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Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 71
3
, pyrrolidine, i-PrOH; (ii) imidazole, EtOH:H
2
O; (iii)
NaBH
4
; (iv) K(t-OBu), DMSO, aryl halides; (v) (HCHO)
3
, pyrrolidine, L-proline, DMSO; (vi) Br
2
,
CCl
4
; (vii) imidazole, DMF; (viii) NaH, DMF, aryl halides.
N
N
O
O
R
1
R
2
N
N
O
R
1
R
2
O
N
N
O
R
1
R
2
O
N
N
O
R
O
(i)
(i)
(i)
R= (CH
2
)
3
CH
3
, Ph,
4
-OCH
3
Ph
R
1
= H, Cl, Br, CH
3
, OCH
3
, CH=NOH
R
2
= H, Cl
R
1
= Cl, CH=NOH, (E/Z)CH=CH-Ph
R
2
= H, Cl
(49)
(48)
Reagents and conditions: (i), 2-nitroalkanes, piperidine, THF, rt.
A series of benzyloxy furanyl and benzyloxy thiophenyl azoles was synthesized
by Bhandari and coworkers and screened in vitro for antileishmanial activity.
Compound 50 emerged as the most active compound against L. donovani
amastigotes with an IC
50
of 3.04 μM and was more potent than the reference
drugs miltefosine and miconazole [43].
A novel series of trans-2-aryloxy-1,2,3,4,-tetrahydronaphthyl azoles and related
cyclohexyl azoles was synthesized and evaluated in vitro against L. donovani.
Compound 51 was identified as the most active analog with an IC
50
of 0.64
O
NN
O
OH
NN
NN
O
NN
N
N
R
R
1
O
N
OH
N
N
O
N
N
R
1
R
O
OH
NN
N
N
O
NN
R
R
1
NN
O
Br Br
HCl
HCl
(i)
(ii), (iii)
(iv)
(v)
(ii), (iii)
(iv)
(vi) (vii), (iii)
(ix)
R= H, F, NO
2
, CF
3
,
R
1
= H, NO
2
, CF
3
(39)
(40)
(42)
(43)
(46)
(44)
(viii)
(45)
(41)
(47)
(38)
(38)
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72 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
μg/mL and was more potent than the reference drugs sodium stibogluconate and
paromomycin [44].
N
O
O
N
Cl
N
O
N
Cl
Cl
(50) (51)
2.1.3. Pyrazole Derivatives
Bernardino and coworkers synthesized a series of pyrazoles from the key
intermediates 5-amino-1-aryl-1H-pyrazole-4-carbonitriles (52) that were
subjected to aprotic deamination with t-butyl nitrite to generate 1-aryl-1H-
pyrazole-4-carbonitriles (53). The reaction of 53 with HCl followed by treatment
with NH
3
produced 1-aryl-1H-pyrazole-4-carboximidamides (54). The
compounds 53 were treated with CS
2
and ethylenediamine to produce 5-amino-1-
aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (55). The derivatives 54
showed poor activity against L. amazonensis promastigotes with an IC
50
value of
105 μM, whereas the compounds 55 presented good activities against
promastigotes of L. amazonensis with an IC
50
value of 15.5 μM and lower
activities against L. braziliensis and L. infant [45,46].
N
N
NH
2
CN
N
N
CN
N
N
NH
2
HN
N
N
NH
N
RR
R
R
R= Br, NO
2
,
3
,
5
-diCl
(i) (ii)
(52)
(53) (54)
(55)
(iii)
Reagents and conditions: (i) t-butyl nitrile, THF, reflux, 6h; (ii) a)HCl, EtOH, 0
o
C-rt, 5 days; b)
NH
3
, EtOH, rt, 7 days; (iii) ethylenediamine, CS
2
, 14-15 h, 115
o
C.
The antiprotozoal activity of a series of 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-
yl]morpholine derivatives was assayed in vitro. The compound 56 was active
against L. donovani with an IC
50
value of 2.3 μM [47].
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 73
A series of 1H-pyrazole-4-carbohydrazides was synthesized and tested against the
Leishmania parasite. The most active were derivatives 57 and 58, and they were
shown to be more effective against the promastigote form of L. amazonensis than
against L. chagasi and L. braziliensis species. Both compounds were less toxic
than pentamidine and ketoconazole [48].
