Synthesis of 4-pyrido-6-aryl-2-substituted amino pyrimidines as a new class of antimalarial agents

Article abstract of DOI:10.1016/j.bmc.2005.06.052

A series of 2,4,6-trisubstituted pyrimidines were synthesized and evaluated for their in vitro antimalarial activity against Plasmodium falciparum. Of the 18 compounds synthesized, 14 compounds showed MIC in the range of 0.25-2 μg/mL. These compounds are

Full text of DOI:10.1016/j.bmc.2005.06.052

Bioorganic & Medicinal Chemistry 13 (2005) 6226–6232
Synthesis of 4-pyrido-6-aryl-2-substituted amino pyrimidines as
a new class of antimalarial agents
Anu Agarwal,a Kumkum Srivastava,b S. K. Purib and Prem M. S. Chauhana,*
aDivision of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226001, India
bDivision of Parasitology, Central Drug Research Institute, Lucknow 226001, India
Received 3 June 2005; revised 21 June 2005; accepted 22 June 2005
Available online 28 July 2005
Abstract—A series of 2,4,6-trisubstituted pyrimidines were synthesized and evaluated for their in vitro antimalarial activity against
Plasmodium falciparum. Of the 18 compounds synthesized, 14 compounds showed MIC in the range of 0.25–2 lg/mL. These
compounds are in vitro several fold more active than pyrimethamine.
Ó 2005 Published by Elsevier Ltd.
1. Introduction
drugs bind directly to the plasmodial DNA and thereby
prevent the inhibition of DNA synthesis of the malarial
parasites.1,4
Despite continued efforts aimed at complete eradication
of malaria, the disease remains a major health threat in
many areas of the world, especially in tropical and sub-
tropical countries. According to WHO estimates, 40% of
the worldÕs population presently lives under malarial
threat. Plasmodium falciparum is the main cause of se-
vere clinical malaria and death. Endemic mapping indi-
cates that P. falciparum and P. vivax account for 95%
of malarial infections. One of the most crucial obstacles
for eradicating malaria is the widespread resistance of
the malarial parasite to almost all chemotherapeutic
agents. Therefore, it is very necessary to seek for new
drugs attacking crucial targets in the malarial pathogen
in order to combat and relieve this tremendous preva-
lence. The dihydrofolate reductase (DHFR) domain of
P. falciparum is one of the few well-defined targets in
malarial chemotherapy. Pyrimethamine is a specific
inhibitor of the plasmodial DHFR that is essential for
DNA synthesis.1–3
Fatty acid biosynthesis (FAS) is another important tar-
get site in the discovery of new antimalarials. Pyridine-4-
carboxylic hydrazide (isoniazid), which is a frontline
drug in the treatment of tuberculosis, is an inhibitor of
an important enzyme (enoyl-ACP reductase) in the fatty
acid biosynthesis pathway. Thus, pyridine analogues
inhibit the biosynthesis of fatty acids that are fundamen-
tal for the survival of P. falciparum in the host.5
Compounds that act on more than one target site are
more liable to be active. On the basis of these observa-
tions, we have synthesized hybrid derivatives having a
pyrimidine (DHFR inhibitor) along with a pyridine
moiety (fatty acid inhibitor). We had previously found
that triazines substituted with diamine chains (11 and
22) have potent in vitro antimalarial activity.6 Our pre-
vious experience prompted us to synthesize pyrimidine
derivatives having these diamine chains (11 and 22) at
the 2nd position as polyamine inhibitors.
Polyamines, found in all living organisms, are required
for cellular proliferation and differentiation. Malarial
parasites have ornithine decarboxylase (ODC) for poly-
amine biosynthesis, and a number of polyamine ana-
logues inhibit the ODC activity in P. falciparum. These
As part of our ongoing programme devoted to the syn-
thesis of diverse heterocycles as anti-infective agents,7
we had previously reported antimalarial activity in
substituted triazines,6 pyrimidines6 and quinolines.8
This communication describes the in vitro antimalarial
activity of pyrimidine derivatives substituted with dia-
mine chains at the 2nd position and a pyridine nucleus
at the 4th position.
Keywords: Dihydrofolate reductase; Antimalarial; Pyrimidine.
*
Corresponding author. fax: +91 522 2623405; e-mail addresses:
prem_chauhan_2000@yahoo.com; premsc58@hotmail.com
0968-0896/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.bmc.2005.06.052

A. Agarwal et al. / Bioorg. Med. Chem. 13 (2005) 6226–6232
6227
2. Chemistry
O
NH
R
.HCl
N
N
N
+
NH2
H
To synthesize the 2,4,6-trisubstituted pyrimidine com-
pounds (13–21 and 24–32), 4-acetylpyridine was reacted
with different aldehydes in 10% aq NaOH and methanol
to yield the corresponding chalcones 2–10.9 N-(3-imi-
dazol-1-yl-propyl)-guanidine (12) and N-(3-morpholin-
4-yl-propyl)-guanidine (23) were synthesized by reflux-
ing the corresponding amine (11 and 22) with S-meth-
yl-isothiourea sulfate in water according to a reported
procedure.10 The chalcones 2–10 were further cyclized
with substituted guanidine hydrochloride (12 and 23)
in the presence of sodium isopropoxide (synthesized
in situ by adding sodium metal in isopropanol) to afford
the 2,4,6-trisubstituted pyrimidines 13–21 (Scheme 1)
and 24–32 (Scheme 2).
