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Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 91
revealed that compound 174 had an IC
50
value of 0.08 µM and was 3-fold more
active than miltefosine [95].
Navarrete-Vazquez described the synthesis and in vitro antileishmanial activity of
compound 175 (IC
50
value of 1.3 μM), which was 4.5-fold more active than
nitazoxanide and tizoxanide and almost 10-fold more potent than pentamidine
against promastigotes of L. Mexicana [96].
R
SH
PS
R
Ph Ph
+
R
S
N
O
N
O
-
Br
-
S
N
O
N
O
O
-
(i)
(ii)
(iii)
(iv)
(172)
R = H, F (Z and E isomers ), R = Cl (E is omer )
(v)
(170) (171)
(173)
Reagents and conditions: (i) CH
2
O, HBr, toluene, 50-60
o
C, 3h; (ii) PS-TPP, toluene, 50
o
C, 48h;
(iii) NaH, THF, RT, 1h; (iv) formylbenzofuroxan, THF, 50
o
C, 8-12 h; (v) m-CPBA, CH
2
Cl
2
, -78 at
0 ºC, 2 h.
S
N
O
2
N
NH
O
O
O
O
N
CO
2
H
HN OH
O
N
OH
(175)
(174)
2.9. Acridine Derivatives
Di Giorgio and coworkers described the synthesis of symmetric and non-
symmetric diaminoacridines by mono- or di-acylation. The reaction of proflavine
(176) with different benzoyl chlorides or different anhydrides yielded the
corresponding amides 177. The derivatives acridinyl acetamide and acridinyl
benzamide showed antileishmanial activities against L. infantum with IC
50
values
between 0.11-341.5 µM and 0.03-12.8 µM fo r the promastigote and amastigote
forms, respectively. Symmetric conformation with acetylamino or benzoylamino
substituents was essential for antileishmanial activity [97].
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92 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
NH
2
N
NH
2
N
N
N
H
R
O
H
R
O
R= CH
3
, Ph
(i)
(176)
(177)
Reagents and conditions: (i) appropriate anhydrides or benzoylchlorides, py, TEA, 1h, 80
o
C.
2.10. Coumarine and Pyrane Derivatives
Azas and coworkers synthesized a series of 4-arylcoumarin derivatives via a
ligand-coupling reaction of the coumarin ring with substituted phenyl derivatives.
The treatment of the appropriate 4-hydroxycoumarins (178) with triflic anhydride
gave 4-trifluoromethylsulfonyloxycoumarin (179). In modified Suzuki conditions,
the C-4 arylation was performed with arylboronic acids in the presence of a
palladium catalyst and CuI as a cocatalyst. The 4-(3,4-dimethoxyphenyl)-6,7-
dimethoxycoumarin (180) exhibited potent activity against L. donovani
amastigotes with an IC
50
value of 1.1 µM and a selec tivity index twice than the
reference amphotericin B [98].
O
OH
O
H
3
CO
H
3
CO
O
OSO
2
CF
3
O
H
3
CO
H
3
CO
O
O
H
3
CO
H
3
CO
OCH
3
OCH
3
(i)
(ii)
(178)
(179)
(180)
Reagents and conditions: (i) (CF
3
SO
2
)
2
O, Et
3
N, CH
2
Cl
2
; (ii) ArB(OH)
2
, Pd(PPh
3
)
4
, CuI, Na
2
CO
3
,
toluene, 110
o
C.
Copp and coworkers described the synthesis of pseudopyronines A and B. The
target acylpyrone skeletons 181 and 182 were obtained by the cyclization of β-
oxo acids using carbonyldiimidazole. Reduction of the α-acyl group of the 2H-
pyran-2-one (181) utilizing NaCNBH
3
afforded the natural product 183.
Deacylation of 182 with H
2
SO
4
yielded 6-heptyl-4-hydroxy-2-pyrone (184) with
subsequent acylation by hexanoyl chloride affording the 2H-pyran-2-one (185),
which, after reduction, provided pseudopyronine B (186).
