Synthesis of 2,4,6-trisubstituted pyrimidine and triazine heterocycles as antileishmanial agents

Article abstract of DOI:10.1016/j.bmc.2006.08.009

A series of 2,4,6 trisubstituted pyrimidines and triazines have been synthesized and screened for its in vitro antileishmanial activity profile in promastigote model. Nine compounds have shown >94% inhibition against promastigotes at a concentration of 10

Full text of DOI:10.1016/j.bmc.2006.08.009

Bioorganic & Medicinal Chemistry 14 (2006) 7706–7715
Synthesis of 2,4,6-trisubstituted pyrimidine and triazine
heterocycles as antileishmanial agents
Naresh Sunduru,a Anu Agarwal,a Sanjay Babu Katiyar,a Nishi,b Neena Goyal,c
Suman Guptab and Prem M. S. Chauhana,*
aDivision of Medicinal Chemistry, Central Drug Research Institute, Lucknow 226001, India
bDivision of Parasitology, Central Drug Research Institute, Lucknow 226001, India
cDivision of Biochemistry, Central Drug Research Institute, Lucknow 226001, India
Received 20 June 2006; revised 8 August 2006; accepted 9 August 2006
Available online 30 August 2006
Abstract—A series of 2,4,6 trisubstituted pyrimidines and triazines have been synthesized and screened for its in vitro antileishma-
nial activity profile in promastigote model. Nine compounds have shown >94% inhibition against promastigotes at a concentration
of 10 lg/mL.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
stibogluconate (Pentostam) and meglumine antimonate
(Glucantime), despite the fact that they exhibit renal
and cardiac toxicity. Although new drugs, that is,
amphotericin B and its lipid complex are quite effective
but they are expensive and out of the reach of poor
people.2,5 Newly introduced first orally active drug mil-
tefosine, a phosphocholine analogue, is quite effective
presenting severe gastrointestinal problems and also
shows teratogenic effects and cannot be used in the preg-
nant women.6,7 The search for new drugs continues,
with bisphosphonates, for example, residronate and
pamidronate. It is also known that these drugs also con-
tribute to increased co-infections leishmaniasis-AIDS.
No treatment has proven effective in achieving radical
cure of visceral leishmaniasis when it is associated with
HIV infection. Therefore, development of more effective
and safer chemotherapeutic agents for treating Leishma-
nias remains desirable.8
Leishmaniasis is caused by different species belonging to
the genus Leishmania, a protozoan which is transmitted
to humans by the bite of an insect vector, phlebotomine
sandfly. Leishmaniasis has an overwhelming impact on
the global public health and is endemic in many tropical
and subtropical regions of the world. It affects around
12 million people of the world and 350 million are esti-
mated to be prone to the disease, of which around 1.7
million people will be infected each year.1–3 Infection
by various strains of Leishmania causes a wide spectrum
of disease in humans, with many different clinical
manifestations, that is, cutaneous, mucocutaneous and
visceral. Visceral form of Leishmaniasis, commonly
known as Kala-azar, is caused by the parasite Leishman-
ia donovani, which affects 61 out of the 88 countries
worldwide. It attacks the phagocytic cells of the spleen,
liver, and bone marrow, and is fatal in more than 90% of
the untreated cases.4
R
N
N
N
SCH3
R1
There is still no effective vaccine for Kala-azar and che-
motherapy remains the most effective control measure.
The drugs for the treatment of leishmaniasis are sodium
R
N
N
N
N
R1
N
NH2
15-27
34-47
Keywords: Dihydrofolate reductase; Pyrimidine; Triazine; Antileish-
manial agents.
Compounds of both synthetic and natural origin com-
prising a diverse group of chemical structures have been
reported as antileishmanial agents. These include mostly
*
Corresponding author. Tel.: +91 522 2212411; fax: +91 522
2623405; e-mail addresses: prem_chauhan_2000@yahoo.com;
premsc58@hotmail.com
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.08.009

N. Sunduru et al. / Bioorg. Med. Chem. 14 (2006) 7706–7715
7707
the nitrogen heterocycles as quinolines,9 acridines,10
O
O
phenothiazines,11 pyrimidines,12 purines,13 bis-benzami-
dines,14 pyrazolo[3,4-b]pyridine,15 benzothiazoles,16
triazines,17 and imidazolidine.18 Other classes of com-
pounds include buparvaquone-oxime,19 chalcones,20
quinines,21 amino acid esters and amides,22 amino
alcohols,23 alkyl phospholipids,24 ether phospholipids,25
sulfanilamides,26 artemisinin,27 and certain Platinum
complexes.28
a
+
N
CHO
CH3
N
X
X
1
13, X = S
14, X = O
b
X
N
N
Dihydrofolate reductase (DHFR) is an important target
site in most of the parasitic diseases. Most of the clini-
cally used DHFR inhibitors show less selectivity for
leishmanial enzymes.29 This is due to the fact that the
gene for pteridine reductase (PTR1) is amplified in some
leishmanial mutants. PTR1 can reduce pterins and fo-
lates and therefore act as a bypass for DHFR inhibition.
This implies that antifolate drugs must simultaneously
target both DHFR and PTR1 to be successful antileish-
manials.30 A number of compounds having pyrimidine
and triazine moiety are reported to be potent inhibitors
of PTR1 in Leishmania.17,31 Pyridine, pyrimidine, and
triazine class of compounds are previously reported to
be potential antileishmanial agents. Based on these
observations we hypothesized and synthesized hybrid
derivatives having both pyridine with pyrimidine moiety
and pyrazole with triazine moiety. The synthesized com-
pounds can act as an inhibitor of PTR1 as well as an
inhibitor of DHFR and thus can act as potential antile-
ishmanial agents.
N
NH2
26, X = S
27, X = O
Scheme 2. Reagents and conditions: (a) 10% aq NaOH, methanol,
0 ꢁC rt, 30 min; (b) GuanidineÆHCl, sodium isopropoxide, isopropanol,
reflux, 8 h.
14 were further cyclized with guanidine hydrochloride
in the presence of sodium isopropoxide (synthesized
in situ by adding sodium metal in isopropanol) to afford
the 2,4,6-trisubstituted pyrimidines 15–25 (Scheme 1)
and 26, 27 (Scheme 2).
To synthesize the 2,4,6-trisubstituted triazine com-
pounds (34–47), substituted acetophenone was reacted
with CS2 in presence of NaH followed by methylation
with methyl iodide35,36 to yield corresponding 3,3-bis-
methylsulfanyl-1-(substituted-phenyl)-propenone (28,
29). The compounds 28, 29 were cyclized with hydrazine
hydrate37,38 in methanol to obtain corresponding 5-
methylsulfanyl-3-(substituted-phenyl)-1H-pyrazole (30,
31). The compounds 30, 31 were further reacted with
cyanuric chloride (2,4,6-trichloro-1,3,5-triazine) in pres-
ence of K2CO3 in dry THF to yield corresponding 2,4-
dichloro-6-[5-methylsulfanyl-3-(substituted-phenyl)-pyr-
azol-1-yl]-[1, 3,5]-triazine (32, 33), which were subjected
to nucleophilic substitution with different amines to af-
ford the final targeted compounds 34–47 (Scheme 3).
As part of our ongoing program devoted to the synthesis
of diverse heterocycles as anti-infective agents,32 we had
previously reported antiparasitic activity in substituted
pyrimidines, pyridines, triazines, and quinolines.33 This
communication describes the synthesis of 2,4,6-substi-
tuted pyrimidines and triazines as antileishmanial
agents.
2. Chemistry
3. Antileishmanial activity
To synthesize the 2,4,6-trisubstituted pyrimidine com-
pounds (15–27), 4-acetylpyridine was reacted with differ-
ent aldehydes in 10% aq NaOH and methanol to yield
the corresponding chalcones 2–14.34 The chalcones 2–
The L. donovani promastigotes (MHOM/IN/Dd8; origi-
nally obtained from Imperial college, London) were
transfected with firefly luciferase gene and the transfec-
tants were maintained in medium 199 (Sigma chemical
Co., USA) supplemented with 10% fetal calf serum
(GIBCO) and 1% penicillin (50 U/ml), streptomycin
(50 lg/ml) solution (Sigma) under pressure of G418
(Sigma).39
O
O
R
a
R
N
N
CHO
+
CH3
1
2-12
b
The in vitro effect of the compounds on the growth of
promastigotes was assessed by monitoring the luciferase
activity of viable cells after treatment. The transgenic
promastigotes of late log phase were seeded at 5 · 105/
100 ll medium 199 well in 96-well flat-bottomed micro-
titer (MT) plates (CELLSTAR) and incubated for 72 h
in medium alone or in the presence of serial dilutions
of drugs (1–10 lg/ml) in DMSO.40 Parallel dilutions of
DMSO were used as controls. After incubation, an ali-
quot (50 ll) of promastigote suspension was aspirated
R
N
N
N
NH2
15-25
Scheme 1. Reagents and conditions: (a) 10% aq NaOH, methanol,
0 ꢁC rt, 30 min; (b) GuanidineÆHCl, sodium isopropoxide, isopropanol,
reflux, 8 h.

