Syntheses of new substituted triazino tetrahydroisoquinolines and β-carbolines as novel antileishmanial agents

Article abstract of DOI:10.1016/j.ejmech.2005.09.007

A series of triazino tetrahydroisoquinolines (3-5) and β-carboline derivatives (15-27) have been synthesized as novel antileishmanial agents. Among them, compounds 15, 16 and 25 have shown 78.0%, 78.6% and 68.0% in vivo inhibition against Leishmania donov

Full text of DOI:10.1016/j.ejmech.2005.09.007

European Journal of Medicinal Chemistry 41 (2006) 106–113
http://france.elsevier.com/direct/ejmech
Short communication
Syntheses of new substituted triazino tetrahydroisoquinolines
and β-carbolines as novel antileishmanial agents1
Arun Kumar a, Sanjay Babu Katiyar a, Suman Gupta b, Prem M.S. Chauhan a,*
a
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
b
Parasitology Division, Central Drug Research Institute, Lucknow 226001, India
Received 18 January 2005; received in revised form 19 September 2005; accepted 20 September 2005
Available online 13 December 2005
Abstract
A series of triazino tetrahydroisoquinolines (3–5) and β-carboline derivatives (15–27) have been synthesized as novel antileishmanial agents.
Among them, compounds 15, 16 and 25 have shown 78.0%, 78.6% and 68.0% in vivo inhibition against Leishmania donovani at a dose of 50
mg kg–1 × 5 days, respectively, while compounds 3 and 18 exhibited 55.6% and 53.3% in vivo inhibitions, respectively, against L. donovani at a
dose of 50 mg kg–1 × 5 days.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Tetrahydroisoquinoline; β-Carboline; Antileishmanial activity
1. Introduction
tion of high doses and a lengthy course of treatment, resulting
in a marked increase in serious side effects and a decrease in its
efficacy. Two pentavalent antimonial drugs, sodium stiboglu-
conate (Pentostam) and meglumine antimoniate, are current
treatments of choice for leishmaniasis. The drugs which are
used in the treatment of leishmaniasis show high hepatotoxicity
and nephrotoxicity. Most of the drugs develop clinical resis-
tance after a few weeks of treatment [4,5]. Therefore, develop-
ment of more effective and safer chemotherapeutic agents for
treating leishmaniasis remains desirable, and rational ap-
proaches are needed to identify novel drugs against leishmania-
sis. Due to these reasons, it is necessary to discover new
agents, which should be more potent and nontoxic. Most of
presently available drugs have limitations like high toxicity,
variable efficacy or restricted supply [6]; drug resistance is
complicating the treatment of these patients [7].
Leishmaniasis is caused by different species belonging to
the genus Leishmania, a protozoa transmitted by the bite of a
tiny 2–3 mm long insect vector, the phlebotomine sandfly.
Leishmaniasis has an overwhelming impact on the global pub-
lic health especially in the tropical and subtropical countries
[1]. Infection by various strains of leishmania causes a wide
spectrum of diseases in humans, with many different clinical
manifestations, i.e. cutaneous, mucocutaneous and visceral. It
affects 12 million people in the world and 350 million are es-
timated to be prone to the disease [2]. The visceral form of
leishmaniasis, caused by the parasite Leishmania donovani, is
commonly known as kala-azar, in which the phagocytic cells
of the spleen, liver and bone marrow are attacked: this is fatal
in more than 90% of the untreated cases [3]. There is still no
effective vaccine for kala-azar, and chemotherapy remains the
most effective control measure.
A great number of natural and synthetic compounds have
been tested in the past few years against leishmaniasis, they
often possess aza heterocycles such as quinolines [8], acridines
[9], phenothiazines [10], pyrimidines [11,12], purines [13], bis-
benzamidines [14], buparvaquone-oximes [15] and imidazoli-
dines [16]. The importance of isoquinoline and β-carboline
class of compounds is well established in antiparasitic che-
motherapy [17,18]. Moreover, the triazine class of compounds
are known for their DHFR inhibitory activity and are active
The currently available leishmanial drugs depend on penta-
valent antimony compounds that require parenteral administra-
* Corresponding author. Tel.: +91 522 226 2411x4332;
fax: +91 522 262 3405.
E-mail address: prem_chauhan_2000@yahoo.com (P.M.S. Chauhan).
CDRI Communication No. 6459.
1
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.09.007

A. Kumar et al. / European Journal of Medicinal Chemistry 41 (2006) 106–113
107
Table 1
Compd. No
against malaria parasite [17,18]. We have synthesized some
hybrid molecules having triazine heterocycles along with iso-
quinoline and β-carboline groups as possible potential antil-
eishmanial agents. The present paper describes syntheses of
substituted triazino isoquinolines and β-carbolines and their in
vivo antileishmanial activity.
R
3
4
5
2. Chemistry
basis of 13C NMR values which were previously reported in
literature [20]. Compounds (7–10) were separately reacted with
cyanuric chloride in the presence of K2CO3 to obtain com-
pounds (11–14). Compounds (11–14) were subjected to nu-
cleophilic substitution with various amines to afford the tar-
geted compounds 15–27 (Table 2). All the synthesized
compounds were well characterized by spectroscopic data such
as mass, IR NMR and elemental analysis.
The synthesis of triazino isoquinolines (3–5) was carried out
as shown in Scheme 1. The intermediate compound (2) was
synthesized by the reaction of tetrahydroisoquinoline and cya-
nuric chloride in the presence of K2CO3. The compound (2)
was reacted with various amines to yield compounds 3–5
(Table 1).
The synthesis of β-carboline derivatives is shown in Scheme
2. The methyl ester of DL-tryptophan was prepared by the reac-
tion of DL-tryptophan and thionyl chloride in methanol. The
methyl ester was cyclized by Pictet–Spingler cyclization [19]
in the presence of appropriate aromatic aldehydes to afford ( )
cis and ( )trans isomers of β-carboline derivatives. The stereo-
chemistry of the cis and trans isomers was assigned on the
3. Biological activity
The in vivo leishmanicidal activity was determined in gold-
en hamsters (Mesocricotus aurctus) infected with HOM/IN/80/
Scheme 1.