3-Acylpyrones 181 and 185 were the most active compounds against L. donovani,
with IC
50
values of 0.46 and 0.55 mg/mL, respectively [99].
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 93
OO
OH
C
7
H
15
OO
O
OH
C
7
H
15
C
7
H
15
OO
OOH
C
5
H
1
1
C
5
H
11
OO
C
6
H
13
OH
C
5
H
11
OO
O
OH
C
7
H
15
C
5
H
11
OO
C
6
H
13
OH
C
7
H
15
(i)
(ii)
(iii)
(183)
(182)
(184)
(185)
(181)
(i)
(186)
Reagents and conditions: (i) NaCNBH
3
, THF, 2 M HCl, rt, 2.5 h; (ii) 90% H
2
SO
4
, 130
o
C, 1 h; (iii)
hexanoyl chloride, TFA, reflux, 3 h.
2.11. Azepine Derivatives
Compounds containing the azepine unit possess a wide range of biological
activities, and some derivatives are active against promastigotes and intracellular
amastigotes of L. Mexicana [100] and L. chagasi
[101].
Palma and coworkers [100] reported the synthesis of azepine analogs starting from
the available N-benzyl-α-naphthylamines, which, on reaction with allyl bromide,
were converted into N-allyl-N-benzyl-substituted-α-naphthylamines (187). The
introduction of an allyl moiety at the o-position of the amino group was carried out
via an aromatic amino-Claisen rearrangement of the N-allyl derivatives yielding the
products 188. Oxidation and subsequent intramolecular 1,3-dipolar cycloa ddition of
188 was performed to obtain 1,4-epoxytetrahydronaphtho[1,2-b]azepines (189).
Reductive cleavage of the N-O bond of 189 gave exclusively cis-2-aryl-4-
hydroxytetrahydronaphtho[1,2-b]azepines (190). The compounds showed activity
against the intracellular form of L. chagasi promastigotes with IC
50
values between
6.0-183.8 μM.
N
R
2
R
1
R
N
H
R
2
R
1
R
N
H
R
2
R
1
R
N
H
R
2
R
1
R
O
(R, R
1
, R
2
) = H, F, Cl, Br, OCH
3
, CH
3
, NO
2
(i)
(ii)
(iii)
(189)
(187)
(190)
(188)
Reagents and conditions: (i) BF
3
.OEt
2
, 115-125
o
C, 1-4 h; (ii) a) H
2
O
2
, Na
2
WO
4
.2H
2
O, methanol,
0-25
o
C, 45-50 h; b) toluene, reflux, 6-10 h; (iii) Zn, 80% A cOH , 80-82
o
C, 2-5 h.
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94 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
Kunick and coworkers reported a novel type of antileishmanial agents, namely 2-
(3-aryl-3-oxopropenyl)-9-tert-butyl-paullones (191). The authors assume that the
substructure of the chalcones linked in the paullone is an important moiety for
antileishmanial activity. Several compounds of this class showed activity against
L. donovani axenic amastigotes with a growth inhibition (GI
50
) of 50% < 1 μM
and against parasites in host macrophages without exhibiting toxicity for human
host cells [102].
H
N
HN
O
O
(191)
2.12. Porfirine Derivatives
A rational approach in the search for new drugs is to exploit biochemical differences
between the parasite and its mammalian host. One specific example in the case of
Leishmania relates to the biosynthesis of heme, a critical prosthetic group for
proteins involved in metabolism and electron transport. Like other Trypanosomatids,
Leishmania parasites require heme or porphyrins to be preformed for them. Thus,
the heme biosynthetic pathway is essential to the survival of Leishmania, and drugs
that can interfere with the heme acquisition processes of the parasite may prove
useful in treatment of leishmaniases [103]. Boechat and coworkers descri bed the use
of porphyrins as photosensitizers and suggested that they may be essential for good
results in treating leishimanioses [104, 105].
