Synthesis, antileishmanial and antitrypanosomal activities of N-substituted tetrahydro-β-carbolines

Article abstract of DOI:10.1016/j.bmcl.2014.06.030

A series of N-substituted tetrahydro-β-carbolines were synthesized and screened for antileishmanial activity through an in vitro assay that involves promastigotes and axenic amastigotes of Leishmania donovani, the causative agent for visceral leishmaniasis. The thiophen-2-yl analogs 9b and 11f and naphthyl analog 11h were found to show significant activity against promastigotes with IC₅₀ values of 12.7, 9.1 and 22.1 μM, respectively. Analogs 9b and 11h were also effective against axenic amastigotes with IC₅₀ values of 62.8 and 87.6 μM, respectively. The antileishmanial activity of analogs was then tested in human macrophage cell line infected with L. donovani amastigotes and 2-naphthyl linked analog 11h was found to be effective with IC₅₀ value of 28.3 μM. Several analogs also displayed antitrypanosomal activity against Trypanosoma brucei, the causative agent for human African trypanosomiasis. Compounds 11e, 11f and 11h were more effective than others with IC₅₀ values of 1.0, 8.9 and 10.2 μM, respectively. All synthesized analogs were not cytotoxic towards mammalian cell lines including Vero (monkey kidney fibroblasts), HEPG2 (human hepatoma cells), LLC-PK₁ (pig kidney epithelial cells) and THP-1 (human macrophages).

Full text of DOI:10.1016/j.bmcl.2014.06.030

Bioorganic & Medicinal Chemistry Letters 24 (2014) 3247–3250
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, antileishmanial and antitrypanosomal activities
of N-substituted tetrahydro-b-carbolines q
Sudhakar Manda a,b, Shabana I. Khan c, Surendra K. Jain c, Shabber Mohammed a,b, Babu L. Tekwani c,
Ikhlas A. Khan c, Ram A. Vishwakarma a,b, , Sandip B. Bharate a,b,
⇑
⇑
a Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India
b Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India
c National Center for Natural Products Research (NCNPR), School of Pharmacy, University of Mississippi, MS 38677, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of N-substituted tetrahydro-b-carbolines were synthesized and screened for antileishmanial
activity through an in vitro assay that involves promastigotes and axenic amastigotes of Leishmania
donovani, the causative agent for visceral leishmaniasis. The thiophen-2-yl analogs 9b and 11f and naph-
thyl analog 11h were found to show significant activity against promastigotes with IC50 values of 12.7, 9.1
Received 21 April 2014
Revised 7 June 2014
Accepted 9 June 2014
Available online 18 June 2014
and 22.1
values of 62.8 and 87.6
macrophage cell line infected with L. donovani amastigotes and 2-naphthyl linked analog 11h was found to
be effective with IC50 value of 28.3 M. Several analogs also displayed antitrypanosomal activity against
Trypanosoma brucei, the causative agent for human African trypanosomiasis. Compounds 11e, 11f and
11h were more effective than others with IC50 values of 1.0, 8.9 and 10.2 M, respectively. All synthesized
l
M, respectively. Analogs 9b and 11h were also effective against axenic amastigotes with IC50
lM, respectively. The antileishmanial activity of analogs was then tested in human
Keywords:
Tetrahydro-b-carbolines
Antileishmanial
Antitrypanosomal
Leishmania donovani
Leishmaniasis
l
l
analogs were not cytotoxic towards mammalian cell lines including Vero (monkey kidney fibroblasts),
HEPG2 (human hepatoma cells), LLC-PK1 (pig kidney epithelial cells) and THP-1 (human macrophages).
Ó 2014 Elsevier Ltd. All rights reserved.