Scheme 2.

108
A. Kumar et al. / European Journal of Medicinal Chemistry 41 (2006) 106–113
Table 2
Compd. No
TIUC = Times increase of parasites in untreated control an-
imals.
Isomer
R
R1
15
( )cis
CH3
4. Results and discussion
16
( )cis
( )cis
CH3
CH3
The antileishmanial activities of synthesized compounds are
described in Table 3. Out of 16 compounds, seven compounds
were belonged to ( )cis isomers, six compounds were ( )trans
isomers, while three compounds were tetrahydroisoquinolines.
Among the ( )cis isomers, two compounds 15 and 16 showed
promising in vivo activity, 78.0% and 78.6%, respectively,
against L. donovani as evident from the observation period
on day 7 post treatment. One compound 18 has shown moder-
ate activity 53.3% inhibition. In the ( )trans isomers, com-
pound 25 showed 68.0% inhibition while compound 26 exhib-
ited only 28.3% inhibition at tested dose. Rest of the
compounds of trans isomers were found inactive. Two com-
pounds 3 and 4, of the tetrahydroisoquinolines, exhibited
55.6% and 36.1% inhibition, respectively.
Out of seven ( )cis isomers, compound 15 having p-tolyl
group at C-1 and bis-(morpholin)triazine group at N-2, and
compound 16 having the same group at C-1 and bis-(N-phe-
nylpiperazin)triazine at N-2, showed potent antileishmanial ac-
tivities: 78.0% and 78.6% inhibition, respectively, at doses of
50 mg kg–1 × 5 days. If the bis-(N-pyridin-2-yl-piperazin)tria-
zine group was introduced at N-2, the activity was reduced and
compound 17 has shown only 17.7% inhibition. Replacement
of the p-tolyl group by p-chlorophenyl group at C-1 was found
to reduce of antileishmanial activity. The compound 18 having
bis-(morpholin)triazine group at N-2 showed 53.3% inhibition
while compounds 20 and 21 having bis-(N-phenylpiperazin)
triazine and bis-(N-pyridin-2-yl)triazine groups, respectively,
at N-2, exhibited 10.5% and 24.5% inhibition, respectively, at
the tested dose. The compound 19 which has a bis-(N-methyl
piperazin)triazine group at N-2 was inactive.
17
18
19
20
( )cis
( )cis
( )cis
Cl
Cl
Cl
21
( )cis
Cl
22
23
24
( )trans
( )trans
( )trans
CH3
CH3
CH3
25
( )trans
CH3
26
27
( )trans
( )trans
Cl
Cl
DD8 strain of L. donovani obtained by courtesy of P.C.C.
Garnham, Imperial College, London (UK).
For in vivo evaluation of compounds, the method of Bever-
idge [21] as modified by Bhatnagar et al. [22]; Gupta et al. [23]
was employed. Male hamsters weighing 35–40 g each were
infected with 1 × 107 amastigotes and the intensity of infection
after 20 days was assessed by spleen biopsy. Animals with 2+
infections (5–15 amastigotes per 100 cell nuclei) were selected
for screening the compounds. The infected animals were ran-
domized into several groups on the basis of their parasitic bur-
dens. Usually four to six animals were used for each compound
and the same numbers were kept as untreated controls. The
drug treatment was given intraperitoneally for five consecutive
days at 50 mg kg–1 dose level. To assess the effect of test
compounds, spleen biopsies were performed on each animal
after 7 days of last drug administration and amastigote counts
were assessed by Giemsa staining. The percentage inhibition in
amastigote multiplication was calculated using the following
formula:
Among the ( )trans isomers, most of the compounds 22, 23,
24 and 27 were inactive. The compound 25 having a p-tolyl
substituent at C-1 and bis-(N-pyridin-2-yl-piperazin)triazine
group at N-2 exhibited 68.0% inhibition, while compound 26
with a p-chlorophenyl group at C-1 and bis-(morpholin)triazine
group at N-2 showed 28.3% inhibition. SAR study of the
Table 3
Antileishmanial activity of compounds against L. donovani in hamsters
Serial number Compound
number
Dose
mg kg–1
50
In vivo % inhibition
Day 7 PT
55.6
1
3
2
4
50
36.1
3
4
5
6
7
8
9
10
11
15
16
17
18
20
21
25
26
SSG
50
50
50
50
50
50
50
50
78.0
78.6
17.7
53.3
10.5
24.5
68.0
28.3
ANAT × 100
(1)
P:I: ¼ 100 −
INAT × TIUC
P.I. = Percentage inhibition of amastigote multiplication.
ANAT = Actual no. of amastigotes in treated animal.
INAT = Initial no. of amastigotes in treated animals.
50
90.0
PT: post treatment; SSG: reference drug (sodium stibogluconate); a: inactive
compounds are not shown in table.

A. Kumar et al. / European Journal of Medicinal Chemistry 41 (2006) 106–113
109
β-carboline derivatives reveals that the p-tolyl group at C-1 is
6.1. General procedure for synthesis of compounds 3–5
crucial in cis isomers for antileishmanial activity.
To the stirred mixture of compound 2 (2.5 mmol) and
K2CO3 (5.0 mmol) in dry DMF (30 ml) was added corre-
sponding amine (5 mmol). The reaction mixture was refluxed
for 4 h and DMF was evaporated under vacuum. The residue
was dissolved in chloroform, washed with brine solution
(three times) and then with water (three times), dried over an-
hydrous sodium sulfate, concentrated and purified by column
chromatography to obtain compounds 3–5.
5. Conclusion
We have identified some β-carboline-triazine and tetrahy-
droisoquinoline derivatives as potent and less toxic antileish-
manial agents. These compounds can be better than the stan-
dard drug (sodium stibogluconate). Standard drug belongs to
the antimonial class and is associated with nephrotoxicity and
liver toxicity while β-carboline-triazine and tetrahydroisoqui-
noline derivatives do not have any type of metallic atom, so
these molecules can be used as lead molecules for optimiza-
tion work. These β-carboline-triazine and tetrahydroisoquino-
line derivatives will be useful in developing new potential an-
tileishmanial agents.