7708
N. Sunduru et al. / Bioorg. Med. Chem. 14 (2006) 7706–7715
Table 1.
Compound
SCH3
SCH3
CH3
O
a
R
R1
R
R
O
34
35
36
37
38
39
40
41
42
43
44
45
46
47
OCH3
N
N
N
Ph
R= OCH3, Piperidine
28, R= OCH3
29, R= Piperidine
b
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
N
CH3
R
N
N
SCH3
R
c
N
N
O
N
N
N
SCH3
H
30, R= OCH3
31, R= Piperidine
Cl
N
Cl
d
N
32, R= OCH3
33, R= Piperidine
R
HN
N
N
N
SCH3
H3C
HN
N
R1
N
R1
HN H2C
34-47
Scheme 3. Reagents and conditions: (a) CS2, NaH, MeI, THF, 0 ꢁC
reflux; (b) NH2NH2ÆH2O, MeOH, reflux; (c) cyanuric chloride, K2CO3,
THF, reflux; (d) Various amines, K2CO3, THF, reflux.
HN(H2C)2
N
N
O
O
HN(H2C)3
H3CO
from each well of a 96-well plate and mixed with an
equal volume of stready Glo(R) reagent (Promega) and
luminescence was measured by a luminometer. The val-
ues were expressed as relative luminescence unit (RLU).
N
N
N
N ꢀ n
N
CH2Ph
Percentage inhibition ¼
ꢁ 100
N
Where N is average relative luminescence unit (RLU) of
control wells; n is average RLU of treated wells.
N
HN(H2C)3
N
O
O
N
N
N
N CH3
4. Results and discussion
The in vitro biological activities of trisubstituted pyrim-
idines and triazines have shown encouraging results
(Tables 2 and 3) against promastigotes of L donovani.
HN(H2C)2
N
The compound 15 having R as phenyl group exhibited
ꢂ80% inhibition at a concentration of 10lg/mL. Substi-
tution of methoxy group at para position on the phenyl
ring (16) slightly increased the activity having an inhibi-
tion of ꢂ85%.
Compounds 26 and 27 having heterocyclic groups as
furan and thiophene exhibited a sharp reduction in
activity.
The compound 34 having methoxy group as R and phe-
nylpiperazine as R1 has shown no inhibition, while by
substituting R1 with methylpiperazine (35) has shown
increase in inhibition noticeably by 96%, 85%, and
69% at 10, 5, and 2 lg/mL, respectively. Substitution
of R1 with morpholine(36) further increased the inhibi-
tion by 98%, 97%, and 72% at 10, 5, and 2 lg/mL,
respectively, and with piperidine(37) the inhibition in-
creased further at lower concentrations by 98%, 94%,
78%, and 73% at 10, 5, 2, and 1 lg/mL, respectively.
While by substituting R1 with cyclohexylamine(38)
decreased the inhibition by 88% and 87% at 10 and
5 lg/mL, respectively, and with o-toulidine (39) and
Disubstitution of the phenyl ring with methoxy group
(17, 18, 19) further increased the activity and compound
19 has shown 98% and 89% inhibition at a concentration
of 10 and 5 lg/mL, respectively. Trisubstitution of the
methoxy group on the phenyl ring (20, 21) completely
diminished the activity. Substitution of methyl group
on phenyl ring (22) increased the activity, whereas sub-
stitution of thiomethyl group (23) and chloro group
(25) completely diminished the activity. Disubstitution
of methyl group (24) further increased the activity and
the compound 24 has shown 98% and 94% inhibition
at a concentration of 10 and 5 lg/mL, respectively.

N. Sunduru et al. / Bioorg. Med. Chem. 14 (2006) 7706–7715
7709
Table 2.
Compound
The synthesized trisubstituted pyrimidines and triazines
have shown good in vitro activity. These compounds are
new lead in antileishmanial chemotherapy. These com-
pounds can be very useful for further optimization work
in antileishmanial chemotherapy.
R
% inhibition
10 lg/mL
5 lg/mL
15
16
17
18
19
20
21
22
23
24
25
26
27
H
80.5
85.2
94.0
88.2
98.3
NI
NI
NI
62.7
NI
89.4
—
4-OMe
2,5-DiOMe
2,3-DiOMe
3,5-DiOMe
2,4,5-TriOMe
3,4,5-TriOMe
4-Me
6. Experimental
IR spectra were recorded on Beckman Aculab-10, Per-
kin Elmer 881 and FTIR 8210 PC, Schimadzu spec-
trophotometers either on KBr discs or in neat.
Nuclear magnetic resonance (NMR) spectra were
recorded on either Bruker Avance DRX-300 MHz or
Bruker DPX 200 FT spectrometers using TMS as an
internal reference. FAB mass spectra were recorded
on JEOL SX 102/DA 6000 mass spectrometer using
Argon/Xenon (6 kV, 10 mA) as the FAB gas. Chemi-
cal analysis was carried out on Carlo-Erba-1108
instrument. The melting points were recorded on an
electrically heated melting point apparatus and are
uncorrected.
NI
—
95.8
NI
68.4
—
4-SMe
3,4-DiMe
4-Cl
—
98.2
NI
94.0
—
19.7
69.6
NI
NI
—
NI, no inhibition.
Table 3.
Compound
% inhibitiona
10 lg/mL
NI
96.2
5 lg/mL
2 lg/mL
1 lg/mL
34
35
36
37
38
39
40
41
42
43
44
45
46
47
—
—
—
85.1
97.3
94.4
87.4
24.5
59.0
93.0
88.8
—
69.4
72.4
78.1
NI
NI
NI
NI
71.2
—
18.6
36.4
73.2
NI
NI
NI
NI
24.5
—
6.1. General procedure for the synthesis of compounds
2–14
98.4
98.9
88.1
21.5
66.3
94.4
Method A: 1 equiv of 4-acetyl pyridine was added
dropwise to a cooled solution of 10% NaOH, 1.0 equiv
of liquid aldehydes over a period of 30 min. The solu-
tion was maintained at 0 ꢁC for an hour and then was
allowed to stir at room temperature. After some time,
a solid started separating out. The solution was further
stirred for about 1 h. The solid was filtered out and
recrystallized from methanol or ethanol to afford crys-
tals of the chalcone having yield in the range 60–75%.
100
NI
16.5
16.26
—
—
NI
—
NI
—
NI
NI
NI
—
—
—
—
—
NI, no inhibition.
a Pentamidine shows 100% inhibition at dose 10, 5, 2 lg/mL and 95%
Method B: In case of solid aldehydes, the aldehydes (1
equiv) were first dissolved in a minimum quantity of
ethanol or methanol (approx 25 ml) and then 10%
NaOH solution (approx 100 ml) was added to it to give
a clear solution. The solution was cooled up to 0 ꢁC
and 1 equiv of 4-acetyl pyridine was added dropwise
to it, in around 30 min. The solution was maintained
at 0 ꢁC for 1 h and then was allowed to stir at room
temperature. After some time, a solid started separating
out. This was stirred for about an hour. The solid was
filtered out and recrystallized from methanol or ethanol
to give crystals of the chalcone having yield in the range
50–60%.
inhibition at 1 lg/mL.39,40
benzylamine (40) the inhibition decreased drastically.
The compound with same R and with N-ethyl-
aminomorpholine as R1 (41) has shown a little increase
in inhibition by 94% and 93% at 10 and 5 lg/mL, respec-
tively, and with N-propylaminomorpholine as R1 (42)
has shown remarkable increase by 100% inhibition at
10 lg/mL and 88%, 71% at 5 and 2 lg/mL, respectively.
Substitution of R1 with o-methoxyphenylpiperazine (43)
and benzylpiperazine (44) decreased the inhibition dras-
tically. The compounds (45, 46, and 47) also have shown
the decrease in inhibition by substituting R with piperi-
dine in compounds 35, 41, and 42, respectively.
6.1.1. 3-Phenyl-1-pyridin-4-yl-propenone (2). The com-
pound was synthesized using the method A. Yield:
75%; mp 172–174 ꢁC; MS: 210 (M+1); IR (KBr) 3521,
1
1956, 1673, 1595, 1411, 1225 cmꢀ1; H NMR (CDCl3,
5. Conclusion
200 MHz) d (ppm) 8.84 (d, 2H, J = 6.0 Hz), 8.01 (d,
2H, J = 7.8 Hz), 7.86 (d, 1H, J = 15.1 Hz), 7.76 (d, 2H,
J = 6.0 Hz), 7.44–7.40 (m, 3H), 7.36 (d, 1H,
J = 15.1 Hz). Anal. Calcd for C14H11NO: C, 80.36; H,
5.30; N, 6.69. Found: C, 80.56; H, 5.53; N, 6.78.
Leishmaniasis is a disease of developing countries. The
majority of antileishmanial chemotherapy relies on
antimonials and benzamidines, which are highly toxic.
