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Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 81
N
NCl
N
H
HN
CN
N
NC
NCl
N
NCl
H
2
N
N
NCl
N
N
CN
N
CH
2
NH
2
NCl
Cl
(i)
(ii)
(i)
(ii)
(iii) or
(iii)
(105)
(106)
(107)
(108)
(109)
(110)
(111)
(iv)
(95)
+
Reagents and conditions: (i) K
2
CO
3
, DMF, 140
o
C, 24 / 48 h; (ii) LAH, rt, 18 h; (iii) HCO
2
H,
HCHO, reflux, 70
o
C, 20h; (iv) CH
3
CHO, reflux, 70
o
C, 20h.
N
NH
2
N
N
H
S
O
O
Ar
N
Br
Cl
FF
S
Br
Br
R =
(i)
(112)
(113)
,
,
Reagents and conditions: (i) arylsulfonylchlorides, py, 0
o
C, 90 min and then, rt, overnight.
OO
NN
Cl
Cl
N
S
O
O
R
(116)
(114) R= Cl, (115) R= Br
Ablordeppey and coworkers described the synthesis of benzothienoquinolines and
benzofuroquinolines. Substituted anthranilic acids 117 were acylated with suitable
acyl chlorides (118). In a double intramolecular cyclization reaction, the acylated
intermediates were converted to substituted-11-quinolones 119, which were
subsequently converted to benzofuroquinolines and benzothienoquinolines 120 by
chlorination with POCl
3
followed by hydrogenation. The targeted final products
121 were then obtained by methylation reaction. All the derivatives 121 showed
significant activities against L. donovani promastigotes with IC
50
values between
0.23 to >40 μg/mL, and pentamidine was used as the standard drug [71].
Moll and coworkers reported the cyclocondensation of the benzopyrylium salt 122
and different substituted aromatic amines to yield arylisoquinolinium derivatives
123. The derivatives had IC
50
values from 0.54-19.7 μM. Compound 123 showed
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82 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
synergistic action with amphotericin B in vitro, making it a potential candidate for
further in vivo experiments [72].
NH
2
CO
2
H
R
Cl
O
X
N
O
H
X
R
N
X
R
N
X
R
I
+
X= O, S
(i)
(ii)
(iii)
(iv)
(v)
(121)
(120)
(119)
(118)
(117)
R= H, Cl, CN, OCH
3
, CO
2
H, CONH
2
Reagents and conditions: (i) NaOH, H
2
O, rt; (ii) PPA, 130
o
C, 3 h; (iii) POCl
3,
110
o
C, 24 h; (iv)
H
2
, Pd/C, MeOH; (v) CH
3
I, TMS, 110
o
C, reflux, 12 h.
N
H
3
CO
OCH
3
+
O
H
3
CO
OCH
3
+
X
-
X
-
(i)
(123)
(122)
X= TFA
Reagents and conditions: (i) amines, AcOH, rt.
2.5. Quinazoline and Quinoxaline Derivatives
The synthesis of 2,4-disubstituted quinazolines derivatives was described by Sahu
and coworkers. 2,4-Dichloroquinazoline (124) reacted with suitable arenes to
produce 2-chloro-4-aryl quinazolines (125). The derivative 125 was reacted with
different cyclic amines to afford the desired compounds 126, which exhibited IC
50
values of 025-6.2 and 4.17-25.14 μg/mL against promastigotes and intracellular
amastigotes of L. donovani, respectively [73].
N
N
Cl
Cl
N
X
N
N
R
N
N
R
Cl
R= 3-indolyl, 1-methyl-3-indolyl, 2,4,6-triOCH
3
-C
6
H
2
, 2,4-diOCH
3
-C
6
H
3
(i)
(ii)
(126)(125)(124)
X= NH, NCH
3
, CH
2
, O, N4-FPh, 2-Py, Ph
Reagents and conditions: (i) Ar-H, AlCl
3
, DCE, N
2
, 75-80
o
C, 2-3 h; (ii) TEA, dioxane, 90-95
o
C.