6.1.1. 2-(4,6-Di-morpholin-4-yl-[1,3,5]-triazin-2yl)-1,2,3,4-
tetrahydroisoquinoline (3)
Yield: 80%; m.p. 180–183 °C; MS: m/z 382 (M+); IR
(KBr): 2958, 2859, 1547, 1450, 1363 cm–1; 1H NMR
(200 MHz, CDCl3): δ 7.77–7.13 (m, 4H, Ar–H), 4.86 (s, 2H,
N–CH2–Ar), 4.01 (t, 2H, J = 5.78 Hz, N–CH2), 3.75–3.72 (m,
16H, N–CH2, O–CH2), 2.89 (t, 2H, J = 5.78 Hz, Ar–CH2);
13C NMR (50 MHz, CDCl3): δ 30.42, 44.67, 57.34, 60.08,
67.85, 125.23, 126.70, 127.35, 128.65, 136.67, 139.23,
162.88, 165.38; Anal. calcd. for C20H26N6O2: C 62.80, H
6.85, N 21.98; Found: C 62.54, H 6.95, N 21.63%.
6. Experimental
Melting points were recorded on capillary melting point
apparatus and are uncorrected. Both H and 13C NMR spectra
1
were recorded on 200 MHz Bruker FT-NMR (Avance
DPX200) spectrometer using tetramethylsilane as internal
standard and the chemical shifts are reported in δ units. FAB
mass spectra were recorded on JEOL SX 102/DA 6000 mass
spectrometer using argon/xenon (6 kV, 10 mA) as the FAB
gas. Elemental analyses were carried out on Carlo-Erba 1108
instrument or Elementar’s Vario EL III micro-analyzer. All
chromatographic purification was performed with silica gel
60 (100–200 or 200–400 mesh), whereas all TLC (silica gel)
development was performed on silica gel coated (Merck Kie-
sel 60 GF-254, 0.2 mm thickness) sheets. All chemicals were
purchased from Aldrich Chemical Ltd. (Milwaukee, WI,
USA). Solvents used for the chemical synthesis acquired from
commercial sources were of analytical grade, and were used
without further purification unless otherwise stated.
6.1.2. 2-[4,6-Bis-(4-phenylpiperazin-1yl)-[1,3,5]-triazin-2yl-]-
1,2,3,4-tetrahydroisoquinoline (4)
Yield: 70%; m.p. 186–188 °C; MS: m/z 532 (M+); IR
(KBr): 3028, 2852, 1544, 1445, 1371 cm–1; 1H NMR
(200 MHz, CDCl3): δ 7.37–7.14 (m, 4H, Ar–H), 6.99–6.85
(m, 10H, Ar–H), 4.91 (s, 2H, N–CH2–Ar), 4.06–3.94 (t,
10H, J = 5.08 Hz, N–CH2), 3.24 (t, 8H, J = 4.78 Hz,
N–CH2), 2.92 (t, 2H, J = 5.76 Hz, Ar–CH2); 13C NMR (50
MHz, CDCl3): δ 30.82, 44.78, 46.23, 57.25, 60.44, 113.12,
118.43, 125.58, 126.23, 127.12, 128.45, 129.00, 136.34,
139.67, 144.58, 166.69, 167.23; Anal. calcd. for C32H36N8:
C 72.14, H 6.81, N 21.03; Found: C 71.89, H 6.53, N 20.90%.
6.1.3. N,N′-dicyclohexyl-6-(3,4 dihydro-1H-isoquinolin-2-yl-
[1,3,5]-triazine-2,4 diamine (5)
Synthesis of (4,6-dicholro-[1,3,5]-triazin-2-yl)-1,2,3,4-tetra-
hydroisoquinoline (2).
Yield: 76%; m.p. 142–144 °C; MS: m/z 406 (M+); IR
1
(KBr): 3242, 3109, 2925, 2850, 1514, 1429, 1357 cm–1; H
The mixture of cyanuric chloride (1.84 g, 10 mmol) and
K2CO3 (1.12 g, 10 mmol) in dry THF (50 ml) was stirred at
0°C for 10 min. Tetrahydro-isoquinoline (1.33 ml, 10 mmol)
was added drop-wise to the reaction mixture and stirred at r.t.
for 1 h. The solvent was evaporated under vacuum and solid
mass was obtained. The solid residue was dissolved in chloro-
form, washed with water, dried over sodium sulfate, concen-
trated the solution and purified by column chromatography to
obtain compound 2 as a white powder (1.70 g).
NMR (200 MHz, CDCl3): δ 7.36–7.15 (m, 4H, Ar–H), 4.85
(s, 2H, N–CH2–Ar), 3.99 (t, 2H, J = 5.70 Hz, N–CH2), 3.83
(m, 2H, N–CH), 2.89 (t, 2H, J = 5.70 Hz, N–CH2 ), 2.03–1.14
(m, 20H, CH2); 13C NMR (50 MHz, CDCl3): δ 25.10, 25.99,
30.82, 33.67, 52.45, 57.25, 60.44, 125.50, 126.73, 127.62,
128.45, 136.67, 139.85, 166.69, 167.23; Anal. calcd. for
C24H34N6: C 70.90, H 8.30, N 20.67; Found: 70.58, H 8.11,
N 20.33%.
Yield: 60%; m.p. 122–125°C; FAB-MS: 282 (M + 1); IR
1
(KBr): 3019, 2862, 1549, 1445, 1371 cm–1; H NMR (200
6.2. General experimental procedure for the synthesis
of compounds (7–10)
MHz, CDCl3): δ 7.37–7.14 (m, 4H, Ar–H ), 4.91 (s, 2H,
N–CH2–Ar), 4.01 (t, 2H, J = 5.78 Hz, N–CH2), 2.92 (t, 2H,
J = 5.76 Hz, Ar–CH2); Anal. calcd. for C12H10Cl2N4: C 51.27,
H 3.59, N 19.93; Found: C 51.04, H 3.63, N 19.57%.