Jones and coworkers described the growth curves of L. tarentolae exposed to
several different concentrations (1.1-4.2 µM) of carba porphyrin ketals (192) and
N
N
N
H
H
OR
OR
+
Cl
-
R= CH
3
; CH
2
CH
3
(192)
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 95
indicated that these compounds have great promise as potent inhibitors of
Leishania [106].
2.13. Biguanidines, Amidines and Diamidines
Aromatic diamidine -containing compounds have a long history of use in the
treatment of human African trypanosomiasis and leishmaniasis [107-112]. The
main representative of such classes is pentamidine, which is one of the current
therapies for leishmaniasis. Due to their cationic character, diamidines frequently
exhibit high toxicity, such as cardiotoxicity, nephrotoxicity, and pancreatic
complications, and display poor oral bioavailability. To overcome these
limitations, new aromatic dications and their prodrugs 193 have been synthesized
and screened against a number of pathogens including the protozoan parasite
species Trypanosoma and Leishmania [113-115].
Amidine 194 and diamidine groups have been recognized as pharmacophoric
group in antiparasitic drugs. The “reversed” amidines 195 are compounds that
have the imino group of the amidine attached to an aromatic, forming an
“anilino”- nitrogen in contrast to the original amidino aromatic or heteroaromatic,
in which the imino group is directly attached to the aryl ring. This type of
chemical modification has brought the best results for antiparasitic activity.
NH
2
NH
HN
NH
HN
NH
N
H
N
N
N
N
H
N
N
N
N
H
NH
Ph
N
H
NH
NH
2
NNH
2
NH
2
NOH
NH
2
NOCH
3
X
OO
X
R
2
R
1
R
2
R
1
R
2
=
n = 3-6 X = CH, N
R
1
= H, F, Cl, OCH
3
, NO
2
, OH, CO
2
Et, CO
2
H, CONH
2
, CN
(193)
,
,
,
,,
,
,,
,
n
Ar NH
2
NH
Ar N
H
NH
Ph
(194)
(195)
Tidwell and coworkers reported the synthesis and antiprotozoal activities of
cationic bisbenzofurans and phenylbenzofurans. In this series of compounds,
some derivatives displayed activity against L. donovani superior to that of
pentamidine [116, 117].
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96 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
The synthesis and antiprotozoal activity of dicationic bis(phenoxymethyl)
benzenes, bis(phenoxymethyl)naphthalenes, and bis(benzyloxy)naphthalenes were
reported. The reaction between cyanophenol 196 and α,α’-dibromoxylene (197)
gave the dinitrile 198. The nitriles underwent the Pinner reaction to give the
amidine derivative 199, which was active against L. donovani (IC
50
value of 1.3
μM) [118].
HO
CN
Br
Br
O
O
CN
NC
O
O
H
2
N
NH
NH
H
2
N
+
(i)
(ii)
(196)
(197)
(198)
(199)
Reagents and conditions: (i) K
2
CO
3
or Cs
2
CO
3
, DMF; (ii) HCl, EtOH, 1,4-dioxane, then
appropriate amine.
Boykin and coworkers described the syntheses of the azaterphenyl derivatives by
Suzuki coupling of the appropriate aryl halides 200 with the corresponding aryl
boronic acids or esters to form teraryl bis-nitriles (201). The bis-nitriles were
converted to the diamidines by reaction with LiN(TMS)
2
followed by hydrolysis.
Compounds 202 and 203, which have pyridines instead of a phenyl group,
showed a 3- to 4-fold increase in activity over the corresponding terphenyl. This
system can be represented by the 2 most active compounds, 202 and 203, with
IC
50
values of 0.063 and 0.084 μM, respectively. The authors found that the
diamidine system, which is highly active, showed a consistent and distinctive
structure activity relationship against L. donovani axenic amastigotes [119].
A series of compounds with amidoxime group was synthesized using the
Buchwald-Hartwig and Heck reactions. Two amidoximes, 204 and 205, showed
interesting in vitro activities toward L. donovani promastigotes with IC
50
values of
8.3 and 8.8 μM, respectively [120].