Agarwal and coworkers described a synthetic strategy for obtaining quinazoline
derivatives. Tetralone 127 was used as starting material to react with various
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 83
aldehydes, which yielded benzylidenes 128. The cyclization of 128 with guanidine
sulfates gave the quinazoline derivatives 129 and 130. The dihydro- and tetrahydro-
quinazoline derivatives were tested against L. donovani promastigote and amastigote
forms. The compounds with better promastigote inhibition were screened against
amastigotes and exhibited IC
50
values in a range of 2.65-8.95 μg/mL. The reference
drugs used were sodium stibogluconate and pentamidine [74].
O
OR
1
R
N
N
R
1
R
R
2
N
N
R
1
R
R
2
H
+
(i)
(ii)
(127)
(128)
(129)
(130)
R= H, F, Cl; R
1
= H, Cl; R
2
= cyc l ic amine s
Reagents and conditions: (i) aldehydes, 5% alcoholic KOH, ethanol, 0
o
C, rt, 2 h; (ii) substituted
guanidine sulfates, t-BuOK, methanol, reflux, 24 h.
A Clauson-Kaas reaction starting from the 2-nitroanilines was performed to
prepare the intermediates 1-(2-nitrophenyl)pyrroles 131 that were subsequently
reduced and treated with various acid chlorides to generate the acetamides 132.
The 4-substituted pyrrolo[1,2-a]quinoxalines 133 were prepared by cyclization of
these amides according to the Bischler-Napieralski reaction. The quinoxalines
were tested for their in vitro antileishmanial activities on the L. amazonensis and
L. infantum strains and showed IC
50
values from 0.5-36 and 0.5-25 µM,
respectively [75].
R
2
R
1
N
NO
2
R
2
R
1
N
N
H
R
O
N
N
R
R
2
R
1
R
1
= R
2
= H, OCH
3
;
R= alkyl, alkenyl, alkynyl, aryl, cis-trans oxiranyl
(132)
(131)
(133)
(i)
(ii)
(iii)
Reagents and conditions: (i) BiCl
3
, NaBH
4
, EtOH; (ii) RCOCl, Py, dioxane; (iii) a) POCl
3,
toluene, reflux, 4h; b) NaHCO
3
, H
2
O, rt.
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84 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
Monge and coworkers reported a series of quinoxaline N,N’-dioxides that were
tested in vitro against the promastigote form of L. braziliensis. The compounds
134 showed ID
50
values between 1.0 and 50.0 μM, and miltefosine was used as
the reference drug [76]. The sulfonamide derivatives 135 showed IC
50
values
between 2.1-3.1 μM and were almost 10-15-fold less active than the reference
drug amphotericin B [77].
N
NR
R
R
1
R
2
O
O
N
NCl CN
N
H
O
O
O
2
S
R
R= H, F, Cl,
R
1
= SPh, COPh, CO
2
CH
2
CH
3
R
2
= CH
3
, CF
3
, Ph
(134)
R= 2-NO
2
, 4-NO
2
(135)
2.6. Indole Derivatives
Indoles comprise a wide variety of biologically active compounds, and some of
them have been described as antileishmanial agents [78]. An N-alkylation reaction
of tetracyclic indoles 136 with ω-dihaloalkanes provided different indolyl N-alkyl
halide derivatives that were treated with tetraethylmethylene bisphosphonate to
yield the indol bisphosphonates 137. The bisphosphonates were tested in vitro and
showed more than 80% inhibition against both the promastigote and amastigote
stages of L. donovani. The IC
50
values ranged from 1.69-24 μg/mL and were
significant when compared with sodium stibogluconate as reference drug [79].
X
N
H
P
P
O
O
OEt
OEt
EtO
OEt
X
N
( )
n
(i)
(ii)
X= S, CH
2
; n= 4-6;
(137)
(136)
Reagents and conditions: (i) ω-dihaloalkane, NaH, DMF; N
2
, 0
o
C, 2h (ii)
CH
2
[P(O)(OCH
2
CH
3
)
2
]
2
, NaH, THF, N
2
, 0
o
C, 1.5h.