To the stirred solution of DL-tryptophan in methanol was
added thionyl chloride drop-wise with cooling. The reaction

110
A. Kumar et al. / European Journal of Medicinal Chemistry 41 (2006) 106–113
mixture was stirred at r.t. for 1 h and then refluxed for 2 h. The
reaction mixture was allowed to cool at r.t. and then an appro-
priate aromatic aldehyde was added to the reaction mixture.
The reaction mixture was then refluxed for 8 h. The solvent
was removed under vacuum and the solid residue was dis-
solved in water, neutralized with 10% sodium bicarbonate so-
lution and precipitated residue was extracted with ethyl acet-
ate. The organic layer was washed with brine solution (three
times), with water (three times), and dried over sodium sulfate.
The solution was concentrated and the cis isomer and trans
isomer was separated by flash column chromatography using
silica gel column.
6.2.4. ( )trans-1-(4-Chloro-phenyl)-2,3,4,9-tetrahydro-1H-β-
carboline-3-carboxylic acid methyl ester (10)
Yield: 45%; m.p. 200–202 °C; FAB-MS: 341 (M + 1); IR
1
(KBr): 3335, 3239, 3025, 2965, 1743, 1657 cm–1; H NMR
(200 MHz, CDCl3): δ 7.76 (bs, 1H, NH), 7.56 (dd, 1H,
J = 8.22, 1.54 Hz, Ar–H), 7.33–7.12 (m, 7H, Ar–H), 5.37 (s,
1H, CH), 3.98 (dd, 1H, J = 6.54, 2.06 Hz, CH), 3.69 (s, 3H,
OCH3), 3.23–3.16 (m, 2H, CH2). 13C NMR (50 MHz, CDCl3)
: δ 25.08, 52.15, 52.67, 54.79, 109.68, 111.53, 118.93, 120.03,
122.45, 127.65, 128.13, 129.34, 133.54, 137.03, 138.63,
141.52, 173.78; Anal. calcd. for C19H17ClN2O2: C 66.96,
H 5.03, N 8.22; Found: C 66.85, H5.23, N 8.25%.
6.3. General procedure for the synthesis of compounds
(11–14)
6.2.1. ( )cis-1-p-Tolyl-2,3,4,9-tetrahydro-1H-β-carboline-3-
carboxylic acid methyl ester (7)
Yield: 60%; m.p. 146–149 °C; FAB-MS: 321 (M + 1); IR
The mixture of cyanuric chloride (5.0 mmol) and K2CO3
(5.0 mmol) in dry THF (50 ml) was stirred at 0°C for 10
min. The solution of compounds 7 or 8–10 (5 mmol) in dry
THF (30 ml) was added to the stirring mixture drop-wise and
the reaction mixture was left to stir at r.t. for 1 h. After com-
pletion of reaction solvent was evaporated under vacuum and
solid mass was obtained. The solid residue was dissolved in
chloroform, washed with water, dried over sodium sulfate,
concentrated the solution and purified by column chromato-
graphy to obtain compound 11–14.
1
(KBr): 3392, 3233, 3028, 2951, 1743 cm–1; H NMR (200
MHz, CDCl3): δ 7.79 (bs, 1H, NH), 7.53 (dd, 1H, J = 8.54,
2.04, Ar–H), 7.23–7.11 (m, 7H, Ar–H), 5.28 (s, 1H, CH),
3.89, (dd, 1H, J = 6.48, 1.82 Hz, CH), 3.67 (s, 3H, OCH3),
3.20–3.08 (m, 2H, CH2), 2.31 (s, 3H, Ar–CH3). 13C NMR
(50 MHz, CDCl3): δ 21.53, 25.15, 52.49, 54.67, 57.23,
108.78, 111.25, 118.62, 119.67, 122.29, 127.45, 128.74,
129.80, 133.88, 136.64, 138.27, 139.50, 174.54; Anal. calcd.
for C20H20N2O2: C 74.98, H 6.29, N 8.74; Found: C 74.62, H
6.33, N 8.87%.
6.3.1. ( )cis-2-(4,6-Dichloro-[1,3,5]-triazin-2-yl)-1-p-tolyl-
2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic methyl ester
(11)
6.2.2. ( )cis-1-(4-Chloro-phenyl)-2,3,4,9-tetrahydro-1H-β-
carboline-3-carboxylic acid methyl ester (8)
Yield: 60%; m.p. 153–155°C; IR (KBr): 3392, 3028, 2951,
1743 cm–1; FAB-MS: 468 (M + 1); 1H NMR (200 MHz,
CDCl3): δ 7.70 (bs 1H, NH), 7.63–7.06 (m, 9H, Ar–H,
N–CH–Ar), 6.14 (dd, 1H, J = 6.62, 1.98 Hz, N–CH–CO),
3.80 (m, 2H, CH2–Ar), 3.04 (s, 3H, O–CH3), 2.30 (s, 3H,
Ar–CH3); Anal. calcd. for C23H19Cl2N5O2: C 58.98, H 4.09,
N 14.95; Found: C 58.69, H 4.38, N 14.73%.
Yield: 55%; m.p. 156–159 °C; FAB-MS: 341 (M + 1); IR
1
(KBr): 3325, 3243, 3035, 2959, 1741, 1665 cm–1; H NMR
(200 MHz, CDCl3): δ 7.79 (bs, 1H, NH), 7.53 (dd, 1H,
J = 8.20, 1.58 Hz, Ar–H), 7.35–7.10 (m, 7H, Ar–H), 5.35 (s,
1H, CH), 3.97 (dd, 1H, J = 6.58, 2.00 Hz, CH), 3.67 (s, 3H,
OCH3), 3.24–3.11 (m, 2H, CH2). 13C NMR (50 MHz, CDCl3)
: δ 24.96, 52.67, 54.58, 56.77, 109.21, 111.43, 118.82, 120.13,
122.55, 127.23, 128.43, 129.09, 133.44, 136.93, 138.23,
141.33, 173.91; Anal. calcd. for C19H17ClN2O2: C 66.96, H
5.03, N 8.22; Found: C 66.75, H 5.33, N 8.35%.
