tropical Diseases 31
oxadiazole-N-acylhydrazones as anti-Trypanosoma cruzi agents. Bioorg. Med. Chem. 2009,
17, 6682 – 6691.
[39] Palma, A.; Yépes, A. F.; Leal, S. M.; Coronado, C. A.; Esc o b a r, P. Synthesis and in vitro activity
of new tetrahydronaphtho[1,2-b]azepine derivatives against Trypanosoma cruzi and Leishmania
chagasi parasites. Bioorg. Med. Chem. Lett. 2009, 19, 2360 – 2363.
[40] Gómez-Ayala, S.; Castrillón, J. A.; Palma, A.; Leal, S. M.; Escobar, P.; Bah sas, A. Synthesis,
structural elucidation and in vitro antiparasitic activity against Trypanosoma cruzi and
Leishmania chagasi parasites of novel tetrahydr o-1- benzazepi ne deri vati ves. Bioorg. Med. Chem.
2010, 18, 4721 – 4739.
[41] Germain, A. R.; Carmody, L. C.; Dockendorff, C.; Galan-Rodriguez, C.; Rodriguez, A.;
Johnston, S.; Bittker, J. A.; MacPherson, L.; Dandapani, S.; Palmer, M.; Schreiber, S. L.; Munoz,
B. Identification of small-molecule inhibitors of Trypansoma cruzi replication. Bioorg. Med.
Chem. Lett. 2011, 21, 7197 – 7200.
[42] Shi, X.; Ge, J. Liu, B.; Kaiser, M.; Wittlin, S.; Brun, R.; Ihara, M. Synthesis and in vitro
antiprotozoal activities of 5-phenyliminobenzo[a]phenoxazine derivatives. Bioorg. Med Chem.
Lett. 2011, 21, 5804 – 5807.
[43] Salomão, K.; de Souza, E. M.; Carvalho, S. A.; da Silva, E. F.; Fraga, C. A. M.; Barbosa, H. S.;
de Castro, S. L. In vitro and in vivo activities of 1,3,4-thiadiazole- 2-arylhydrazone derivatives of
megazol against Trypanosoma cruzi. Antimicrob. Agents Chemother. 2010, 54, 2023 – 2031.
[44] Bouchikhi, F.; Anizon, F.; Brun, R.; Moreau, P. Biological evaluation of glycosyl-isoindigo
derivatives against the pathogenic agents of tropical diseases (malaria, Chagas disease,
leishmaniasis and human African trypanosomiasis). Bioorg. Med. Chem. Lett. 2011, 21, 6319 –
6321.
[45] Borchhardt, D. M.; Mascarello, A.; Chiaradia, L. D.; Nunes, R. J.; Oliva, G.; Yunes, R. A.;
Andricopulo, A. D. Biochemical evaluation of a series of synthetic chalcone and hydrazide
derivatives as novel inhibitors of cruzain from Trypanosoma cruzi
. J. Braz. Chem. Soc. 2010, 21,
142 – 150.
[46] Pacheco, M. G. O.; da Silva, C. F.; de Souza, E. M.; Batista, M. M.; da Silva, P. B.; Kumar, A.;
Stephens, C. E.; Boykin, D. W.; Soeiro, M. N. C. Trypanosoma cruzi: activity of heterocyclic
cationic molecules in vitro. Exp. Parasitol. 2009, 123, 73 – 80.
[47] Caputto, M. E.; Fabian, L. E.; Benítez, D.; Merlino, A.; Ríos, N.; Cerecetto, H.; Moltrasio, G. Y.;
Moglioni, A. G.; González, M.; Finkielsztein, L. M. Thiosemicarbazones derived from 1-
indanones as new anti-Trypanosoma cruzi agents. Bioorg. Med. Chem. 2011, 19, 6818 – 6826.
[48] Giorgi, M. E.; Ratier, L.; Agusti, R.; Frasch, A. C. C.; Lederkremer, R. M. Synthesis of
PEGylated lactose analogs for inhibition studies on T. cruzi trans-sialidase. Glycoconjugate J.
2010, 27, 549-559.
[49] Campo, V. L.; Sesti-Costa, R.; Carneiro, Z. A.; Silva, J. S.; Schenkman, S.; Carvalho, I. Design,
synthesis and the effect of 1, 2,3-t riazo le sialylmim etic neoglycoconjugates on Trypanosoma cruzi
and its cell surface trans-sialidase. Bioorg. Med. Chem. 2012, 20, 145 – 156.