Therefore, development of more effective and safer
chemotherapeutic agents for treating Leishmaniasis
remains desirable. There is also lack of interest among
Pharmaceutical industry in the discovery of new antile-
ishmanial agent due to a lack of financial incentive.
6.1.2.
3-(4-Methoxy-phenyl)-1-pyridin-4-yl-propenone
(3). The compound was synthesized using the method
A. Yield: 67%; mp 104–106 ꢁC; MS: 240 (M+1); IR

7710
N. Sunduru et al. / Bioorg. Med. Chem. 14 (2006) 7706–7715
(KBr) 3420, 1946, 1683, 1598, 1489, 1411, 1257 cmꢀ1
;
6.1.8. 1-Pyridin-4-yl-3-p-tolyl-propenone (9). The com-
pound was synthesized using the method A. Yield:
76%; mp 138–140 ꢁC; MS: 224 (M+1); IR (KBr) 3290,
1H NMR (CDCl3, 200 MHz) d (ppm) 8.83 (d, 2H,
J = 6.1 Hz), 7.89 (d, 2H, J = 8.6 Hz), 7.82 (d, 1H,
J = 15.4 Hz), 7.75 (d, 2H, J = 6.1 Hz), 7.37 (d, 1H,
J = 15.4 Hz), 6.92 (d, 2H, J = 8.6 Hz), 3.88 (s, 3H,
OMe). Anal. Calcd for C15H13NO2: C, 75.30; H, 5.48;
N, 5.85. Found: C, 75.54; H, 5.59; N, 5.71.
1967, 1689, 1598, 1492, 1412, 1238 cmꢀ1 1H NMR
;
(CDCl3, 200 MHz) d (ppm) 8.84 (d, 2H, J = 6.0 Hz),
7.84 (d, 1H, J = 15.6 Hz), 7.74 (d, 2H, J = 6.0 Hz),
7.54 (d, 2H, J = 8.2 Hz), 7.37 (d, 1H, J = 15.6 Hz),
7.24 (d, 2H, J = 8.2 Hz), 2.39 (s, 3H); Anal. Calcd for
C15H13NO: C, 80.69; H, 5.87; N, 6.27. Found: C,
80.82; H, 5.62; N, 6.42.
6.1.3. 3-(2,5-Dimethoxy-phenyl)-1-pyridin-4-yl-propenone
(4). The compound was synthesized using the method B.
Yield: 67%; mp 128–130 ꢁC; MS: 270 (M+1); IR (KBr)
3299, 1956, 1685, 1597, 1456, 1411, 1259 cmꢀ1
;
1H
6.1.9. 3-(4-Methylsulfanyl-phenyl)-1-pyridin-4-yl-prope-
none (10). The compound was synthesized using the
method A. Yield: 70%; mp 94–96 ꢁC; MS: 256 (M+1);
NMR (CDCl3, 200 MHz) d (ppm) 8.85 (d, 2H,
J = 6.0 Hz), 7.82 (d, 1H, J = 15.4 Hz), 7.77 (d, 2H,
J = 6.0 Hz), 7.39 (d, 1H, J = 15.4 Hz), 7.36 (s, 1H),
7.24 (d, 1H, J = 7.2 Hz), 6.76 (d, 1H, J = 7.2 Hz), 3.88
(s, 3H, OMe), 3.85 (s, 3H, OMe). Anal. Calcd for
C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C,
71.58; H, 5.86; N, 4.97.
1
IR (KBr) 3412, 1956, 1682, 1595, 1415, 1225 cmꢀ1; H
NMR (CDCl3, 200 MHz) d (ppm) 8.83 (d, 2H,
J = 6.1 Hz), 7.82 (d, 1H, J = 14.9 Hz), 7.76 (d, 2H,
J = 6.1 Hz), 7.55 (d, 2H, J = 8.6 Hz), 7.38 (d, 1H,
J = 14.9 Hz), 7.26 (d, 2H, J = 8.6 Hz), 2.52 (s, 3H);
Anal. Calcd for C15H13NOS: C, 70.56; H, 5.13; N,
5.49. Found: C, 70.74; H, 5.34; N, 5.34.
6.1.4. 3-(2,3-Dimethoxy-phenyl)-1-pyridin-4-yl-propenone
(5). The compound was synthesized using the method B.
Mp 134–136 ꢁC; MS: 270 (M+1); IR (KBr) 3291, 1934,
6.1.10. 3-(3,4-Dimethyl-phenyl)-1-pyridin-4-yl-propenone
(11). The compound was synthesized using the method
A. Yield: 67%; mp 168–170 ꢁC; MS: 238 (M+1); IR
1
1686, 1588, 1454, 1418, 1255 cmꢀ1; H NMR (CDCl3,
200 MHz) d (ppm) 8.85 (d, 2H, J = 6.1 Hz), 7.50 (d,
1H, J = 7.2 Hz), 7.82 (d, 1H, J = 15.1 Hz), 7.81 (d, 2H,
J = 6.1 Hz), 7.03 (d, 1H, J = 7.3 Hz), 7.38 (d, 1H,
J = 15.1 Hz), 7.12 (t, 1H, J = 5.2 Hz), 3.93 (s, 3H,
OMe), 3.79 (s, 3H, OMe). Anal. Calcd for
C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C,
71.59; H, 5.36; N, 5.45.
(KBr) 3392, 1952, 1687, 1597, 1424, 1249 cmꢀ1 1H
;
NMR (CDCl3, 200 MHz) d (ppm) 8.84 (d, 2H,
J = 6.0 Hz), 7.89 (d, 2H, J = 7.8 Hz), 7.83 (d, 1H,
J = 15.2 Hz), 7.74 (d, 2H, J = 6.0 Hz), 7.51 (s, 1H),
7.40 (d, 1H, J = 15.2 Hz), 7.29 (d, 2H, J = 7.8 Hz),
2.37 (s, 3H), 2.34 (s, 3H). Anal. Calcd for C16H15NO:
C, 80.98; H, 6.37; N, 5.90. Found: C, 81.24; H, 6.09;
N, 5.68.
6.1.5. 3-(3,5-Dimethoxy-phenyl)-1-pyridin-4-yl-propenone
(6). The compound was synthesized using the method B.
Mp 116–118 ꢁC; MS: 270 (M+1); IR (KBr) 3286, 1952,
6.1.11. 3-(4-Chloro-phenyl)-1-pyridin-4-yl-propenone (12).
The compound was synthesized using the method B.
Yield: 68%; mp 205–207 ꢁC; MS: 244 (M+1); IR (KBr)
1
1678, 1596, 1445, 1411, 1250 cmꢀ1; H NMR (CDCl3,
200 MHz) d (ppm) 8.88 (d, 2H, J = 6.0 Hz), 7.84 (d,
1H, J = 14.8 Hz), 7.76 (d, 2H, J = 6.0 Hz), 7.56 (s,
1H), 7.40 (d, 1H, J = 14.8 Hz), 6.97 (s, 2H), 3.90 (s,
6H, OMe). Anal. Calcd for C16H15NO3: C, 71.36; H,
5.61; N, 5.20. Found: C, 71.59; H, 5.36; N, 5.45.
3297, 1948, 1684, 1598, 1489, 1257 cmꢀ1 1H NMR
;
(CDCl3, 200 MHz) d (ppm) 8.85 (d, 2H, J = 6.1 Hz),
7.86 (d, 1H, J = 15.6 Hz), 7.75 (d, 2H, J = 6.1 Hz), 8.09
(d, 2H, J = 8.6 Hz), 7.38 (d, 1H, J = 15.6 Hz), 7.52
(d, 2H, J = 8.6 Hz). Anal. Calcd for C14H10ClNO:
C, 69.00; H, 4.14; N, 5.75. Found: C, 68.74; H, 4.32; N,
5.44.
6.1.6. 1-Pyridin-4-yl-3-(2,4,5-trimethoxy-phenyl)-prope-
none (7). The compound was synthesized using the
method B. Yield: 67%; mp 160–162 ꢁC; MS: 300
(M+1); IR (KBr) 3282, 1939, 1689, 1598, 1468, 1420,
6.1.12. 1-Pyridin-4-yl-3-thiophen-2-yl-propenone (13).
The compound was synthesized using the method A.
Yield: 60%; mp 98–100 ꢁC; MS: 216 (M+1); IR (KBr)
1
1232 cmꢀ1; H NMR (CDCl3, 200 MHz) d (ppm) 8.82
(d, 2H, J = 5.9 Hz), 7.84 (d, 1H, J = 15.6 Hz), 7.72 (d,
2H, J = 5.9 Hz), 7.64 (s, 1H), 7.37 (d, 1H,
J = 15.6 Hz), 6.72 (s, 1H), 3.96 (s, 3H, OMe), 3.92 (s,
3H, 2OMe). Anal. Calcd for C17H17NO4: C, 68.21; H,
5.72; N, 4.68. Found: C, 67.98; H, 5.94; N, 4.91.