African trypanosomiasis
The diseases caused by kinetoplastid parasites affect millions of
people in the developing world. Leishmaniasis, African trypanoso-
miasis, and Chagas disease are the most prevalent kinetoplastid
diseases that pose major human health challenge. Leishmaniasis
is caused by protozoan parasites that belong to the genus Leish-
mania and is transmitted by the bite of certain species of sand fly
(subfamily: phlebotominae). Most of the visceral leishmaniasis
cases are observed in countries like India, Bangladesh, Sudan and
Brazil.1 Trypanosomiasis (also called as sleeping sickness) primar-
ily occurs in sub-Saharan Africa; and is caused by the parasite
Trypanosoma brucei, transmitted by tsetse flies.2,3 Most of the cur-
rent antiparasitic drugs are decades old and have many limitations,
including the emergence of drug resistance.4–9 There has always
been a continuous search for new drugs for these diseases with
improved efficacy and less side-effects.10,11
are also present in beverages and foods. This class of compounds
exhibit psychopharmacological,13 antitumor,14,15 antileishma-
nial,16 antitrypanosomal,17,18 anti-HIV,19 antiinflammatory,20 and
variety of other pharmacological activities. The b-carboline alka-
loids harmane (1), harmine (2) and harmaline (3) have been
reported to possess antileishmanial activity.21 Harmane (1) and
harmine (2) strongly inhibited the growth of intracellular amastig-
otes with IC50 values of 0.27 and 0.23
(2) appeared the most efficient compound toward the promasti-
gote stage of the parasite (IC50 = 3.7 M). Harmane (1) and harma-
line (3) showed comparatively lesser activity in promastigotes
stage, with IC50 values of 19.2 and 116.8
M, respectively.21 Har-
maline (3) showed an interesting amastigote-specific activity with
an IC50 of 1.16 M. The pyrimidine substituted b-carboline alkaloid
annomontine (4) and N-hydroxy annomontine (5) were reported to
show activity (IC50 = 34.8 and 252.7 M, respectively) against
Leishmania brazilensis.22 The compound 6 has shown potent activ-
ity against Trypanosoma cruzi (IC50 0.40
M).17 Harmine (2) was
also reported to be effective against T. brucei (IC50 74
M).18 Fur-
lM, respectively. Harmine
l
l
l
A large number of natural products have been reported to
exhibit antileishmanial and antitrypanosomal activities.12 The
b-carboline alkaloids are widely distributed in plant kingdom and
l
l
l
thermore, structurally related canthin-6-one alkaloids have also
shown trypanocidal activity in vivo in the mouse model of acute
or chronic T. brucei infection.23 The structures of b-carboline alka-
loids 1–6 are shown in Figure 1.
q
IIIM Communication number. IIIM/1671/2014.
Corresponding authors. Tel.: +91 191 2569111; fax: +91 191 2569333.
E-mail addresses: ram@iiim.res.in (R.A. Vishwakarma), sbharate@iiim.res.in (S.B.
⇑
Bharate).
http://dx.doi.org/10.1016/j.bmcl.2014.06.030
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

3248
S. Manda et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3247–3250
R
N
N
N
a
NH
N
MeO
MeO
+
R
Cl
N
H
N
H
2
N
H
3
N
H
7
N
H
CH3
CH3
CH3
1
10a-h
11a-h
O
N
N
N
N
N
N
NO2
11a: R =
11b: R =
N
H
N
OH
N
11e: R =
11f: R =
O
S
N
N
N
N
N
N
Cl
O
H2N
H2N
N
H
5
6
4
11g: R =
11h: R =
11c: R =
11d: R =
N
Figure 1. Structures of biologically active b-carboline alkaloids.
O
Based on the literature precedence for antileishmanial21,22 and
antitrypanosomal17,18 activities of b-carboline alkaloids, herein
we report the synthesis and evaluation of antileishmanial and
anti-trypanosomal activities of a series of N-substituted tetrahy-
dro-b-carbolines. For NH-substitutions, we have selected moieties
such as N-methylpiperazine (which is present in 6)17 and its struc-
tural variants (e.g., morpholine). Furthermore, several antileishma-
nial scaffolds consists of benzoyl,24–26 piperazinoyl,17 furyl,27
naphthyl27 functionalities; thus various CO- and CH2-linked aryl
and heteroaryl moieties were incorporated to understand the
structural requirements for antileishmanial activities.
