Pyrido[1,2-a]pyrimidin-4-ones: Ligand-based Design, Synthesis, and Evaluation as an Anti-inflammatory Agent

Article abstract of DOI:10.1002/jhet.2950

In the present study, a series of novel pyrido[1,2-a]pyrimidin-4-one derivatives (1–45) were synthesized, characterized, and evaluated for their anti-inflammatory activity. The structures of all newly synthesized compounds were confirmed by ¹H

Full text of DOI:10.1002/jhet.2950

Month 2017
Pyrido[1,2-a]pyrimidin-4-ones: Ligand-based Design, Synthesis, and
Evaluation as an Anti-inflammatory Agent
Sunil B. Jadhav,a,b Samreen Fatema,a,b Rajesh B. Patil,c Jaiprakash N. Sangshetti,d and Mazahar Farooquia,b
*
aPost Graduate and Research Center, Department of Chemistry, Maulana Azad College, Aurangabad 431001,
Maharashtra, India
bDr. Rafiq Zakaria College for Women, Navkhanda, Aurangabad 431001, Maharashtra, India
cSmt. Kashibai Navale College of Pharmacy, Pune-Saswad Road, Kondhwa (Bk), 411048 Pune, Maharashtra, India
dY.B. Chavan College of Pharmacy, Rauza Bagh, Aurangabad 431001, Maharashtra, India
*
E-mail: mazahar_64@rediffmail.com
Received September 19, 2016
DOI 10.1002/jhet.2950
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
In the present study, a series of novel pyrido[1,2-a]pyrimidin-4-one derivatives (1–45) were synthesized,
characterized, and evaluated for their anti-inflammatory activity. The structures of all newly synthesized com-
pounds were confirmed by 1H NMR, 13C NMR, mass spectroscopy, and C, H, and N analyses. Preliminary
these newly synthesized compounds were evaluated for their in vitro cyclooxygenase (COX)-2/COX-1 inhib-
itory activity. The celecoxib, a COX-2 inhibitor, was used as a reference standard drug. In this inhibitory study,
compounds 42, 43, 44, and 45 were found to have significant in vitro inhibitory profile as compared with the
reference drug. These compounds were then subjected to their in vivo anti-inflammatory assay by using
carrageenan-induced rat paw edema method in next level of screening. Later, these same compounds were
tested for their ulcerogenic property. Based on these activity data, the compound 43 (in vitro COX-2 activity
—IC50 = 0.4 μM, SI = 400, in vivo anti-inflammatory activity—72% inhibition after 3 h, and 0.38%—
Ulcer index) was emerged as most promising anti-inflammatory agent with very low ulcerogenic action.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
pyrimidinone and tetrahedron pyrido[1,2-a]pyrimidinone
are well-known nucleus in drug discovery since they
possess extensive range of biological activity along with
anti-inflammatory property [7,8]. Moreover, marketed
antipsychotic drugs Risperidone and Paliperidone
Cyclooxygenases (COX) enzymes play an active role
in the synthesis of prostaglandin (PG) H2, which further
involve in biosynthesis of PGs, prostacyclins, and
thromboxanes [1]. There are two isoforms of COX,
COX-1 and COX-2 [2,3]. COX-1, which plays role in
housework activities, typically involves in the protection
of gastric mucosa, platelets aggregation, and renal blood
flow, while COX-2 is expressed in inflammation and pain
[4]. Hence, the molecule that inhibits enzymatic activities
of COX-2 has found to be a great therapeutic value.
Traditional non-steroidal anti-inflammatory runners like
ibuprofen, dichlofenac, and aspirin are non-selective;
however, they exhibit superior selectivity for COX-1 than
COX-2.
comprise
of
tetrahedropyrido[1,2-a]pyrimidin-4-one
pharmacophore [9].
The trans-azo derivative [10] and various naturally
occurring trans-stilbenoids have been reported as COX
inhibitors. As an example, resveratrol is a phytoalexin
found in grapes skin and red wine displays moderate
COX-1 inhibitory activity [11]. Also, the derivatives
of resveratrol are documented for selective COX-2
inhibition [12].
Looking at the side effects of COX-1 inhibition like
ulceration and GI irritation, superior selectivity toward
COX-2 is a clinical need. Selective COX-2 inhibitors,
especially the Coxibs, were highly appreciated initially.
Fused pyrimidones are reported for their anti-
inflammatory activity [5,6]. Particularly, pyrido[1,2-a]
© 2017 Wiley Periodicals, Inc.

S. B. Jadhav, S. Fatema, R. B. Patil, J. N. Sangshetti, and M. Farooqui
Vol 000
Successively, cardiovascular adverse effects made them
necessary for the alternative. So, the development of
new scaffold for COX-2 inhibition is a challenge for
medicinal chemist.
program started with preparation of different pyrazole
aldehydes (D), one of the key precursor as shown in
scheme according to the procedure reported in literature
[20]. Here, commercially available different substituted
acetophenones (A) were refluxed with commercially
available various phenylhydrazines (B) in acidic medium
by using ethanol as a solvent, to give corresponding
imines (C). These imines (C) upon treatment
with POCl3 in DMF underwent cyclization to give
different pyrazole aldehydes (D) in good yield as key
precursors via Vilsmeier Haack reaction conditions
(Fig. 1). Access to another important precursors for the
In continuation with our research activities [13–16],
current research was targeted toward the design and
synthesis of improved anti-inflammatory agent devoid
of adverse effects. While designing, we boarded on
molecular structure utilizing ligand-based drug design
approach. Our interest was on pyrido[1,2-a]pyrimidin-4-
one scaffold, trans-stilbene nuclei from trans-stilbenoids,
and N-phenyl pyrazole moiety of celecoxib; therefore,
these three moieties were combined together to get a
novel hybrid heterocyclic molecule; in addition, we also
gave premises to biologically active styryl quinazoline-
4-one derivatives reported for their various biological
activities [17,18] including their COX-2 inhibitory
profile [19]. Hence, in our novel molecule, a phenyl
ring was introduced at particular location of pyrimidin-
4-one ring for the structural similarity with styryl
quinazoline-4-ones (Fig. 1). Thus, a series of 45
molecules were synthesized and subjected for their
in vivo COX-2 activity; later, selected compounds were
tested for their in vivo anti-inflammatory activity and
ulcerogenic liability.
preparation
of
pyrido[1,2-a]pyrimidin-4-one
was
achieved by following the process reported in literature
[21]. 2-Amino pyridine (E) was treated with
ethylacetoacetate (F) at reflux temperature in acetic acid
to yield 2-methyl-pyrido[1,2-a]pyrimidin-4-one (G). This
intermediate (G), when treated with iodine and ceric
ammonium nitrate in acetonitrile at reflux temperature
gave 3-iodo-2-methyl-pyrido[1,2-a]pyrimidin-4-one (H)
in moderate to good yield. Finally, the requisite key
precursor
2-methyl-3-phenyl-pyrido[1,2-a]pyrimidin-4-
one (I) was obtained by treating 3-iodo Intermediate
(H) with coupling partner phenylboronic acid using
palladium catalyzed Suzuki cross-coupling reaction
conditions. The last step of this synthetic work was the
preparation of the novel targeted compounds (1–45;
Table 1), which involve the condensation of different
pyrazole aldehydes (D) with 2-methyl-3-phenyl-
pyrido[1,2-a]pyrimidin-4-one (I) using sodium ethoxide
at reflux temperature in ethanol. All the newly
synthesized compounds were isolated in moderate to
RESULT AND DISCUSSIONS
Chemistry. The synthetic chemistry employed for the
preparations of pyrido[1,2-a]pyrimidin-4-one derivatives
(1–45) is outlined in scheme. In brief, the synthetic
Figure 1. Pharmacophoric model. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Pyrido[1,2-a]pyrimidin-4-ones: Ligand-based Design, Synthesis, and Evaluation
as an Anti-inflammatory Agent
1
Table 1
good yield and were characterized by ES-MS, H NMR
spectral data, and elemental analysis. It was observed
that the quantity required for 13C NMR was not soluble
in DMSO and MeOH, due to which it was difficult to
run the 13C NMR spectra and so, they are not included
in the current report.
Substitution strategy for compounds C1–45, D1–45 and 1–45.
ID
R1
R2
R3
R4
R5
R6
Me
1
2
3
4
5
6
7
8
H
H
H
H
H
OMe
H
H
Me
H
H
OMe
H
H
Me
H
OMe
H
H
Me
H
H
OMe
H
H
H
OMe
H
H
Me
H
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
OMe
OMe
OMe
OMe
OMe
Me
Me
Me
Me
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
H
H
H
H
H
H
H
Me
H
OMe
H
H
H
Me
H
H
H
OMe
H
H
H
Me
H
H
H
OMe
H
H
H
Me
H
H
H
OMe
H
H
H
Me
H
H
H
Me
H
OMe
H
H
H
Me
H
H
H
OMe
H
H
H
Me
H
H
H
OMe
H
H
H
Me
H
H
H
OMe
H
H
H
Me
H
H
H
H
H
OMe
H
H
H
Me
H
H
H
OMe
H
H
H
Me
H
H
H
OMe
H
H
H
Me
H
H
H
OMe
H
H
H
H
H
H
H
OMe
H
H
H
Me
H
H
H
OMe
H
H
H
Me
H
H
H
OMe
H
H
H
Me
H
H
H
OMe
H
Me
Me
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
Me
Me
Me
Me
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
Me
Me
Me
Me
COX-1/COX-2 inhibition study.
The targeted
compounds (1–45) were synthesized with methyl/
methoxy variation across R1–R6 on the phenyl rings.
After structural confirmation by spectroscopic techniques,
the synthesized compounds were subjected to in vitro
COX1/2 inhibition activity (Table 2).
Me
Me
Me
Me
Me
Me
Me
The activity was judged by noticing reduction in PG
production along with concerned enzymes in the presence
of these compounds at various concentrations of 10ꢀ5
,
10ꢀ6, 10ꢀ7, and 10ꢀ8 M.