O
2-10
23
R
b
NH
NH2
MeS
.H2SO4
a
2
N
N
N
NH
N
NH2
O
N
22
24-32
O
Scheme 2. Reagents and conditions: (a) (i) water, reflux, 15 min; (ii)
barium chloride, reflux, 15 min; (b) sodiumisopropoxide, isopropanol,
reflux, 8 h.
3. Biological activity
(MIC). Pyrimethamine was used as the standard refer-
ence drug. Activity of all the tested compounds is given
in Table 1.
The in vitro antimalarial assay was carried out in 96-
well microtitre plates according to the micro assay of
Rieckmann et al.11 The culture of P. falciparum NF-
54 strain is routinely being maintained in the RPMI-
1640 medium supplemented with 25 mM HEPES, 1%
D-glucose, 0.23% sodium bicarbonate and 10% heat-
inactivated human serum.12 The asynchronous parasite
of P. falciparum was synchronized after 5% D-sorbitol
treatment to obtain parasitized cells harbouring only
the ring stage.13 For carrying out the assay, an initial
ring-stage parasitaemia of ꢀ1% at 3% haematocrit in
total volume of 200 lL of RPMI-1640 medium was
uniformly maintained. The test compound in 20 lL
volume at required concentration (ranging between
0.125 and 50 lg/mL) in duplicate wells were incubated
with parasitized cell preparation at 37 °C in candle jar.
After 36–40 h incubation, the blood smears from each
well were prepared and stained with Giemsa stain.
The slides were microscopically observed to record
maturation of ring-stage parasites into trophozoites
and schizonts in the presence of different concentra-
tions of compounds. The test concentration, which
inhibits the complete maturation into schizonts, was
recorded as the minimum inhibitory concentration
4. Results and discussion
The in vitro biological activities of the synthesized
pyrimidine derivatives have shown encouraging results
against P. falciparum. Of the 18 synthesized com-
pounds, two compounds 15 and 16 have shown MIC
of 0.25 lg/mL, whereas 12 compounds have shown
MIC in the range of 1–2 lg/mL. Compound 13 having
phenyl group showed a MIC of 2 lg/mL. Substitution
on the phenyl ring with methyl (14), methoxy (17) or
chloro (21) group increased the activity of compounds
having a MIC of 1 lg/mL. Replacement of the methyl
group on the phenyl ring with thiomethyl group (15)
and disubstitution with methyl group (16) increased
the activity to 0.25 lg/mL. Di- (18) or trisubstitution
(19 and 20) with methoxy group reduced the activity
having a MIC of 2 lg/mL. On substituting the imidaz-
ole propyl amine chain at 2nd position of the pyrimi-
dine ring with morpholine propyl amine chain the
activity followed almost similar pattern. In general,
O
O
R
R
NH
a
CHO
+
.HCl
N
N
+
N
N
CH3
NH2
N
H
2-10
1
12
R
c
NH
NH2
MeS
.H2SO4
2
b
N
N
N
NH
N
NH2
N
13-21
N
11
N
Scheme 1. Reagents and conditions: (a) 10% aq NaOH, methanol 0 °C, rt, 30 min; (b) (i) water, reflux, 15 min; (ii) barium chloride, reflux, 15 min;
(c) sodiumisopropoxide, isopropanol, reflux, 8 h.

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A. Agarwal et al. / Bioorg. Med. Chem. 13 (2005) 6226–6232
Table 1. Antimalarial in vitro activity against P. falciparum
6.1. General procedure for the synthesis of compounds
2–10
Compound
R
MIC (lg/mL)
13
14
15
16
17
18
19
20
21
24
25
26
27
28
29
30
31
32
H
4-Me
2
1
6.1.1. Method A. To a cooled solution of 10% NaOH,
1.0 equiv of liquid aldehydes were added. To this solu-
tion, 1.0 equiv of 4-acetylpyridine was added dropwise
in about a period of 30 min. The solution was main-
tained at 0 °C for an hour and then allowed to stir at
room temperature. After some time, a solid started sep-
arating out. The solution was further stirred for about
1 h. The solid was filtered and recrystallized from meth-
anol or ethanol to afford crystals of the chalcone having
yield in the range 60–75%.
4-SMe
3,4-DiMe
4-OMe
0.25
0.25
1
2,5-DiOMe
2,4,5-TriOMe
3,4,5-TriOMe
4-Cl
2
2
2
1
H
4-Me
10
2
4-SMe
3,4-DiMe
4-OMe
1
1
6.1.2. Method B. In case of aldehydes that were solid, the
aldehyde (1 equiv) was first dissolved in minimum quan-
tity of ethanol or methanol (approximately 25 mL) and
then 10% NaOH solution (approximately 100 mL) was
added to it to give a clear solution. The solution was
cooled up to 0 °C in an ice bath placed below it. Then,
1 equiv of 4-acetylpyridine was added dropwise to it,
in around a period of 30 min. The solution was main-
tained at 0 °C for 1 h and then allowed to stirred
at room temperature. After some time, a solid started
separating out. This was stirred for about an hour.
The solid was filtered and recrystallized from methanol
or ethanol to give crystals of the chalcone having yield
in the range 50–60%.