3292, 2932, 1948, 1682, 1445, 1250 cmꢀ1 1H NMR
;
(CDCl3, 200 MHz) d (ppm) 8.84 (d, 2H, J = 6.1 Hz),
7.86 (d, 1H, J = 14.9 Hz), 7.80 (d, 1H, J = 3.8 Hz),
7.74 (d, 2H, J = 6.1 Hz), 7.48 (d, 1H, J = 4.6 Hz), 7.40
(d, 1H, J = 14.8 Hz), 7.14 (t, 1H, J = 4.5 Hz). Anal.
Calcd for C12H9NOS: C, 66.95; H, 4.21; N, 6.51. Found:
C, 66.68; H, 4.369; N, 6.27.
6.1.7. 1-Pyridin-4-yl-3-(3,4,5-trimethoxy-phenyl)-prope-
none (8). The compound was synthesized using the
method B. Yield: 67%; mp 194–196 ꢁC; MS: 300
(M+1); IR (KBr) 3278, 1943, 1687, 1596, 1457, 1445,
6.1.13. 3-Furan-2-yl-1-pyridin-4-yl-propenone (14). The
compound was synthesized using the method A. Yield:
65%; mp 125–127 ꢁC; MS: 200 (M+1); IR (KBr) 3286,
1
1245 cmꢀ1; H NMR (CDCl3, 200 MHz) d (ppm) 8.79
(d, 2H, J = 6.0 Hz), 7.82 (d, 1H, J = 15.2 Hz), 7.70 (d,
2H, J = 6.0 Hz), 7.37 (d, 1H, J = 15.2 Hz), 7.30 (s,
2H), 3.98 (s, 3H, 2OMe), 3.95 (s, 3H, OMe). Anal. Calcd
for C17H17NO4: C, 68.21; H, 5.72; N, 4.68. Found: C,
68.47; H, 5.98; N, 4.31.
1952, 1678, 1596, 1445, 1411, 1250 cmꢀ1 1H NMR
;
(CDCl3, 200 MHz) d (ppm) 8.86 (d, 2H, J = 6.0 Hz),
7.88 (d, 1H, J = 15.2 Hz), 7.74 (d, 2H, J = 6.0 Hz),
7.58 (d, 1H, J = 3.9 Hz), 7.40 (d, 1H, J = 15.2 Hz),

N. Sunduru et al. / Bioorg. Med. Chem. 14 (2006) 7706–7715
7711
6.88 (d, 1H, J = 4.4 Hz), 6.65 (t, 1H, J = 4.4 Hz). Anal.
Calcd for C12H9NO2: C, 72.35; H, 4.55; N, 7.03. Found:
C, 72.57; H, 4.37; N, 7.36.
3H, OMe), 3.77 (s, 3H, OMe). 13C (CDCl3, 50 MHz):
167.4, 164.2, 163.9, 162.3, 161.9, 150.5, 146.3, 145.7,
122.8, 122.4, 121.4, 120.6, 116.4, 106.7, 57.2, 56.7. Anal.
Calcd for C17H16N4O2: C, 66.22; H, 5.23; N, 18.17.
Found: C, 66.38; H, 5.38; N, 18.35.
6.2. General procedure for the synthesis of compounds
15–27
6.2.5. 4-(3,5-Dimethoxy-phenyl)-6-pyridin-4-yl-pyrimi-
din-2-ylamine (19). Yield: 70%; mp 130–132 ꢁC; MS:
309 (M+1); IR (KBr) 3387, 2993, 1668, 1511, 1451,
To a solution of 1.1 equiv of guanidine hydrochloride in
50 mL isopropanol, 1.1 equiv of sodium metal was added.
The reaction mixture was refluxed for 2 h and then differ-
ent chalcones (2–14, 1.0 equiv) were added to it and re-
fluxed for 8 h. The solvent was removed from the
reaction mixture under reduced pressure. Water was add-
ed and the aqueous phase was extracted with chloroform.
The organic phases were dried over anhydrous Na2SO4,
filtered, and concentrated. The crude product was puri-
fied by crystallization from methanol or ethanol or some-
times by column chromatography on silica gel (2%
Methanol in chloroform) to afford the pure compounds.
1
1257 cmꢀ1; H NMR (CDCl3, 200 MHz) d (ppm) 8.77
(d, 2H, J = 5.9 Hz), 7.89 (d, 2H, J = 5.9 Hz), 7.67 (s,
1H), 7.54 (s, 1H), 6.95 (s, 2H), 5.28 (s, 2H, NH2), 3.87
(s, 6H, OMe). 13C (CDCl3, 50 MHz): 167.2, 164.7,
164.2, 161.8, 161.2, 150.4, 145.4, 139.3, 121.2, 107.9,
105.2, 57.3. Anal. Calcd for C17H16N4O2: C, 66.22; H,
5.23; N, 18.17. Found: C, 66.38; H, 5.44; N, 18.38.
6.2.6. 4-Pyridin-4-yl-6-(2,4,5-trimethoxy-phenyl)-pyrimi-
din-2-ylamine (20). Yield: 72%; mp 176–178 ꢁC; MS: 339
(M+1); IR (KBr) 3428, 2981, 1654, 1509, 1458,
1
6.2.1. 4-Phenyl-6-pyridin-4-yl-pyrimidin-2-ylamine (15).
Yield: 70%; mp 176–178 ꢁC; MS: 249 (M+1), IR (KBr)
1254 cmꢀ1; H NMR (CDCl3, 200 MHz) d (ppm) 8.75
(d, 2H, J = 6.1 Hz), 7.90 (d, 2H, J = 6.1 Hz), 7.83 (s,
1H), 7.65 (s, 1H), 6.61 (s, 1H), 5.24 (s, 2H, NH2), 3.97
(s, 3H, OMe), 3.93 (s, 6H, 2OMe). 13C (CDCl3,
50 MHz): 167.2, 164.6, 163.9, 157.1, 155.8, 154.6,
147.3, 144.3, 121.6, 118.9, 114.2, 107.6, 98.3, 57.2,
57.0, 56.6. Anal. Calcd for C18H18N4O3: C, 63.89; H,
5.36; N, 16.56. Found: C, 63.74; H, 5.49; N, 16.68.
3387, 2993, 1668, 1511, 1451, 1257 cmꢀ1 1H NMR
;
(CDCl3, 200 MHz) d (ppm) 8.75 (d, 2H, J = 5.9 Hz),
8.09 (d, 2H, J = 7.8 Hz), 7.90 (d, 2H, J = 5.9 Hz),
7.520-7.49 (m, 3H), 7.45 (s, 1H), 5.28 (s, 2H, NH2).
13C (CDCl3, 50 MHz): 167.4, 164.2, 164.0, 150.9,
145.4, 137.6, 131.2, 129.3, 127.6, 121.5, 104.7. Anal.
Calcd for C15H12N4: C, 72.56; H, 4.87; N, 22.57. Found:
C, 72.38; H, 4.56; N, 22.74.
6.2.7. 4-Pyridin-4-yl-6-(3,4,5-trimethoxy-phenyl)-pyrimi-
din-2-ylamine (21). Yield: 74%; mp 206–208 ꢁC; MS: 339
(M+1); IR (KBr) 3396, 2990, 1666, 1515, 1452,
6.2.2. 4-(4-Methoxy-phenyl)-6-pyridin-4-yl-pyrimidin-2-
ylamine (16). Yield: 68%; mp 128–130 ꢁC; MS: 279
(M+1), IR (KBr) 3410, 2986, 1664, 1524, 1442,
1
1256 cmꢀ1; H NMR (CDCl3, 200 MHz) d (ppm) 8.77
(d, 2H, J = 6.2 Hz), 7.91 (d, 2H, J = 6.2 Hz), 7.41 (s,
1H), 7.31 (s, 2H), 5.28 (s, 2H, NH2), 3.98 (s, 6H,
OMe), 3.92 (s, 3H, OMe). 13C (CDCl3, 50 MHz):
167.1, 164.8, 163.9, 157.2, 155.6, 154.4, 140.8, 134.6,
121.6, 105.1, 104.7, 61.4, 56.8. Anal. Calcd for
C18H18N4O3: C, 63.89; H, 5.36; N, 16.56. Found: C,
63.68; H, 5.14; N, 16.34.
1
1262 cmꢀ1; H NMR (CDCl3, 200 MHz) d (ppm) 8.77
(d, 2H, J = 6.0 Hz), 8.04 (d, 2H, J = 8.8 Hz), 7.89 (d,
2H, J = 6.0 Hz), 7.45 (s, 1H), 7.03 (d, 2H, J = 8.8 Hz),
5.21 (s, 2H, NH2), 3.88 (s, 3H, OMe). 13C (CDCl3,
50 MHz): 167.4, 164.4, 163.9, 162.9, 150.4, 145.5,
129.9, 128.6, 121.0, 114.0, 104.2, 55.4. Anal. Calcd for
C16H14N4O: C, 69.05; H, 5.07; N, 20.13. Found: C,
69.28; H, 5.23; N, 20.32.
6.2.8. 4-Pyridin-4-yl-6-p-tolyl-pyrimidin-2-ylamine (22).