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 97
Reagents and conditions: (i) Pd(PPh
3
)
4
, Na
2
CO
3
, toluene, 80
o
C; (ii) a) LiN(TMS)
2
, THF, rt,
overnight; b) HCl (gas), ethanol, rt, overnight; (iii) 4-cyanophenylboronic acid, Pd(PPh
3
)
4
,
Na
2
CO
3
, toluene, 80
o
C.
O
S
O
O
N
H
2
N
OH
O
S
O
O
N
H
2
N
OH
HN
N
NH
2
HO
(204) (205)
2.14. Sulfonamide Derivatives
González-Rosende reported a series of sulfonamides (206-215) obtained by
reaction of the amines with the corresponding sulfonyl chloride. The
leishmanicidal activity of the compounds was evaluated in vitro against the
cultured promastigotes of L. infantum. The pyrimidines, pyrazine, pyridine,
thiazoles, isoxazole, pyrazole, indazole, indanes and aniline derivatives were
found to be active compounds with IC
50
values between <1 to 224 μM. The p-
nitrobenzenesulfonamides and the p-nitroaniline derivatives were the most active
compounds [121].
2.15. Hydrazone and Hydrazide Derivatives
From biological studies it was possible to observe that some of the substituents on
the phenyl ring of quinoxalinone hydrazones influenced their activity [122]. In
addition, the hydrazone group plays an important role in the antimicrobial
activity. Furthermore, a number of hydrazide -hydrazone compounds were found
to possess interesting antibacterial, antifungal, anticonvulsant, anti-inflammatory,
antimalarial and antituberculosis activities [123].
R= B(OH)
2
, Cl, Br
X
NC N
HN
H
2
NNH
2
NH
NN
N
HN
H
2
NNH
2
NH
R
(HO)
2
B
+
(i)
(ii)
(i),
(ii)
(iii)
Y= Cl, Br
(200)
(201)
(202)
(203)
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98 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
Rando and coworkers described the coupling reaction of suitable hydrazides 216
with nitrofuran or nitrothiophene aldehydes (217) for the synthesis of 5-
nitrofuran-2-yl/thiophen-2-ylmethylidene benzohydrazide derivatives (218). The
nitroderivatives were tested in vitro against L. donovani promastigote form and
exhibited IC
50
values of 0.62-38.45 µM for the nitrofuran and 0.41-8.52 µM for
nitrothiophene derivatives, which are equivalent to or lower than the values of the
standards pentamidine and amphotericin B [124].
X
O
H
O
2
N
N
O
H
NH
2
N
O
H
N
X
NO
2
R
R
(i)
(218)
X = S, O
R= H, F, Cl, OCH
3
, N(CH
3
)
2
, NH
2
, OH, CH
3
, CF
3
, NO
2
, SO
2
NH
2
+
(217)
(216)
Reagents and conditions: (i) EtOH:H
2
O (2:5), reflux, 15min - 1h.
2.16. Chalcone Derivatives
Chalcones, one of the major classes of natural products, have widespread
distribution in fruits, vegetables, spices, tea and soy-based foodstuffs. They have
S
N
R
1
R
2
N
H
S
O
O
R
N
N
H
N
H
S
O
O
N
H
S
O
O
R
N
N
N
H
S
O
O
R
N
N
R
1
R
1
N
H
S
O
O
R
N
H
S
O
O
NO
2
N
N
N
R
1
R
1
N
H
S
O
CH
3
O
N
N
H
3
C
N
H
S
O
O
NO
2
H
O
N
H
3
C
N
H
S
O
O
R
N
HO
N
H
O
2
N
R = H,
4
-Cl,
4
-NO
2
R
1
= R
2
= H, CH
3
(211)
(215)
(207)
R= H,
4
-F,
4
-Cl,
4
-Br,
2
-NO
2
,
3
-NO
2
,
4
-NO
2
,
4
-OMe
R
1
= H, CH
3
R=
4
-Cl,
2
-NO
2
(209)(208 )
2-, 3-, 4- positions
R= H,
4
-Cl,
4
-NO
2
(214 )
R= H,
4
-Cl,
4
-NO
2
(206)
(210)
(213)
(212)
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 99
recently become subjects of great interest because of their biological activities
[125]. Chalcones are 1,3-diaryl-2-propen-1-ones belonging to the flavonoid
family. Chemically, they consist of open-chain flavonoids in which the two
aromatic rings are bonded by a three-carbon α,β-unsaturated carbonyl system. A
vast number of naturally occurring chalcones are polyhydroxylated on the aryl
rings. The properties of the phenolic groups present in many chalcones or plant
extracts rich in these compounds have raised interest in their as drugs or food
preservatives [126]. Chalcones have been reported to possess many useful
properties, including anti-inflammatory, antimicrobial, antifungal, antioxidant,
cytotoxic, antitumor and anticancer activities [127, 128].