2
2,5-DiOMe
2,4,5-TriOMe
3,4,5-TriOMe
4-Cl
10
10
10
2
MIC = minimum inhibiting concentration for the development of ring-
stage parasite into the schizont stage during 40 h incubation. Standard
drug, pyrimethamine; MIC 10 lg/mL.
the imidazole-propyl-amine-substituted compounds 13–
21 showed better activities in comparison with their
corresponding
morpholine-propyl-amine-substituted
compounds 24–32. Monosubstitution on the phenyl
ring improved the activity, whereas disubstitution on
the phenyl ring with methyl group further increased
the activity. Di- or trisubstitution with methoxy group
decreased the activity.
6.1.3. 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 cmÀ1; H NMR (CDCl3,
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.
5. Conclusion
The 18 2,4,6-trisubstituted pyrimidines 13–21 and 24–32
were synthesized as pyrimethamine analogues. Of the
synthesized compounds, two compounds showed MIC
of 0.25 lg/mL. Five compounds showed MIC of 1 lg/
mL, whereas seven compounds showed MIC of 2 lg/
mL. These compounds are 5–40 times more potent than
pyrimethamine. These identified pyrimidines are new
leads in antimalarial chemotherapy. These molecules
can be very useful for further optimization work in
malarial chemotherapy.
6.1.4. 1-Pyridin-4-yl-3-p-tolyl-propenone (3). The com-
pound was synthesized using the method A. Yield:
76%; mp 138–140 °C; MS: 224 (M+1); IR (KBr) 3290,
1967, 1689, 1598, 1492, 1412, 1238 cmÀ1 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. Experimental
6.1.5. 3-(4-Methylsulfanyl-phenyl)-1-pyridin-4-yl-prope-
none (4). The compound was synthesized using the
method A. Yield: 70%; mp 94–96 °C; MS: 256 (M+1);
IR spectra were recorded on Beckman Aculab-10, Per-
kin–Elmer 881 and FTIR 8210 PC, Scimadzu spectro-
photometers 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 refer-
ence. FAB mass spectra were recorded on JEOL SX
102/DA 6000 mass spectrometer using argon/xenon
(6 kV, 10 mA) as the FAB gas. Chemical analyses were
carried out on Carlo-Erba-1108 instrument. The melting
points were recorded on an electrically heated melting
point apparatus and were uncorrected.
1
IR (KBr) 3412, 1956, 1682, 1595, 1415, 1225 cmÀ1; 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.
6.1.6. 3-(3,4-Dimethyl-phenyl)-1-pyridin-4-yl-propenone
(5). The compound was synthesized using the method

A. Agarwal et al. / Bioorg. Med. Chem. 13 (2005) 6226–6232
6229
A. Yield: 67%; mp 168–170 °C; MS: 238 (M+1); IR
(KBr) 3392, 1952, 1687, 1597, 1424, 1249 cmÀ1 1H
C14H10ClNO: C, 69.00; H, 4.14; N, 5.75. Found: C,
68.74; H, 4.32; N, 5.44.
;
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.
6.2. General procedure for the synthesis of compounds
13–21
To a solution of 1.0 equiv of N-(3-imidazol-1-yl-propyl)-
guanidine hydrochloride in 50 mL of isopropanol,
1.1 equiv of sodium metal was added. The reaction mix-
ture was refluxed for 2 h and then different chalcones (2–
10, 1.0 equiv) were added to it and refluxed for 8 h. The
solvent was removed from the reaction mixture under
reduced pressure. Water was added and the aqueous
phase was extracted with chloroform and washed with
brine solution. The organic phase was dried over anhy-
drous Na2SO4, filtered and concentrated. The crude
product was purified by crystallization from methanol
or ethanol or sometimes by column chromatography
on neutral alumina (chloroform/hexane, 1:2) to yield
the pure compounds.
6.1.7.
3-(4-Methoxy-phenyl)-1-pyridin-4-yl-propenone
(6). The compound was synthesized using the method
A. Yield: 67%; mp 104–106 °C; MS: 240 (M+1); IR
(KBr) 3420, 1946, 1683, 1598, 1489, 1411, 1257 cmÀ1
;
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.
6.1.8. 3-(2,5-Dimethoxy-phenyl)-1-pyridin-4-yl-propenone
(7). The compound was synthesized using the method B.
Yield: 67%; mp 128–130 °C; MS: 270 (M+1); IR (KBr)
6.2.1. (3-Imidazol-1-yl-propyl)-(4-phenyl-6-pyridin-4-yl-
pyrimidin-2-yl)-amine (13). Yield: 65%; mp decomposes
at 210 °C; MS: 357 (M+1); IR (KBr) 3416, 2932, 1645,
3299, 1956, 1685, 1597, 1456, 1411, 1259 cmÀ1
;
1H
1574, 1484, 1319, 1280 cmÀ1 1H NMR (CDCl3,
;
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.
200 MHz): d (ppm) 8.77 (d, 2H, J = 6.0 Hz), 8.06 (d,
2H, J = 7.8 Hz), 7.92 (d, 2H, J = 6.0 Hz), 7.55 (s, 1H),
7.52–7.47 (m, 3H), 7.45 (s, 1H), 7.09 (d, 1H,
J = 4.4 Hz), 6.97 (d, 1H, J = 4.4 Hz), 5.44 (s, 1H, NH),
4.13 (t, 2H, J = 5.1 Hz), 3.64 (m, 2H), 2.25 (t, 2H,
J = 5.1 Hz). 13C NMR (CDCl3, 50 MHz): 166.4, 165.4,
162.7, 150.3, 145.4, 137.8, 137.1, 127.8, 129.6, 128.9,
125.1, 120.8, 119.2, 103.4, 44.8, 39.1, 31.5. Anal. Calcd
for C21H20N6: C, 70.77; H, 5.66; N, 23.58. Found: C,
70.52; H, 5.44; N, 23.34.