6.3.2. ( )cis-1-(4-Chlorophenyl)-2-(4,6-dichloro-[1,3,5]-
triazin-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic
acid methyl ester (12)
Yield 55%; m.p. 232–235°C; FAB-MS: 489 (M + 1); IR
(KBr): 3225, 2952, 1736, 1558, 1520 cm–1; 1H NMR
(200 MHz, CDCl3): δ 7.72 (bs, 1H, NH), 7.63–7.16 (m, 9H,
Ar–H, N–CH–Ar), 6.15 (dd, 1H, J = 6.42, 1.96 Hz,
N–CH–CO), 3.71–3.18 (m, 2H, CH2–Ar), 3.10 (s, 3H,
O–CH3); Anal. calcd. for C22H16Cl3N5O2: C 54.06, H 3.30,
N 14.33; Found: C 53.86, H 3.13, N 14.21%.
6.2.3. ( )trans-1-p-Tolyl-2,3,4,9-tetrahydro-1H-β-carboline-3-
carboxylic acid methyl ester (9)
Yield: 40%; m.p. 188–190 °C; FAB-MS: 321 (M + 1); IR
1
(KBr): 3349, 3245, 3033, 2958, 1745, 1645 cm–1; H NMR
(200 MHz, CDCl3): δ 7.66 (bs, 1H, NH), 7.55 (dd, 1H,
J = 8.58, 2.10 Hz, Ar–H), 7.23–7.02 (m, 7H, Ar–H), 5.31 (s,
1H, CH), 3.93 (dd, 1H, J = 6.54, 2.08 Hz, CH), 3.68 (s, 3H,
OCH3), 3.22–3.10 (m, 2H, CH2), 2.32 (s, 3H, Ar–CH3); 13C
NMR (50 MHz, CDCl3): δ 21.50, 25.12, 52.47, 52.92, 55.09,
108.79, 111.31, 118.62, 119.82, 122.29, 127.45, 128.73,
129.80, 133.88, 136.60, 138.29, 139.47, 174.52; Anal. calcd.
for C20H20N2O2: C 74.98, H 6.29, N 8.74; Found: C 74.78, H
6.52, N 8.75%.
6.3.3. ( )trans-2-(4,6-Dichloro-[1,3,5]-triazin-2-yl)-1-p-tolyl-
2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic methyl ester
(13)
Yield: 55%; m.p. 113–115°C; FAB-MS: 468 (M + 1); IR
(KBr): 3398, 3029, 2953, 1744, 1552 cm–1; 1H NMR
(200 MHz, CDCl3): δ 7.96 (bs, 1H, NH), 7.53–7.07 (m, 8H,

A. Kumar et al. / European Journal of Medicinal Chemistry 41 (2006) 106–113
111
Ar–H), 6.61 (s, 1H, N–CH–Ar), 4.79 (dd, J = 6.66, 2.04 Hz,
1H, N–CH–CO), 3.64 (s, 3H, O–CH3), 3.43–3.33 (m, 2H,
CH2–Ar), 2.16 (s, 3H, Ar–CH3); Anal. calcd. for
C23H19Cl2N5O2: C 58.98, H 4.09, N 14.95; Found: C 58.40,
H 4.48, N 14.78%.
165.45, 166.78, 172.73; Anal. calcd. for C43H45N9O2: C
71.74, H 6.30, N 17.51; Found: C 71.92, H 6.62, N 17.38%.
6.4.3. ( )cis-2-[4,6-Bis-(4-pyridin-2-yl-piperazin-1-yl)- [1,3,
5]-triazin-2-yl]-1-p-tolyl-2,3,4,9-tetrahydro-1H-β-carboline-3-
carboxylic acid methyl ester (17)
Yield: 60% ); m.p. 149–152 °C; FAB-MS: 722 (M + 1); IR
6.3.4. ( )trans-1-(4-Chlorophenyl)-2-(4,6-dichloro-[1,3,5]-
triazin-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic
acid methyl ester (14)
Yield: 54%; m.p. 189–192°C; FAB-MS: 489 (M + 1); IR
(KBr): 3364, 2969, 2854, 1537, 1560, 1432, 1354, 1260
cm–1; 1H NMR (200 MHz, CDCl3): δ 7.84 (bs, 1H, NH),
7.53–7.09 (m, 8H, Ar–H), 6.81 (s, 1H, N–CH–Ar), 4.76 (dd,
J = 6.58, 2.08 Hz, 1H, N–CH–CO), 3.57 (s, 3H, O–CH3),
3.22–3.11 (m, 2H, CH2); Anal. calcd. for C22H16Cl3N5O2:
C 54.06, H 3.30, N 14.33; Found: C 53.86, H 3.13, N 14.21%.
1
(KBr): 3394, 2930, 1736, 1597, 1432, 1366 cm–1; H NMR
(200 MHz, CDCl3): δ 8.21 (d, 2H, J = 3.7 Hz, Py–H), 7.78
(bs, 1H, NH) 7.53–6.61 (m, 15H, Ar–H, Py–H, N–CH–Ar),
6.20 (dd, 1H, J = 6.82, 1.96 Hz, N–CH–CO), 3.94 (t, 8H,
J = 5.14 Hz, N–CH2), 3.60 (t, 8H, J = 4.48 Hz, N–CH2),
3.15–3.12 (m, 2H, CH2), 3.03 (s, 3H, O–CH3), 2.28 (s, 3H,
Ar–CH3); 13C NMR (50 MHz, CDCl3): 21.46, 21.93, 43.44,
45.56, 50.86, 51.90, 52.55, 107.60, 109.01, 111.25, 113.91,
118.92, 119.91, 122.38, 127.31, 128.98, 129.17, 131.97,
136.76, 137.50, 137.98, 138.61, 148.42, 159.88, 165.68,
166.14, 173.21; Anal. calcd. for C41H43N11O2: C 68.22,
H 6.00, N 21.25; Found: C 68.03, H 5.85, N 21.07%.
6.4. General procedure for the synthesis of compounds 15–27
The mixture of compound 11 (or 12, 13, 14) (2 mmol),
appropriate amine (4 mmol) and K2CO3 (4 mmol) in THF
(40 ml) was refluxed for 6 h. The reaction mixture was filtered
and the solvent was evaporated under vacuum. The residue
was dissolved in chloroform, washed with water, dried over
sodium sulfate and purified with column chromatography to
yield compound 15–21.