A series of tetrahydro-b-carboline analogs were synthesized
starting from commercially available tetrahydro-b-carboline 7.
The reaction of tetrahydro-b-carboline 7 with different acyl halides
in CH2Cl2 in presence of sodium hydroxide produced N-acyl b-
carbolines 9a–n in 63-82% yield (Scheme 1).
Scheme 2. Reagents and conditions: (a) K2CO3, CH3CN, 3 h, rt, 66–78%.
activity of the compounds was tested in vitro against a culture of
Leishmania donovani promastigotes, axenic amastigotes and mac-
rophage amastigotes. Several compounds showed significant
antileishmanial activity against promastigotes. As presented in
Table 1, the thiophen-2-yl analogs 9b and 11f and naphthyl analog
11h showed activity against promastigotes with IC50 values of 12.7,
lM, respectively. Other compounds displaying good
anti-promastigote activity include benzofuran analog 9d (IC50
M), biphenyl analogs 9f and 9i (IC50 values 75.3 and
M), and anthracene analog 11d (IC50 16.0 M). Compounds
9b, 9d, 9e, 9f, 9i, 11e, 11f and 11h also showed activity against axe-
9.1 and 22.1
49.5
39.6
l
l
l
nic amastigotes. However, only compound 11h displayed activity
against macrophage amastigotes, with IC50 of 28.3 lM. None of
the compounds were toxic to differentiated THP-1 macrophage
Similarly, a series of N-alkylated b-carbolines were synthesized
by treatment of tetrahydro-b-carboline 7 with different heterocy-
cle linked alkyl halides in acetonitrile in presence of potassium car-
bonate. The N-alkylated products 11a–h were formed in 66–78%
yield (Scheme 2).
cells.
The antitrypanosomal activity of all analogs was evaluated
against a culture of T. brucei.30 Results are shown in Table 1. Several
compounds were effective in inhibiting the growth of T. brucei try-
pomastigotes. The 2-nitrofurn-2-yl linked analog 11e was the most
All compounds were tested for in vitro antileishmanial, anti-
trypanosomal and cytotoxic activities.26,28,29 The antileishmanial
potent with IC50 value of 1.0 lM, and IC90 of 28.1 lM. Further, the
thiophen-2-yl linked analog 11f and naphthyl linked analog 11h
were found to possess promising antitrypanosomal activity with
IC50/IC90 values of 8.9/14.5 and 10.2/17.6 lM, respectively.
O
R
a
NH
N
+
R
Cl
N
H
7
N
H
O
It is noteworthy to mention that thiophen-2-yl linked analogs
9b, 9g and 11f displayed better antileishmanial activity in compar-
ison to other analogs. Next, the anthracene and naphthyl linked
analogs 11d and 11h were best antileishmanial agents among
remaining analogs. The analog 11f showed comparable anti-
promastigote activity to that of reference drug pentamidine.
Interestingly, thiophen-2-yl analog 11f and anthracene and naph-
thyl linked analogs 11d and 11h also displayed better anti-trypan-
osomal activity than other analogs. Compounds 9e, 11c, 11d, 11e,
11f and 11h showed better antitrypanosomal activity than refer-
ence drug DFMO.
On comparison of biological data with harmanes 1–3, it was
observed that the analog 11f displayed better anti-promastigote
activity than harmane (1). Compounds 11e and 11f displayed bet-
ter antitrypanosomal activity than harmine (2). The comparative
antileishmanial and antitrypanosomal activity of harmane class
of compounds 1–3 and N-substituted tetrahydro-b-carbolines
11f–11h is shown in Table 2.