N
N
N
N
Boc
O
H
N
N
N
H
N
H
O
X
Y
(56)
(
57
) X = Br, Y = NO
2
(
58
) X = NO
2
, Y = Cl
2.1.4. Thiadiazole Derivatives
Foroumadi and coworkers described the synthesis of a series of compounds
derived from 1,3,4-thiadiazole [49]. The treatment of 5-nitroimidazole (59), 5-
nitrofurane (60) and 5-nitrothiophene (61) with thiosemicarbazide followed by
cyclization gave 2-amino-1,3,4-thiadiazole (62). The reaction of amine 62 with
NaNO
2
followed by HCl gave 2-chloro-1,3,4-thiadiazole (63). The reaction of
compound 63 with piperazine gave N-piperazinyl compound followed by N-
aroylation with appropriate benzoyl chlorides or thiophen-2-carbonyl chlorides
afforded target compounds 64. The most potent compounds against the
promastigote form of L. major were found to be an N-(5-chloro-thiophen-2-yl)
carbonyl derivative and N-benzoyl analog with IC
50
values of 9.35 and 10 μM,
respectively [50].
Continuing the study of the synthesis and in vitro evaluation against L. major,
Foroumadi and coworkers maintained the same synthetic strategy to obtain a
series of compounds derived from 5-nitrofuran -2-yl-1,3,4-thiadiazol (65) and 5-
nitrothiophen-2-yl-1,3,4-thiadiazol (66) by exchange of the imidazole ring by
furan and thiophene, respectively. The compound nitrofuran, containing 2-
chlorobenzoyl on the piperazine ring of this series, was potent against the
promastigote form of L. major [51] and the 2,5-disubstituted-1,3,4-thiadiazoles
are active against drug-resistant wild-type species related to cutaneous and
visceral leishmaniasis caused by L. major, L. infantum and L. tropica, even
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74 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
though they exhibited different growth inhibition profiles at different
concentrations [52].
Canto-Cavalheiro and coworkers reported a series of salts of mesoionic
compounds 1,3,4-thiadiazolium-2-phenylamine (67) derivatives that were
evaluated against promastigotes of L. amazonensis, L. braziliensis and L. chagasi.
The halogen derivatives exhibited very potent antileishmanial activity with ED
50
approximately 10 µM for the three species [53].
N
N
CH
3
O
2
N
CHO
Y
O
2
N
CH(OAc)
2
Z
N
N
S
Y
NH
2
O
2
N
Z
NN
S
Y
Cl
O
2
N
Z
N
N
S
Y
N
N
O
R
O
2
N
Z
Cl
SS
Cl
S
Br
Cl
Cl
(i)
(ii)
(iii)
(iv)
(64) Z= N-CH
3
; Y= N
(65) Z=O; Y=CH
(66) Z= S, Y=CH
or
(v)
R=
(62)
(63)
(59)
(60) Z=O; Y=CH
(61) Z= S, Y=CH
Reagents and conditions: (i) thiosemicarbazide, EtOH, HCl, reflux; (ii) ammonium ferric sulfate,
H
2
O, reflux; (iii) NaNO
2
, HCl, Cu; (iv) piperazine, EtOH, reflux; (v) appropriate thio phen-2-
carbonyl chlorides or benzoyl chlorides, benzene, pyridine, rt.
S
NN
H
R
Cl
-
(67)
R= H, F, C l, Br, OH, OCH
3
, NO
2
, CN, OCH
2
CH
3
2.1.5. Oxadiazole Derivatives
Cerecetto and coworkers described the in vitro activity of furoxans and furazans
against the promastigote form of L. braziliensis and L. pifanoi strains. Derivatives
68-71 showed ID
50
values between 1.0 and 50.0 µM. Miltefosine was used as the
reference drug [54].
2.2. Pyridinone and Dihydropyridine Derivatives
Tempone and coworkers described the in vitro activity of eight clinically used
1,4-dihydropyridines. They were tested against Leishmania and T. cruzi parasites
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 75
and showed that these derivatives represent an important class of compounds.
