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Dengue Fever
Organic Compounds to Combat Neglected Tropical Diseases 61
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Organic Compounds to Combat Neglected Tropical Diseases, 2014, 63-121 63
CHAPTER 3
LEISHMANIASIS
An Overview of New Synthetic Antileishmanial Candidates
Nubia Boechat
*
and Luiz Carlos da Silva Pinheiro
Oswaldo Cruz Foundation – Fiocruz, Institute of Drug Technology -
Farmanguinhos, Department of Organic Synthesis. 21041-250, Rio de Janeiro,
RJ, Brazil
Abstract: Leishmaniasis is considered by the World Health Organization to be one of
the world’s most neglected diseases. The current drugs used to treat leishmaniasis were
developed more than 40 years ago and are toxic. In addition, they generate resistance,
and coinfection with the AIDS virus has worsened the situation of this disease. The
purpose of this chapter is to review the various synthetic compounds described between
2002 and 2012 that have been tested against Leishmania spp. and that could be
considered possible prototypes for treating this disease. Compounds were organized into
20 chemical classes.
Keywords: Leishmaniasis, prototypes, synthesis.
1. INTRODUCTION
Leishmaniasis is considered by the World Health Organization (WHO) to be one
of the world’s most neglected diseases. This disease threatens approximately 350
million people, of which 12 million are currently infected. Approximately 2
million new infections occur each year in 88 countries of tropical and temperate
regions [1].
This disease can be caused by 20 different species of Leishmania and can be
transmitted by the female phlebotomine sandfly of the genus Phlebotomus or
Lutzomyia [2, 3]. Leishmaniasis can manifest in the following three ways:
cutaneous (CL), mucocutaneous (MCL) and visceral (VL, also called “kala-azar”)
*Address correspondence to Nubia Boechat: Oswaldo Cruz Foundation – Fiocruz, Institute of Drug
Technology - Farmanguinhos, Department of Organic Synthesis. 21041-250, Rio de Janeiro, RJ, Brazil;
Tel/Fax: +55 21 39772458; E-mail: boechat@far.fiocruz.br
Send Orders for Reprints to reprints@benthamscience.net
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64 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
[4]. Leishmania parasites that cause CL and MCL are L. Mexicana,
L. braziliensis, L. tropica and L. major. While L. donovani, L. infantum, L.
chagasi are those that are responsible for VL, the most lethal form of the disease,
which, if untreated, can be fatal.
1.1. Current Drugs in Use
Treatment of leishmaniasis is complicated because there are different causative
species and various clinical manifestations. A serious problem is related to
coinfection with HIV/AIDS.
Over the past few years, various drugs that were
previously developed for other diseases have also been tested and showed variable
efficacy [5-11].
Since the early 20th century, the pentavalent antimonial compounds, Glucantime
®
(meglumine antimoniate) (1) and Pentostam
®
(sodium stibogluconate) (2) were
the first choice for leishmaniasis treatment despite their high cost and serious side
effects [12]. The misuse of those drugs, incomplete treatment and inappropriate
prescription guidelines have been described as the major reasons of the emergence
of resistance of Leishmania parasites against pentavalent antimonials [13-17].
Amphotericin B (3) is widely used for visceral leishmaniasis. More effective and
less toxic are the following three new pharmaceutical formulations of
amphotericin B: liposomal ampho B (L-AmB: Ambiosome
®
), amphotericin B
OOH
OOHOH
OH
OH OH O
OH
CO
2
H
O
HO
O
HO
NH
2
OH
OH
HO
OH
HO
NH
H
3
C
HO
Sb
O
O
OH
O
Sb
OO
Sb
O
O
OOOO
H
HO OH
OH OH
H
HH
O
O
OH O
Na
Na
Na
(3)
(1)
.
9
H
2
O
(2)
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 65
colloidal dispersion (ABCD: Amphocil
®
) and amphotericin B lipid complex
(ABL: Abelcit
®
) [18-22].
In the diamidine class of compounds, pentamidine (4) was first synthesized in the
late 1930s and is currently produced by Sanofi-Aventis. Its efficacy has gradually
declined over the years, and serious adverse effects are associated with this drug
[23, 24].