8a-m
9a-n
O
NH
Cl
N
N
9h: R =
9i: R =
9a: R =
9b: R =
O
O
NO2
S
CF3
9c: R =
9j: R =
O
N
CH3
NO2
N
N CH3
9k: R =
9l: R =
9d: R =
9e:R =
O
H3C
N
Br
O
S
9f: R =
9g: R =
9m: R =
9n R =
N
In order to investigate the selectivity of the synthesized com-
pounds toward leishmania/trypanosoma parasites, their in vitro
cytotoxicity,29 was determined up to a highest concentration of
H3C
N
N
S
25 lg/mL against three mammalian cell lines (Vero: monkey
kidney fibroblasts, HEPG2: human hepatoma cells and LLC-PK1:
Scheme 1. Reagents and conditions: (a) CH2Cl2, NaOH, 0 °C, 15 min then rt, 3 h, 63–
82%.
pig kidney epithelial cells). Most of the compounds were not toxic

S. Manda et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3247–3250
3249
Table 1
In vitro antileishmanial and antitrypanosomal activity of tetrahydro b-carboline analogsa,b
Entrya
IC50/IC90 (lM)
L. donovani
T. brucei
Promastigotes
Axenic amastigotes
Macrophage amastigotes
Trypamastigotes
9b
9c
12.7/36.6
66.7/—
62.8/107.3
na
na
na
na
na
9d
9e
9f
9g
49.5/120.2
27.5/—
75.3/111.2
26.0/—
116.2/—
96.5/122.4
83.4/110.0
na
na
na
na
na
na
13.7/23.9
na
na
9i
9j
39.6/69.1
52.6/—
37.1/76.0
na
na
na
na
na
11a
11b
11c
11d
11e
121.3/—
117.7/—
na
16.0/76.0
33.8/—
9.1/25.6
22.1/28.1
4.8/6.1
0.3/0.4
na
na
na
na
na
na
na
na
na
28.3/>32
2.0/3.1
0.2/0.5
nt
26.2/—
29.7/—
15.9/26.3
11.0/18.8
1.0/28.1
8.9/14.5
10.2/17.6
0.0041/0.0070
nt
80.4/103.6
116.7/—
na
87.59/—
>29.4/>29.4
0.3/0.4
nt
11f
11h
Pentamidine
Amph. B
DFMO
nt
28.0/68.2
na, not active; nt, not tested;—IC90 was not obtained; DFMO,
a
-difluoromethylornithine.
a
The general synthetic procedure and representative experimental data is shown in Refs. 31,32.
b
Compounds 9a, 9h, 9k, 9l, 9m, 9n and 11g were found to be inactive in all these assays, and thus are not listed in this table.
Table 2
Agricultural Research Service Specific Cooperative Agreement No.
58-6408-2-0009 and US Department of Defense CDMRP Grant
#W81XWH-09-2-0093 (B.L.T.) are acknowledged for financial sup-
port. The chemistry work at the IIIM was supported by CSIR 12th
FYP grant BSC-0205.
Comparison of antileishmanial and antitrypanosomal activity of harmane class of
compounds 1–3 and N-substituted tetrahydro-b-carbolines 11e, 11f and 11h
Entry
IC50
L. donovani
(lM)
T. brucei
Promastigotes
Axenic amastigotes
1a
2a
19.2
3.7
116.8
33.83
9.13
0.27
0.23
1.16
116.66
na
nr
74
nr
1.01
8.90
10.16
Supplementary data
3a
Supplementary data (experimental procedures and spectral
data scans) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.bmcl.2014.06.030.
11e
11f
11h
22.11
87.59
a
Data from literature; nr: data not available in literature; na: not active.