Castro and coworkers reported the synthesis of a series of chalcones. For example,
4-methoxychalcone (221) was obtained by aldolic condensation of acetophenone
(219) with 4-methoxybenzaldehyde (220) [129]. Treatment of 221 with
chlorosulfonic acid afforded the sulfonyl chloride derivative 222. Preparation of
the sulfonamides 223 was accomplished by the reaction of the sulfonyl chloride
derivative with different amines. Most of the sulfonamide derivatives
demonstrated an inhibitory profile against L. braziliensis (IC
50
3.5-69.0 µM)
better than the 4-methoxychalcone (221) with IC
50
value of 16.6 µM. Although
the compounds showed lower activity than amphotericin B, they were more active
than pentamidine isothionate [130, 131].
O
H
3
CO
H
OO
OCH
3
O
OCH
3
S
Cl
O
O
O
S
N
O
O
H
OCH
3
+
(i)
(ii)
(iii)
(223)
(221)
(222)
(219)
(220)
Reagents and conditions: (i) EtOH/H
2
O, NaOH, (ii) HClSO
3
, rt, one week; (iii) amines, MeOH, rt, 2h.
A natural citrus flavonoid tangeretin, a 4H-chromen-4-one derivative (224), was
used as starting material to obtain the corresponding chalcones 225 after various
reaction steps. The antileishmanial activity of 225 derivatives were determined in
vitro against promastigotes of L. donovani (IC
50
values ranged from 0.4-44 µM)
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100 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
and against intracellular amastigotes of L. amazonensis (IC
50
value of 26 µM)
[132].
R
3
R
4
O
OCH
3
H
3
CO
H
3
CO
R
1
R
2
O
OCH
3
H
3
CO
H
3
CO
H
3
CO
O
OMe
(224)
R
1
= H, OH, OMe; R
2
=R
4
= H, OMe; R
3
= OH, NH
2
,NO
2
(225)
Kunick and coworkers described a Heck-type reaction starting from Mannich
bases such as 226 with aryl iodides 227 to synthesize the chalcones 228 in a
parallel reactor station. An initial screening of the compounds showed a range of
2.1-98.7% inhibition of amastigote growth at 15 µM. For chalcones that showed
more than 90% inhibition, the GI
50
was determined, and values ranged from 2.5-
7.6 µM [133].
R
O
N
H
CH
3
CH
3
+
R
O
R
1
R=
S
O
N
R
1
=
O
IR
1
N
O
H
Ph
Cl
-
+
,
,
,
(i)
,
(228)
(226)
(227)
Reagents and conditions: Pd(OAc)
2
, DMF, TEA, 140
o
C, parallel reactor station, 30 min.
Suryawanshi and coworkers described the reacti on of dihydro-α-ionone (229) with
suitable aldehyde in the presence of KF/Al
2
O
3
under microwave irradiation to give
chalcone derivatives 230 and 231. The compounds were tested for in vitro activity
against L. donovani promastigotes (98%-100%) as well in a mastigotes (80%-95%).
However, in in vivo assays they showed low activity in the hamster model [134].
O
R = H, OCH
3
; R
1
= OCH
3
, Cl, NO
2
O
R
R
1
O
N
(i)
(231)
(230)
(229)
Reagents and conditions: KF/Al
2
O
3
, microwave.
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