6.4.4. ( )cis-1-(4-Chlorophenyl)-2-(4,6-di-morpholin-4yl-[1,3,
5]-triazin-2yl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic
acid methyl ester (18)
Yield: 69%; m.p. 154–156 °C; FAB-MS: 590 (M + 1); IR
1
(KBr): 3396, 3029, 2852, 1735, 1539 cm–1; H NMR (200
MHz, CDCl3): δ 7.90 (bs, 1H, NH), 7.60–7.11 (m, 9H,
Ar–H, N–CH–Ar), 6.14 (dd, 1H, J = 6.84, 1.96 Hz, N–CH–
CO), 3.73–3.64 (m, 16H, N–CH2, O–CH2), 3.27–3.14 (m, 2H,
CH2), 3.02 (s, 3H, O–CH3); 13C NMR (50 MHz, CDCl3): δ
22.61, 44.32, 50.68, 51.71, 52.15, 67.18, 109.35, 111.43,
118.97, 119.92, 122.65, 127.48, 128.59, 130.12, 131.09,
133.78, 136.56, 140.45, 165.49, 166.23, 172.79; Anal. calcd.
for C30H32ClN7O4: C 61.06, H 5.12, N 16.61; Found: C 60.73,
H 5.18, N 16.34%.
6.4.1. ( )cis-2-(4,6-Di-morpholin-4yl-[1,3,5]-triazin-2-yl)-1-p-
tolyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid
methyl ester (15)
Yield: 66%; m.p. 175–178 °C; FAB-MS: 570 (M + 1); IR
(KBr): 3312, 2924, 1736, 1592, 1436, 1359, 1261 cm–1;
1H NMR (200 MHz, CDCl3): δ 7.70 (bs, 1H, NH), 7.60–7.03
(m, 9H, Ar–H, N–CH–Ar), 6.15 (dd, 1H, J = 6.82, 1.96 Hz, N–
CH–CO), 3.72–3.62 (m, 16H, N–CH2, O–CH2), 3.58 (s, 3H,
O–CH3), 3.12–3.01 (m, 2H, CH2), 2.32 (s, 3H, Ar–CH3); 13C
NMR (50 MHz, CDCl3): δ 21.69, 22.78, 44.84, 50.89, 51.78,
52.59, 67.23, 109.35, 111.23, 118.25, 119.96, 122.10, 127.23,
127.74, 129.65, 133.92, 136.83, 137.48, 139.39, 165.38,
166.49, 172.62; Anal. calcd. for C31H35N7O4: C 65.36, H
6.19, N 17.21; Found: C 65.03, H 5.91, N 16.98%.
6.4.5. ( )cis-2-[4,6-Bis-(4-methylpiperazin-1-yl)-[1,3,5]-
triazin-2-yl]-1-(4-chlorophenyl)-2,3,4,9-tetrahydro-1H-β-
carboline-3-carboxylic acid methyl ester (19)
Yield: 72%; m.p. 172–175 °C; FAB-MS: 616 (M + 1); IR
(KBr): 3426, 3038, 2937, 2808, 1733, 1596, 1435, 1356 cm–1;
1H NMR (200 MHz, CDCl3) δ 8.15 (bs, 1H, NH), 7.60–7.11
(m, 9H, Ar–H, N–CH–Ar), 6.16 (dd, 1H, J = 6.78, 1.90 Hz,
N–CH–CO), 3.82 (t, 8H, J = 4.82 Hz, N–CH2), 3.54–3.10
(m, 2H, CH2), 3.06 (s, 3H, O–CH3), 2.41 (t, 8H, J = 5.12 Hz,
N–CH2), 2.30 (s, 6H, N–CH3); 13C NMR (50 MHz, CDCl3):
δ 22.72, 43.39, 46.53, 50.42, 51.63, 51.83, 55.31, 109.23,
111.15, 119.06, 1119.82, 122.42, 127.27, 128.56, 130.53,
131.02, 133.69, 136.77, 140.38, 165.48, 166.00, 173.00; Anal.
calcd. for C32H38ClN9O2; C 62.37, H 6.22, N 20.46; Found:
C 62.03, H 5.89, N 20.11%.
6.4.2. ( )cis-2-[4,6-Bis(4-phenylpiperazin-1-yl)-[1,3,5]-triazin-
2-yl]-1-p-tolyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic
acid methyl ester (16)
Yield: 65%); m.p. 188–190 °C; FAB-MS: 720 (M + 1); IR
1
(KBr): 3408, 2944, 2850, 1737, 1537 cm–1; H NMR (200
MHz, CDCl3): δ 7.72 (bs, 1H, NH), 7.60–6.86 (m, 19H,
Ar–H, N–CH–Ar), 6.21 (dd, 1H, J = 6.40, 1.90 Hz, N–CH–
CO), 3.98 (t, 8H, J = 4.78 Hz, N–CH2), 3.21 (t, 8H, J = 5.12
Hz, N–CH2), 3.16–3.10 (m, 2H, CH2), 3.02 (s, 3H, O–CH3),
2.28 (s, 3H, Ar–CH3); 13C NMR (50 MHz, CDCl3): δ 21.69,
22.58, 43.48, 45.63, 50.87, 51.88, 52.59, 109.01, 111.23,
117.12, 118.72, 120.02, 120.79, 122.43, 127.32, 127.78,
129.02, 129.68, 134.12, 136.82, 137.58, 139.39, 146.12,
6.4.6. ( )cis-2-[4,6-Bis-(4-phenylpiperazin-1-yl)-[1,3,5]-
triazin-2-yl]-1-(4-chlorophenyl)-2,3, 4,9-tetrahydro-1H-β-
carboline-3-carboxylic acid methyl ester (20)
Yield: 65%; m.p. 172–174 °C; FAB-MS: 740 (M + 1); IR
1
(KBr): 3244, 3059, 2850, 1726, 1537, 1490, 1222 cm–1; H

112
A. Kumar et al. / European Journal of Medicinal Chemistry 41 (2006) 106–113
NMR (200 MHz, CDCl3): δ 8.87 (bs, 1H, NH), 7.90–6.89 (m,
19H, Ar–H, N–CH–Ar), 6.18 (dd, 1H, J = 6.80, 2.00 Hz, N–
CH–CO), 3.97 (t, 8H, J = 4.78 Hz, N–CH2), 3.20 (t, 8H,
J = 5.18 Hz, N–CH2), 3.12–3.08 (m, 2H, CH2), 3.08 (s, 3H,
O–CH3); 13C NMR (50 MHz, CDCl3): δ 22.63, 43.45, 45.78,
50.78, 51.89, 52.68, 109.78, 111.22, 118.92, 119.15, 119.89,
120.78, 122.72, 127.09, 128.19, 129.58, 130.42, 131.13,
133.65, 136.79, 140.38, 147.28, 165.43, 166.23, 172.82; Anal.