References and notes
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In summary, we have identified tetrahydro-b-carboline analogs
possessing significant antileishmanial activity against L. donovani
promastigotes. The thiophen-2-yl linked analog 11f and naphthyl
linked analog 11h were most promising antileishmanial agents,
exhibiting IC50 values of 9.1 and 22.1 lM, respectively. The naph-
thyl linked analog 11h displayed promising antileishmanial activ-
ity against promastigotes, axenic amastigotes, macrophage
amastigotes, and also displayed antitrypanosomal activity against
T. brucei. This indicates its potential for further lead optimization
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Acknowledgments
S.M. is thankful to the CSIR for award of a Senior Research
Fellowship. Authors thank analytical department, IIIM for NMR,
MS and IR analysis of the synthesized compounds. John Trott is
acknowledged for technical support in biological activity testing
at the NCNPR. United States Department of Agriculture (USDA),

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32. General procedure for the synthesis of N-substituted 1,2,3,4-tetrahydro-b-
carbolines 11a–d. To the solution of 1,2,3,4-tetrahydro-b-carboline (7,
1.2 mmol) in acetonitrile was added K2CO3 (1.8 mmol) followed by addition
of corresponding heterocyclic alkyl chloride (1.2 mmol). The reaction mixture
was stirred at rt for 3 h. Completion of the reaction was monitored by TLC.
After completion of the reaction, reaction mixture was diluted with ethyl
acetate and was washed with water. The organic layer was separated and dried
over anhydrous sodium sulfate. The solvent was evaporated under reduced
pressure and crude product was purified by silica gel (#100–200) column
chromatography using EtOAc: hexane as mobile phase to get desired aryl
methylene linked 1,2,3,4-tetrahydro-b-carbolines 9a–d in 66–78% yield. 2-
(Anthracen-10-yl-methyl)-1,2,3,4-tetrahydro-beta-carboline (11d). yellow
solid; yield 66%; mp 222–225 °C; 1H NMR (400 MHz, DMSO-d6, ppm):
d
10.50 (br s, NH, 1H), 8.70 (s, 1H), 8.60 (d, J = 8.5 Hz, 2H), 8.15 (d, J = 8.0 Hz, 2H),
7.85–7.51 (m, 4H), 7.25 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 8.0 Hz,1H), 6.97 (t,
J = 7.5 Hz, 1H), 6.92 (t, J = 7.7 Hz, 1H), 4.85 (s, 2H), 3.65 (s, 2H), 2.98 (s, 2H); 13
C
NMR (100 MHz, DMSO-d6, ppm): d 166.8 (C), 135.7 (C), 132.7 (C), 131.6 (C),
131.4 (CH), 130.9 (C), 130.7 (C), 129.8 (C), 128.6 (CH), 127.1 (CH), 126.5 (C),
125.7 (CH), 125.0 (CH), 120.1 (CH), 118.1 (CH), 117.2 (CH), 110.7 (CH) 106.3
(C), 64.9 (CH2), 52.5 (CH2) 50.6 (CH2), 49.5 (CH2); IR (KBr): mmax 3401, 3054,
2959, 2931, 2872, 1723, 1623, 1598, 1453, 1380, 1286, 1122, 1073 cmÀ1; ESI-
MS: m/z 363.17 [M+H]+; HRMS: m/z 363.1823 calcd for C26H23N2+H+
31. General procedure for the synthesis of N-substituted 1,2,3,4-tetrahydro-b-
carbolines 9a–m. To the suspension of 1,2,3,4-tetrahydro-b-carboline (7,
1.2 mmol) in CH2Cl2 (3 ml) at 0 °C was added slowly an aqueous solution of
4 N NaOH (1.2 mol). After 5 min stirring at 0 °C, aryl/heteroaryl or cycloalkyl
acyl chloride (1.2 mmol) was added dropwise. The mixture was stirred for
15 min at 0 °C and further stirred at rt for 3 h. Completion of the reaction was
monitored by TLC. After completion of the reaction, reaction mixture was
diluted with CH2Cl2 and was washed with water. Organic layer was separated
and dried over anhydrous sodium sulfate. The solvent was evaporated under
reduced pressure and crude product was purified by silica gel (#100–200)
column chromatography using EtOAc: hexane as mobile phase to get desired
aryl/cycloalkyl-carbonyl linked 1,2,3,4-tetrahydro-b-carbolines 9a–m in 63–
82% yield. The spectral data for representative compounds is provided here. 2-
(5-Nitrothiophen-2-yl-carbonyl)-1,2,3,4-tetrahydro-beta carboline (9b). Red
solid; yield 75%; mp 217–219 °C; 1H NMR (400 MHz, DMSO-d6, ppm): d 10.92
(br s, NH, 1H), 8.31 (s, 1H), 7.59 (s, 1H), 7.42 (d, J = 8 Hz, 1H), 7.32 (d, J = 7.6 Hz,
1H), 7.08 (t, J = 7.2 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 4.85 (br s, 2H), 3.94 (br s, 2H),
2.85 (br s, 2H); 13C NMR (100 MHz, DMSO-d6, ppm): d 161.6 (CO), 152.6 (C),
145.0 (C), 136.5 (C), 130.4 (C), 129.7 (CH), 128.7 (CH), 126.8 (C), 121.5 (CH),
119.1 (CH), 118.0 (CH), 111.6 (CH), 107.2 (C), 55.3 (CH2), 46.2 (CH2), 22.1 (CH2);
IR (KBr): mmax 3392, 2921, 1614, 1536, 1507, 1448, 1415, 1346, 1334, 1232,
(363.1855).