6.1.9. 1-Pyridin-4-yl-3-(2,4,5-trimethoxy-phenyl)-prope-
none (8). 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,
6.2.2. (3-Imidazol-1-yl-propyl)-(4-pyridin-4-yl-6-p-tolyl-
pyrimidin-2-yl)-amine (14). Yield: 76%; mp 168–170 °C;
MS: 371 (M+1); IR (KBr) 3412, 2926, 1638, 1580,
1
1232 cmÀ1; 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.
1
1480, 1325, 1272 cmÀ1; H NMR (CDCl3, 200 MHz):
d (ppm) 8.75 (d, 2H, J = 6.1 Hz), 7.99 (d, 2H,
J = 7.9 Hz), 7.90 (d, 2H, J = 6.1 Hz), 7.51 (s, 1H), 7.44
(s, 1H), 7.30 (d, 2H, J = 7.9 Hz), 7.08 (d, 1H,
J = 4.9 Hz), 6.95 (d, 1H, J = 4.9 Hz), 5.51 (s, 1H, NH),
4.09 (t, 2H, J = 4.6 Hz), 3.60 (t, 2H, J = 4.6 Hz), 2.43
(s, 3H, Me), 2.19 (m, 2H). 13C NMR (CDCl3,
50 MHz): 166.8, 165.5, 163.5, 150.9, 145.6, 141.7,
137.5, 134.9, 131.8, 129.9, 127.4, 121.4, 119.3, 103.5,
44.9, 39.0, 31.6, 21.8. Anal. Calcd for C22H22N6: C,
71.33; H, 5.99; N, 22.69. Found: C, 71.52; H, 5.68; N,
22.34.
6.1.10. 1-Pyridin-4-yl-3-(3,4,5-trimethoxy-phenyl)-prope-
none (9). 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,
1
1245 cmÀ1; 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.
6.2.3. [4-(4-Methylsulfanyl-phenyl)-6-pyridin-4-yl-pyrimi-
din-2-yl]-(3-imidazol-1-yl-propyl)-amine (15). Yield: 74%;
mp 90–92 °C; MS: 403 (M+1); IR (KBr) 3420, 2948,
1
6.1.11.
3-(4-Chloro-phenyl)-1-pyridin-4-yl-propenone
1636, 1584, 1486, 1325, 1265 cmÀ1; H NMR (CDCl3,
(10). The compound was synthesized using the method
B. Yield: 68%; mp 205–207 °C; MS: 244 (M+1); IR
200 MHz): d (ppm) 8.77 (d, 2H, J = 6.0 Hz), 7.99 (d,
2H, J = 8.7 Hz), 7.89 (d, 2H, J = 6.0 Hz), 7.53 (s, 1H),
7.43 (s, 1H), 7.35 (d, 2H, J = 8.7 Hz), 7.09 (d, 1H,
J = 4.1 Hz), 6.96 (d, 1H, J = 4.2 Hz), 5.43 (s, 1H, NH),
4.11 (t, 2H, J = 4.9 Hz), 3.60 (t, 2H, J = 4.8 Hz), 2.54
(s, 3H, SMe), 2.20 (m, 2H). 13C NMR (CDCl3,
50 MHz): 166.7, 165.1, 163.7, 150.8, 145.8, 142.8,
(KBr) 3297, 1948, 1684, 1598, 1489, 1257 cmÀ1 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

6230
A. Agarwal et al. / Bioorg. Med. Chem. 13 (2005) 6226–6232
137.6, 134.4, 127.8, 126.4, 125.1, 121.4, 119.5, 103.6,
45.1, 39.2, 31.7, 18.7. Anal. Calcd for C22H22N6S: C,
65.65; H, 5.51; N, 20.88. Found: C, 65.22; H, 5.75; N,
20.54.
J = 4.6 Hz), 2.21 (m, 2H). 13C NMR (CDCl3,
50 MHz): 164.5, 162.6, 162.1, 154.1, 152.3, 150.8,
146.3, 143.9, 137.5, 125.0, 121.6, 119.3, 118.9, 114.2,
107.6, 98.3, 57.2, 57.0, 56.6, 44.9, 38.9, 31.5. Anal. Calcd
for C24H26N6O3: C, 64.56; H, 5.87; N, 18.82. Found: C,
64.35; H, 5.98; N, 18.57.
6.2.4. [4-(3,4-Dimethyl-phenyl)-6-pyridin-4-yl-pyrimidin-
2-yl]-(3-imidazol-1-yl-propyl)-amine (16). Yield: 65%;
mp 126–128 °C; MS: 385 (M+1); IR (KBr) 3426, 2924,
6.2.8. (3-Imidazol-1-yl-propyl)-(4-pyridin-4-yl-6-(3,4,5-
trimethoxy-phenyl)-pyrimidin-2-yl)-amine (20). Yield:
64%; mp 134–136 °C; MS: 447 (M+1); IR (KBr) 3427,
1
1648, 1576, 1486, 1328, 1284 cmÀ1; H NMR (CDCl3,
200 MHz): d (ppm) 8.75 (d, 2H, J = 6.0 Hz), 7.90 (d,
2H, J = 6.0 Hz), 7.83 (s, 1H), 7.77 (d, 1H, J = 6.9 Hz),
7.51 (s, 1H), 7.44 (s, 1H), 7.28 (d, 1H, J = 6.9 Hz),
7.07 (d, 1H, J = 4.2 Hz), 6.96 (d, 1H, J = 4.2 Hz), 5.43
(s, 1H, NH), 4.10 (t, 2H, J = 4.9 Hz), 3.62 (t, 2H,
J = 4.9 Hz), 2.37 (s, 3H), 2.34 (s, 3H), 2.19 (m, 2H).