[50] Rosso, V. S.; Szajnman, S. H.; Malayil, L.; Galizzi, M.; Moreno, S. N. J.; Docampo, R.;
Rodriguez, J. B. Synt hesis a nd biol ogical e valuat ion of ne w 2-al kylam inoethyl -1,1-bi sphos phonic
acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase.
Bioorg. Med. Chem. 2011, 19, 2211 – 2217.
[51] Nogueira, A. J. M.; de Lima, M. E. F.; da Costa, J. B. N.; Alves, E. S. S. ; dos Anjos, D. O.;
Vannier-Santos, M. A.; Lanfredi-Rangel, A. Síntese, caracterização e estudo da atividade
inibitória de novas dialquilfosforilarilidrazonas sobre o crescimento de tripanossomatídeos. Quim.
Nova 2011, 34, 1365 – 1369.
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32 Organic Compounds to Combat Neglected Tropical Diseases, 2014, 32-62
CHAPTER 2
DENGUE FEVER
Recent Advances in the Discovery of Small Organic Molecules for
the Prevention and Treatment of Dengue Fever
Lucas Cunha Dias de Rezende
1
, Victor Hugo Aquino
2
and Flavio da Silva
Emery
1,*
1
Department of Pharmaceutical Sciences, FCFRP/USP, Ribeirao Preto - SP,
Brazil, Av. do Café s/n. CEP: 14040-903, Ribeirão Preto, SP, Brazil;
2
Department of Clinical, Toxicological and Bromatological Analysis,
FCFRP/USP, Ribeirao Preto - SP, Brazil, Av. do Café s/n. CEP: 14040-903,
Ribeirão Preto, SP, Brazil
Abstract: Dengue fever (DF) is the most important mosquito-borne viral disease,
affecting around 100 million people mainly in tropical and subtropical countries. The
dengue virus (DENV) is a member of the Flaviviridae family and possesses a single
positive-stranded RNA genetic material encoding a single polyprotein, which is cleaved
into structural and nonstructural proteins. The consequences of DENV infections range
from fever to haemorrhagic manifestations, and the treatment of the disease is restricted
to symptomatic relief. Medicinal chemistry approaches allied with synthetic methods
can be of great importance for developing effective treatment for this disease, and the
scientific literature provides interesting results of studies that mainly targeted viral
processes to give rise to novel drugs. Viral entry, RNA replication, and polyprotein
cleavage have been the main, although not the only, focus in the development of novel
anti-viral compounds for the prevention and treatment of DF. In this chapter, we focus
on the new trends in the development of bioactive small molecules.
Keywords: Dengue fever, dengue hemorrhagic fever, antiviral, drug discovery.
1. TREATMENT
A specific treatment for DF is not yet available and the clinical management of
the disease is restricted to rehydration of the patient and the administration of
*Address correspondence to Flavio da Silva Emery: Department of Pharmaceutical Sciences,
FCFRP/USP, Ribeirao Preto - SP, Brazil. Av. do Café s/n. CEP: 14040-903, Ribeirão Preto, SP, Brazil;
Tel/Fax: +55 16 3602-0658; E-mail: flavioemery@fcfrp.usp.br
Send Orders for Reprints to reprints@benthamscience.net
Dengue Fever
Organic Compounds to Combat Neglected Tropical Diseases 33
paracetamol to relieve fever and headache, with the main objectives being to
avoid the development of severe disease and to relieve the patient's symptoms [1].
Reinforcing this scenario, there is an urgent need for specific therapeutic
treatments directed against DENV, for example treatments that inhibit flavivirus
infection or involve vaccination against it. Various synthetic and natural
compounds, that have inhibitory effects on different flaviviruses, have been
studied in vitro and in vivo with respect to their effects on DENV. However, these
studies have only resulted in experimental therapeutics; the compounds failed to
different extents in their clinical trials. Although they have been unsuccessful to
date, structure- and ligand-based studies have provided a lot of helpful
information for the ongoing search on small organic molecules for the treatment
of DF [2].
2. A MEDICINAL CHEMISTRY OVERVIEW OF DENGUE
Regarding the target of treatments, there are 2 common approaches for
discovering novel small organic molecules with therapeutic potential against the
DF pathologic agent: the viral target-based approach, in which compounds are
designed to interact directly with viral biomacromolecules, hampering their
activity; and the host target-based approach, in which human proteins, essential
for the DENV life cycle and that can be given as drugs, are targeted [3].
Among the most important viral processes and biomacromolecules targeted in the
development of anti-flavivirus agents are viral entry, viral RNA polymerase, and
viral protease [4, 5]. As for host proteins, cellular receptors, through which the
virus gains entry into the host, and proteins reported to bind to the viral RNA and
enable viral replication, are robust targets for anti-viral drug development.
