Synthesis and anti-leishmanial activity of 1-aryl-β-carboline derivatives against Leishmania donovani

Article abstract of DOI:10.1016/j.bmcl.2012.04.115

β-carbolines from various natural and synthetic sources have been known to show diverse biological activities. As a part of our current ongoing project to search for potent natural product-derived anti-leishmanial compounds, we have synthesized a series of substituted 1-aryl-β-carboline derivatives. A total of 22 compounds were synthesized and tested in vitro against Leishmania donovani, out of which 6 compounds (4, 5, 10, 11, 19 and 22) showed notably more activity than the standard miltefosine (IC₅₀ 12.07 ± 0.82 μM), with compound 4 being the most potent (IC ₅₀ 2.16 ± 0.26 μM).

Full text of DOI:10.1016/j.bmcl.2012.04.115

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3905–3907
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and anti-leishmanial activity of 1-aryl-b-carboline derivatives
against Leishmania donovani
Vikrantsinh M. Gohil a, Keyur G. Brahmbhatt a, Philippe M. Loiseau b, Kamlesh K. Bhutani a,
⇑
a Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160062, India
b Groupe Chimiothérapie Antiparasitaire, UMR 8076 CNRS Faculté de Pharmacie, Université Paris-Sud, Rue Jean-Baptiste Clément, F-92290 Chatenay-Malabry, France
a r t i c l e i n f o
a b s t r a c t
Article history:
b-carbolines from various natural and synthetic sources have been known to show diverse biological
activities. As a part of our current ongoing project to search for potent natural product-derived anti-leish-
manial compounds, we have synthesized a series of substituted 1-aryl-b-carboline derivatives. A total of
22 compounds were synthesized and tested in vitro against Leishmania donovani, out of which 6 com-
pounds (4, 5, 10, 11, 19 and 22) showed notably more activity than the standard miltefosine (IC50
Received 19 March 2012
Revised 24 April 2012
Accepted 26 April 2012
Available online 2 May 2012
12.07 0.82
l
M), with compound 4 being the most potent (IC50 2.16 0.26
lM).
Keywords:
b-Carboline
Ó 2012 Elsevier Ltd. All rights reserved.
1-Aryl-b-carboline
Anti-leishmanial
Miltefosine
Leishmaniasis, caused by the protozoan parasite of genus
Leishmania, is a group of neglected parasitic disease. It is mani-
fested in visceral, mucocutaneous, or cutaneous forms. Leishmani-
asis is prevalent in 88 countries throughout the world and affects
more than 12 million people with more than 90% of visceral leish-
maniasis (VL) patients located in India, Sudan, Brazil and Bangla-
desh.1 The drugs currently used for the treatment of
leishmaniasis include miltefosine, sodium stibogluconate, meglu-
mine antimoniate, pentamidine, amphotericin B, and paromomy-
cin.2 All of these drugs are either expensive or have too many
side effects and are toxic. Besides, current treatment regimen is
lengthy, has poor compliance and also resistance to these drugs
have been observed in several cases.3 Hence, there is a significant
unmet need to identify and develop cheaper, safer and effective
molecules for the treatment of leishmaniasis.
leishmanial activity (IC50 34.8 l
M) against Leishmania brazilensis.9
Moreover, several synthetically modified b-carboline derivatives
have also been studied against leishmaniasis.10–13 Our group had
previously reported the synthesis of this group of compounds for
anti-HIV activity.14,15 As a part of our current ongoing project
to search for potent natural product-derived anti-leishmanial
compounds, we have synthesized a series of 1-aryl-b-carboline
derivatives. In this Letter, we are reporting the results of synthesis
and biological evaluation of novel 1-aryl-b-carboline derivatives
against promastigotes of Leishmania donovani, the causative organ-
ism for visceral leishmaniasis.
The overall strategy for the synthesis of b-carboline derivatives
is depicted in Scheme 1. Briefly, 1-(4-nitrophenyl)-2,3,4,9-tetrahy-
dro-1H-pyrido[3,4-b]indole-3-carboxylic acid (1) was obtained
by Pictet–Spengler condensation, reacting DL-tryptophan and
p-nitro-benzaldehyde in acidic conditions.16 Compound 1 was aro-
matized and decarboxylated in a single step using Jones oxidation
to give 1-(4-nitrophenyl)-9H-pyrido[3,4-b]indole (2). The 4-nitro
group was reduced using stannous chloride to give the amino
Natural products have always been a prolific starting point for
many drug development programs, especially for anti-infective
and antitumor agents.4–6 Many alkaloids have been reported to
be active against leishmaniasis, including b-carbolines (Fig 1).3
The b-carboline alkaloid harmaline isolated from Peganum harmala
(Syrian Rue) has been reported to show a strong amastigote spe-
cific activity with an IC50 of 1.16 l
M.7 The metabolite harmine
occurring in same plant has also shown significant activity
in vivo.8 The pyrimidine-b-carboline alkaloid annomontine,
isolated from Annona foetida, has been reported to show anti-
N
N
H
N
N
N
N
H
N
H
O
O
N
H2N
Harmaline
Harmine
Annomontine
⇑
Corresponding author.
E-mail address: kkbhutani@niper.ac.in (K.K. Bhutani).
Figure 1. Anti-leishmanial b-carboline alkaloids.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.04.115