13C NMR (CDCl3, 50 MHz): 167.0, 163.5, 163.3,
150.8, 145.7, 140.4, 137.5, 137.2, 135.2, 130.6, 129.9,
128.6, 125.0, 121.5, 119.3, 103.5, 44.9, 38.9, 31.6, 20.4,
20.2. Anal. Calcd for C23H24N6: C, 71.85; H, 6.29; N,
21.86. Found: C, 71.52; H, 6.55; N, 21.64.
2930, 2864, 1658, 1591, 1513, 1442, 1356 cmÀ1 1H
;
NMR (CDCl3, 200 MHz): d (ppm) 8.78 (d, 2H,
J = 5.9 Hz), 7.93 (d, 2H, J = 5.9 Hz), 7.53 (s, 1H), 7.35
(s, 1H), 7.30 (s, 2H), 7.08 (d, 1H, J = 4.2 Hz), 6.96 (d,
1H, J = 4.2 Hz), 4.12 (t, 2H, J = 4.8 Hz), 3.60 (t, 2H,
J = 4.8 Hz), 2.20 (m, 2H). 13C NMR (CDCl3,
50 MHz): 167.2, 162.8, 163.2, 154.1, 150.8, 145.4,
140.8, 137.6, 134.6, 125.1, 121.6, 119.3, 105.1, 102.7,
61.4, 56.8, 44.8, 39.0, 31.6. Anal. Calcd for
C24H26N6O3: C, 64.56; H, 5.87; N, 18.82. Found: C,
64.41; H, 5.65; N, 18.62.
6.2.5. (3-Imidazol-1-yl-propyl)-[4-(4-methoxy-phenyl)-6-
pyridin-4-yl-pyrimidin-2-yl]-amine (17). Yield: 72%; mp
140–142 °C; MS: 387 (M+1); IR (KBr) 3422, 2926,
6.2.9. [4-(4-Chloro-phenyl)-6-pyridin-4-yl-pyrimidin-2-yl]-
(3-imidazol-1-yl-propyl)-amine (21). Yield: 67%; mp
decomposes at 170 °C; MS: 391 (M+1); IR (KBr)
1
1638, 1580, 1480, 1325, 1272 cmÀ1; H NMR (CDCl3,
200 MHz): d (ppm) 8.76 (d, 2H, J = 6.0 Hz), 8.05 (d,
2H, J = 8.8 Hz), 7.91 (d, 2H, J = 6.0 Hz), 7.53 (s, 1H),
7.41 (s, 1H), 7.08 (d, 1H, J = 4.2 Hz), 7.01 (d, 2H,
J = 8.8 Hz), 6.96 (d, 1H, J = 4.2 Hz), 4.12 (t, 2H,
J = 4.9 Hz), 3.88 (s, 3H, OMe), 3.60 (t, 2H,
J = 4.9 Hz), 2.19 (m, 2H). 13C NMR (CDCl3,
50 MHz): 166.8, 163.6, 162.9, 161.2, 150.4, 145.5,
137.6, 129.9, 128.6, 125.0, 121.0, 119.3, 114.0, 103.6,
55.4, 44.9, 38.9, 31.6. Anal. Calcd for C22H22N6O: C,
68.38; H, 5.74; N, 21.75. Found: C, 68.52; H, 5.98; N,
21.51.
3426, 2933, 2839, 1656, 1510, 1448, 1356 cmÀ1 1H
;
NMR (CDCl3, 200 MHz): d (ppm) 8.77 (d, 2H,
J = 5.9 Hz), 8.06 (d, 2H, J = 7.9 Hz), 7.94 (d, 2H,
J = 5.9 Hz), 7.47 (d, 2H, J = 7.9 Hz), 7.53 (s, 1H), 7.40
(s, 1H), 7.07 (d, 1H, J = 4.5 Hz), 6.96 (d, 1H,
J = 4.5 Hz), 4.12 (t, 4H, J = 4.7 Hz), 3.60 (t, 4H,
J = 4.7 Hz), 2.22 (m, 2H). 13C NMR (CDCl3,
50 MHz): 165.6, 162.4, 161.9, 158.9, 145.6, 137.7,
135.2, 134.4, 130.2, 128.8, 125.1, 121.2, 119.4, 104.1,
44.9, 38.9, 31.7. Anal. Calcd for C21H19ClN6: C, 64.53;
H, 4.90; N, 21.50. Found: C, 64.34; H, 4.76; N, 21.65.
6.2.6. [4-(2,5-Dimethoxy-phenyl)-6-pyridin-4-yl-pyrimi-
din-2-yl]-(3-imidazol-1-yl-propyl)-amine (18). Yield:
59%; mp 114–116 °C; MS: 417 (M+1); IR (KBr) 3439,
6.3. General procedure for the synthesis of compounds
24–32
2993, 1652, 1575, 1509, 1462, 1465, 1350 cmÀ1
;
1H
The chalcones 2–10 were cyclized with N-(3-morpholin-
4-yl-propyl)-guanidine hydrochloride by a similar meth-
od as that of compounds 13–21.