Miltefosine (5) is orally administered and was initially developed as an antitumor
drug, but it showed activity against leishmaniasis and has been registered in India
for the treatment of visceral leishmaniasis. Early clinical studies demonstrated a
94% cure rate, but the efficacy is variable for Leishmania spp. Miltefosine
presents certain limitations such as high-level teratogenicity, clinical resistance
and high cost [25-27].
Paromomycin (6) is indicated for the treatment of acute and chronic intestinal
amebiasis and acts synergistically with antimonials in vitro against leishmaniasis.
It is well tolerated, showing results comparable to amphotericin B [28, 29].
Sitamaquine (7), an orally active drug in development by the Walter Reed Army
Institute in collaboration with GlaxoSmithKline, is in preclinical and clinical tests.
Sitamaquine has demonstrated oral efficacy against L. donovani, and studies are
OO
NH
2
NH
H
2
N
NH
O
P
O
N
O
O
-
+
NH
2
H
2
N
O
HO
O
O
HO
O
O
OH
NH
2
OH
OH
OH
O
OH
H
2
N
HO
NH
2
N
O
H
3
C
N
N
H
(4)
(5)
(6)
(7)
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66 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
being conducted to characterize its pharmacokinetic profile, safety and tolerability
when compared with amphotericin B [30-33].
2. NEW SYNTHETIC COMPOUNDS AS ANTILEISHMANIAL
CANDIDATES
Several functional groups and heterocyclic rings have been associated as
pharmacophoric groups with leishmanicidal activity. Groups such as amidine,
diamidine, guanidine and polyamine as well as small heterocyclic moieties,
including the following imidazole, pyrazole, thiadiazole, triazole, dioxazole and
piperazine, are frequently found in leishmanicidal compounds. Activity has also
been associated with quinolines, pyrazolopyrimidines, triazolopyrimidines,
imidazopyrimidines, chalcones and naphthoquinones.
Here, we present various synthetic compounds described between 2002 and 2012
that have been tested against Leishmania and that could be considered possible
prototypes. This review is organized by the chemical class of the compounds.
2.1. Azole Derivatives
Azoles represent one of the most important classes of antiparasitic drugs. The
imidazolic antifungals ketoconazole (8) and triazolic itraconazole (9) have been used
to treat cutaneous leishmaniasis with variable success rates [34]. They inhibit the C-
14 demethylation of lanosterol, which interferes with the production of leishmanial
ergosterol, an essential component of their membrane structure. Thus, azole s such as
imidazole, pyrazole, triazole, thiadiazole, oxazole and oxadiazole have become
important synthetic targets in the development of drugs for parasitic diseases.
N
N
O
O
O
N
N
Cl Cl
H
O
(8)
N
N
O
O
O
N
N
N
Cl Cl
H
N
N
N
O
(9)
2.1.1. Triazole Derivatives
1,4-Dicyanophenyl-1H-1,2,3-triazoles (12) were prepared by the copper(I)-
catalyzed 1,3-dipolar cycloaddition reaction of 3- or 4-azidobenzonitriles (10) and
suitable ethynylbenzonitriles (11). Using the modified Pinner method, the
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 67
resulting dinitriles 12 were transformed to imidate esters, which reacted with
ethanolic solutions of ammonia, isopropylamine or ethylenediamine followed by
treatment with aqueous HCl to afford congeners 13 as dihydrochloride salts. In
this paper, the authors reported that the type and placement of cationic moieties as
well as the nature of aromatic substituents can influence the antiprotozoal activity.
The compounds were tested in vitro against L. donovani and showed IC
50
values
(concentration for 50% growth inhibition) in a range of 4.3-58 µM [35].
NN
N
R
1
R
2
NC
CN
R
2
R
1
NN
N
R
R
NH
2
NH
HN
NH
N
H
N
N
3
R
1
R
2
R
1
= R
2
= H, OH, OMe
(i)
R =
(13)
,
,
(12)
(10)
(11)
(ii)
+
Reagents and conditions: (i) sodium ascorbate, CuSO
4
.5H
2
O, DMF/H
2
O or t-BuOH/H
2
O, 24-48 h;
(ii) 1,4-dioxane-EtOH, HCl
(g)
, rt, and then: amines, EtOH, rt, 4 days.