Me
Me
Me
H
Me
H
H
H
Me
The compound (1) has shown satisfactory COX-2
inhibition activity (IC50 = 68 μM) even the selectivity
was very poor (SI = 5.6). After encouraged from the
preliminary results of compound 1, we kept methoxy
group at R6 position and then one by one substitution
(methyl/methoxy) across R1–R5 was introduced to get a
set of six compounds (2–7), in which the compounds 2
and 4 have shown better selectivity (SI = 24.38 and
11.75, respectively), but taken as a whole, the inhibition
was on inferior side. In order to improve the inhibition,
next set of compounds 8–13 were synthesized, where
compound 11 showed maximum potency (IC50 = 4 μM)
with poor selectivity (SI = 13.33), while compound 13
has displayed highest selectivity index (SI = 114).
However, both of these compounds were not as good as
standard used for COX-2 inhibition.
H
H
For the further optimization, two different series of
derivatives comprising compounds 14–21 and 22–29
(where R6 was fixed by OCH3 group) were synthesized.
Unhappily, none of the compound from these series was
potent; both the selectivity and COX-2 activity was
insignificant, prompting us that OCH3 group at R6 might
be responsible for poor potency.
By considering the above fact, we then explored the
structure–activity relationship course and replaced R6 by
methyl group and methoxy group was shifted at R1
position. These changes produce another set of
compounds 30–37 where the methoxy group was shifted
across R2–R5. Unfortunately, the previously mentioned
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. B. Jadhav, S. Fatema, R. B. Patil, J. N. Sangshetti, and M. Farooqui
Vol 000
Table 2
presence of methyl group at R1 position is essential for
the potency. Further, we fixed R1 position with methyl
group and modifications were prepared and tested.
Compounds 42, 43, 44, and 45 showed decent COX-2
inhibition potency in all. However, compounds 42 and 44
have shown a poor selectivity ratio (SI = 40 and
SI = 63). The compound 45 has displayed good potency
(COX-2 IC50 = 0.67 μM), but selectivity (SI = 335)
was less compared with standard celecoxib. Whereas
compound 43 displayed as most active of all (COX-2
IC50 = 0.4 μM) with better inhibition than the standards
used along with better selectivity ration (SI = 400) than
celecoxib.
IC50 (μM) for the compounds 1–45 (COX-1 and COX-2).
IC50 (μM)
Sr. No
COX-1
12
2.42
8.4
5.7
1.7
COX-2
Selectivity Index
1
2
3
4
5
6
7
8
68
59
78
67
18
85
7.6
67
42
108
4
5.6
24.38
9.28
11.75
10.58
5.0
6.33
23.1
6.26
120
13.33
0.76
35
4.25
20.2
1.76
5.6
15.1
5.41
7.01
34.28
5.55
7.16
8.12
19.70
10.76
3.18
21
5.66
2.25
12
8.80
11.53
9.8
17
1.2
2.9
6.7
0.9
0.3
67
1.4
16
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
Celecoxib
In-vivo anti-inflammatory activity.
The in vivo anti-
51
49
68
99
12
84
91
65
134
144
50
43
65
67
84
14
67
68
34
67
59
45
40
45
65
59
34
9
inflammatory study was carried for active compounds 42,
43, 44, and 45. The experiment was performed as per
the procedure previously described in literature [22].
Compound 42 showed only 31% inhibition after 3 h
when compared with celecoxib (67% inhibition after 3 h).
Compounds 44 and 45 with good COX-2 inhibition
(COX-2 IC50 = 0.63 μM and 0.67 μM, respectively)
displayed moderate in vivo profile (52% and 49%
inhibitions, respectively, after 3 h). Derivative 43 with
COX-2 IC50 = 0.40 μM and maximum selectivity
(SI = 400) displayed decent in vivo profile with 72% of
inhibition after 3 h. This result indicates that compound
43 was found superior than standard celecoxib (COX-2
IC50 = 15 μM, SI = 375, 67% inhibition after 3 h)
(Table 3).
Ulcerogenicity. Compounds 42, 43, 44, and 45 were
subjected to ulcerogenic effect. The study was performed
according to literature [23,24]. Compounds 42, 43, 44,
and 45 did not cause any gastric ulceration. Hence,
gastric tolerance of these compounds was better than that
of celecoxib. This result proves that these compounds are
safe on gastric mucosa. The result is mentioned in
Table 4.
4.9
6.8
15
6.0
12
19
4.2
9.0
6.0
8
3.4
7.8
4.4
3.2
12
15
5.6
6.7
3.9
4.6
4.0
7
11.2
9.2
6.55
11.3
150
4.33
12.05
40
400
63
335
375
9
3
0.08
15
3.9
0.01
0.001
0.01
0.002
0.04
65
47
0.52
0.4
0.63
0.67
Molecular docking studies on COX-1/2.
In order to
illustrate the binding interactions of most and least active
compounds at the binding site of COX-1/2 isoenzyme,
docking studies were performed with AUTODOCK VINA
[25]. The solved X-ray crystal structures (COX-1, PDB:
3KK6; COX-2, PDB: 3LN1) of COX-1/2 isoenzyme
with bound celecoxib, a COX-2 selective inhibitor, were
used for docking studies. In brief, the docking protocol
consisted of protein refinement where nonstandard
residues were removed from crystal structure. To attain the
native structure of enzyme, energy minimization was
carried out in UCSF CHIMERA by using 10 000 steepest
descent steps until gradient converses to 0.01 A0. The 2D
structures of compounds were transformed to 3D in
Marvin sketch. The resulting 3D structures were optimized
by using MM Universal force field in ARGUSLAB 4.0.1
with Broyden-Fletcher-Golfarb-Shanno search until the
15
modification was unable to deliver the better potency for
COX inhibition. Based on this result, we assumed that in
order to get the improved inhibitory potency, methyl
group might be essential at R1 position. Accordingly,
methoxy group was removed and another set of
compounds 38–45 was synthesized with variation of
methyl/methoxy at R2–R5. In this series, compound 39
displayed significant improvement in COX-2 inhibitory
activity (IC50 = 9 μM) along with selectivity (SI = 150).
From previously mentioned results, we confirmed that the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Pyrido[1,2-a]pyrimidin-4-ones: Ligand-based Design, Synthesis, and Evaluation
as an Anti-inflammatory Agent
Table 3
In vivo anti-inflammatory data for active compound.
Change in rat paw volume (mL) after drug administration
In vivo anti-inflammatory inhibition (% Inhibition)
ID
0 h
1 h
2 h
3 h
1 h
22
2 h
26
64.12
48.00
42.11
—
3 h
31
72.00
52.14
49.00
—
42
43
44
45
0.36 0.04*
0.39 0.03*
0.33 0.04*
0.41 0.01*
0.31 0.03*
0.29 0.10*
0.438 0.03*
0.451 0.04*
0.395 0.05*
0.472 0.06*
0.41 0.04*
0.350 0.01*
0.493 0.03*
0.454 0.04*
0.423 0.08*
0.514 0.05*
0.49 0.04*
0.363 0.10*
0.553 0.05*
0.468 0.07*
0.464 0.02*
0.552 0.05*
0.59 0.04*
0.382 0.08*
39
34.11
38.09
—
Control
Celecoxib
40
59
67
Data were analyzed by one-way ANOVA followed by Dunnet’s test (n = 6). Dose levels–test compounds and celecoxib (25 mg/kg).
*P < 0.05 significant from control sample.
Table 4
Table 5
Ulcerogenicity for active compound.
Binding free energy output of AUTODOCK VINA.
Compound
Dose mg/kg/day Time in days
Ulcer index
Binding free energy in Kcal/mol
42
43
44
45
25
25
25
25
4
4
4
4
4
4
0.25 0.03**
0.38 0.05**
0.22 0.07**
0.29 0.09**
0.53 0.22**
----
ID
COX-1
COX-2
2
5
6
7
ꢀ2.7
ꢀ2.9
ꢀ2.4
ꢀ2.8
ꢀ2.8
ꢀ3
ꢀ3.2
ꢀ3.9
ꢀ3.2
ꢀ4.1
ꢀ3.2
ꢀ4.1
ꢀ3.2
ꢀ3.1
ꢀ3.1
ꢀ3.1
ꢀ3
Celecoxib
Control
25
CMC 1% w/v
8
Data were analyzed by one-way ANOVA followed by Dunnet’s test
(n = 6).
**P < 0.01 significant from control sample.
11
13
15
17
18
20
21
26
28
38
39
42
43
44
45
cele
ꢀ2.9
ꢀ2.5
ꢀ2.3
ꢀ2.7
ꢀ0.7
ꢀ2.6
ꢀ1.4
ꢀ2.4
ꢀ2.4
ꢀ3.1
ꢀ3.4
ꢀ3.7
ꢀ3.4
ꢀ3.6
ꢀ3.2
gradient converses to 0.001 kcal/mol/A0. In AUTODOCK
VINA run, grid box of size 14 × 14 × 14 A0 with center
ꢀ33.996, 43.834, and ꢀ6.086 for COX-1 and 32.522,
ꢀ22.915, and ꢀ15.769 for COX-2 was chosen. Docking
studies were validated by docking the celecoxib at the
binding site. Docking produced the pose of celecoxib with
root mean square deviation below 1° at the binding site of
both proteins (Fig. S1 in the Supporting Information).
From among the docking results, the results for 20 most
active or least active compounds along with standard
drugs are shown in Table 5.