Chauhan and coworkers described the synthesis of indole derivatives. From the
reaction of indole-3-carbaldehyde (138) with (p-cyanophenoxy)pentylbromide
compound 139 was obtained. The condensation of 139 with 2-thiohydantoin
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 85
furnished compound 140. Compound 140 showed growth inhibition against the
amastigotes of L. donovani with an IC
50
value of 18.2 μM [80].
N
H
H
O
N
H
O
O
CN
N
N
S
O
H
H
HN
N
H
S
O
N
O
CN
O
NC
Br
(i)
(ii)
(140)
5
5
(138)
5
(139)
Reagents and conditions: (i) toluene, NaOH, TBAB, rt; (ii) ethanolamine, EtOH, 60
o
C.
Homodimers of bis-β-carbolinium were obtained from the reaction of symmetrical
dihalogeno-linkers with 6-chloro-norharmane. The most active compound was the
dimer 141 with an IC
50
value of 0.5 μM. The meta substituted aryl linker was 100-
fold more active than the corresponding dimer with the para substituted linker.
This suggests that relative orientation of the two nostocarboline units has an
impact on the activity against L. Donovani [81, 82].
N
N
Cl
H
N
N
Cl
H
X
X
(141)
Indolylglyoxylamide derivatives have been synthesized and evaluated in vitro
against the amastigote form of L. donovani. Compound 142 (D/cis) has been
identified as the most active analog with an IC
50
value of 5.17 μM and was several
fold more potent than the standard drugs sodium stibogluconate and pentamidine
[83].
A series of 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1H-β-carboline
derivatives was synthesized and evaluated for antileishmanial activity against
L. donovani. Compound 143 exhibited the best antileishmanial activity with an
IC
50
value of 1.93 mg/mL against amastigotes and was more active than the
reference drugs sodium stibogluconate and pentamidine [84].
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86 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
N
H
N
N
N
Cl
Cl
H
3
CO
OCH
3
N
H
O
N
O
O
NH
O
(143)
(142)
In another paper, Chauhan and coworkers described the synthesis and in vitro
antileishmanial activity against L. donovani for a series of [1,2,4]triazinoindole-
triazine derivatives. Compound 144 showed an IC
50
value of 4.01 μM and
exhibited 20- and 10-fold more selectivity when compared with the standard
drugs pentamidine and sodium stibogluconate, respectively [85].
The synthesis and antiparasitic activities of the acetylated glycosylisoindigo
derivatives were describe by Moreau and coworkers. The compounds were tested
in vitro against the following causative agents of tropical diseases : malaria,
Chagas' disease, human African trypanosomiasis and leishmaniasis. The most
active compound against L. donovani was the azaisoindigo 145 with an IC
50
value
of 0.84 μΜ [86].
N
N
N
N
S
N
N
N
N
N
N
N
O
AcO
OAc
O
N
Br
O
OAc
OAc
H
(145)
(144)
2.7. Purine, Pyrazolopyrimidine, Pyrazolopyridine and Thienopyridine
Derivatives
Silva and coworkers described the reaction of the key intermediate 6-thiopurine
146 to obtain new leishmanicidals. Thiopurine was reacted with 1-bromo-3-
chloropropane and subsequently treated with thioethylamine to produce derivative
147. Compound 146 was also treated with 2-bromoacetate followed by hydrolysis
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 87
with KOH, yielding the derivative 148. The corresponding derivative 149 was
produced by several steps from 146. All compounds were evaluated against L.
amazonensis and L. chagasi and showed activity only against promastigotes of L.
amazonensis (IC
50
29-50 μM). Derivative 149 was the most active compound,
with an IC
50
value of 29 μM [87].