Tekwani and coworkers reported the reaction of azido acid 14 with
O-tritylhydroxylamine to give O-tritylated hydroxamates (15). A subsequent
cycloaddition reaction between these derivatives and terminal alkynes resulted in
O-trityl protected aryltriazolylhydroxamates (16), which was followed by the
deprotection of the O-trityl group, giving new aryltriazolylhydroxamates (17).
The effects of derivatives of 17 on the viability of the promastigote stage of
L. donovani showed in vitro antileishmanial activities with IC
50
values in the
range of 4.55-40 µg/mL [36].
OH
O
N
3
N
N
N
N
O
R
H
OH
N
H
O
N
3
OTrityl
N
N
N
N
O
R
H
OTrityl
(i)
(ii)
(iii)
(15)
(14)
R= P h, p-N ,N-dimethylan ilyl, 2- p y ridyl,
2-thienyl, 3-bip h en yl, 2- quin o linyl
n = 6-9
(16)
(17)
Reagents and conditions: (i) NH
2
–O–Trityl, IBCF, THF, -15
o
C, 2 h; (ii) CuI, Hunig’s base, THF,
rt; (iii) BF
3
.OEt
2
, THF, rt, 20 min, TFA/thioanisole (1:1), 0
o
C, 3 h.
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68 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
Boechat and coworkers reported the synthesis of 1,2,3-triazolic compounds from
the reaction of diazomalonaldehyde (18) with appropriate aromatic amine
hydrochlorides (19) to yield N-substituted-phenyl-1,2,3-triazole-4-carbaldehyde
(20). The reaction of derivatives of 20 with DAST (N,N-diethylaminosulfur
trifluoride) yielded 4-difluoromethyl-1,2,3-triazoles derivatives (21). The
carbaldehyde 20 (3-Cl) and the difluoromethylated 21 (3-Cl) showed IC
50
values
of 2.8 and 2.6 µM, respectively, when tested against L. amazonensis [37].
O
O
HH
N
2
NH
3
Cl
R
1
R
1
N
N
N
CHO
R
1
N
N
N
CHF
2
+
-
+
R
1
=
4
-Cl;
4
-Br;
4
-CH
3
;
4
-OCH
3
;
2
,
5
-OCH
3
;
3
-Cl;
3
,
5
-Cl;
3
-CN;
4
-CN;
4
-NO
2
;
2
-OCH
3
;
3
,
4
-OCH
3
(i) (ii)
(18)
(19)
(20)
(21)
Reagents and conditions: (i) H
2
O, rt, 24h, (ii) DAST, CH
2
Cl
2
, rt, 24h
2.1.2. Imidazole Derivatives
Boechat and coworkers also reported the condensation between N-aryl-amidines
(22) and 2-bromomalonaldehyde (23) leading exclusively to 5-carbaldehyde
imidazoles (24). Using DAST, the carbaldehyde group was readily converted into
a difluoromethyl group generating the derivatives 25. When tested against
L. amazonensis, the difluoromethylated derivative 25 (4-Cl) showed an IC
50
of 1.7
µM [37].
N
NH
2
HO O
H
Br
H
N
N
CHO
N
N
CHF
2
R
R
R
+
R= H;
4
-Cl;
4
-Br;
4
-F;
4
-NO
2
;
4
-CF
3
;
4
-CN;
4
-CH
3
;
4
-OCH
3
;
2
,
6
-F;
2
-CH
3
;
3
-OCF
3
(i)
(ii)
(22)
(23) (24) (25)
Reagents and conditions: (i) AcOH, TEA, i-PrOH, rt, 17h; (ii) DAST, CH
2
Cl
2
, rt, 24h.
Siddiqui and coworkers used N-arylation of imidazole (26) with different aryl
halides (27) using hexadecyltrimethylammonium bromide as a catalyst to
synthesize the compound 4-(1H-imidazol-1-yl) benzaldehyde (28), which reacted
with a number of substituted aromatic acetophenones to yield 3-[4-(1H-imidazol-
1-yl) phenyl]prop-2-en-1-ones (29). All the compounds were tested in vitro
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 69
against L. major promastigotes and showed significant activities with IC
50
values
between 0.63-0.99 µg/mL [38].
N
H
N
F
CHO
N
N
CHO
O
N
N
R
(i)
(ii)
(29)
(28)
+
R= H, F, Cl, Br, I, OCH
3
(27)
(26)
Reagents and conditions: (i) K
2
CO
3
, C
16
H
33
(CH
3
)
3
N
+
Br, DMF, 100
o
C; (ii) MeOH, NaOH, 25
o
C.