NMR (CDCl3, 200 MHz): d (ppm) 8.77 (d, 2H,
J = 5.9 Hz), 7.95 (d, 2H, J = 5.9 Hz), 7.56 (s, 1H), 7.38
(s, 1H), 7.32 (s, 1H), 7.22 (d, 1H, J = 6.8 Hz), 7.08 (d,
1H, J = 4.3 Hz), 6.95 (d, 1H, J = 4.3 Hz), 6.71 (d, 1H,
J = 6.8 Hz), 4.12 (t, 2H, J = 4.7 Hz), 3.87 (t, 2H,
J = 4.6 Hz), 3.84 (s, 3H, OMe), 3.82 (s, 3H, OMe),
2.21 (m, 2H). 13C NMR (CDCl3, 50 MHz): 164.9,
162.6, 162.2, 154.3, 152.9, 150.8, 146.1, 137.7, 128.3,
125.1, 121.6, 119.4, 116.9, 116.6, 113.7, 107.9, 56.9,
56.3, 44.9, 39.0, 31.6. Anal. Calcd for C23H24N6O2: C,
66.33; H, 5.81; N, 20.18. Found: C, 66.49; H, 5.62; N,
20.54.
6.3.1. (3-Morpholin-4-yl-propyl)-(4-phenyl-6-pyridin-4-
yl-pyrimidin-2-yl)-amine (24). Yield: 70%; mp 202–
204 °C; MS: 376 (M+1); IR (KBr) 3431, 2949, 1816,
1
1649, 1593, 1507, 1461, 1355 cmÀ1; H NMR (CDCl3,
200 MHz): d (ppm) 8.77 (d, 2H, J = 5.9 Hz), 8.11 (d,
2H, J = 7.8 Hz), 7.96 (d, 2H, J = 5.9 Hz), 7.52–7.49
(m, 3H), 7.42 (s, 1H), 3.79 (t, 4H, J = 4.6 Hz), 3.66 (t,
2H, J = 4.2 Hz), 2.63 (t, 2H, J = 4.5 Hz), 2.56 (t, 4H,
J = 4.6 Hz), 1.96–1.91 (m, 2H). 13C NMR (CDCl3,
50 MHz): 165.2, 162.1, 161.7, 150.3, 145.4, 137.2,
127.8, 129.6, 128.9, 120.8, 103.4, 66.5, 45.6, 44.1, 39.5,
31.5. Anal. Calcd for C22H25N5O: C, 70.38; H, 6.71;
N, 18.65. Found: C, 70.52; H, 6.43; N, 18.37.
6.2.7. (3-Imidazol-1-yl-propyl)-(4-pyridin-4-yl-6-(2,4,5-
trimethoxy-phenyl)-pyrimidin-2-yl)-amine (19). Yield:
60%; mp 129–131 °C; MS: 447 (M+1); IR (KBr) 3429,
2929, 2864, 1662, 1577, 1549, 1510, 1460, 1359 cmÀ1
;
1H NMR (CDCl3, 200 MHz): d (ppm) 8.75 (d, 2H,
J = 6.1 Hz), 7.91 (d, 2H, J = 6.1 Hz), 7.81 (s, 1H), 7.65
(s, 1H), 7.52 (s, 1H), 7.07 (d, 1H, J = 4.2 Hz), 6.96 (d,
1H, J = 4.2 Hz), 6.62 (s, 1H), 4.12 (t, 2H, J = 4.6 Hz),
3.97 (s, 3H, OMe), 3.92 (s, 6H, 2OMe), 3.62 (t, 2H,
6.3.2. (3-Morpholin-4-yl-propyl)-(4-pyridin-4-yl-6-p-tol-
yl-pyrimidin-2-yl)-amine (25). Yield: 77%; mp 123–
125 °C; MS: 390 (M+1); IR (KBr) 3429, 2934, 2872,
1638, 1579, 1510, 1468, 1356, 1278 cmÀ1 1H NMR
;
(CDCl3, 200 MHz): d (ppm) 8.75 (d, 2H, J = 6.1 Hz),

A. Agarwal et al. / Bioorg. Med. Chem. 13 (2005) 6226–6232
6231
8.03 (d, 2H, J = 7.9 Hz), 7.94 (d, 2H, J = 6.1 Hz), 7.41
(s, 1H), 7.30 (d, 2H, J = 7.9 Hz), 3.78 (t, 4H,
J = 4.5 Hz), 3.63 (t, 2H, J = 4.3 Hz), 2.62 (t, 2H,
J = 4.1 Hz), 2.56 (t, 4H, J = 4.5 Hz), 2.43 (s, 3H, Me),
1.94–1.90 (m, 2H). 13C NMR (CDCl3, 50 MHz): 165.5,
162.5, 162.0, 150.2, 145.4, 138.1, 133.6, 130.1, 127.2,
121.2, 101.5, 66.6, 45.7, 44.2, 39.5, 31.5, 18.9. Anal.
Calcd for C23H27N5O: C, 70.92; H, 6.99; N, 17.98.
Found: C, 70.68; H, 6.74; N, 17.74.