ꢀ3
ꢀ3.2
ꢀ3.2
ꢀ3.3
ꢀ4
ꢀ4.5
ꢀ4.6
ꢀ4.3
ꢀ4.3
ꢀ3.9
The structural differences between COX-1 and COX-2
are due to two amino acid residues. Replacement of
Ile517 in COX-1 by a hydrophobic smaller Val in COX-2
is the most important difference (Fig. S2). This
modification in the COX-2 enzyme creates additional side
pocket, which is a pre-requisite for COX-2 selectivity
[26]. Further, the presence of His513 instead of Arg499
in the COX-1 enzyme also contributes toward COX-2
selectivity. In our docking studies, docked poses of most
active compounds (42, 43, 44, and 45) were found to
occupy the binding site of COX-2 iso-enzyme more
favorably (Fig. 2). Phenyl-pyrido[1,2-a]pyrimidin-4-one
ring occupies the hydrophobic cavity where CF3 group of
celecoxib interacts. As this cavity is made by most of the
hydrophobic residues like val, it is evident that lager
groups or rings could improve the COX-2 selectivity. The
presence of CH3 group (R6) was found crucial in these
most active compounds. The presence of OCH3 group
probably is too bulky to accommodate in the
hydrophobic cavity surrounded by hydrophobic residues
like Ala, Tyr, Gly, and Phe. Similarly, the substitution by
OCH3 on phenyl ring (R1–R5) is too bulky to
accommodate third cavity where SO2NH2 group of
celecoxib binds. In case of least active compounds (13,
20, and 21), the docked poses show that the bulky OCH3
groups contribute toward the lower affinity to COX-2
binding site.
In case of docking with COX-1 iso-enzyme, it was
found that the most active compounds (42, 43, 44, and
45) occupy the binding site but the phenyl-pyrido[1,2-a]
pyrimidin-4-one ring could not occupy the cavity where
CF3 group of celecoxib binds. Here again, we found that
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. B. Jadhav, S. Fatema, R. B. Patil, J. N. Sangshetti, and M. Farooqui
Vol 000
Figure 2. Docked poses of A: most active compounds (42, 43, 44, and 45) and B: least active compounds (13, 20, and 21) along with docked pose of
celecoxib shown in black color. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 3. Docked poses of A: most active compounds (39, 42, 43, 44, and 45); B: least active compounds (17, 20, and 26) along with celecoxib shown in
black color. [Color figure can be viewed at wileyonlinelibrary.com]
the OCH3 substitution on phenyl ring (R1–R5) is too bulky
to accommodate the cavity where –CF3 group of celecoxib
binds. Phenyl-pyrido[1,2-a]pyrimidin-4-one ring occupies
the extended hydrophobic cavity surrounded by Ala, Tyr,
Gly, and Phe. In case of least active compounds (17, 20,
and 26), the presence of OCH3 on phenyl ring was found
unfavorable for binding (Fig. 3). Interactions of most
active and least active compounds with COX-2 and
COX-1 are given in Figures S3A, S3B, S4A, and S5B,
respectively.
very effective with respect to COX-2 selectivity. In
addition, in vivo profile of 42 (31% inhibition after 3 h)
was poor, while in vivo profiles for 44 and 45 (52.14 and
49% inhibition, respectively, after 3 h) were moderate.
Whereas, the compound 43 (72% inhibition after 3 h)
was emerged as a best anti-inflammatory agent and found
superior than that of celecoxib. Additionally, 42, 43, 44,
and 45 demonstrated superior ulcerogenic index as
compared with celecoxib. On the basis of these findings,
compound 43 was identified as a lead candidate within
current description.
CONCLUSION
EXPERMENTAL
Present article deals with synthesis of pyrido[1,2-a]
pyrimidin-4-ones derivatives as selective COX-2
inhibitors. Looking to in vitro assay (COX-1 and COX-2
inhibitions), compounds 42, 43, 44, and 45 were potent
candidates; however, compounds 43 and 45 were found
Chemistry.
The melting points of the synthesized
compound were determined in open capillary tubes by
using VMP-D melting point apparatus (Veego Instrument
Corporation, Mumbai, India) and are uncorrected. The H
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Pyrido[1,2-a]pyrimidin-4-ones: Ligand-based Design, Synthesis, and Evaluation
as an Anti-inflammatory Agent
NMR and 13C NMR for the compound synthesized were
recorded on Varian Mercury (Switzerland) plus 400 by using
TMS as an internal standard and DMSO-d6 solvent and
chemical values are given δ scales. The spectra of mass were
recorded on mass spectrometer (Acquity, Waters Corpora-
tion). Microanalyses were carried out on elementar (Vario
Micro Cube, Germany). The follow-up of reactions was
monitored by thin-layer chromatography (TLC) on silica
gel-precoated aluminum sheets (Type 60, F254, Merck,
Germany), and the spots were detected by exposer to UV
lamp at λ 254 nm for 20–30 s. Necessary chemicals were or-
dered from Sigma-Aldrich and Spectrochem (INDIA). Com-
mercial grade solvents were used without their purifications.
General procedure for synthesis of pyrazole aldehyde (D).
A mixture of various acetophenones (1 mol) (A) and
phenyl hydrazines (1 mol) (B) were heated in ethanol (10
volume of A) in presence of (3 mL) acetic acid at reflux
temperature for 30 min. Resulting yellow solid product
was separated by the filtration. This solid was washed by
cold ethanol (20 mL) and was suck dried under vacuum.
A mixture of N,N-dimethylformamide (2.5 mol), POCl3
(2.5 mol), was stirred together at 0°C for 30 min.The
previously mentioned solid was added to this reaction
mixture at 0°C with constant stirring. The reaction
mixture was then allowed to warm up to room
temperature and stirred for 12–14 h. Reactions were
monitored by TLC techniques; after completion of the
reaction, reaction mixture was poured on crushed ice
where upon the solid was separated. It was filtered and
washed by saturated aqueous NaHCO3 solution followed
by water. The solid was crystalized from ethanol to get
white crystalline product D in an average 70% yield.
Synthesis of 2-methyl-pyrido[1,2-a]pyrimidin-4-one (G).
(13.20 g, 0.024 mol), and iodine (3.78 g, 0.03 mol) in
acetonitrile (100 mL) was stirred at 80°C for 5–6 h.
Conversion was monitored by TLC; later, the heating
was removed and reaction mixture was cooled to room
temperature. Solvent was removed under reduced
pressure; distilled water (80 mL) was added to
residue and stirred it for 1 h at room temperature.
Yellow solid (12 g) of 2-methyl-3-iodo-pyrido[1,2,a]
pyrimidin-4-one H was obtained after filtration. 1H
NMR (400 MHz, DMSO-d6): δ ppm: 2.37 (s, 3H,
pyrimidinone CH3), 7.09 (d, 1H, J = 8.0 Hz, ArH),
7.44–7.46 (m, 2H, ArH), 8.54 (d, J = 8.6 Hz, ArH);
ES-MS 287.3 (M + 1).
Then H (3.8 g, 0.013 mol) was taken in toluene
(125 mL), to that Pd[(C6H5)3P]4 (0.615 g, 0.00053 mol),
and a solution of Na2CO3 (0.082 g, 0.00078 mol) in
water (50 mL) were added. Further, a solution of
phenylboronic acid (2.1 g, 0.017 mol) in ethanol (50 mL)
was added and reaction mixture was stirred at refluxed
for 2 h. After completion, the reaction was cooled and
the solvent was removed under reduced pressure. The
residue was partitioned in ethyl acetate (500 mL) and
water (100 mL). The organic layer was washed by brine
(100 mL) and was removed to afford crude product; it
was then purified by column chromatography by using
silica (60–120) and methanol chloroform as eluent to get
yellow solid 2-methyl-3-phenyl-pyrido[1,2-a]pyrimidin-
4-one I in 1.8 g (52%) yield. 1H NMR (400 MHz,
DMSO-d6): δ ppm: 2.1 (s, 3H, pyrimidinone CH3), 7.12
(d, J = 8.01 Hz, ArH), 7.32–7.40 (m, 4H, ArH), 8.10
(m, 2H, ArH), 8.78 (d, J = 8.2 Hz, ArH near to nitrogen);
ES-MS 237 (M + 1).
General method for coupling of (D) and (I).
Sodium
Ethyl acetoacetate F (39 g, 0.3 mol) was added to a stirred
mixture of 2-aminopyridine E (92 g, 1.0 mol) and acetic
acid (200 mL). The mixture was refluxed for 15 h. The
reaction mixture was then cooled to room temperature,
and acetic acid was removed to afford dark brown crude
solid. It was dissolved in ethyl acetate (250 mL) and
washed with saturated NaHCO3 solution (200 mL × 2)
followed by saturated brine solution (200 mL). Organic
layer was dried over anhydrous Na2SO4, and solvent was
concentrated under vacuum to afford the crude product.
The crude was purified by column chromatography nby
using silica (60–120) to give white solid of 2-methyl-
pyrido[1,2-a]pyrimidin-4-one G (75 g, 49%). Conversion
ethoxide (2 mol) was added to a stirred mixture of
2-methyl-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (1 mol)
and pyrazole aldehyde (1.5 mol) in ethanol (10 volume);
reaction mixture was stirred at reflux for 13 h. Reaction
mixture (transparent solution) was allowed to cool to
room temperature. The product (precipitated solid) was
obtained after filtration.
3-Phenyl-2-[2-(3-phenyl-1-p-tolyl-1H-pyrazol-4-yl)-vinyl]-
pyrido[1,2-a]pyrimidin-4-one (1).