2.1. Viral Serine Protease Inhibitors
Serine endoprotease NS3 is a viral enzyme that is activated when complexed in the
protease domain (NS3pro) to the integral membrane protein NS2B (essentially in the
hydrophilic central portion NS2BH), forming the complex NS2B-NS3 and,
consequently, the protease active site. The complex NS2B-NS3 is involved in the
processing of polyproteins, playing a pivotal role in viral replication, and has
therefore emerged as a suitable target for the development of therapeutics for DF [4,
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34 Organic Compounds to Combat Neglected Tropical Diseases Rezende et al.
6]. Besides the screening of small molecule libraries, the most prominent approach
for the development of an NS2B-NS3 inhibitor has been to explore the medicinal
chemistry of peptidomimetics similar to the protease catalytic substrate [6].
Among the natural products, 2 compounds isolated from Boesenbergia rotunda
have been reported to have strong inhibitory activity against NS3 protease. Even
at low concentrations, the cyclohexenyl chalcone derivatives panduratin A and 4-
hydroxypanduratin A were reported to have inhibitory activities towards the
DENV NS3 protein. In general, these natural compounds and similar derivatives
can be efficiently synthesised through the Diels–Alder cycloaddition of ring-
substituted chalcones and (E)-ocimene (Scheme 1) [7, 8]. The activity of these
compounds has been the subject of theoretical studies aimed at the design of novel
lead compounds [7].
Scheme 1: Top: The structures of panduratin A and 4-hydroxypanduratin A. Bottom: Application
of the Diels-Alder reaction to synthesise these compounds.
Compounds with α-ketoamides have also been evaluated in terms of their
inhibitory effects against DENV serine proteases. Some of these evaluations have
arisen on the basis of the rationale that the oxygen nucleophile in serine proteases
can be covalently bound to various electrophiles, resulting in enzymatic
inhibition. Several examples of the successful development of serine protease
O
OH
OH
O
O
OH
OH
HO
O
OH
OH
R
O
OH
OH
R
Panduratin A 4-Hydroxypanduratin A
+
24 h, 150ºC
85 - 95%
Dengue Fever
Organic Compounds to Combat Neglected Tropical Diseases 35
inhibitors by using the strategy of covalent protease inhibition are described in the
scientific literature, providing support for this approach. In this context, aldehyde
is a common electrophilic functional group known to act as an electrophilic trap
interacting with the nucleophilic serine residues in the enzyme’s active site. The
more electrophilic α-ketoamide is present in several protease inhibitors,
pharmaceuticals, and natural products, including inhibitors of the serine protease
from HCV. Consequently, it is also a prominent approach for developing small
molecules to covalently inhibit DENV NS2B-NS3 [9].
Scheme 2: Synthetic approaches to obtain a diversity-oriented library of α-ketoamides. The most
active core and the most promising compounds are boxed.
In the search for DENV NS2B-NS3 inhibitors, a very elegant study looked for
ideal structural cores bearing α-ketoamide derivatives. Applying 3 different
synthetic routes (Scheme 2): aldolic condensation (a), direct aldehyde coupling
(b), and the Passerini reaction (c), a library of 53 compounds bearing the β,γ-
unsaturated α-ketoamide and similar derivatives were synthesised and assayed for
their anti-dengue activity. The application of structure–activity relationship (SAR)
analysis to 11 prototype compounds, with punctual modifications such as
reduction of the linker length between the electrophilic trap and the cyclic
Ar
O
H
Ar
O
H
R
3
O
H
O
O
OH
Ar
O
O
OK
Ar
O
O
N
R
1
R
2
O
O
N
R
1
R
2
N
R
2
Ar
O
O
N
R
1
R
2
R
3
OH
O
H
N
R
2
R
3
O
O
H
N
R
2
O
O
N
R
1
R
2
O
O
H
N
HN
O
O
H
N
HO
O
O
+
KOH/MeOH
HNR
1
R
2
,
HATU, HOAt,
NEt3, DMF
+
+
DBU or
Cu(OTf)
2
, CH(OMe)
3
,
S: CH
2
Cl
2
SiCl
4
, CH
2
Cl
2
Dess–Martin
CH
2
Cl
2
Most active core
Promising Compounds
a) Aldolic Condensation
b) Direct Coupling
c) Passerini Reaction
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36 Organic Compounds to Combat Neglected Tropical Diseases Rezende et al.
structure, reduction/epoxidation of the ketones, and methylation of the linker,
allowed the definition of a core structure that had optimal inhibitory
characteristics, which was the initially designed structure (Scheme 2) [9].