calcd. for C42H42ClN9O2: C 68.14, H 5.71, N 17.02; Found: C
67.96, H 5.85, N 16.65%.
118.76, 119.91, 122.28, 127.39, 128.00, 129.58, 134.09,
136.82, 137.54, 139.11, 165.23, 166.81, 172.54; Anal. calcd.
for C33H41N9O2; C 66.53, H 6.94, N 21.16; Found: C 66.47, H
6.63, N 20.87%.
6.4.10. ( )trans-2-[4,6-Bis-(4-phenylpiperazin-1-yl)-[1,3,5]-
triazin-2-yl]-1-p-tolyl-2,3,4,9-tetrahydro-1H-β-carboline-3-
carboxylic acid methyl ester (24)
Yield: 69%; m.p. 171–174 °C; FAB-MS: 720 (M + 1); IR
1
(KBr): 3368, 3035, 2929, 1736, 1595, 1433, cm–1; H NMR
(200 MHz, CDCl3): δ 7.86 (bs, 1H, NH), 7.53–6.83 (m, 19H,
Ar–H, N–CH–Ar), 4.74 (dd, J = 7.68, 4.74 Hz, 1H, N–CH–
CO), 3.85 (t, 8H, J = 4.76 Hz, N–CH2), 3.59 (s, 3H, O–CH3),
3.53–3.46 (m, 2H, CH2), 3.23 (t, 8H, J = 4.54 Hz, N–CH2),
2.32 (s, 3H, Ar–CH3); 13C NMR (50 MHz, CDCl3): δ 21.52,
22.67, 43.38, 45.95, 52.18, 54.28, 56.79, 109.84, 111.32,
117.09, 118.89, 120.09, 120.78, 122.82, 127.20, 127.79,
129.07, 129.68, 133.77, 136.46, 137.31, 139.32, 145.48,
165.18, 166.79, 172.68; Anal. calcd. for C43H45N9O2: C
71.74, H 6.30, N 17.51; Found: C 71.44, H 6.03, N 17.29%.
6.4.7. ( )cis-2-[4,6-Bis-(4-pyridin-2-yl-piperazin-1-yl-)-[1,3,
5]-triazin-2-yl]-1-(4-chlorophenyl)-2,3,4,9-tetrahydro-1H-β-
carboline-3-carboxylic acid methyl ester (21)
Yield: 68%; m.p. 146–149 °C; FAB-MS: 742 (M + 1); IR
(KBr): 3379, 3095, 2937, 2850,1739, 1566, 1373 cm–1; H
1
NMR (200 MHz, CDCl3): δ 8.20 (d, 2H, J = 3.92 Hz, Py–H),
7.93 (bs, 1H, NH), 7.53–6.9 (m, 15 H, Ar–H, Py–H, N–CH–
Ar), 6.07 (dd, 1H, J = 6.58, 1.90 Hz, N–CH–CO), 4.01 (t, 8H,
J = 4.30 Hz, N–CH2), 3.9 (t, 8H, J = 4.68 Hz, N–CH2), 3.15–
3.10 (m, 2H, CH2), 3.07 (s, 3H, O–CH3); 13C NMR (50 MHz,
CDCl3): δ 22.65, 43.45, 45.78, 50.76, 51.89, 52.58, 107.60,
109.10, 111.20, 118.98, 119.92, 122.35, 127.32, 128.95,
129.67, 131.95, 133.75, 136.76, 137.50, 137.98, 138.61,
148.52, 159.65, 165.65, 166.12, 172.79; Anal. calcd. for
C40H40ClN11O2: C 64.72, H 5.43, N 20.76; Found: C 64.33,
H 5.66, N 20.47%.
6.4.11. ( )trans-2-[4,6-Bis-(4-pyridin-2-yl-piperazin-1-yl)-[1,3,
5]-triazin-2-yl]-1-p-tolyl-2,3,4,9-tetrahydro-1H-β-carboline-3-
carboxylic acid methyl ester (25)
Yield: 61%; m.p. 199–201 °C; FAB-MS: 722 (M + 1); IR
(KBr): 3369, 3068, 2923, 1735, 1595, 1433, 1353, 1240 cm–1;
1H NMR (200 MHz, CDCl3): δ 8.18 (d, 2H, J = 3.66 Hz, Py–
H), 8.07 (bs, 1H, NH), 7.53–7.08 (m, 14H, Ar–H, Py–H), 6.89
(s, 1H, N–CH–Ar), 4.80 (dd, J = 7.80, 4.78 Hz, 1H, N–CH–
CO), 3.79 (t, 8H, J = 4.78 Hz, N–CH2), 3.58 (s, 3H, O–CH3),
3.49 (t, 8H, J = 4.68 Hz, N–CH2), 3.24-3.14 (m, 2H, CH2),
2.30 (s, 3H, Ar–CH3); 13C NMR (50 MHz, CDCl3): 21.52,
22.81, 43.33, 45.54, 52.32, 54.29, 56.84, 107.57, 109.00,
111.38, 113.84, 118.75, 120.02, 122.38, 127.34, 127.73,
129.65, 134.33, 136.92, 137.49, 137.94, 139.46, 148.38,
159.86, 165.47, 166.94, 172.81; Anal. calcd. for
C41H43N11O2: C 68.22, H 6.00, N 21.25; Found: C 68.19, H
5.95, N 21.15%.