Yield 67%; mp 198–
200°C; 1H NMR (400 MHz, DMSO-d6): δ ppm: 2.20
(s, 3H, Ar-CH3), 6.80 (d, J = 16 Hz, olefinic H near to
pyrazole), 7.05 (d, 1H, J = 8.19 Hz, ArH), 7.20 (s, 1H,
ArH), 7.30–7.45 (m, 6H ArH, and olefinic H near to
pyrimidone ring), 7.46–7.60 (m, 3H, ArH), 7.80–7.85 (m,
2H, ArH), 8.00 (m, 1H, ArH), 8.20–8.29 (m, 3H, ArH),
8.30 (a, 1H, pyrazole ring H), 8.90 (s, 1H, ArH near to
nitrogen); 13C NMR (100 MHz, DMSO-d6): 21.6
(Ar-CH3), 108.6, 115.3, 121.3, 121.4, 125.3, 125.9,
129.2, 130.1, 131.2, 136.3, 137.1, 139.2, 146.1, 150.1,
150.5, 163.8; ES-MS m/z 481.3 [M + 1]. Anal. Calcd
for C32H24N4O.Anal. Calcd for C32H24N4O (480.5):
1
was monitored by TLC techniques. H NMR (400 MHz,
DMSO-d6): δ ppm: 2.35 (s, 3H, pyrimidinone CH3), 6.15
(s, 1H, pyrimidinone H), 7.01 (d, 1H, J = 8.05 Hz, ArH),
7.35–7.37 (m, 2H, ArH), 8.42 (d, 1H, J = 8.5 Hz, ArH
near to nitrogen); ES-MS 161 (M + 1).
Synthesis of 2-methyl-3-phenyl-pyrido[1,2-a]pyrimidin-4-one
(I).
A mixture of 2-methyl-pyrido [1,2-a]pyrimidin-
4-one G (11.9 g, 0.05 mol), ceric ammonium nitrate
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. B. Jadhav, S. Fatema, R. B. Patil, J. N. Sangshetti, and M. Farooqui
Vol 000
C, 79.98; H, 5.03; N, 11.66. Found C, 79.73; H, 5.29;
N, 11.55.
2-{2-[1-(4-Methoxy-phenyl)-3-(2-methoxy-phenyl)-1H-
pyrazol-4-yl]vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (2).
107.2, 117.8, 119.3, 120.1, 121.5, 121.9, 123.4, 123.9, 126.3,
129.2, 129.9, 131.4, 136.2, 139.2, 145.9, 150.2, 158.3,
164.8(C═O); ES-MS m/z 511.3 [M + 1]. Anal. Calcd for
C33H26N4O2. (510.3): C, 77.64; H, 5.13; N, 10.97. Found C,
Yield 61%; mp 212–214°C; 1H NMR (400 MHz,
DMSO-d6): δ ppm: 3.95 (s, 3H, Ar-OCH3), 3.99 (s, 3H,
Ar-OCH3), 6.70 (d, J = 16 Hz, Hz, 1H, olefinic H near to
pyrazole ring), 7.00 (s, 1H, ArH), 7.24–7.60 (m, 8H,
ArH, and olefinic H near to pyrimidinone), 7.80–8.00
(m, 5H, ArH), 8.15–8.22 (m, 3H, ArH), 8.32 (s, 1H,
pyrazole ring H), 8.95 (s, 1H ArH). 13C NMR (100 MHz,
DMSO-d6): 53.8 (Ar-OCH3), 54.2 (Ar-OCH3), 104.6,
117.2, 119.1 (olefinic C near to pyrazole ring), 120.3,
121.3, 121.9. 123.4. 126.2. 129.2, 136.1, 139.1, 154.3,
155.1, 164.2; ES-MS m/z 527.60 [M + 1]. Anal. Calcd for
C33H26N4O3 (526.5): C, 75.27; H, 4.98; N, 10.64. Found
78.01; H, 5.09; N, 11.18.
2-{2-[1-(4-Methoxy-phenyl)-3-m-tolyl]-1H-pyrazol-4-yl]-
vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (6). Yield 55%;
1
mp 210–212°C; H NMR (400 MHz, DMSO-d6): δ ppm:
2.34 (s, 3H, Ar-CH3), 3.98 (s, 3H, Ar-OCH3), 6.60
(d, 1H, J = 16 Hz, olefinic H near to pyrazole), 7.20–7.30
(m, 6H, ArH), 7.45–7.65 (m, 4H, ArH, and olefinic
H near to pyrimidinone), 7.80–8.00 (m, 3H, ArH), 8.23
(s, 1H, pyrazole ring H), 8.99 (s, 1H, ArH); 13C NMR
(100 MHz, DMSO-d6): 22.2 (Ar-CH3), 56.3 (Ar-OCH3),
105.2, 114.3, 118.3, 119.3, 121.6, 121.9, 123.4, 123.5,
126.4, 129.1, 129.2, 131.5, 134.2, 136.2, 139.2, 145.9,
148.3, 150.2, 158.3, 164.1(C═O); ES-MS m/z 511.3
[M + 1]. Anal. Calcd for C33H26N4O2. (510.3): C, 77.64;
C, 75.16; H, 5.09; N, 11.06.
2-{2-[1-(4-Methoxy-phenyl)-3-(3-methoxy-phenyl)-1H-
pyrazol-4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (3).
H, 5.13; N, 10.97. Found C, 77.99; H, 5.03; N, 11.08.
1
Yield 77%; mp 211–213°C; H NMR (400 MHz, DMSO-
2-{2-[1-(4-Methoxy-phenyl)-3-p-tolyl-1H-pyrazol-4-yl]-vinyl}-
d6): δ ppm: 3.97 (s, 3H, Ar-OCH3), 3.99 (s, 3H, Ar-OCH3),
6.80 (d, 1H, J = 16 Hz, olefinic H near to pyrazole ring),
7.00 (s, 1H, ArH), 7.24–7.60 (m, 8H, ArH, and olefinic H
near to pyrimidinone), 7.80–8.00 (m, 4H, ArH), 8.21–8.29
(m, 3H, ArH), 8.33 (s, 1H, pyrazole ring H), 8.95 (s, 1H
ArH near to nitrogen); 13C NMR (100 MHz, DMSO-d6):
54.6 (Ar-OCH3), 55.1(Ar-OCH3), 103.9, 116.3, 118.9,
120.1, 121.9, 123.2. 124.2, 127.3, 129.1, 131.9, 136.6,
139.1, 143.1, 149.1, 150.2, 154.2, 163.1(C═O); ES-MS m/
z 527.60 [M + 1]. Anal. Calcd for C33H26N4O3 (526.5):
C, 75.27; H, 4.98; N, 10.64. Found C, 75.76; H, 4.76;
3-phenyl-pyrido[1,2-a]pyrimidin-4-one (7).
Yield 49%; mp
1
237–239°C; H NMR (400 MHz, DMSO-d6): δ ppm: 2.32
(s, 3H, Ar-CH3), 3.91 (s, 3H, Ar-OCH3), 6.60 (d, 1H,
J = 16 Hz, olefinic H near to pyrazole ring), 7.00 (d, 1H,
J = 7.01 Hz, ArH), 7.21–7.45 (m, 4H, ArH, and olefinic H
near to pyrimidinone), 7.60–7.70 (m, 3H, ArH), 7.80–8.00
(m, 3H, ArH), 8.00–8.12 (m, 4H, ArH), 8.21 (s, 1H,
pyrazole ring H), 8.99 (s, 1H, ArH near to nitrogen);
13C NMR (100 MHz, DMSO-d6): 22.4 (Ar-CH3), 54.3
(Ar-OCH3), 107.2, 116.3, 117.3, 119.4, 121.1, 121.9, 123.5,
123.9, 126.1, 129.1, 130.1, 131.5, 134.2, 136.2, 139.2,
145.9, 148.3, 150.2, 158.3, 164.1(C═O); ES-MS m/z 511.3
N, 11.09.
2-{2-[1,3-Bis-(4-methoxy-phenyl)-1H-pyrazol-4-yl]-vinyl}-3-
[M + 1]. Anal. Calcd for C33H26N4O2. (510.3): C, 77.64; H,
5.13; N, 10.97. Found C, 77.88; H, 5.23; N, 11.08.
phenyl-pyrido[1,2-a]pyrimidin-4-one (4).
Yield 62%; mp
234–236°C; 1H NMR (400 MHz, DMSO-d6): δ ppm:
3.93 (s, 3H, Ar-OCH3), 3.95 (s, 3H Ar-OCH3), 6.65 (d, 1H,
J = 16 Hz, olefinic H near to pyrazole), 7.20 (s, 1H, ArH),
7.25–7.35 (m, 6H, ArH, and olefinic H near pyrimidinone),
7.65–8.00 (m, 6H, ArH), 8.20–8.28 (m, 3H, ArH), 8.37 (s,
1H, pyrazole ring H), 9.00 (s, 1H, ArH near to nitrogen);
13C NMR (100 MHz, DMSO-d6): 54. 6(Ar-OCH3),
55.1(Ar-OCH3), 108.2, 115.8, 118.2, 121.3, 121.9, 123.4,
123.9, 126.3, 129.2, 129.9, 131.4, 136.2, 139.2, 145.9,
150.2, 151.7, 159.2, 163.7 (C═O); ES-MS m/z 527.60
2-{2-[3-(2-Methoxy-phenyl)-1-p-tolyl-1H-pyrazol-4-yl]-vinyl}-
3-phenyl-pyrido[1,2-a]pyrimidin-4-one (8).
Yield 64%; mp
1
214–216°C; H NMR (400 MHz, DMSO-d6): δ ppm: 2.34
(s, 3H, Ar-CH3), 3.95 (s, 3H, Ar-OCH3), 6.88 (d, 1H,
J = 16 Hz, olefinic H near to pyrazole ring), 7.05–7.10
(m, 3H, ArH), 7.40–7.48 (m, 6H, ArH, and olefinic H near
to pyrimidinone), 7.50 (d, 1H, J = 7.93 Hz, ArH), 7.58–7.75
(m, 2H, ArH), 7.89–8.00 (m, 4H, ArH), 8.23 (s, 1H,
pyrazole ring H), 8.99 (s, 1H, ArH near to nitrogen); 13C
NMR (100 MHz, DMSO-d6): 22.9 (Ar-CH3), 56.4,
(Ar-OCH3), 106.2, 117.1, 119.4, 120.1, 121.2, 121.9, 123.7,
124.9, 126.1, 129.1, 130.3, 131.5, 133.2, 136.4, 139.8,
144.5, 149.2, 150.9, 157.3, 163.2 (C═O); ES-MS m/z 511.3
[M + 1]. Anal. Calcd for C33H26N4O2. (510.3): C, 77.64; H,
[M + 1]. Anal. Calcd for C33H26N4O3 (526.5): C, 75.27; H,
4.98; N, 10.64. Found C, 75.12; H, 5.17; N, 11.09.