Further investigations into their mode of action could be useful in the
development of new agents against leishmaniasis and Chagas’ disease [55].
The synthesis of the pyridinones from γ-pyrone 72 was described by Suryawanshi
and coworkers. Compound 73 was prepared from the reaction between the γ-
pyrone 72 and dibromopentane. The reaction of 73 with aniline furnished dimeric
pyridinone 74 and monomeric pyridinone 75. The pyridinones 74 and 75 were
subjected to in vitro antileishmanial screening against L. donovani promastigotes
and amastigotes. The dimeric pyrone 73 showed good leishmanicidal activity, and
the potency of this compound was greatly enhanced by the N-substitution of an
oxygenated function of pyrone. The pyridinones tested against promastigotes
showed significant activity, with an IC
50
of 4.04-9.98 µg/mL, whereas against the
amastigote stage in macrophages, they showed an IC
50
from 5.32 to 9.64 µg/mL.
The activities of those compounds were higher when compared with miltefosine
but lower in relation to amphotericin B [56].
O
O
OH
O
O
O
O
O
O
N
O
O
N
O
R
R
O
O
O
O
N
O
O
R
(ii)
(i)
(73)
(72)
(74) (75)
R= Ph, Bz,
2
,
6
-diCH
3
Ph,
2
,
3
-diCH
3
,
4
-NO
2
Ph,
2
-OCH
3
Ph,
2
-OCH
3
Ph,
4
-FPh,
4
-ClPh, c-hex
+
Reagents and conditions: (i) K
2
CO
3
, DMF, rt, 12h; (ii) amines, EtOH, 120-125 ºC, 24h.
O
NN
S
R
Ph
O
O
O
O
NN
S
R
Ph
O
O
O
NN
S
R
Ph
O
O
O
O
NN
SPh
NH
2
O
(O)
n
-Ph, -CH=CH
2
, -CH
2
CH
2
OEt, -C H
2
CH
2
SEt,
-CH
2
CONH
2
, -CH
2
CH
2
NH(p-OCH
3
Ph)
R=
(68)
n= 0,1
(69) (70)
(71)
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76 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
N
OR
3
O
R
3
O
O
O
O
O
O
O
R
2
N
O
O
O
OR
1
OR
3
O
R
3
O
O
R
2
R
1
= H, CH
3
, CH
2
Ph
R
2
= H,
4
-CH
3
,
2
-OCH
3
,
4
-OCH
3
,
4
-F,
4
-Cl,
4
-Br,
3
,
4
-diCl
R
3
= CH
3
, CH
2
CH
3
(76)
(77)
Tripathi and coworkers described 1-phenyl-4-glycosyl-dihydropyridines (76 and
77) as potent antileishmanial agents. The synthesis of these compounds started
with the reaction of xylofuranosyl dialdoses or pyranosyl with methylacetoacetate
and the appropriate aniline in the presence of tetrabutylammonium hydrogen
sulfate. The compounds were screened in vitro and in vivo against L. donovani
and showed IC
50
values ≤15 mg/mL and a better selectivity index (SI) than the
standard drugs pentamidine and miltefosine [57].
2.3. Pyrimidine and Pyrimidone Derivatives
Commercially available chloro-pyrimidines (78) and desired amines were used by
Whitlock and coworkers to synthesize 2-pyridyl pyrimidine derivatives 79. The
antileishmanial activity of these compounds was then determined on L. donovani.
Sixteen compounds were equally active or more active than the standard agent
miltefosine, with IC
50
values from 0.26-0.70 µM [58].
NN
N
R
R
1
Cl
NN
N
R
R
1
R
2
(i)
(78)
(79)
R= CH
3
, CF
3
R
1
= H, Cl R
2
= amines
Reagent and condition: (i) amines, Et
3
N, EtOH, reflux.
Suryawanshi and coworkers also described the synthesis and in vivo activity of 4-
N-substituted terpenyl pyrimidines derivatives against L. donovani. The reaction
of ketene dithioacetal 80 with guanidine furnished terpenyl pyrimidine 81.
Compound 81 displayed 66% inhibition at 50 mg/kg in a hamster model [59-61].