Yield: 75%; mp 182–184 ꢁC; MS: 263 (M+1); IR (KBr)
6.2.3. 4-(2,5-Dimethoxy-phenyl)-6-pyridin-4-yl-pyrimi-
din-2-ylamine (17). Yield: 67%; mp 194–196 ꢁC; MS:
309 (M+1), IR (KBr) 3415, 2998, 1648, 1520, 1451,
3387, 2993, 1668, 1511, 1451, 1257 cmꢀ1 1H NMR
;
(CDCl3, 200 MHz) d (ppm) 8.75 (d, 2H, J = 6.1 Hz),
7.98 (d, 2H, J = 7.9 Hz), 7.88 (d, 2H, J = 6.1 Hz), 7.45
(s, 1H), 7.31 (d, 2 H, J = 7.9 Hz), 5.39 (s, 2H, NH2),
2.42 (s, 3H, Me). 13C (CDCl3, 50 MHz): 167.3, 164.2,
163.8, 150.9, 145.5, 141.7, 134.8, 129.9, 127.5, 121.5,
104.4, 21.9. Anal. Calcd for C16H14N4: C, 73.26; H,
5.38; N, 21.36. Found: C, 73.32; H, 5.61; N, 21.59.
1
1248 cmꢀ1; H NMR (CDCl3, 200 MHz) d (ppm) 8.78
(d, 2H, J = 5.9 Hz), 7.89 (d, 2H, J = 5.9 Hz), 7.52 (s,
1H), 7.44 (s, 1H), 7.22 (d, 1H, J = 6.8 Hz), 6.71 (d,
1H, J = 6.8 Hz), 5.17 (s, 2H, NH2), 3.84 (s, 3H, OMe),
3.82 (s, 3H, OMe). 13C (CDCl3, 50 MHz): 167.4,
164.6, 163.9, 162.2, 161.9, 152.9, 146.1, 128.3, 121.6,
116.9, 116.3, 113.7, 107.9, 56.9, 56.3. Anal. Calcd for
C17H16N4O2: C, 66.22; H, 5.23; N, 18.17. Found: C,
66.44; H, 5.42; N, 18.45.
6.2.9. 4-(4-Methylsulfanyl-phenyl)-6-pyridin-4-yl-pyrimi-
din-2-ylamine (23). Yield: 72%; mp 184–186 ꢁC; MS: 295
(M+1), IR (KBr) 3407, 2987, 1672, 1532, 1462,
1
1262 cmꢀ1; H NMR (CDCl3, 200 MHz) d (ppm) 8.77
6.2.4. 4-(2,3-Dimethoxy-phenyl)-6-pyridin-4-yl-pyrimi-
din-2-ylamine (18). Yield: 65%; mp 162–164 ꢁC; MS:
309 (M+1); IR (KBr) 3399, 2993, 1662, 1518, 1455,
(d, 2H, J = 6.1 Hz), 8.02 (d, 2H, J = 8.6 Hz), 7.88 (d,
2H, J = 6.1 Hz), 7.46 (s, 1H), 7.35 (d, 2H, J = 8.6 Hz),
5.28 (s, 2H, NH2), 2.54 (s, 3H, SMe). 13C (CDCl3,
50 MHz): 167.3, 164.3, 163.9, 151.2, 145.8, 142.8,
134.4, 127.8, 126.4, 121.4, 104.2, 18.7. Anal. Calcd for
C16H14N4S: C, 65.28; H, 4.79; N, 19.03. Found: C,
65.44; H, 4.59; N, 19.23.
1
1257 cmꢀ1; H NMR (CDCl3, 200 MHz) d (ppm) 8.76
(d, 2H, J = 6.1 Hz), 7.90 (d, 2H, J = 6.1 Hz), 7.72 (s,
1H), 7.42 (d, 1H, J = 8.2 Hz), 7.18 (t, 1H, J = 6.8 Hz),
7.02 (d, 1H, J = 8.4 Hz), 5.26 (s, 2H, NH2), 3.93 (s,

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N. Sunduru et al. / Bioorg. Med. Chem. 14 (2006) 7706–7715
6.2.10. 4-(3,4-Dimethyl-phenyl)-6-pyridin-4-yl-pyrimidin-
2-ylamine (24). Yield: 68%; mp 182–184 ꢁC; MS: 277
(M+1); IR (KBr) 3428, 2968, 1654, 1526, 1458,
6.3.1. 1-(4-Methoxy-phenyl)-3,3-bis-methylsulfanyl-prop-
enone (28). Yield: 96%; mp 90 ꢁC; FAB-MS: 255
(M+1); IR(KBr): 3059, 3012, 2918, 2843, 1693, 1610,
1
1257 cmꢀ1; H NMR (CDCl3, 200 MHz) d (ppm) 8.75
1598, 1473, 1344, 831 cmꢀ1 1H NMR (200 MHz,
;
(d, 2H, J = 6.1 Hz), 7.94 (d, 2H, J = 6.1 Hz), 7.80 (d,
1H, J = 7.9 Hz), 7.47 (s, 1H), 7.37 (s, 1H), 7.25 (d, 1H,
J = 7.9 Hz), 5.46 (s, 2H, NH2), 2.36 (s, 3H), 2.34 (s,
3H). 13C (CDCl3, 50 MHz): 167.2, 164.1, 163.9, 150.8,
145.4, 141.6, 134.7, 129.8, 127.4, 121.4, 104.4, 20.3,
20.1. Anal. Calcd for C17H16N4: C, 73.89; H, 5.84; N,
20.27. Found: C, 73.68; H, 5.61; N, 20.45.
CDCl3): d (pap) 7.91 (d, 2H, J = 8.84 Hz, Are-H), 6.93
(d, 2H, J = 8.84 Hz, Are-H), 6.75 (s, 1H, @CH), 3.86
(s, 3H, OCH3), 2.55 (s, 3H,SCH3), 2.52 (s, 3H, SCH3);
Anal. Calcd for C12H14O2S2: C, 56.66; H, 5.55. Found:
C, 56.78; H, 5.52.
6.3.2. 3,3-Bis-methylsulfanyl-1-(4-piperidin-1-yl-phenyl)-
propenone (29). Yield: 72%; mp 110 ꢁC; FAB-MS: 308
(M+1); IR(KBr): 3011, 2928, 1658, 1596, 1517, 1470,
6.2.11. 4-(4-Chloro-phenyl)-6-pyridin-4-yl-pyrimidin-2-
ylamine (25). Yield: 72%; mp 242–244 ꢁC; MS: 283
(M+1); IR (KBr) 3426, 2976, 1662, 1518, 1454,
1
1355, 833 cmꢀ1; H NMR (200 MHz, CDCl3): d (ppm)
7.85 (d, 2H, J = 8.63 Hz, Ar-H), 6.86 (d, 2H,
J = 8.63 Hz, Ar-H), 6.76 (s, 1H, @CH), 3.31 (t, 4H,
J = 4.70 Hz, NCH2), 2.54 (s, 3H,SCH3), 2.50 (s, 3H,
SCH3), 1.65-1.56 (m, 6H, CH2); Anal. Calcd for
C16H21NOS2: C, 62.50; H, 6.88; N, 4.56. Found: C,
62.71; H, 6.93; N, 4.59.
1
1260 cmꢀ1; H NMR (CDCl3, 200 MHz) d (ppm) 8.75
(d, 2H, J = 6.0 Hz), 8.02 (d, 2H, J = 7.9 Hz), 7.92 (d,
2H, J = 6.0 Hz), 7.46 (d, 2H, J = 7.9 Hz), 7.41 (s, 1H),
5.26 (s, 2H, NH2). 13C (CDCl3, 50 MHz): 167.4, 164.6,
163.9, 155.9, 145.6, 135.2, 134.4, 130.2, 128.8, 121.2,
104.4. Anal. Calcd for C15H11ClN4: C, 63.72; H, 3.92;
N, 19.82. Found: C, 63.98; H, 3.67; N, 19.65.
6.4. General procedure for the synthesis
of compounds 30, 31
6.2.12.
4-Pyridin-4-yl-6-thiophen-2-yl-pyrimidin-2-yl-
amine (26). Yield: 65%; mp Decomposes at 210 ꢁC;
MS: 255 (M+1); IR (KBr) 3412, 2989, 1654, 1522,
The solution of compounds 28, 29 (1 equiv) and hydra-
zine hydrate (1.2 equiv) in MeOH was refluxed for 4 h.
The solvent was removed under reduced pressure to give
solid residue which was dissolved in CHCl3 and washed
with water (three times), dried over anhydrous Na2SO4,
concentrated, and crystallized with CHCl3-hexane to
obtain respective compounds 30, 31 yielding in the range
of 65–70%.
1456, 1248 cmꢀ1
;
1H NMR (CDCl3, 200 MHz) d
(ppm) 8.76 (d, 2H, J = 6.0 Hz), 7.91 (d, 2H,
J = 6.0 Hz), 7.76 (d, 1H, J = 3.8 Hz), 7.48 (d, 1H,
J = 4.6 Hz), 7.41 (s, 1H), 7.15 (t, 1H, J = 4.5 Hz). 13C
(CDCl3, 50 MHz): 167.2, 164.2, 163.8, 151.3, 145.4,
144.2, 128.1, 125.8, 123.2, 121.2, 104.6. Anal. Calcd
for C13H10N4S: C, 61.40; H, 3.96; N, 22.03. Found: C,
61.64; H, 4.18; N, 22.41.