3.84 (s, 3H, OMe), 3.82 (s, 3H, OMe), 3.77 (t, 4H,
J = 4.8 Hz), 3.65 (t, 2H, J = 4.6 Hz), 2.61 (t, 2H,
J = 4.4 Hz), 2.56 (t, 4H, J = 4.8 Hz), 1.92–1.88 (m,
2H). 13C NMR (CDCl3, 50 MHz): 164.9, 162.7, 162.3,
154.2, 152.9, 150.8, 146.1, 128.3, 121.6, 116.9, 116.5,
113.7, 107.8, 67.2, 56.9, 56.3, 45.5, 44.8, 39.5, 31.6. Anal.
Calcd for C24H29N6O3: C, 66.19; H, 6.71; N, 16.08.
Found: C, 66.42; H, 6.43; N, 16.37.
6.3.7. (3-Morpholin-4-yl-propyl)-(4-pyridin-4-yl-6-(2,4,5-
trimethoxy-phenyl)-pyrimidin-2-yl)-amine (30). Yield:
68%; mp 121–123 °C; MS: 466 (M+1); IR (KBr) 3402,
6.3.3. [4-(4-Methylsulfanyl-phenyl)-6-pyridin-4-yl-pyrimi-
din-2-yl]-(3-morpholin-4-yl-propyl)-amine (26). Yield:
74%; mp 124–126 °C; MS: 422 (M+1); IR (KBr) 3427,
2926, 1638, 1580, 1480, 1325, 1272 cmÀ1 1H NMR
;
2930, 2864, 1654, 1591, 1513, 1442, 1345 cmÀ1
;
1H
(CDCl3, 200 MHz): d (ppm) 8.74 (d, 2H, J = 6.1 Hz),
7.93 (d, 2H, J = 6.1 Hz), 7.77 (s, 1H), 7.71 (s, 1H),
6.61 (s, 1H), 6.01(s, 1H, NH), 3.97 (s, 3H, OMe), 3.93
(s, 6H, 2OMe), 3.79 (t, 4H, J = 4.6 Hz), 3.66 (t, 2H,
J = 4.2 Hz), 2.63 (t, 2H, J = 4.5 Hz), 2.56 (t, 4H,
J = 4.6 Hz), 1.96–1.91 (m, 2H). 13C NMR (CDCl3,
50 MHz): 164.8, 162.6, 162.1, 154.3, 152.5, 150.7,
146.3, 143.9, 121.6, 118.9, 114.2, 107.6, 98.3, 67.3,
57.2, 57.0, 56.6, 45.6, 44.8, 39.5, 31.5. Anal. Calcd for
C25H31N5O4: C, 64.50; H, 6.71; N, 15.04. Found: C,
64.76; H, 6.54; N, 15.32.
NMR (CDCl3, 200 MHz): d (ppm) 8.77 (d, 2H,
J = 6.2 Hz), 8.06 (d, 2H, J = 8.6 Hz), 7.95 (d, 2H,
J = 6.2 Hz), 7.40 (s, 1H), 7.36 (d, 2H, J = 8.6 Hz), 3.79
(t, 4H, J = 4.6 Hz), 3.66 (t, 2H, J = 4.2 Hz), 2.63 (t,
2H, J = 4.5 Hz), 2.56 (t, 4H, J = 4.6 Hz), 2.52 (s, 3H,
SMe), 1.96–1.91 (m, 2H). 13C NMR (CDCl3,
50 MHz): 165.7, 163.1, 162.7, 150.8, 145.8, 142.8,
134.4, 127.8, 126.4, 121.4, 102.2, 66.2, 45.5, 44.0, 39.5,
31.5, 18.4. Anal. Calcd for C23H27N5OS: C, 65.53; H,
6.46; N, 16.61. Found: C, 65.41; H, 6.32; N, 16.37.
6.3.4. [4-(3,4-Dimethyl-phenyl)-6-pyridin-4-yl-pyrimidin-
2-yl]-(3-morpholin-4-yl-propyl)-amine (27). Yield: 70%;
mp 92–94 °C; MS: 404 (M+1); IR (KBr) 3424, 2976,
6.3.8. (3-Morpholin-4-yl-propyl)-(4-pyridin-4-yl-6-(3,4,5-
trimethoxy-phenyl)-pyrimidin-2-yl)-amine (31). Yield:
65%; mp 137–139 °C; MS: 466 (M+1); IR (KBr) 3415,
2864, 1668, 1589, 1506, 1456, 1356 cmÀ1
;
1H NMR
2948, 1636, 1584, 1486, 1325, 1265 cmÀ1 1H NMR
;
(CDCl3, 200 MHz): d (ppm) 8.77 (d, 2H, J = 6.1 Hz),
7.97 (d, 2H, J = 6.1 Hz), 7.87 (s, 1H), 7.82 (d, 1H,
J = 6.9 Hz), 7.42 (s, 1H), 7.23 (d, 1H, J = 6.9 Hz), 3.77
(t, 4H, J = 4.7 Hz), 3.62 (t, 2H, J = 4.4 Hz), 2.60 (t,
2H, J = 4.1 Hz), 2.56 (t, 4H, J = 4.7 Hz), 2.37 (s, 3H,
Me), 2.34 (s, 3H, Me), 1.94–1.90 (m, 2H). 13C NMR
(CDCl3, 50 MHz): 166.6, 162.9, 162.7, 150.8, 145.9,
140.2, 137.4, 135.6, 130.5, 128.6, 125.0, 121.5, 102.6,
66.4, 45.5, 44.1, 39.5, 31.5, 20.4, 20.2. Anal. Calcd for
C24H29N5O: C, 71.44; H, 7.24; N, 17.36. Found: C,
71.24; H, 7.36; N, 17.57.