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 77
OSMe
SMe
NN
SMe
NH
2
(80)
(81)
(i)
Reagents and conditions: (i) guanidine, i-PrOH.
The synthesis of a series of 2,4,6-trisubstituted pyrimidines and 1,3,5-triazines
were described by Chauhan and coworkers. The reaction of compounds 82 with
cyanuric chloride gave the corresponding triazinyl derivatives 83, which, when
treated with different amines, afforded the final target compounds 84. To
synthesize pyrimidinyl derivatives, the raw material 82 was oxidized to the
corresponding sulfone 85, which was treated with various amines to yield target
compounds 86. These compounds were screened for in vitro and in vivo
antileishmanial activity against L. donovani. The pyrimidines showed in vitro
inhibition of 80-100% against promastigotes, whereas against amastigotes, they
showed IC
50
values in a range of 0.89-9.68 mg/mL. The in vivo assays showed
moderate inhibition of 48-56% [62].
R
NN
NH
2
SCH
3
OCH
3
H
3
CO
R
NN
NH
2
SO
2
CH
3
OCH
3
H
3
CO
NN
NH
2
R
1
OCH
3
H
3
CO
R
N
N
HN
SCH
3
OCH
3
H
3
CO
N
N
N
Cl
Cl
R
N
N
HN
SCH
3
OCH
3
H
3
CO
N
N
N
R
1
R
1
R
(82)
(i)
(iii)
(ii)
(iv)
(84)
(83)
(86)
(85)
R= H, OCH
3
R
1
= amines
Reagents and conditions: (i) cyanuric chloride, K
2
CO
3
, THF, reflux; (ii) amines, K
2
CO
3
, THF,
reflux; (iii) m-CPBA, DCM, 0
o
C-rt; (iv) amines, THF, 100
o
C, closed steel vessel.
Fan and coworkers reported a green and efficient preparation of pyrano[3,2-
c]pyridone and pyrano[4,3-b]pyran derivatives in a one-pot, three-component
reaction of aldehyde 87, 4-hydroxy-pyridin-2(1H)-one (88) and malononitrile
(89). The hybrid compound 90 inhibited L. donovani growth and showed an IC
50
of 10.6 μM [63].
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78 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
O
N
HN
CHO
O
O
OH
HO
N
O
OH
H
NC CN
HN
O
O
CN
NH
2
O
N
HN
O
O
OH
HO
(i)
+
+
(90)
(87)
(88)
(89)
Reagents and conditions: (i) [bmim][BF
4
], 80
o
C.
2.4. Quinoline and Isoquinoline Derivatives
Tempone and coworkers described the synthesis of quinoline derivatives from
enaminone 91. The cyclization of 91 yielded 4-hydroxyquinolines (92), which,
after treatment with phosphorus oxychloride, gave the 4-chloroquinoline
derivatives 93. The compounds were tested against L. chagasi and showed IC
50
values in a range of 0.091-18.78 μM and 3.55->15 μM for promastigotes and
amastigotes, respectively [64].
O
R
N
H
OEt
N
R
OH
N
R
Cl
(92)
(93)
(i)
(ii)
R=
(91)
,
Reagents and conditions: (i) PhO
2
. 250
o
C; (ii) POCl
3
The synthesis of amodiaquine analogs was reported by Bertinara and coworkers.
The target molecules were prepared by the reaction of 4-amino-2-
(hydroxymethyl)phenol (94) with 4,7-dichloroquinolone (95). The intermediate
96 was treated with tert-butylcarbamate followed by hydrolysis to give the amine
intermediate 97. The target compound 98 was obtained by reaction of 97 with
phenylisocyanate. The synthesized compounds proved to be active against
L. donovani intracellular amastigotes, with IC
50
values in the 1.83-17.7 μM range.
Compound 96 showed the best IC
50
value of 1.83 μM [65].
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 79
OH
OH
NH
2
N
Cl
Cl
NCl
N
OH
N
H
Et
NH
2
NCl
N
OH
N
H
Et
N
H
N
O
H
NCl
N
OH
Cl
H
.HCl
.HCl
+
(i)
(ii)
(iii)
(iv)
(v)
(96)
(97)
.