In a second SAR approach keeping the most active core intact and modifying the
aromatic substituent, 28 compounds were assayed for their anti-dengue activity
and the electron-donating residues (e.g. methoxy and pyridyl) were observed to
promote inhibitory activity while the electron-withdrawing residues (e.g. nitro,
cyano, and fluoro) diminished inhibitory activity in most cases. Additionally,
indole substituents greatly enhanced the anti-dengue activity. The effects of
various substituents on the ketoamide nitrogen were studied and it was observed
that the substituent size could be extended to longer alkyl chains, but cyclohexyl
and phenyl groups were less tolerated. Based on the assumption that the
substituent on the alpha-ketoamide nitrogen occupied the S10-pocket, moieties
resembling serine were explored and remarkable activity was observed (Scheme
2) [9].
Based on the enzyme structure, a 3-aryl-2-cyanoacrylamide scaffold was designed
as anchor pharmacophore for inhibitors of the DENV protease. This core shares
similarities to β,γ-unsaturated α-ketoamides but contains a nitrile group, which
can act as an electrophilic trap for the enzymatic serine. Using a synthetic
approach where 2-cyanoacetamide derivatives were coupled with carbonyl
compounds (Scheme 3), 86 analogues were obtained and applied in a SAR study.
This new class of 3-aryl-2-cyanoacrylamides was found to inhibit DENV NS2B-
NS3 protease. Higher activity was observed with a para-substituted aromatic
system with high electron density, an amide or acid residue, and planar molecule
geometry. Pronounced activity and selectivity towards the viral enzyme was
observed in a primary para-hydroxy cyanoacrylamide derivative (Scheme 3) [10].
An aminobenzamide -based scaffold was explored as an inhibitor of DENV
protease. A library was synthesised from para and meta aminobenzoates, which
were converted to isocyanates followed by functionalization with propargylamine
and click chemistry -based coupling with several azides (Scheme 4). The
compound that had the highest activity showed an IC
50
for protease inhibition of
6.82 ± 0.09 µM [11].
Dengue Fever
Organic Compounds to Combat Neglected Tropical Diseases 37
O
O
N
R
3
O
N
R
1
R
2
O
R
3
O
N
R
2
R
1
NH
2
O
N
HO
HR
3
(amine)
Most promising comp ou nd
rt, 20 h
base - rt or reflux
2 - 20 h
Scheme 3: The synthetic approach used to obtain a libr ary of compounds containing the 3 -aryl-2-
cyanoacrylamide scaffold and the most promising compound in terms of its activity.
NH
2
OMe
O
N
C
O
OMe
O
NH
C
O
H
N
OMe
O
NH
C
O
H
N
NN
N
R
1
OM
e
O
LiOH
NH
C
O
H
N
NN
N
R
1
OH
O
NH
C
O
H
N
NN
N
R
1
NH
O
R
2
NH
C
O
NH
N
N
N
NH
O
O
F
Trichloromethyl
chloroformate
propargyl
amine
substituted azide
and ascorbate
CDI/
Amine
IC
50
= 6.82µM
Scheme 4: The synthetic approach used to obtain anti-dengue aminobenzamide derivatives and the
most active compound from the series (boxed).
The application of the EUDOC docking program in an in silico screen for 2
enzymatic sites using the Mayo Clinic small molecule database resulted in 3 hits
[12]. One of the promising compounds, the anthraquinone derivative ARDP0006,
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38 Organic Compounds to Combat Neglected Tropical Diseases Rezende et al.
which competitively inhibits DENV protease, was further studied. Using similar
anthraquinoidal compounds that were commercially available, 4 compounds were
found to have better activity than the lead compound (Scheme 5) [13].
Acridone, a tricyclic molecular scaffold that resembles an anthraquinone, was also
explored. A series of N-substituted acridones synthesised using anilino-benzoic
acids as the starting material were assayed. The compound that was most active
against DENV in this series showed an EC
50
of 2.5 µM in a viral inhibition assay
(Scheme 6).
O
O
OH OH
NO
2
NO
2
ARDP0006
O
O
NH
2
NH
2
NH
2
NH
2
O
O
OH
HO OH
OH
N
N
NO
2
O
2
N
O
O
OH OH
Structurally related compounds showing higher enzymatic inhibition
Scheme 5: Left: ARDP0006, an anthraquinone derivative obtained from computational screening.
Right Anthraquinoidal deriva t i ves that had higher activity.