2-{2-[1-(4-Methoxy-phenyl)-3-o-tolyl-1H-pyrazol-4-yl]-vinyl}-
3-phenyl-pyrido[1,2-a]pyrimidin-4-one (5).
Yield 71%; mp
1
215–217°C; H NMR (400 MHz, DMSO-d6): δ ppm: 2.34
(s, 3H, Ar-CH3), 3.99 (s, 3H, Ar-Ar-OCH3), 6.69 (d, 1H,
J = 15.7 Hz, olefinic H near to pyrazole ring), 7.05–7.23
(m, 6H, ArH), 7.30–7.40 (m, 4H, ArH and olefinic H near to
pyrimidinone), 7.45–7.70 (m, 3H, ArH), 7.80–8.00 (m, 4H.
ArH), 8.22 (s, 1H, pyrazole ring H) 8.99 (s, 1H, ArH); 13C
NMR (100 MHz, DMSO-d6): 21 (Ar-CH3), 55 (Ar-OCH3),
5.13; N, 10.97. Found C, 77.79; H, 5.35; N, 10.65.
2-{2-[3-(3-Methoxy-phenyl)-1-p-tolyl-1H-pyrazol-4-yl]vinyl}-
3-phenyl-pyrido[1,2-a]pyrimidin-4-one (9). Yield 55%; mp
1
231–233°C; H NMR (400 MHz, DMSO-d6) δ ppm: 2.32
(s, 3H, Ar-CH3), 3.95 (s, 3H, Ar-OCH3), 6.69 (d, 1H,
16 Hz, olefinic H near to pyrazole), 7.10–7.30 (m, 6H,
ArH), 7.34–7.45 (m, 4H, ArH, and olefinic H near to
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Pyrido[1,2-a]pyrimidin-4-ones: Ligand-based Design, Synthesis, and Evaluation
as an Anti-inflammatory Agent
pyrimidinone), 7.60–7.79 (m, 3H, ArH), 7.85–8.05 (m,
4H, ArH), 8.32 (s, 1H, pyrazole ring H), 8.90 (s, 1H,
ArH); 13C NMR (100 MHz, DMSO-d6): 21.9 (Ar-CH3),
56.1 (Ar-OCH3), 106.4, 116.9, 119.1, 120.6, 121.4,
121.8, 123.9, 124.2, 126.4, 129.1, 130.9, 131.8, 133.2,
135.6, 139.2, 145.1, 149.3, 151.4, 157.2, 163.4 (C═O);
ES-MS m/z 511.3 [M + 1]. Anal. Calcd for C33H26N4O2.
(510.3): C, 77.64; H, 5.13; N, 10.97. Found C, 77.80; H,
5.23; N, 11.03.
2-[2-(1,3-Di-p-toly1–1H-pyrazol-4-yl)vinyl]-3-phenyl-pyrido
[1,2-a]pyrimidin-4-one (13). Yield 53%; mp 235–237°C;
1H NMR (400 MHz, DMSO-d6) δ ppm: 2.27 (s, 3H,
Ar-CH3), 2.31 (s, 3H, Ar-CH3), 6.58 (d, 1H, J = 16 Hz,
olefinic H near to pyrazole ring), 7.00–7.10 (m, 2H,
ArH), 7.22–7.34 (m, 4H, ArH), 7.42 (d, 1H, J = 16 Hz,
olefinic H near to pyrimidinone), 7.50–7.70 (m, 4H,
ArH), 7.78–8.00 (m, 4H, ArH), 8.12–8.20 (m, 3H, ArH),
8.32 (s, 1H, pyrazole ring H), 8.99 (s, 1H, ArH near to
nitrogen); 13C NMR (100 MHz, DMSO-d6): 22.1
(Ar-CH3), 23.8 (Ar-CH3), 107.1, 117.6, 119.1, 120.3,
120.9, 121.2, 121.4, 122.8, 123.9, 124.2, 125.9, 126.4,
127.9, 128.9, 129.5, 130.6, 131.7, 132.4, 133.9,
134.8, 135.3, 135.9, 136.1, 138.3, 144.6, 149.7, 150.7,
162.5 (C═O); ES-MS m/z 495.3 [M + 1]. Anal. Calcd for
C33H26N4O. (494.60): C, 80.14; H, 5.30; N, 11.33.
2-{2-[3-(4-Methoxy-phenyl)-1-p-tolyl-1H-pyrazol-4-yl]vinyl}-
3-phenyl-pyrido[1,2-a]pyrimidin-4-one (10). Yield 54%; mp
1
212–213°C; H NMR (400 MHz, DMSO-d6) δ ppm: 2.37
(s, 3H, Ar-CH3), 3.95 (s, 3H, Ar-OCH3), 6.60 (d. 1H,
16 Hz, olefinic H near to pyrazole), 7.10–7.23 (m, 4H,
ArH), 7.34–7.42 (m, 5H, ArH, and olefinic H near to
pyrimidinone), 7.65–7.77 (m, 3H, ArH), 7.80–8.00 (m,
3H, ArH), 8.04–8.12 (m, 3H, ArH), 8.33 (s, 1H, pyrazole
ring H), 8.99 (s. 1H, ArH near to nitrogen); 13C NMR
(100 MHz, DMSO-d6): 22.1 (Ar-CH3), 56.1, (Ar-OCH3),
106.0, 117.4, 118.4, 120.2, 121.4, 121.6, 122.4, 124.1,
125.8, 129.1, 130.3, 131.4, 133.4, 136.1, 139.4, 144.7,
149.4, 151.2, 157.8, 163.6 (C═O); ES-MS m/z 511.3
[M + 1]. Anal. Calcd for C33H26N4O2 (510.3): C, 77.64;
H, 5.13; N, 10.97. Found C, 77.99; H, 5.07; N, 11.00.
3-phenyl-2-[2–3-o-toly1–1-p-tolyl-1H-pyrazol-4-yl)vinyl]-
Found C, 80.23; H, 5.08; N, 11.01.
2-{2-[3-(2,3-Dimethoxy-phenyl)-1-(4-methoxy-phenyl)-1H-
pyrazol-4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one
1
(14). Yield 46%; mp 224–227°C; H NMR (400 MHz,
DMSO-d6) δ ppm: 3.68 (s, 3H, Ar-OCH3), 3.95 (s, 3H,
Ar-OCH3), 3.98 (s, 3H, Ar-OCH3), 6.77 (d, 1H,
J = 16.2 Hz, olefinic H near to pyrazole), 7.23–7.43 (m,
5H, olefinic H near to pyrazole and ArH), 7.49–8.01
(m, 4H, ArH), 8.12–8.23 (m, 5H, ArH), 8.32 (s, 1H,
pyrazole ring H), 9.00 (s, 1H, ArH near to nitrogen); 13C
NMR (100 MHz, DMSO-d6): 56.1 (Ar-OCH3), 58.1
(Ar-OCH3), 58.7 (Ar-OCH3), 109.2, 118.6, 119.1, 120.5,
121.7, 122.9, 123.6, 124.5, 125.9, 126.4, 127.7, 128.7,
128.9, 130.1, 131.9, 132.8, 133.9, 134.8, 136.5, 138.1,
144.5, 149.9, 150.7, 158.1, 158.9, 162.9 (C═O); ES-MS
m/z 557.3 [M + 1]. Anal. Calcd for C34H28N4O4.
(556.60): C, 73.37; H, 5.03; N, 10.07. Found C, 73.23; H,
pyrido[1,2-a]pyrimidin-4-one (11).
Yield 68%; mp 233–
235°C; 1H NMR (400 MHz, DMSO-d6) δ ppm: 2.37
(s, 3H, Ar-CH3), 2.40 (s, 3H, Ar-CH3), 6.99 (d, 1H,
J = 16 Hz, olefinic H near to pyrazole), 7.05–7.10
(m, 3H, ArH), 7.28–7.35 (m, 4H, ArH), 7.45–7.65
(m, 5H, olefinic H near to pyrimidinone, and ArH), 7.98–
8.04 (m, 4H, ArH), 8.32 (s, 1H, pyrazole ring H), 9.00
(s, 1H, ArH); 13C NMR (100 MHz, DMSO-d6): 22.9
(Ar-CH3), 23.2 (Ar-CH3), 104.2, 116.1, 119.4, 120.3,
120.4, 121.2, 121.5, 123.2, 124.7, 126.1, 126.9, 127.2,
129.4, 130.3, 131.5, 133.2, 136.1, 139.1, 144.5, 149.2,
150.9, 163.8 (C═O); ES-MS m/z 495.3 [M + 1]. Anal.
Calcd for C33H26N4O. (494.60): C, 80.14; H, 5.30; N,
11.33. Found C, 80.23; H, 5.08; N, 11.09.
5.09; N, 10.22.