N
N
N
N
SH
H
N
N
N
N
S
H
S
NH
2
N
N
N
N
SCH
2
CO
2
H
H
O
N
N
N
N
S
H
HO OH
OCH
3
(146)
(147)
(148)
(149)
(i)
(ii)
(iii) (iv)
Reagents and conditions: (i) 1-bromo-3-chloropropane, EtOH, 0
o
C for 30 min-1h (rt); (ii)
thioethylamine 48 h, 25
o
C; (iii) 2-bromoacetate, DMF, 0
o
C, 30 min (iv) KOH, MeOH / H
2
O, 24
h, 25
o
C.
Jorda and coworkers reported the ability of pyrazolo[4,3-d]pyrimidine and purines
derivatives to inhibit leishmanial CRK3 protein kinase activity and to kill axenic
amastigotes of L. donovani. Pyrazolopyrimidines 150 were markedly more potent
inhibitors of CRK3/CYC6 than the corresponding purines and showed IC
50
values
of 57.9 and >100 μM, respectively [88].
N
N
H
N
N
HN
R
R= 4-FPh, 3-ClP h, 2-OHBn, Adamantan-1-yl
(150)
A series of 1H-pyrazolo[3,4-b]pyridine derivatives was synthesized by Echevarria
and coworkers using the condensation reaction between the appropriate aniline
with 4-chloro-1H-pyrazolo[3,4-b]pyridine (151), which yielded the target
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88 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
compounds 152 and 153. The Mannich reaction is also an alternative to obtain the
molecule 153. These compounds were tested against promastigote forms of L.
amazonensis and showed IC
50
values of 0.39 and 0.12 μM, respectively [89].
N
N
N
R
Cl
O
O
N
N
N
R
NH O
O
HO
N
N
N
R
NH O
O
HO
N
R= CH
3
, Ph
(i)
(iii)
(ii)
(151)
(152)
(153)
Reagents and conditions: (i) 4-hydroxyaniline, Δ; (ii) (CH
3
CH
2
)
2
NH, HCOH, 2-propanol; (iii)
diethylaminomethyl-4-acetylaminophenol.
Castro and coworkers described the synthesis of thieno[2,3-b]pyridine derivatives
through the reaction of appropriate anilines with 4-chlorothieno[2,3-b]pyridine-5-
carbonitrile (154) without solvents, producing the derivatives 4-
(phenylamino)thieno[2,3-b]pyridine-5-carbonitriles (155), which were
subsequently treated with ethylenediamine and CS
2
to yield the target compounds
156. Inhibition of 95.4% of the L. amazonensis was achieved with 50µM of 156,
which has better efficacy than glucantime [90].
N
S
NH
CN
H
3
CO
N
S
CN
Cl
N
S
NH
N
H
N
H
3
CO
(156)
(i)
(ii)
(154)
(155)
Reagents and conditions: (i) anilines, 140
o
C, 4h; (ii) NH
2
(CH
2
)
2
NH
2
, CS
2
, HCl 6N, reflux, 24h.
The synthesis of tetrahydro[1]benzothieno[2,3-d]pyrimidine derivatives (BTP) and
their in vitro evaluation against T. cruzi, M. tuberculosis, L. amazonensis, and six
human cancer cell lines was described by Hammond and co workers. The synthesis
of the BTP derivative began with the preparation of 2-amino-4,5,6,7-
tetrahydrobenzo[b]thienophene-3-carboxylic acid ethyl ester (157) using a Gewald
reaction. Compound 157 reacted with an excess of formamide yielded the cyclic
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 89
pyrimidinone 158, which underwent chlorination with POCl
3
to give 159.
Nucleophilic displacement with aqueous hydrazine formed the corresponding
aromatic hydrazine derivative 160. The synthesis of BTP 161 was conclude d with
the formation of a Schiff base between 160 and an appropriate aldehyde or ket one.
Compound 161 was highly selective in vitro against L. amazonensis with an IC
50
value of 1.7 μM [91].
S
CO
2
Et
NH
2
N
NH
S
O
N
N
S
Cl
N
N
S
HN
NH
2
N
N
S
NH
N
Cl
(i)
(ii)
(iii)
(iv)
(158) (159)
(160)
(161)
(157)
Reagents and conditions: (i) diethyl amine, EtOH, rt, sonication, 30 min; (ii) formamide, reflux, 6
h; (iii) POCl
3,
reflux, 3 h; (iv) hydrazine, MeOH, reflux, 3 h; (v) aldehyde or ketone, EtOH, reflux,
2-72 h.