Bhandari and coworkers [39] synthesized a series of imidazoles (30 and 31), which
were assayed against L. donovani. Ketones 32 reacted with pyrrolidine and
formaldehyde under asymmetric Mannich conditions in the presence of L-proline to
give the corresponding products 33. Subsequent replacement of the pyrrolidine with
imidazole followed by reduction gave the hydroxyl intermediates 34. Condensation
of the 34 isomer with substituted aryl halides furnished the required ethers 30.
To form imidazoles 31, a regioselective ring opening of styrene epoxide (35) or
phenoxy methyl oxirane (36) with imidazole gave the corresponding alcohols 37.
A nucleophilic aromatic substitution with aryl fluoride derivatives generated the
targeted aryloxy ethers (31).
The imidazole derivatives 30 and 31 inhibited the promastigote form at 94-100%
in a concentration of 10 μg/mL, whereas against the amastigote form, they
showed an IC
50
value in the range of 0.47-4.85 μg/mL [39].
In another paper, Bhandari and coworkers [39] described the synthesis of a new
series of bis and mono imidazoles. The Mannich reaction on cyclohexanone (38)
with pyrrolidine gave 2,6-bis-pyrrolidin-1-ylmethyl-cyclohexanone (39) which,
on reaction with imidazole followed by reduction, gave the corresponding
hydroxy derivative 40. The reaction of 40 with aryl halides furnished the desired
2,6-bisimidazolylmethyl-cyclohexyl aryl ethers (41).
For the synthesis of the imidazoles 42, cyclohexanone (38) was reacted with
pyrrolidine under Mannich conditions to give 2-pyrrolidin-1-ylmethyl-
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70 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
cyclohexanone (43). The subsequent replacement of the pyrrolidine with
imidazole followed by reduction led to the cis/trans mixture of 2-imidazol-1-
ylmethyl-cyclohexanol (44). The trans-isomer 44 was condensed with substituted
aryl halides to obtain the corresponding ethers 42.
Reagents and conditions: (i) pyrrolidine, (HCHO)
n
, L-proline/DMSO, 6-8 h; (ii) corresponding
Mannich salt, imidazole, EtOH:H
2
O, 5 h; (iii) NaBH
4
/MeOH, 2 h; (iv) K(t-OBu), DMSO, aryl
halides, 2-3 h; (v) imidazole, EtOH, refl ux, 5 h.
Bromination of cyclohexanone (38) gave the 2,6-dibromo derivative (45), which,
upon reaction with imidazole followed by reduction, gave the 2,6-di-imidazol-1-yl
cyclohexanol (46). Condensation of this hydroxy compound with substituted aryl
halides gave the required aryloxy bisimidazolyl (47).
All bisimidazolyl 41 showed high activities against L. donovani amastigotes with
IC
50
values in a range of 0.588 to 2.437 μg/mL. The derivatives 47 exhibited
interesting activity (IC
50
of 3.00 and 3.02 μg/mL), whereas monoimidazolyl
analogs 42 showed inhibitory activity with IC
50
values ranging from 0.71 to 4.57
μg/mL [40].
A simple and efficient approach to synthesize 2H-benzimidazole 1,3-dioxide
derivatives 48 is the reaction of benzofuroxan analogs 49 with different
nitroalkanes. Compounds 48 were tested against L. braziliensis with ID
50
(50%
inhibitory dose) values in a range of 3.5-50 mM and showed better or similar
activities than the reference drugs nifurtimox and miltefosine [41, 42].
O
N
N
R
1
R
2
R
R
3
O
R
R
O
N
R
3
R
OH
N
N
R
3
O
N
OH
N
R
O
O
N
N
O
R
R
2
R
1
(i)
(ii), (iii) (iv)
R= CH
3
, Ph; R
1
= H, F, NO
2
, CF
3
, R
2
= H, NO
2
, CF
3
; R
3
= H, CH
3
(34)
(32) (33)
(30)
(v)
(iv)
(v)
R= Ph, PhOCH
2
; R
1
= H, F, NO
2
; R
2
= H, NO
2
, CF
3
(35)
(36)
(31)
(37)
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