3
CF
3
CO
2
H
(98)
(95)
(94)
Reagents and conditions: (i) EtOH, reflux, 2.5 h; (ii) conc. HCl, reflux, 18 h; (iii)
EtNHCH
2
CH
2
NHBoc, Et
3
N, CH
3
CN, rt, 18 h; (iv) CF
3
CO
2
H, CH
2
Cl
2
, rt, 6 h; (v) Et
3
N, PhNCO,
CH
3
CN, rt.
Jain and coworkers reported the synthesis of 8-quinolinamines from commercially
available 6-methoxy-8-nitroquinoline (99), which was converted to
8-quinolinamine (100) in four steps. Starting from 4-methoxy-2-nitro-5-
pentyloxyaniline (101), the 8-quinolinamine (102) was synthesized in three steps.
Compounds 100 and 102, upon reaction with suitably side chain-protected
Cbz/Boc-L/D-amino acids followed by deprotection, provided the
8-quinolinamine derivatives 103 and 104, respectively. Compounds 103 and 104
were tested in vitro against L. donovani promastigotes and exhibited
antileishmanial activity with IC
50
values of 2.7-19 μg/mL. The activity was
comparable to pentamidine but less potent than amphotericin B [66].
Borne and coworkers reported the synthesis of chloroquine analogs from the
reaction of 4,7-dichloroquinoline (95) with isoquinuclidine-6-carbonitrile (105) to
give 106, which, following reduction of the nitrile group, gave 107. The
secondary amine 108 was obtained by dimethylation. The analogue 109 was
prepared from 105, where the quinoline ring is bonded to the isoquinuclidine
through a methyleneamine bridge. Methylation of 105 with formaldehyde and
formic acid gave 110, which was reduced to yield 111. The amine 111 reacted
with 95 to yield the target product 109. Compounds 108 and 109 displayed potent
in vitro activity against L. donovani with IC
50
values of 1.9 and 3.0 μg/mL,
respectively, comparable to pentamidine, but are 10- to 40-fold less potent than
amphotericin B [67].
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80 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
Silva and coworkers reported the synthesis of quinolin-8-ylarylsulfonamides (113)
from the reaction of 8-aminoquinolines (112) with various arylsulfonylchlorides.
The quinolinylarylsulfonamides 113 were active against promastigote forms of
L. amazonensis and L. chagasi with IC
50
values ranging from 2.12 to 2.85 µM and
0.45 to 0.56 µM, respectively, 2-fold than the control amphotericin B in the
L. chagasi bioassay [68].
The synthesis of benzenesulfonyl-2-methyl-1,2,3,4-tetrahydroquinoline
derivatives was described Mazzieri and coworkers. The preparation of
tetrahydroquinoline derivatives was carried out by reduction of quinoline with
NaBH
4
/NiCl
2
.6H
2
O followed by condensation with the appropriate
benzenesulfonyl chloride. The derivatives 114 and 115 were tested against
L. donovani and showed moderate growth inhibition with IC
50
values of 18.87 and
21.35 μM, respectively [69].
Mondal and coworkers described the synthesis of binuclear derivatives of
quiniline 116 by reaction of 8-hydroxyquinoline with dihaloalkanes. The in vivo
investigation of all synthesized compounds against L. donovani promastigotes and
amastigotes suggested the importance of the presence of a halogen substituent,
which was found to be more important than the hydrophobic chain length. The
absence of Cl afforded a less active bis-quinoline derivative. The activity of a
compound with a CH
2
unit was higher than that of hydrophobic chains with 3-5
carbon atoms in the ether bridge between quinoline moieties [70].
N
NO
2
H
3
CO
N
NH
H
3
CO
C(CH
3
)
3
NH
2
NH
2
N
NH
H
3
CO
C
2
H
5
H
11
C
5
O
N
N
NH
H
3
CO
O
NH
2
RH
C
2
H
5
H
11
C
5
O
NH
2
OC
5
H
11
NO
2
H
3
CO
N
NH
H
3
CO
C(CH
3
)
3
H
N
O
NH
2
R
R=L
/
D- amino acid
(103)
(104)
(100)
(102)
(99)
(101)
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