2.8. Benzimidazole, Benzothiazole, Benzoxadiazole and Benzoxazole
Derivatives
Navarrete-Vázquez described the synthesis of benzimidazole-pentamidine
hybrids. The alkylation of 4-hydroxybenzaldehydes with 1,5-dibromopentane
yields the bis-aldehydes 162. The conversion of the resulting bis-aldehydes to the
respective benzimidazole 163 was performed by the following two different
methods: 1) by treatment with adequately substituted 1,2-phenylenediamine; 2)
one-pot reduction-cyclization reaction of 2-nitroanilines in the presence of sodium
dithionite. The derivatives 163 were up to 26-fold more active than pentamidine
and exhibited high bioactivity against L. mexicana, with IC
50
values between
0.36-1.06 μM [92].
O
O
CHO
OHC
R
2
R
2
O
N
H
N
R
1
CH
2
R
2
R
1
= H, CH
3
, NO
2
, OCH
3
, CF
3
(162)
(ii)
n = 5
n
(163)
2
R
2
= H, OCH
3
(i) or
Reagents and conditions: (i) Na
2
S
2
O
5
, DMF, 90
o
C, 20 h; (ii) Na
2
S
2
O
4
, H
2
O:EtOH, 80
o
C, 10-14 h.
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90 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
Ihara and coworkers reported the synthesis of fluorinated rhodacyanine
derivatives by the reaction of rhodanine 164 with N,N-diphenylformamidine
followed by treatment with acetic anhydride to yield 165, which was treated with
N-methyl-2-methylbenzothiazolium salt (166) to provide merocyanine (167). The
reaction of 167 with methyl p-toluenesulfonate followed by condensation with
168 afforded the target compound 169. Compound 169 exhibited an IC
50
value of
0.011 µM for in vitro activity against L. donovani and an IC
50
value of 0.353 µM
in an in vitro assay in macrophages. In vivo ∼95% inhibition was observed at
dosages ranging from 1.3 to 12.5 mg/kg [93].
S
S
O
S
S
O
N
Ac
Ph
S
S
O
S
N
S
S
O
S
N
N
S
F
Cl
N
S
F
TsO
N
S
TsO
(i),
(ii)
(iii)
(iv),
(v),
(vi)
(169)
(164)
(165)
(167)
+
(166)
+
(168)
Reagents and conditions: (i) N,N-diphenylformamidine (ii) Ac
2
O / TEA; (iii) Ac
2
O / TEA; (iv)
TsOMe, DMF, toluene, 150
o
C; (v) MeCN, TEA, 75
o
C; (vi) HCl, MeOH, 80
o
C.
The synthesis of 2-(arylthio)vinylbenzo[1,2-c]1,2,5-oxadiazole N-oxide was
accomplished by Porcal and coworkers, who described an efficient Wittig reaction
performed in mild conditions with polymer-supported triphenylphosphine (PS-
TPP). Treatment of tiophenol 170 with paraformaldehyde and HBr followed by
PS-TPP yielded the corresponding polymer-bound phosphonium salt 171. The
reaction of the salt 171 with NaH followed by the condensation with
formylbenzofuroxan and the concomitant cleavage of the resin resulted in the
compounds 172. The oxidation of these benzofuroxanyl derivatives with m-CPBA
gives 2-(arylsulfinyl)vinylbenzo[1,2-c]1,2,5-oxadiazole N-oxide (173).
Benzofuroxans 172 and 173 were assayed in vitro against L. pifanoi (IC
50
4.3-4.6
µM). The compounds 172 and 173 showed better results against L. braziliensis,
with IC
50
values in the range of 0.9-4.6 µM [94].
The synthesis and antiprotozoal activity of benzoxazole derivatives were reported
by Kozikowski and coworkers. The screening for inhibition of L. donovani
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