(CDCl3, 200 MHz): d (ppm) 8.76 (d, 2H, J = 6.1 Hz),
7.95 (d, 2H, J = 6.1 Hz), 7.35 (s, 1H), 7.32 (s, 2H),
3.97 (s, 6H, OMe), 3.92 (s, 3H, OMe), 3.77 (t, 4H,
J = 4.8 Hz), 3.65 (t, 2H, J = 4.7 Hz), 2.61 (t, 2H,
J = 4.1 Hz), 2.56 (t, 4H, J = 4.8 Hz), 1.92–1.88 (m,
2H). 13C NMR (CDCl3, 50 MHz): 167.2, 162.8, 163.2,
154.1, 150.8, 145.4, 140.8, 134.6, 121.6, 105.1, 102.7,
67.3, 61.4, 56.8, 45.6, 44.8, 39.5, 31.5. Anal. Calcd for
C25H31N5O4: C, 64.50; H, 6.71; N, 15.04. Found: C,
64.68; H, 6.54; N, 15.36.
6.3.9. [4-(4-Chloro-phenyl)-6-pyridin-4-yl-pyrimidin-2-yl]-
(3-morpholin-4-yl-propyl)-amine (32). Yield: 70%; mp
116–118 °C; MS: 410 (M+1); IR (KBr) 3412, 2936,
6.3.5. [4-(4-Methoxy-phenyl)-6-pyridin-4-yl-pyrimidin-2-
yl]-(3-morpholin-4-yl-propyl)-amine (28). Yield: 68%;
mp 122–124 °C; MS: 406 (M+1); IR (KBr) 3439, 2934,
1
1642, 1578, 1488, 1324, 1284 cmÀ1; H NMR (CDCl3,
2865, 1673, 1575, 1510, 1462, 1350 cmÀ1
;
1H NMR
200 MHz): d (ppm) 8.76 (d, 2H, J = 6.1 Hz), 8.04 (d,
2H, J = 8.4 Hz), 7.93 (d, 2H, J = 6.1 Hz), 7.47 (d, 2H,
J = 8.4 Hz), 7.37 (s, 1H), 6.1 (s, 1H, NH), 3.79 (t, 4H,
J = 4.8 Hz), 3.65 (t, 2H, J = 4.4 Hz), 2.60 (t, 2H,
J = 4.3 Hz), 2.52 (t, 4H, J = 4.8 Hz), 1.97–1.92 (m,
2H). 13C NMR (CDCl3, 50 MHz): 165.6, 162.4, 161.9,
158.9, 145.6, 135.2, 134.4, 130.2, 128.8, 121.2, 104.1,
66.5, 45.6, 44.1, 39.5, 31.5. Anal. Calcd for
C22H24ClN5O: C, 64.46; H, 5.90; N, 17.09. Found: C,
64.65; H, 5.68; N, 17.42.
(CDCl3, 200 MHz): d (ppm) 8.77 (d, 2H, J = 6.0 Hz),
8.11 (d, 2H, J = 8.8 Hz), 7.96 (d, 2H, J = 6.0 Hz), 7.39
(s, 1H), 7.03 (d, 2H, J = 8.8 Hz), 3.88 (s, 3H, OMe),
3.77 (t, 4H, J = 4.8 Hz), 3.65 (t, 2H, J = 4.7 Hz), 2.61
(t, 2H, J = 4.1 Hz), 2.56 (t, 4H, J = 4.8 Hz), 1.92–1.88
(m, 2H). 13C NMR (CDCl3, 50 MHz): 165.4, 162.4,
162.2, 161.9, 150.4, 145.5, 129.9, 128.6, 121.0, 114.0,
101.6, 66.5, 55.5, 45.6, 44.1, 39.5, 31.5. Anal. Calcd for
C23H27N5O2: C, 68.13; H, 6.71; N, 17.27. Found: C,
68.35; H, 6.65; N, 17.39.
6.3.6. [4-(2,5-Methoxy-phenyl)-6-pyridin-4-yl-pyrimidin-
2-yl]-(3-morpholin-4-yl-propyl)-amine (29). Yield: 66%;
mp 112–114 °C; MS: 436 (M+1); IR (KBr) 3409, 2943,
Acknowledgments
A.A. thanks the Council of Scientific and Industrial Re-
search (India) for the award of Senior Research Fellow-
ship. The authors are also thankful to SAIF Division,
CDRI, Lucknow for providing spectroscopic data.
CDRI Communication No. 6738.
1
1645, 1574, 1484, 1319, 1280 cmÀ1; H NMR (CDCl3,
200 MHz): d (ppm) 8.77 (d, 2H, J = 6.0 Hz), 7.95 (d,
2H, J = 6.0 Hz), 7.40 (s, 1H), 7.33 (s, 1H), 7.22 (d, 1H,
J = 6.8 Hz), 6.74 (d, 1H, J = 6.8 Hz), 6.01 (s, 1H, NH),

6232
A. Agarwal et al. / Bioorg. Med. Chem. 13 (2005) 6226–6232
Agarwal, S. K.; Bhaduri, A. P.; Singh, S. N.; Fatima, N.;
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