2-{2-[3-(2,4-Dimethoxy-phenyl)-1-(4-methoxy-phenyl)-1H-
pyrazol-4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one
1
(15). Yield 53%; mp 235–237°C; H NMR (400 MHz,
DMSO-d6) δ ppm: 3.62 (s, 3H, Ar-OCH3), 3.90 (s, 3H,
Ar-OCH3), 3.96 (s, 3H, Ar-OCH3), 6.30 (d, 1H,
J = 16 Hz olefinic H near to pyrazole), 7.08 (d, 1H,
J = 8.09 Hz, ArH), 7.41 (d, 1H, J = 15.8 Hz, olefinic H
near to pyrimidinone), 7.42–7.80 (m, 6H, ArH), 7.93–
8.03 (m, 2H, ArH), 8,21 (s, 1H, pyrazole H), 9.09–9.13
(m, 3H, ArH near to nitrogen); 13C NMR (100 MHz,
DMSO-d6): 56.4 (Ar-OCH3), 58.5 (Ar-OCH3), 58.9
(Ar-OCH3), 110.1, 120.1, 120.9, 121.9, 122.9, 123.8,
124.9, 125.8, 126.9, 127.6, 128.5, 129.1, 130.1, 131.9,
132.8, 133.9, 134.8, 136.1, 138.4, 144.7, 149.2, 151.4,
155.8, 157.3, 158.9, 163.9 (C═O); ES-MS m/z 557.3
[M + 1]. Anal. Calcd for C34H28N4O4. (556.60): C, 73.37;
3-phenyl-2-[2–3-m-toly1–1-p-tolyl-1H-pyrazol-4-yl)vinyl]-
pyrido[1,2-a]pyrimidin-4-one (12).
Yield 74%; mp 234–
236°C; 1H NMR (400 MHz, DMSO-d6) δ ppm: 2.31
(s, 3H, Ar-CH3), 2.38 (s, 3H, Ar-CH3), 6.49 (d, 1H,
J = 16 Hz, olefinic H near to pyrazole ring), 7.03–7.09
(m, 3H, ArH), 7.37–7.61 (m, 5H, ArH and olefinic H
near to pyrimidinone), 7.99–8.05 (m, 3H, ArH), 8.31
(s, 1H, pyrazole ring H), 9.05–9.15 (m, 3H, ArH); 13C
NMR (100 MHz, DMSO-d6): 22.9 (Ar-CH3), 23.2
(Ar-CH3), 105.9, 117.1, 119.8, 120.4, 120.9, 121.2,
122.8, 123.7, 124.5, 125.6, 126.9, 127.8, 128.9, 129.1,
130.3, 131.5, 133.5, 135.3, 135.9, 136.1, 138.3, 144.5,
149.2, 150.1, 162.9 (C═O); ES-MS m/z 495.3 [M + 1].
Anal. Calcd for C33H26N4O. (494.60): C, 80.14; H, 5.30;
N, 11.33. Found C, 79.99; H, 5.08; N, 11.23.
H, 5.03; N, 10.07. Found C, 73.23; H, 5.23; N, 10.22.
2-{2-[3-(2,5-Dimethoxy-phenyl)-1-(4-methoxy-phenyl)-1H-
pyrazol-4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one
1
(16). Yield 56%; mp 239–241°C; H NMR (400 MHz,
DMSO-d6) δ ppm: 3.62 (s, 3H, Ar-OCH3), 3.90 (s, 3H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. B. Jadhav, S. Fatema, R. B. Patil, J. N. Sangshetti, and M. Farooqui
Vol 000
Ar-OCH3), 3.96 (s, 3H, Ar-OCH3), 6.20 (d, 1H,
J = 16.2 Hz, olefinic H near to pyrazole), 7..00 (d, 1H,
J = 8.11 Hz, ArH), 7.05–7.10 (m, 4H, ArH), 7.38 (t, 2H,
ArH), 7.45–7.65 (m, 6H, olefinic H near to pyrimidinone
and ArH), 7.98–8.04 (m, 3H, ArH), 8.21 (s, 1H, pyrazole
ring H). 9.05 (s, 1H, ArH near to nitrogen); 13C NMR
(100 MHz, DMSO-d6): 56.2 (Ar-OCH3), 56.4 (Ar-
OCH3), 57.4 (Ar-OCH3), 109.3, 119.6, 120.1, 120.5,
121.7, 122.3, 122.9, 123.5, 124.7, 125.3, 126.7, 127.5,
128.9, 130.4, 131.9, 132.8, 133.7, 134.8, 136.3, 138.4,
144.4, 148.2, 151.2, 157.4, 158.2, 163.3 (C═O); ES-MS
m/z 557.3 [M + 1]. Anal. Calcd for C34H28N4O4.
(556.60): C, 73.37; H, 5.03; N, 10.07. Found C, 74.20;
H), 8.88 (s, 1H, ArH near to nitrogen). 13C NMR
(100 MHz, DMSO-d6): 21.3 (Ar-CH3), 56.7 (Ar-OCH3),
58.1 (Ar-OCH3), 107.13 117.4, 119.2, 120.7, 120.4,
120.6, 121.2, 121.4, 122.4, 122.9, 123.6, 124.2, 125.8,
126.1, 127.5, 128.3, 130.4, 131.2, 132.2, 133.4, 134.8,
136.9, 138.6, 144.8, 148.9, 153.5, 159.2, 163.6 (C═O);
ES-MS m/z 541.3 [M
+
1]. Anal. Calcd for
C34H28N4O3. (540.6): C, 75.40; H, 5.21; N, 10.36.
Found C, 75.49; H, 5.08; N, 10.00.
2-{2-[3-(2-Methoxy-5-methyl-phenyl)-1-(4-Methoxy-phenyl)-
1H-pyrazol-4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one
1
(20). Yield 78%; mp 204–206°C; H NMR (400 MHz,
DMSO-d6) δ ppm: 2.37 (s, 3H, Ar-CH3), 3.82 (s, 3H, Ar-
OCH3), 3.95 (s, 3H, Ar-OCH3), 6.80 (d, 1H, J = 16 Hz,
olefinic H near to pyrazole), 7.00 (m, 1H, ArH), 7.25–7.43
(m, 8H, ArH and olefinic H near to pyrimidinone), 7.60
(m, 1H, ArH), 7.72 (m, 2H, ArH), 8.00 (m, 2H, ArH),
8.20–8.30 (m, 3H, ArH and pyrazole ring H), 8.90 (s, 1H,
ArH near to mitrogen); 13C NMR (100 MHz, DMSO-d6):
21.9 (Ar-CH3), 56.7 (Ar-OCH3), 58.5 (Ar-OCH3), 108.1
118.4, 119.8, 120.5, 120.9, 120.8, 121.7, 121.8, 122.2,
122.5, 123.7, 124.9, 125.3, 126.7, 127.8, 128.9, 130.5,
131.6, 132.0, 133.7, 134.9, 136.7, 138.9, 143.2, 148.7,
152.5, 157.9, 163.1 (C=O); ES-MS m/z 541.3 [M + 1].
Anal. Calcd for C34H28N4O3. (540.6): C, 75.40; H, 5.21;
H, 5.63; N, 12.20.
2-{2-[3-(2,6-Dimethoxy-phenyl)-1-(4-methoxy-phenyl)-1H-
pyrazol-4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one
1
(17). Yield 56%; mp 243–245°C; H NMR (400 MHz,
DMSO-d6) δ ppm: 3.78(s, 3H, Ar-OCH3), 3.89 (s, 3H,
Ar-OCH3), 3.96 (s, 3H, Ar-OCH3), 6.67 (d, 1H,
J = 16.3 Hz, olefinic H near to pyrazole), 7.25–7.56 (m,
8H, ArH and olefinic H near to pyrimidinone), 7.65
(m, 2H, ArH), 7.80–7.85 (m, 2H, ArH), 8.00 (d, 1H,
J = 6.9 Hz, ArH), 8.20–8.33 (m, 4H, prazole ring H and
ArH), 8.90 (s, 1H, ArH); 13C NMR (100 MHz, DMSO-
d6): 56.5 (Ar-OCH3), 56.3 (Ar-OCH3), 58.5 (Ar-OCH3),
109.1, 119.1, 120.2, 120.9, 121.4, 122.8, 122.9, 123.5,
124.8, 125.7, 126.7, 127.2, 128.7, 130.9, 131.6, 132.3,
133.5, 134.5, 136.7, 138.1, 144.9, 149.1, 151.1, 157.1,
158.3, 163.5 (C═O); ES-MS m/z 557.3 [M + 1]. Anal.
Calcd for C34H28N4O4. (556.60): C, 73.37; H, 5.03; N,
N, 10.36. Found C, 75.33; H, 5.20; N, 10.62.
2-{2-[3-(2-Methoxy-6-methyl-phenyl)-1-(4-Methoxy-phenyl)-
1H-pyrazol-4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one
1
(21). Yield 47%; mp 233–235°C; H NMR (400 MHz,
DMSO-d6): δ ppm: 2.37 (s, 3H, Ar-CH3), 3.95 (s,
3H, Ar-OCH3), 3.99 (s, 3H, Ar-OCH3), 6.80 (d,
J = 16 Hz, 1H, olefinic H near to pyrazole), 7.00 (d, 1H,
J = 7.88 Hz, ArH), 7.20–7.24 (m, 3H, ArH), 7.30–7.65
(m, 4H, ArH and olefinic H near to pyrimidinone), 7.80–
8.00 (m, 5H, ArH), 8.20–8.35 (m, 4H, ArH and pyrazole
ring H), 8.99 (s, 1H, ArH near to nitrogen); 13C NMR
(100 MHz, DMSO-d6): 21.3 (Ar-CH3), 56.6 (Ar-OCH3),
57.5 (Ar-OCH3), 109.1 119.4, 120.1, 120.9, 121.3, 121.8,
122.2, 122.9, 123.9, 124.5, 125.8, 126.9, 127.1, 128.9,
130.9, 131.9, 132.4, 133.0, 134.9, 136.7, 138.9, 143.2,
148.7, 152.6, 157.1, 162.8 (C═O); ES-MS m/z 541.3
[M + 1]. Anal. Calcd for C34H28N4O3. (540.6): C, 75.40;
10.07. Found C, 73.80; H, 4.99; N, 10.00.
2-{2-[3-(2-Methoxy-3-methyl-phenyl)-1-(4-Methoxy-phenyl)-
1H-pyrazol-4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one
1
(18). Yield 49%; mp 229–231°C; H NMR (400 MHz,
DMSO-d6) δ ppm: 2.34 (s, 3H, Ar-CH3), 3.89 (s, 3H, Ar-
CH3), 3.97 (s, 3H, Ar-OCH3), 6.70 (d, 1H, J = 8.00 Hz,
ArH), 7.24 (m, 4H, ArH), 7.42 (m, 4H, ArH), 7.62–7.80
(m, 5H, ArH), 8.20–8.35 (m, 4H, ArH), 9.00 (s, 1H, ArH);
13C NMR (100 MHz, DMSO-d6): 21.1 (Ar-CH3), 56.7
(Ar-OCH3), 57.1 (Ar-OCH3), 107.1, 117.2, 119.1, 120.1,
120.5, 120.9, 121.7, 122.3, 122.9, 123.5, 124.7, 125.3,
126.7, 127.5, 128.9, 130.4, 131.9, 132.8, 133.7, 134.8,
136.3, 138.4, 144.4, 148.2, 153.5, 157.1, 163.1 (C═O);
ES-MS m/z 541.3 [M + 1]. Anal. Calcd for C34H28N4O3.