6.4.1. 3-(4-Methoxy-phenyl)-5-methylsulfanyl-1H-pyra-
zole (30). Yield: 68%; mp 113–115 ꢁC; FAB-MS: 221
(M+1); IR(KBr): 3456, 3111, 3022, 2933, 2868, 1611,
6.2.13. 4-Furan-2-yl-6-pyridin-4-yl-pyrimidin-2-yl-amine
(27). Yield: 62%; mp Decomposes at 220 ꢁC; MS: 239
1505, 1459, 1328, 831 cmꢀ1 1H NMR (200 MHz,
;
(M+1), IR (KBr) 3416, 2979, 1654, 1518, 1456 cmꢀ1
;
CDCl3): d (ppm) 7.55 (d, 2H, J = 8.77 Hz, Ar-H), 6.93
(d, 2H, J = 8.77 Hz, Ar-H), 6.46 (s, 1H, pyrazole-H),
3.83 (s, 3H, OCH3), 2.52 (s, 3H, SCH3); Anal. Calcd
for C11H12N2OS: C, 59.97; H, 5.49; N, 12.72. Found:
C, 59.86; H, 5.57; N, 12.75.
1H NMR (CDCl3, 200 MHz) d (ppm) 8.75 (d, 2H,
J = 6.0 Hz), 7.88 (d, 2H, J = 6.0 Hz), 7.76 (d, 1H,
J = 3.8 Hz), 7.41 (s, 1H), 6.98 (d, 1H, J = 4.6 Hz), 6.72
(t, 1H, J = 4.5 Hz). 13C (CDCl3, 50 MHz): 167.3,
164.2, 163.6, 154.1, 151.3, 145.4, 142.1, 121.2, 110.9,
105.1, 104.6. Anal. Calcd for C13H10N4O: C, 65.54; H,
4.23; N, 23.52. Found: C, 65.68; H, 4.08; N, 23.24.
6.4.2. 1-[4-(5-Methylsulfanyl-1H-pyrazol-3-yl)-phenyl]-
piperidine (31). Yield: 65%; m.p. 134-136 ꢁC; FAB-MS:
274 (M + 1); IR(KBr): 3451, 3031, 2907, 1618, 1580,
1
6.3. General procedure for the synthesis of compounds 28,
29. The mixture, 1 equiv of phenyl-substituted actophe-
none and 1 equiv of carbondisulfide in dry THF, was
added dropwise to an ice-cold stirred suspension of
NaH (2 equiv) in dry THF over a period of 30 min.
The reaction mixture was stirred for 1 h at room temper-
ature and then refluxed for 4 h. The methyl iodide (2.5
equiv) was added in excess by cooling the reaction mix-
ture during 5 min and was allowed to stir for 1 h at
room temperature. Further the reaction mixture was re-
fluxed with stirring for 12 more hours. The solvent was
removed under reduced pressure and the resultant resi-
due was dissolved in chloroform. The organic phase
was washed with water (three times), dried over anhy-
drous Na2SO4. The solution was concentrated and crys-
tallized with CHCl3-hexane to afford the respective
compounds 28, 29 yielding in the range of 80–90%.
1490, 1371, 833 cmꢀ1; H NMR (200 MHz, CDCl3): d
(ppm) 7.47 (d, 2H, J = 8.78 Hz, Ar-H), 6.94 (d, 2H,
J = 8.78 Hz, Ar-H), 6.41 (s, 1H, pyrazole-H), 3.22 (t,
4H, J = 4.75 Hz, NCH2), 2.52 (s, 3H, SCH3), 1.71–1.62
(m, 6H, CH2); Anal. Calcd for C15H19N3S: C, 65.90;
H, 7.00; N, 15.37. Found: C, 65.95; H, 7.16; N, 15.42.
6.5. General procedure for the synthesis of compounds 32, 33
The solution of compound 30, 31 (1 equiv) in dry THF
was added dropwise to an ice-cold mixture of cyanuric
chloride (1.5 equiv) and K2CO3 (2 equiv) in dry THF.
The reaction mixture was stirred at room temperature
for 1 h and then refluxed with stirring for 8 h. The reac-
tion mixture was filtered and solvent was evaporated un-
der vacuum to dryness. The solid mass was dissolved in

N. Sunduru et al. / Bioorg. Med. Chem. 14 (2006) 7706–7715
7713
CHCl3, washed with water (three times) dried over
anhydrous Na2SO4, concentrated, and purified with col-
umn chromatography to afford respective compounds
32, 33 yielding in the range of 70–80%.
7.88 (d, 2H, J = 8.30 Hz, Ar-H), 6.95 (d, 2H,
J = 8.30 Hz, Ar-H), 6.41 (s, 1H, pyrazole-H), 4.10–3.95
(m, 8H, NCH2), 3.85 (s, 3H, OCH3), 2.62–2.45 (m,
11H, NCH2, SCH3), 2.32 (s, 6H, NCH3), 13C NMR
(50 MHz, CDCl3): d (ppm) 165.50, 162.84, 160.50,
153.98, 144.95, 128.01, 114.29, 103.10, 55.28, 46.61,
43.87, 18.28; Anal. Calcd for C24H33N9OS: C,
58.16; H, 6.71; N, 25.43. Found: C, 58.24; H, 6.67; N,
25.59.
6.5.1. 2,4-Dichloro-6-[3-(4-methoxy-phenyl)-5-meth-
ylsulfanyl-pyrazol-1-yl]-[1,3,5]triazine (32)
Yield: 82%; mp 186 ꢁC; FAB-MS: 368 (M+1); IR(KBr):
3005, 2967, 2934, 2841, 1610, 1519, 1464, 1385,
1
846 cmꢀ1; H NMR (200 MHz, CDCl3): d (ppm) 7.55
6.6.3. 2-[3-(4-Methoxy-phenyl)-5-methylsulfanyl-pyrazol-
1-yl]-4,6-di-morpholin-4-yl-[1,3,5]triazine (36). Yield:
57%; mp 223–225 ꢁC; FAB-MS: 470 (M+1); IR(KBr):
3045, 2969, 2914, 2857, 1584, 1500, 1425, 1383,
(d, 2H, J = 8.82 Hz, Ar-H), 6.93 (d, 2H, J = 8.82 Hz,
Ar-H), 6.49 (s, 1H, pyrazole-H), 3.86 (s, 3H, OCH3),
2.58 (s, 3H, SCH3); Anal. Calcd for C14H11Cl2N5OS:
C, 45.66; H, 3.01; N, 19.02. Found: C, 45.73; H, 3.15;
N, 19.13.
1
834 cmꢀ1; H NMR (200 MHz, CDCl3): d (ppm) 7.86
(d, 2H, J = 8.80 Hz, Ar-H), 6.94 (d, 2H, J = 8.80 Hz,
Ar-H), 6.40 (s, 1H, pyrazole-H), 3.98–3.87 (m, 8H,
OCH2), 3.84 (s, 3H, OCH3), 3.82–3.78 (m, 8H,
NCH2), 2.55 (s, 3H, SCH3), 13C NMR (50 MHz,
CDCl3): d (ppm) 165.47, 162.80, 160.54, 154.04,
144.91, 127.98, 114.29, 103.12, 67.18, 55.67, 44.49,
18.20; Anal. Calcd for C22H27N7O3S: C, 56.27; H,
5.80; N, 20.88. Found: C, 56.43; H, 5.91; N, 20.79.
6.5.2. 2,4-Dichloro-6-[5-methylsulfanyl-3-(4-piperidin-1-
yl-phenyl)-pyrazol-1-yl]-[1,3,5]triazine (33)
Yield: 45%; mp 178 ꢁC; FAB-MS: 421 (M+1); IR(KBr):
3035, 2947, 1623, 1575, 1497, 1365, 835 cmꢀ1; 1H NMR
(200 MHz, CDCl3): d (ppm) 7.74 (d, 2H, J = 8.71 Hz,
Ar-H), 6.91 (d, 2H, J = 8.71 Hz, Ar-H), 6.48 (s, 1H, pyr-
azole-H), 3.24 (t, 4H, J = 4.74 Hz, NCH2), 2.54 (s, 3H,
SCH3), 1.69–1.57 (m, 6H, CH2); Anal. Calcd for
C18H18Cl2N6S: C, 45.66; H, 3.01; N, 19.02. Found: C,
45.73; H, 3.15; N, 19.13.