6.4.8. ( )trans-2-(4,6-Di-morpholin-4-yl-[1,3,5]-triazin-2-yl)-
1-p-tolyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid
methyl ester (22)
Yield: 69%; m.p. 216–220 °C (dec.); FAB-MS: 570 (M +
1); IR (KBr): 3312, 3069, 2924, 1736, 1592, 1436, 1359, 1261
1
cm–1; H NMR (200 MHz, CDCl3): δ 7.84 (s, 1H, NH), 7.53–
7.08 (m, 8H, Ar–H), 6.84 (s, 1H, N–CH–Ar), 4.72 (dd,
J = 7.66, 4.68 Hz, 1H, N–CH–CO), 3.75–3.66 (m, 16H,
N–CH2, O–CH2), 3.57 (s, 3H, O–CH3), 3.21–3.19 (m, 2H,
CH2), 2.31 (s, 3H, Ar–CH3); 13C NMR (50 MHz, CDCl3):
21.49, 22.74, 44.14, 52.25, 54.23, 56.76, 67.22, 109.15,
111.33, 118.76, 120.06, 122.42, 127.31, 127.71, 129.63,
134.10, 136.85, 137.55, 139.30, 165.46, 166.85, 172.67; Anal.
calcd. for C31H35N7O4: C 65.36, H 6.19, N 17.21; Found: C
65.17, H 6.38, N 17.48%.
6.4.12. ( )trans-1-(4-chlorophenyl)-2-(4,6-di-morpholin-4yl-
[1,3,5]-triazin-2yl)-2,3,4,9-tetrahydro-1H-β-carboline-3-
carboxylic acid methyl ester (26)
Yield: 68%; m.p. 224–227 °C (dec.); FAB-MS: 590 (M
6.4.9. ( )trans-2-[4,6-Bis-(4-methylpiperazin-1-yl)-[1,3,5]-
triazin-2-yl]-1-p-tolyl-2,3,4,9-tetrahydro-1H-β-carboline-3-
carboxylic acid methyl ester (23)
+ 1); IR (KBr): 3364, 3059, 2969, 2854, 1537, 1560, 1432,
1
1354, 1260 cm–1; H NMR (200 MHz, CDCl3): δ 7.79 (bs,
1H, NH), 7.52–7.10 (m, 8H, Ar–H), 6.76 (s, 1H, N–CH–Ar),
4.78 (dd, J = 7.82, 4.78 Hz, 1H, N–CH–CO), 3.74–3.65 (m,
16H, N–CH2, O–CH2), 3.57 (s, 3H, O–CH3), 3.24–3.21 (m,
2H, CH2); 13C NMR (50 MHz, CDCl3): δ 22.78, 44.67,
52.22, 54.32, 56.79, 67.78, 109.39, 111.76, 119.12, 120.02,
122.72, 127.43, 128.43, 130.33, 131.12, 133.79, 136.58,
139.97, 165.55, 166.00, 172.83; Anal. calcd. for
C30H32ClN7O4: C 61.06, H 5.12, N 16.61; Found: C 60.78,
H 5.24, N 16.45%.
Yield: 63%; m.p. 160–162 °C; FAB-MS: 596 (M + 1); IR
(KBr): 3387, 3078, 2936, 2855, 1739, 1543, 1443, 1359, 1259
1
cm–1; H NMR (200 MHz, CDCl3): δ 8.43 (s, 1H, NH), 7.53-
7.08 (m, 8H, Ar–H), 6.93 (s, 1H, N–CH–Ar), 4.60 (dd,
J = 7.76, 4.62 Hz, 1H, N–CH–CO), 3.90 (t, 8H, J = 5.08 Hz,
N–CH2), 3.57 (s, 3H, O–CH3), 3.19-3.09 (m, 2H, CH2), 2.35
(t, 8H, J = 4.92 Hz, N–CH2), 2.31 (s, 3H, Ar–CH3), 2.25 (s,
6H, N–CH3); 13C NMR (50 MHz, CDCl3): δ 21.49, 22.61,
43.32, 46.54, 52.19, 53.99, 55.31, 56.57, 109.53, 111.24,

A. Kumar et al. / European Journal of Medicinal Chemistry 41 (2006) 106–113
113
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6.4.13. ( )trans-2-[4,6-Bis-(4-methylpiperazin-1-yl)-[1,3,5]-
triazin-2-yl]-1-(4-chlorophenyl)-2,3,4,9-tetrahydro-1H-β-
carboline-3-carboxylic acid methyl ester (27)
Yield: 65%; m.p. 181–183 °C; FAB-MS: 616 (M + 1); IR
(KBr): 3345, 3069, 2932, 1726, 1552, 1440, 1357, 1278 cm–1;
1H NMR (200 MHz, CDCl3) δ 8.12 (bs, 1H, NH), 7.53–7.09
(m, 8H, Ar–H), 6.81 (s, 1H, N–CH–Ar), 4.76 (dd, 7.76, 4.88
Hz, 1H, N–CH–CO), 3.69 (t, 8H, J = 4.9 Hz, N–CH2), 3.57 (s,
3H, O–CH3), 3.22–3.11 (m, 2H, CH2), 2.35 (t, 8H, J = 5.14
Hz, N–CH2), 2.28 (s, 6H, N–CH3); 13C NMR (50 MHz,
CDCl3): 22.78, 43.33, 46.48, 52.30, 54.26, 55.22, 56.39,
109.19, 111.36, 118.83, 120.12, 122.54, 127.23, 127.78,
129.07, 133.47, 136.91, 137.32, 141.37, 165.14, 166.83,
172.57; Anal. calcd. for C32H38ClN9O2; C 62.37, H 6.22, N
20.46; Found: C 62.13, H 5.95, N 20.24%.
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We two us (A.K. and S.B.K.) thanks to CSIR New Delhi for
the award of Senior Research Fellowship (SRF). We are also
thankful to Shiv Ram for his help in evaluating the biological
activity. We are also thankful to SAIF Division, CDRI, Luck-
now for providing spectroscopic data.
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