(540.6): C, 75.40; H, 5.21; N, 10.36. Found C, 75.87; H,
H, 5.21; N, 10.36. Found C, 75.24; H, 5.08; N, 10.28.
2-{2-[3-(3-Methoxy-2-methyl-phenyl)-1-(4-Methoxy-phenyl)-
1H-pyrazol-4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one
1
(22). Yield 69%; mp 219–223°C; H NMR (400 MHz,
5.08; N, 10.33.
DMSO-d6): δ ppm: 2.33 (s, 3H, Ar-CH3), 3.97 (s, 3H, Ar-
OCH3), 3.99 (s, 3H, Ar-OCH3), 6.60 (d, 1H, J = 16.1 Hz,
olefinic H near to pyrazole), 7.00–7.20 (m, 3H, ArH),
7.24–7.35 (m, 3H, ArH), 7.40–7.60 (m, 3H, olefinic H
near to pyrimidinones and ArH), 7.65–7.70 (m, 2H, ArH),
7.80–8.00 (m, 5H, ArH), 8.23 (s, 1H, pyrazole ring H),
8.99 (s, 1H, ArH near to nitrogen); 13C NMR (100 MHz,
DMSO-d6): 23.9 (Ar-CH3), 56.9 (Ar-OCH3), 57.9 (Ar-
OCH3), 106.3, 118.1, 120.7, 120.9, 121.9, 122.2, 122.9,
2-{2-[3-(2-Methoxy-4-methyl-phenyl)-1-(4-Methoxy-phenyl)-
1H-pyrazol-4-yl]-vinyl}-3-phenyl-3-phenyl-pyrido[1,2-a]
pyrimidin-4-one (19).
NMR (400 MHz, DMSO-d6): δ ppm: 2.34 (s, 3H, Ar-
CH3), 3.87 (s, 3H, Ar-OCH3). 3.95 (s, 3H, Ar-OCH3),
6.60 (d, 1H, J = 16 Hz, olefinic H near to pyrazole),
7.25 (m, 4H, ArH), 7.34–7.40 (m, 4H, ArH and olefinic
H near pyrimidinone), 7.65 (m, 2H, ArH), 7.82–8.00
(m, 4H, ArH), 8.22–8.30 (m, 3H, ArH and pyrazole ring
Yield 53%; mp 219–222°C; 1H
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Pyrido[1,2-a]pyrimidin-4-ones: Ligand-based Design, Synthesis, and Evaluation
as an Anti-inflammatory Agent
123.9, 124.8, 125.7, 126.9, 127.8, 129.1, 130.9, 131.9,
132.4, 133.0, 134.9, 136.1, 137.5, 138.9, 143.2, 148.7,
151.9, 157.8, 162.5 (C═O); ES-MS m/z 541.3 [M + 1].
Anal. Calcd for C34H28N4O3. (540.6): C, 75.40; H, 5.21;
N, 10.36. Found C, 76.00; H, 5.09; N, 10.29.
2-{2-[3-(4-Methoxy-2-methyl-phenyl)-1-(4-Methoxy-phenyl)-
Ar-CH3), 3.97 (s, 3H, Ar-OCH3), 6.60 (d, 1H,
J = 15.5 Hz, olefinic H near to pyrazole), 7.05 (d, 1H,
J = 8 Hz, ArH), 7.20–7.35 (m, 4H, ArH), 7.45–7.51 (m,
2H, olefinic H near to pyrimidinone and ArH), 7.80–7.85
(m, 3H, ArH), 8.00 (d, 1H, J = 6.89 Hz, ArH), 8.20–8.32
(m, 5H, pyrazole ring H and ArH), 8.99 (s, 1H, ArH near
to nitrogen); 13C NMR (100 MHz, DMSO-d6): 21.7
(Ar-CH3),, 22.4 (Ar-CH3), 56.6 (Ar-OCH3), 107.9, 118.9,
119.6, 120.7, 120.9, 121.5, 122.9, 122.8, 123.4, 124.7,
125.8, 126.7, 126.2, 127.0, 130.1, 131.7, 132.1, 133.6,
133.9, 134.4 136.2, 137.5, 138.7, 142.8, 143.3, 148.2,
157.7, 163.1 (C═O); ES-MS m/z 525.6 [M + 1]. Anal.
Calcd for C34H28N4O2. (524.6): C, 77.84; H, 5.39; N,
1H-pyrazol-4-yl]-vinyl}-pyrido[1,2-a]pyrimidin-4-one (23).
Yield
1
66%; mp 213–215°C; H NMR (400 MHz, DMSO-d6): δ
ppm: 2.34 (s, 3H, Ar-CH3), 3.89 (s, 3H, Ar-OCH3), 3.97 (s,
3H, Ar-OCH3), 670 (d, 1H, J = 16.2 Hz, olefinic H near to
pyrazole), 7.20–7.35 (m, 3H, ArH), 7.40–7.55 (m, 4H, olefinic
H near to pyrimidine and ArH), 7.70–8.00 (m, 4H, ArH),
8.00–8.20 (m, 6H, pyrazole ring H and ArH), 8.99 (s, 1H,
ArH near to nitrogen); 13C NMR (100 MHz, DMSO-d6): 23.8
(Ar-CH3), 56.1 (Ar-OCH3), 57.7 (Ar-OCH3), 107.3, 118.5,
120.1, 120.9, 121.3, 122.5, 122.4, 123.6, 124.6, 125.9, 126.9,
127.6, 129.1, 130.7, 131.6, 132.7, 133.2, 134.5, 136.5, 137.7,
138.9, 142.4, 143.1, 148.5, 152.1, 157.8, 162.9 (C═O); ES-
MS m/z 541.3 [M + 1]. Anal. Calcd for C34H28N4O3. (540.6):
10.68. Found C, 77.87; H, 5.99; N, 10.80.
2-{2-[3-(2,4-Dimethyl-phenyl)-1-(4-Methoxy-phenyl)-1H-
pyrazol-4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one
(27).
Yield 63%; mp 249–251°C; DMSO-d6): δ ppm:
2.34 (s, 3H, Ar-CH3), 2.38 (s, 3H, Ar-CH3), 3.99 (s, 3H,
Ar-OCH3), 6.60 (d, 1H, J = 16 Hz, olefinic H near to
pyrazole), 7.10 (d, 1H, J = 7.09 Hz, ArH), 7.30–7.62 (m,
5H, olrfinic H near to pyrimidinone and ArH), 7.65–7.80
(m, 4H, ArH), 7.80–7.85 (m, 3H, ArH), 8.00 (d, 1H,
J = 7.2 Hz, ArH), 8.20–8.22 (m, 2H, pyrazole ring H and
ArH), 8.80 (s, 1H, ArH near to nitrogen); 13C NMR
(100 MHz, DMSO-d6): 21.9(Ar-CH3),, 22.7 (Ar-CH3),
56.9 (Ar-OCH3), 106.5, 117.9, 119.6, 120.1, 120.4,
121.75, 122.8, 122.9, 123.4, 124.7, 125.8, 126.9, 127.2,
127.9, 130.1, 130.9, 131.7, 132.6, 133.8, 134.3, 134.9
136.1, 137.9, 138.7, 142.8, 143.1, 148.4, 157.7, 163.5
(C═O); ES-MS m/z 525.6 [M + 1]. Anal. Calcd for
C34H28N4O2. (524.6): C, 77.84; H, 5.39; N, 10.68. Found
C, 75.40; H, 5.21; N, 10.36. Found C, 75.01; H, 5.27; N, 10.08.
2-{2-[3-(5-Methoxy-2-methyl-phenyl)-1-(4-Methoxy-phenyl)-
1H-pyrazol-4-yl]-vinyl}-pyrido[1,2-a]pyrimidin-4-one (24).
Yield
1
59%; mp 227–230°C; H NMR (400 MHz, DMSO-d6): δ
ppm: 2.37 (s, 3H, Ar-CH3), 3.82 (s, 3H, Ar-OCH3), 3.95 (s,
3H, Ar-OCH3), 6.60 (d, 1H, J = 15.8 Hz, olefinic H near to
pyrazole), 7.20–7.60 (m, 6H, olefinic H near to pyrimidinone
and ArH), 7.65–8.00 (m, 5H, ArH), 8.20–8.30 (m, 6H,
pyrazole ring H and ArH), 8.99 (s, 1H, ArH near to nitrogen);
13C NMR (100 MHz, DMSO-d6): 23.1 (Ar-CH3), 56.4 (Ar-
OCH3), 57.9 (Ar-OCH3), 109.1, 118.1, 120.4, 120.8, 121.6,
122.7, 122.9, 123.4, 124.7, 125.2, 126.2, 127.1, 127.9, 130.7,
131.6, 132.7, 133.2, 134.4 136.1, 137.7, 138.3, 142.4, 143.1,
148.6, 152.9, 157.1, 163.2 (C═O); ES-MS m/z 541.3
[M + 1]. Anal. Calcd for C34H28N4O3. (540.6): C, 75.40; H,
C, 78.00; H, 5.09; N, 10.52.