6.6.4. 2-[3-(4-Methoxy-phenyl)-5-methylsulfanyl-pyrazol-
1-yl]-4,6-di-piperidin-1-yl-[1,3,5]triazine (37). Yield: 81%;
mp 170 ꢁC; FAB-MS: 466 (M+1); IR(KBr): 3000, 2929,
2853, 1595, 1498, 1422, 1399, 835 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): d (ppm) 7.87 (d, 2H, J = 8.61 Hz,
Ar-H), 6.93 (d, 2H, J = 8.61 Hz, Ar-H), 6.38 (s, 1H, pyr-
azole-H), 3.90–3.86 (m, 8H, NCH2), 3.83 (s, 3H, OCH3),
2.51 (s, 3H, SCH3), 1.67–1.53 (m, 12H, CH2), 13C NMR
(50 MHz, CDCl3): d (ppm) 165.15, 162.86, 160.33,
153.58, 144.68, 127.96, 114.19, 102.73, 55.65, 44.97,
26.26, 25.23, 18.28; Anal. Calcd for C24H31N7OS: C,
61.91; H, 6.71; N, 21.06. Found: C, 61.89; H, 6.53; N,
21.27.
6.6. General procedure for the synthesis of compounds
34–47
The mixture of compounds 32, 33 (1 equiv), different
amines (2 equiv) listed in Table 1, and K2CO3 (2 equiv)
in dry THF was refluxed for 8 h. The reaction mixture
was filtered and the solvent was evaporated under vac-
uum. The solid residue was dissolved in CHCl3,
washed with water (three times), dried over anhydrous
Na2SO4. The solution was concentrated and purified
with column chromatography using silica-gel as adsor-
bent to obtain respective compounds 34–47 in good
yield.
6.6.5.
N,N0-Dicyclohexyl-6-[3-(4-methoxy-phenyl)-5-
methylsulfanyl-pyrazol-1-yl]-[1,3,5]triazine-2,4-diamine
(38). Yield: 65%; mp 112–114 ꢁC; FAB-MS: 494 (M+1);
IR(KBr): 3429, 3007, 2929, 2852, 1592, 1497, 1381,
1
836 cmꢀ1; H NMR (200 MHz, CDCl3): d (ppm) 7.86
6.6.1. 2-[3-(4-Methoxy-phenyl)-5-methylsulfanyl-pyrazol-
1-yl]-4,6-bis-(4-phenyl-piperazin-1-yl)-[1,3,5]triazine (34).
Yield: 98%; mp 198–200 ꢁC; FAB-MS: 620 (M+1);
IR(KBr): 3000, 2963, 2898, 2862, 1589, 1496, 1426,
(d, 2H, J = 8.44 Hz, Ar-H), 6.93 (d, 2H, J = 8.44 MHz,
Ar-H), 6.37 (s, 1H, pyrazole-H), 4.12–3.98 (m, 2H,
CH), 3.83 (s, 3H, OCH3), 2.50 (s, 3H, SCH3), 2.14–
1.90 (m, 4H, CH2), 1.75–1.62 (m, 4H, CH2), 1.42–1.17
(m, 12H, CH2), 13C NMR (50 MHz, CDCl3): d (ppm)
165.66, 162.62, 160.45, 154.06, 145.39, 128.19, 125.30,
114.17, 103.13, 55.64, 33.68, 25.94, 25.15, 18.32; Anal.
Calcd for C26H35N7OS: C, 63.26; H, 7.15; N, 19.86.
Found: C, 63.41; H, 7.07; N, 19.83.
1
1357, 838 cmꢀ1; H NMR (200 MHz, CDCl3): d (ppm)
7.88 (d, 2H, J = 8.32 Hz, Ar-H), 7.32 (d, 2H,
J = 8.32 Hz, Ar-H), 7.00-6.87 (m, 10H, Ar-H), 6.40 (s,
1H, pyrazole-H), 4.14-4.06 (m, 8H, NCH2), 3.85 (s,
3H, OCH3), 3.28–3.21 (m, 8H, NCH2), 2.55 (s, 3H,
SCH3), 13C NMR (50 MHz, CDCl3): d (ppm) 165.40,
162.89, 160.54, 154.04, 151.67, 144.96, 129.66, 128.04,
120.77, 117.09, 103.14, 55.71, 49.88, 43.86, 18.30; Anal.
Calcd for C34H37N9OS: C, 65.89; H, 6.02; N, 20.34.
Found: C, 65.97; H, 6.23; N, 20.51.
6.6.6. 6-[3-(4-Methoxy-phenyl)-5-methylsulfanyl-pyrazol-
1-yl]-N,N0-di-o-tolyl-[1,3,5]triazine-2,4-diamine (39). Yield:
81%; mp 182–184 ꢁC; FAB-MS: 510 (M+1); IR(KBr):
3227, 3011, 2965, 2915, 2835, 1613, 1581, 1498, 1424,
1
834 cmꢀ1; H NMR (200 MHz, CDCl3): d (ppm) 7.87
6.6.2. 2-[3-(4-Methoxy-phenyl)-5-methylsulfanyl-pyrazol-
1-yl]-4,6-bis-(4-methyl-piperazin-1-yl)-[1,3,5]triazine (35).
Yield: 65%; mp 168–170 ꢁC; FAB-MS: 496 (M+1);
IR(KBr): 3000, 2963, 2898, 2862, 1589, 1496, 1426,
(d, 2H, J = 8.74 Hz, Ar-H), 7.25–7.07 (m, 6H, Ar-H),
6.94 (d, 2H, J = 8.74 Hz, Ar-H), 6.36 (s, 1H, pyrazole-
H), 3.84 (s, 3H, OCH3), 2.52 (s, 3H, SCH3), 2.32 (s, 6H,
Ar-CH3), 13C NMR (50 MHz, CDCl3): d (ppm) 165.64,
163.00, 160.66, 154.65, 146.21, 136.27, 130.90, 128.28,
1
1357, 838 cmꢀ1; H NMR (200 MHz, CDCl3): d (ppm)

7714
N. Sunduru et al. / Bioorg. Med. Chem. 14 (2006) 7706–7715
126.79, 114.30, 103.62, 55.71, 18.62, 18.14; Anal. Calcd
for C28H27N7OS: C, 65.99; H, 5.34; N, 19.24. Found: C,
66.08; H, 5.29; N, 19.39.
6.6.11. 2,4-Bis-(4-benzyl-piperazin-1-yl)-6-[3-(4-methoxy-
phenyl)-5-methylsulfanyl-pyrazol-1-yl]-[1,3,5]triazine (44).
Yield: 85%; mp 176–178 ꢁC; FAB-MS: 648 (M+1);
IR(KBr): 3027, 2934, 2906, 2862, 1588, 1496, 1422,
6.6.7.
N,N0-Dibenzyl-6-[3-(4-methoxy-phenyl)-5-meth-
1399, 845 cmꢀ1 1H NMR (200 MHz, CDCl3): d
;
ylsulfanyl- pyrazol-1-yl]-[1,3,5]triazine-2,4-diamine (40).
Yield: 65%; mp 168–170 ꢁC; FAB-MS: 510 (M+1);
IR(KBr): 3276, 3029, 2922, 2835, 1590, 1496, 1428,
(ppm) 7.85 (d, 2H, J = 8.61 Hz, Ar-H), 7.33–7.29 (m,
10H, Ar-H), 6.92 (d, 2H, J = 8.61 Hz, Ar-H) 6.37 (s,
1H, pyrazole-H), 3.90–3.85 (m, 8H, NCH2), 3.83 (s,
3H, OCH3), 3.55 (s, 4H, NCH2), 2.51–2.42 (m, 11H,
SCH3, NCH2), 13C NMR (50 MHz, CDCl3): d (ppm)
165.53, 162.78, 160.36, 153.89, 151.76, 144.87, 129.64,
128.72, 127.99, 127.60, 114.26, 102.91, 63.53, 55.68,
53.37, 44.23, 18.24; Anal. Calcd for C36H41N9OS: C,
66.74; H, 6.38; N, 19.46. Found: C, 66.81; H, 6.41;
N, 19.37.
1
1379, 835 cmꢀ1; H NMR (200 MHz, CDCl3): d (ppm)
7.86 (d, 2H, J = 8.35 Hz, Ar-H), 7.38–7.28 (m, 10H,
Ar-H), 6.93 (d, 2H, J = 8.35 Hz, Ar-H), 6.38 (s, 1H, pyr-
azole-H), 4.66–4.58 (m, 4H, NCH2), 3.83 (s, 3H, OCH3),
2.48 (s, 3H, SCH3), 13C NMR (50 MHz, CDCl3): d
(ppm) 165.59, 162.72, 160.53, 154.15, 145.71, 139.12,
128.88, 128.15, 127.98, 127.60, 114.34, 103.25, 55.71,
45.25, 18.26; Anal. Calcd for C28H27N7OS: C,
65.99; H, 5.34; N, 19.24. Found: C, 65.94; H, 5.47; N,
19.21.