CO
2
H
Cl
R
1
R
2
R
3
R
4
H
2
N
CO
2
HR
1
R
2
R
3
R
4
N
H
H
2
SO
4
R
1
R
2
R
3
R
4
N
H
O
R
1
R
2
R
3
R
4
N
O
Cl N
O
K2CO3/Cu
Allyil bro mide
Ethanone
+
EC
50
=2.5µM
Scheme 6: The synthetic methodology employed to obtain N-substituted acridones and the most
active from in the series (boxed).
Another strategy for developing inhibitors of the NS2B-NS3 enzyme complex is
the peptidomimetic approach, an example of substrate-based drug design in which
Dengue Fever
Organic Compounds to Combat Neglected Tropical Diseases 39
compounds are rationally designed to mimic the substrate peptide. From a series
of 17 tripeptide aldehydes synthesised using solution-phase chemistry, good
inhibition of DENV protease was observed for Lys-Arg-Arg with a phenylacetyl
substitution (Table 1) [14]. Other results obtained from the peptidomimetic
approach that were also assayed included peptides synthesised through N-terminal
acetylation and C-terminal amidation that shared similarities with viral
polyprotein [15], conformationally restricted cyclic peptides [16], and retro-
peptide hybrids [17] (Table 1).
A fused-bicyclic structure is commonly applied to the design of peptidomimetic
compounds, including commercially available anti-viral compounds such as
Danuravir, which bears the bis-tetrahydrofuranyl moiety. Isomannide has a fused
bicyclic structure and has already been used as a starting point for the construction
of peptidomimetic serine protease inhibitors. Isomannide hydroxyls was tosylated
with tosyl chloride, following which the tosyl was substituted for an azide with
NaN
3,
and then palladium-catalyzed reduction of the azide moiety to an amine
was performed with molecular hydrogen. The bis-amino derivative of isomannide
was then coupled with several oxazolone derivatives commonly used as amino
acid precursors. Even though the library was not tested against DENV NS2B-
NS3, its inhibitory activity against serine protease was assayed in a hepatitis C
virus (HCV) serine protease and the novel scaffold and synthetic approach could
be modified to achieve good anti-dengue lead compounds (Scheme 7) [18].
Table 1. Peptidemimetic inhibitors of DENV NS3-NS2B protease
Entry Peptide IC
50
References
1 GLPVCGSEESRRGCNTPGCRRSWPVCTRR
Cyclic peptide - isomer A
4.3 µM [14]
2 GLPVCGSEESRRGCNTPGCRRSWPVCTRR
Cyclic peptide - isomer B
9.3 µM [14]
3 Benzoyl-KRR 9.5 µM [16]
4 Phenylacetyl-KRR 6.7 µM [16]
5 Ac-RTSKKR-CONH2 12.1 µM [15]
6 Ac-KKR-CONH2 22.3 µM [15]
7 Ac-FAAGRK-CONH2 25.9 µM [15]
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40 Organic Compounds to Combat Neglected Tropical Diseases Rezende et al.
O
O
HO
OH
O
O
H
2
N
NH
2
N
H
O
R
2
H
R
1
O
O
H
N
N
H
O
N
H
R
1
O
R
2
O
HN
R
1
R
2
O
1. TsCl
2.NaN
3
3. H
2
,Pd/C
Scheme 7: The synthetic approach used for the development of a fused-bicyclic peptidomimetic
compound from isomannide.
Five-membered multi-heterocyclic rings are somewhat controversial in the
medicinal chemistry field due to their ability to interact with a variety of
biological targets. DENV NS2B-NS3, together with other enzymatic targets, was
explored in a screen of 163 derivatives of 5-membered multi-heterocyclics
(Scheme 8). Thiohydantoin and rhodanine derivatives, obtained from the
cyclization of diverse amino acids, were shown to be most potent against NS2B-
NS3. The aromaticity of substituents bonded to the multiheterocyclic rings
seemed to be fundamental to their activity; actually, the vast majority of
thiohydantoin and rhodanine cycles substituted with aromatic cycles showed at
least intermediary inhibition of NS2B-NS3 while all non-aromatic derivatives
were virtually inactive [19].
Scheme 8: The synthetic procedure used to obtain thiohydantoin and rhodanin e.
The inhibition of DENV NS2B-NS3 protease by benzo-[d]-isothiazol-3(2H)-one
derivatives bearing a triazole cycle synthesised via click chemistry coupling of
propargyl-functionalized isothiazolone heterocycles, and structurally diverse
azides to form derivatives was the objective of a study with interesting
observations (Scheme 9). Through this synthetic strategy, a library comprising 33
compounds was obtained; for 6 of these somewhat promising enzymatic and viral
inhibition was observed (Scheme 9) [20].
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