3906
V. M. Gohil et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3905–3907
O
O
OH
OH
NH
ii)
i)
O2N
CHO
NH2
N
H
N
H
p-Nitrobenzaldehyde
DL-Tryptophan
1
NO2
N
N
N
iv)
iii)
N
H
N
N
H
H
R
O
HN
3
NH2
4-22
NO2
2
Scheme 1. Synthesis of 1-aryl-b-carboline derivatives by Pictet-Spengler route: Reagents and conditions: (i) 1 N H2SO4, H2O, EtOH, reflux, 4 h, 84%; (ii) K2Cr2O7, glacial-
CH3COOH, 5 min, 90% (iii) SnCl2/HCl, EtOH, 70 °C, 30 min, 85%; (iv) Acyl chloride, anhydrous CH2Cl2, rt, 1–5 h, 60–89%.
compound (3), which was reacted with various substituted acyl
chlorides using anhydrous dichloromethane as solvent to give
the desired compounds (4–22) in good yields (60–89%).
The synthesized compounds were evaluated against promastig-
otes of Leishmania donovani according to the protocol described
by Chollet et al.17 The compounds 1 and 2 did not exhibit any
dard drug (miltefosine, IC50 12.07 0.82
lM) with IC50 of
9.68 0.87 and 7.70 0.79 M respectively. The stearic properties
l
of the napthyl substituent in case of compound 5 and 7 were
important, as 1-napthyl derivative (7) was totally inactive whereas
2-napthyl derivative (5) showed potent anti-leishmanial activity
(IC50 8.84 0.34
also exhibited potent anti-leishmanial activity (IC50 6.38
0.12 M), whereas the compound containing a substituted furan
ring (20) showed moderate activity (IC50 30.08 6.16 M). The
lM). The compound containing furan ring (10)
anti-leishmanial activity (IC50 >100
verted to 3, it showed moderate anti-leishmanial activity (IC50
46.57 9.36 M), suggesting that 4-amino group on the phenyl
lM), however when 2 was con-
l
l
l
moiety gave better anti-leishmanial activity compared to the nitro
derivative (2). Various substituted derivatives (4–22) were pre-
pared to further improve the activity of the core moiety (Fig 2).
The activity of the compounds is graphically presented in Figure
3. It was observed that long chain b-carboline anilides (9, 12 and
compound containing isostere of furan that is thiophene (8), how-
ever showed less activity compared to the furan derivative (10).
Modifications of E ring also showed some interesting results. The
substitution of halogen atoms on the E ring was also important
as 2,4-difluoro derivative (13) was inactive, whereas 3,4-difluoro
derivative (14) showed activity comparable to that of the standard
18) did not show any anti-leishmanial activity (IC50 >100
however compound containing methyl group (4) (IC50
2.16 0.26 M) was the most active compound in the series. The
lM),
drug (13.1 0.43
(22) on the E ring was the second most active compound in the
series with an IC50 of 5.31 0.70 M. Compound containing an
lM). The compound containing 4-cyano group
l
un-substituted aryl derivative (11) and the cinnamoyl derivative
l
(19) also showed a better anti-leishmanial activity than the stan-
electron donating group like methyl or methoxy at the para posi-
N
N
H
R
HN
R=
O
-CH3
11
12
13
18
19
4
5
6
F
20
21
O
O
F
7
8
F
14
15
CF3
F
22
S
CN
9
16
17
O
10
Figure 2. Synthesized 1-aryl-b-carboline derivatives.

V. M. Gohil et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3905–3907
3907
Figure 3. Anti-leishmanial activities of the synthesized compounds: Results are expressed as the concentration inhibiting parasite growth by 50% (IC50) after a 3-day
incubation period (n = 3). Standard (miltefosine) showed IC50 of 12.07 0.82
lM, six compounds (shown in the shaded region) showed an IC50 less than the standard.
tion in the E ring (6 and 16) showed activity comparable to that of
standard (12.35 1.58 and 14.26 0.33 M) whereas those con-
taining bulkier group like tert-butyl (15) were inactive. The cyto-
toxicity of the compounds was evaluated on peritoneal murine
macrophages according to procedure adapted from Peyron et
al.18 with an incubation period of 72 h. The CC50 (cytotoxic concen-
trations 50%) of all compounds were more than 50 lM, indicating
that the selectivity index (CC50/IC50) of the most active compound
(4) was greater than 20.
In conclusion, six compounds (4, 5, 10, 11, 19, and 22) showed
anti-leishmanial activity that was better than the standard
miltefosine and three compounds (6, 14 and 16) showed activity
that was comparable to standard, suggesting that this group of
compounds can be further explored for getting potent anti-leish-
manial compounds.
References and notes
l
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Acknowledgments
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VMG is thankful to Council of Scientific and Industiral Research
(CSIR), Govt of India, for providing Senior Research Fellowship for
carrying out this work.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.04.
115.
18. Peyron, C.; Benhida, R.; Bories, C.; Loiseau, P. M. Bioorg. Chem. 2005, 33, 439.