2-(5-Chlorothiophen-2-yl-methyl)-1,2,3,4-tetrahydro-beta-
carboline (11f). white solid; yield 73%; mp 191–193 °C; 1H NMR (400 MHz,
DMSO-d6, ppm): d 10.70 (br s, NH, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.26 (d,
J = 8.0 Hz, 1H), 7.02–6.90 (m, 4H), 3.92 (s, 2H), 3.60 (s, 2H), 2.90 (t, J = 5.6 Hz,
2H), 2.65 (t, J = 5.3 Hz, 2H); 13C NMR (100 MHz, DMSO-d6, ppm): d 142.6 (C),
135.7 (C), 132.2 (C), 127.1 (C), 126.6 (CH), 126.1 (C), 125.2 (CH), 120.2 (CH),
118.1 (CH), 117.2 (CH), 110.7 (CH), 106.1 (C), 55.6 (CH2), 50.0 (CH2), 49.4 (CH2),
20.8 (CH2); IR (KBr): mmax 3152, 2922, 2848, 2805, 1620, 1448, 1328,1236,
1204, 1100, 1006 cmÀ1; ESI-MS: 303 [M+H]+; HRMS: m/z 303.0708 calcd for
C
16H16ClN2S+H+ (303.0717). 2-(Naphthalen-2-yl-methyl)-1,2,3,4-tetrahydro-
beta-carboline (11h). white solid; yield 80%; mp165–167 °C; 1H NMR
(400 MHz, CDCl3, ppm): d 7.85–7.82 (m, 3H), 7.63–7.57 (m, 2H), 7.50–7.45
(m, 2H), 7.29–7.27 (m, 2H), 7.14–7.04 (m, 2H), 3.94 (s, 2H), 3.70 (s, 2H), 2.97 (t,
2H, J = 5.0 Hz), 2.85 (t, 2H, J = 5 Hz); 13C NMR (100 MHz, CDCl3 ppm): d 136.6
(c), 136.0 (C), 133.3 (C), 132.8 (C), 131.8 (C), 128.0 (CH), 127.9 (C), 127.7 (CH),
127.6 (CH), 127.5 (CH), 127.3 (CH), 126.0 (CH), 125.6 (CH), 121.3 (CH), 119.3
(CH), 117.9 (CH), 110.6 (CH), 108.4 (C), 62.1 (2CH), 51.0 (2CH), 50.2 (2CH), 21.2
(2CH); IR (CHCl3): mmax 3401, 2923, 2852, 2353, 1625, 1454, 1384, 1019,
741 cmÀ1
C
;
ESI-MS: m/z 313.03 [M+H]+; HRMS: m/z 313.1730 calcd for
1032 cmÀ1
C
;
ESI-MS: m/z 350.01 [M+Na]+; HRMS: m/z 328.0728 calcd for
22H21N2+H+ (313.1699).
16H13N3O3S+H+ (328.0750).