6.6.12. 6-[5-Methylsulfanyl-3-(4-piperidin-1-yl-phenyl)-
pyrazol-1-yl]-N,N0-bis-(3-morpholin-4-yl-propyl)-[1,3,5]-
triazine-2,4-diamine (45). Yield: 60%; mp 62 ꢁC; FAB-
MS: 638 (M+1); IR(KBr): 3314, 2936, 2853, 2815,
6.6.8. 6-[3-(4-Methoxy-phenyl)-5-methylsulfanyl-pyrazol-
1-yl]-N,N0-bis-(2-morpholin-4-yl-ethyl)-[1,3,5]triazine-2,4-
diamine (41). Yield: 40%; mp 78 ꢁC; FAB-MS: 556
(M+1); IR(KBr): 3296, 3012, 2953, 2855, 1591, 1498,
1589, 1500, 1435, 1379, 808 cmꢀ1
;
1H NMR
(200 MHz, CDCl3): d (ppm) 7.77 (d, 2H, J = 8.06 Hz,
Ar-H), 6.93 (d, 2H, J = 8.06 Hz, Ar-H) 6.36 (s, 1H, pyr-
azole-H), 3.72–3.68 (m, 8H, OCH2), 3.52–3.45 (m, 4H,
NCH2), 2.77 (t, 4H, J = 6.67, NCH2), 2.50–2.36 (m,
15H, SCH3, NCH2), 1.81–1.64 (m, 10H, CH2), 13C
NMR (50 MHz, CDCl3): d (ppm) 166.21, 162.27,
154.33, 152.62, 145.13, 127.59, 115.95, 103.03, 67.24,
57.19, 54.06, 50.26, 40.66, 29.01, 26.02, 24.65, 18.20;
Anal. Calcd for C32H48N10O2S: C, 60.35; H, 7.60; N,
21.99. Found: C, 60.39; H, 7.62; N, 21.91.
1
1426, 1380, 839 cmꢀ1; H NMR (200 MHz, CDCl3): d
(ppm) 7.86 (d, 2H, J = 8.74 Hz, Ar-H), 6.94 (d, 2H,
J = 8.74 Hz, Ar-H), 6.39 (s, 1H, pyrazole-H), 3.84 (s,
3H, OCH3), 3.75–3.69 (m, 8H, OCH2), 3.52–3.49 (m,
4H, NCH2), 2.64–2.53 (m, 12H, NCH2), 2.52 (s, 3H,
SCH3), 13C NMR (50 MHz, CDCl3): d (ppm) 166.28,
162.68, 160.53, 154.25, 145.38, 128.22, 114.21, 103.34,
67.31, 57.61, 55.68, 53.74, 37.43, 18.25; Anal. Calcd for
C26H37N9O3S: C, 56.20; H, 6.71; N, 22.69. Found: C,
56.37; H, 6.87; N, 22.81.
6.6.13. 6-[5-Methylsulfanyl-3-(4-piperidin-1-yl-phenyl)-
pyrazol-1-yl]-N,N0-bis-(2-morpholin-4-yl-ethyl)-[1,3,5]tri-
azine-2,4-diamine (46). Yield: 70%; mp 75–78 ꢁC; FAB-
MS: 610 (M+1); IR(KBr): 3300, 2933, 2836, 2814,
6.6.9. 6-[3-(4-Methoxy-phenyl)-5-methylsulfanyl-pyrazol-
1-yl]-N,N0-bis-(3-morpholin-4-yl-propyl)-[1,3,5]triazine-2,4-
diamine (42). Yield: 65%; mp 152–154 ꢁC; FAB-MS: 584
(M+1); IR(KBr): 3266, 3015, 2927, 2814, 1588, 1496,
1590, 1500, 1456, 1382, 808 cmꢀ1
;
1H NMR
(200 MHz, CDCl3): d (ppm) 7.71 (d, 2H, J = 8.02 Hz,
Ar-H), 6.87 (d, 2H, J = 8.02 Hz, Ar-H) 6.30 (s, 1H, pyr-
azole-H), 3.75–3.66 (m, 8H, OCH2), 3.50–3.43 (m, 4H,
NCH2), 3.19–3.15 (m, 4H, NCH2), 2.57–2.31 (m, 15H,
SCH3, NCH2), 1.92–1.76 (m, 6H, CH2), 13C NMR
(50 MHz, CDCl3): d (ppm) 166.24, 162.55, 154.62,
152.73, 143.68, 127.73, 115.93, 103.28, 67.29, 57.61,
53.76, 50.29, 37.54, 26.07, 24.69, 18.23; Anal. Calcd
for C30H44N10O2S: C, 59.19; H, 7.28; N, 23.01. Found:
C, 59.43; H, 7.35; N, 23.23.
1
1426, 1378, 835 cmꢀ1; H NMR (200 MHz, CDCl3): d
(ppm) 7.85 (d, 2H, J = 8.45 Hz, Ar-H), 6.93 (d, 2H,
J = 8.45 Hz, Ar-H), 6.38 (s, 1H, pyrazole-H), 3.84 (s,
3H, OCH3), 3.77–3.66 (m, 8H, OCH2), 3.55–3.43 (m,
4H, NCH2), 2.58–2.38 (m, 15H, SCH3, NCH2), 1.81–
1.79 (m, 4H, CH2), 13C NMR (50 MHz, CDCl3): d
(ppm) 166.34, 162.53, 160.46, 154.03, 145.32, 128.12,
114.21, 103.14, 67.38, 57.71, 55.66, 54.14, 40.51, 25.85,
18.26; Anal. Calcd for C28H41N9O3S: C, 57.61; H,
7.08; N, 21.59. Found: C, 57.75; H, 7.13; N, 21.67.
6.6.14. 2,4-Bis-(4-methyl-piperazin-1-yl)-6-[5-methylsulfa-
nyl-3-(4-piperidin-1-yl-phenyl)-pyrazol-1-yl]-[1,3,5]triazine
(47). Yield: 50%; mp 68–70 ꢁC; FAB-MS: 550 (M+1);
IR(KBr):2936, 2855, 2800, 1659, 1583, 1502, 1426,
6.6.10. 2-[3-(4-Methoxy-phenyl)-5-methylsulfanyl-pyra-
zol-1-yl]-4,6-bis-[4-(2-methoxy-phenyl)-piperazin-1-yl]-[1,3,
5]triazine (43). Yield: 88%; mp 158–160 ꢁC; FAB-MS: 680
(M+1); IR(KBr): 3001, 2948, 2907, 2828, 1586, 1499,
1
1379, 806 cmꢀ1; H NMR (200 MHz, CDCl3): d (ppm)
1
1425, 1378, 836 cmꢀ1; H NMR (200 MHz, CDCl3): d
7.80 (d, 2H, J = 8.54 Hz, Ar-H), 6.95 (d, 2H,
J = 8.54 Hz, Ar-H) 6.38 (s, 1H, pyrazole-H), 3.57–3.49
(m, 12H, NCH2), 2.60 (t, 8H, J = 5.00, NCH2), 2.52 (s,
3H, SCH3), 2.35 (s, 6H, N-CH3), 1.82–1.67 (m, 6H,
CH2), 13C NMR (50 MHz, CDCl3): d (ppm) 165.24,
162.75, 154.23, 152.62, 144.60, 127.51, 116.02, 102.93,
55.23, 52.85, 46.52, 43.97, 26.06, 24.68, 18.23; Anal.
Calcd for C28H40N10S: C, 61.28; H, 7.35; N, 25.52.
Found: C, 61.47; H, 7.32; N, 25.57.
(ppm) 7.88 (d, 2H, J = 8.57 Hz, Ar-H), 7.04–6.88 (m,
10H, Ar-H), 6.41 (s, 1H, pyrazole-H), 4.20–4.08 (m, 8H,
NCH2), 3.91 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.15–
3.04 (m, 8H, NCH2), 2.54 (s, 3H, SCH3), 13C NMR
(50 MHz, CDCl3): d (ppm) 165.34, 162.90, 160.46,
153.90, 152.73, 144.88, 141.55, 128.01, 123.74, 121.47,
118.84, 114.26, 103.00, 55.69, 51.26, 44.46, 18.29; Anal.
Calcd for C36H41N9O3S: C, 63.60; H, 6.08; N, 18.54.
Found: C, 63.59; H, 6.16; N, 18.66.

N. Sunduru et al. / Bioorg. Med. Chem. 14 (2006) 7706–7715
7715
H.; Garnier, T.; Croft, S. L.; Ja¨rvinen, T. Bioorg. Med.
Chem. 2004, 12, 3497–3502.
Acknowledgments
20. Liu, M.; Wilairat, P.; Croft, S. L.; Tand, A. L. C.; Goa, M.
L. Bioorg. Med. Chem. 2003, 11, 2729–2738.
21. Kayser, O.; Kiderlen, A. F.; Laastsch, H.; Croft, S. L.
Acta Trop. 2000, 76, 131–138.
22. Rabinovitch, M.; Zilberfarb, V. Parasitology 1988, 96,
289.
N.S. thanks Council of Scientific and Industrial Re-
search (India) for the award of Junior Research Fellow-
ship. We are also thankful to S.A.I.F., CDRI, Lucknow,
for providing spectroscopic data. CDRI Communica-
tion No. 6977.
23. Del Olmo, E.; Alves, M.; Lopez, J. L.; Inchaustti, A.;
Yalu, G.; Arias de, R. A.; Feliano, S. A. Bioorg. Med.
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