2-{2-[3-(2,5-Dimethyl-phenyl)-1-(4-Methoxy-phenyl)-1H-
pyrazol-4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one
1
(28). Yield 57%; mp 219–221°C; H NMR (400 MHz,
5.21; N, 10.36. Found C, 75.24; H, 5.38; N, 10.29.
DMSO-d6): δ ppm: 2.31 (s, 3H, Ar-CH3), 2.38 (s, 3H,
Ar-CH3), 3.97 (s, 3H, Ar-OCH3), 6.60 (d, 1H,
J = 16.2 Hz, olefinic H near to pyrazole), 7.05 (d, 1H,
J = 7.65 Hz, ArH), 7.20–7.23 (m, 3H, ArH), 7.39–7.45
(m, 5H, ArH and olefinic H near to pyrimidinone), 7.50–
7.65 (m, 4H, ArH), 7.80–8.00 (m, 3H, ArH), 8.22 (s. 1H,
pyrazole ring H), 8.99 (s, 1H, ArH near to nitrogen); 13C
NMR (100 MHz, DMSO-d6): 21.1 (Ar-CH3),, 22.9 (Ar-
CH3), 57.8 (Ar-OCH3), 106.5, 117.7, 119.9, 120.7, 120.9,
121.7, 122.6, 122.9, 123.5, 124.7, 125.9, 126.3, 127.4,
127.9, 130.5, 130.9, 131.9, 132.8, 133.9, 134.5, 134.9
136.6, 137.9, 138.5, 142.9, 143.4, 148.6, 157.9, 163.9
(C═O); ES-MS m/z 525.6 [M + 1]. Anal. Calcd for
C34H28N4O2. (524.6): C, 77.84; H, 5.39; N, 10.68. Found
2-{2-[3-(6-Methoxy-2-methyl-phenyl)-1-(4-Methoxy-phenyl)-
1H-pyrazol-4-yl]-vinyl}-pyrido[1,2-a]pyrimidin-4-one (25).
Yield
1
56%; mp 244–246°C; H NMR (400 MHz, DMSO-d6): δ
ppm: 2.33 (s, 3H, Ar-CH3), 3.87 (s, 3H, Ar-OCH3), 3.97
(s, 3H, Ar-OCH3), 6.60 (d, 1H, J = 16 Hz, olefinic H near to
pyrazole), 7.05 (d, 1H, J = 7.89 Hz, ArH), 7.20–7.30 (m, 4H,
ArH), 7.34–7.65 (m, 6H, olefinic H near to pyrimidinone and
ArH), 7.80–8.00 (m, 3H, ArH), 8.20–8.34 (m, 3H, pyrazole
ring H and ArH), 8.99 (s, 1H, ArH near to nitrogen); 13C
NMR (100 MHz, DMSO-d6): 23.9 (Ar-CH3), 56.1 (Ar-
OCH3), 57.5 (Ar-OCH3), 106.9, 117.8, 119.1, 120.7, 120.9,
121.8, 122.9, 122.8, 123.7, 124.1, 125.4, 126.1, 126.9, 127.9,
130.7, 131.6, 132.4, 133.7, 134.8 136.5, 137.9, 138.8, 142.8,
143.9, 148.9, 153.9, 157.7, 163.9 (C═O); ES-MS m/z 541.3
[M + 1]. Anal. Calcd for C34H28N4O3. (540.6): C, 75.40; H,
C, 77.09; H, 5.89; N, 10.55.
2-{2-[3-(2,6-Dimethyl-phenyl)-1-(4-Methoxy-phenyl)-1H-
pyrazol-4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one
5.21; N, 10.36. Found C, 75.24; H, 5.29; N, 10.77.
2-{2-[3-(2,3-Dimethyl-phenyl)-1-(4-Methoxy-phenyl)-1H-
pyrazol-4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one
1
(29). Yield 66%; mp 212–214°C; H NMR (400 MHz,
1
(26). Yield 59%; mp 218–221°C; H NMR (400 MHz,
DMSO-d6): δ ppm: 2.33 (s, 3H, Ar-CH3), 2.37 (s,
DMSO-d6): δ ppm: 2.33 (s, 3H, Ar-CH3), 2.37 (s, 3H,
3H, Ar-CH3), 3.97 (s, 3H, Ar-OCH3), 6.77 (d, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. B. Jadhav, S. Fatema, R. B. Patil, J. N. Sangshetti, and M. Farooqui
Vol 000
J = 8.22 Hz, ArH), 6.88–7.00 (m, 2H, olefinic H near to
pyrazole and ArH), 7.20–7.34 (m, 4H, ArH), 7.40–7.60
(m, 3H, olefinic H near to pyrimidinone and ArH), 7.80–
8.00 (m, 3H, ArH), 8.20–8.24 (m, 5H, pyrazole ring H
and ArH), 8.99 (s, 1H, ArH near to nitrogen); 13C NMR
(100 MHz, DMSO-d6): 21.5 (Ar-CH3),, 21.9 (Ar-CH3),
54.6 (Ar-OCH3), 106.7, 117.9, 119.9, 120.6, 120.9, 121.9,
122.7, 122.9, 123.9, 124.9, 125.5, 126.4, 127.8, 127.7,
130.6, 130.4, 131.9, 132.9, 133.9, 134.6, 134.9 136.4,
137.0, 138.6, 142.4, 143.7, 148.7, 157.9, 163.2 (C═O);
ES-MS m/z 525.6 [M + 1]. Anal. Calcd for C34H28N4O2.
(524.6): C, 77.84; H, 5.39; N, 10.68. Found C, 78.00; H,
5.41; N, 10.88.
ring H and ArH), 8.99 (s, 1H, ArH near to nitrogen);
13C NMR (100 MHz, DMSO-d6): 21.9 (Ar-CH3), 54.8
(Ar-OCH3), 55.9 (Ar-OCH3), 104.6, 116.9, 120.2,
120.9, 121.7, 122.8, 122.9, 123.7, 124.4, 125.8, 126.5,
126.9, 127.1, 128.3, 130.8, 131.9, 132.8, 133.9, 134.9,
134.6, 136.7, 137.7, 143.9, 148.1, 154.9, 157.6, 163.1
(C═O); ES-MS m/z 541.3 [M + 1]. Anal. Calcd for
C34H28N4O3. (540.6): C, 75.40; H, 5.21; N, 10.36.
Found C, 75.01; H, 5.02; N, 10.27.
2-{2-[3-(2,6-Dimethoxy-phenyl)-1-p-tolyl-1H-pyrazol-4-yl]-
vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (33). Yield 64%;
1
mp 228–230°C; H NMR (400 MHz, DMSO-d6): δ ppm:
2.32 (s, 3H, Ar-CH3), 3.87 (s, 3H, Ar-OCH3), 3.91 (s, 3H,
Ar-OCH3), 6.60 (d, 1H, 16 Hz, olefinic H near to pyrazole),
7.00–7.20 (m, 2H, ArH), 7.34–7.45 (m, 5H, olefinic H near
to pyrimidinone ArH), 7.55–7.65 (m, 3H, ArH), 7.70 (m,
2H, ArH), 7.80–7.82 (m, 2H, ArH), 8.00 (d, 1H,
J = 7.09 Hz, ArH), 8.23 (s, 1H, pyrazole ring H), 8.99 (s,
1H, ArH near to nitrogen); 13C NMR (100 MHz, DMSO-
d6): 21.1 (Ar-CH3), 54.1(Ar-OCH3), 55.2 (Ar-OCH3),
105.1, 117.9, 120.4, 120.9, 121.1, 122.9, 123.9, 124.8,
125.9, 126.7, 126.9, 127.5, 128.1, 130.4, 131.0, 132.7,
133.2, 134.0, 134.9, 136.7, 137.6, 143.6, 148.6, 154.9,
157.0, 163.5 (C═O); ES-MS m/z 541.3 [M + 1]. Anal.
Calcd for C34H28N4O3. (540.6): C, 75.40; H, 5.21; N,
10.36. Found C, 75.01; H, 5.39; N, 10.87.
2-{2-[3-(2,3-Dimethoxy-phenyl)-1-p-tolyl-1H-pyrazol-4-yl]-
vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (30).
Yield 57%;
1
mp 217–219°C H NMR (400 MHz, DMSO-d6): δ ppm:
2.27 (s, 3H, Ar-CH3), 2.31 (s, 3H, Ar-CH3), 3.97 (s, 3H, Ar-
OCH3), 6.60 (d, 1H, J = 16 Hz, olefinic H near to pyrazole),
7.00 (d, 1H, J = 8.22 Hz, ArH), 7.22–7.30 (m, 4H, ArH),
7.35–7.45 (m, 5H, olefinic H near to pyrimidinone and ArH),
7.60–8.00 (m, 4H, ArH), 8.20–8.30 (m, 3H, pyrazole ring H
and ArH), 8.90 (s, 1H, ArH near to nitrogen); 13C NMR
(100 MHz, DMSO-d6): 21.9 (Ar-CH3), 54.6 (Ar-OCH3), 54.9
(Ar-OCH3), 108.1, 118.3, 119.4, 120.2, 120.9, 121.5, 122.6,
122.9, 123.3, 124.4, 125.2, 126.3, 126.9, 127.1, 127.7, 130.4,
131.9, 132.5, 133.5, 134.2, 134.9 136.9, 137.0, 143.7, 148.7,
154.9, 157.9, 163.2 (C═O); ES-MS m/z 541.3 [M + 1]. Anal.
Calcd for C34H28N4O3. (540.6): C, 75.40; H, 5.21; N, 10.36.
Found C, 75.01; H, 4.88; N, 10.01.
2-{2-[3-(2-Methoxy-3-Methyl-phenyl)-1-p-tolyl-1H-pyrazol-
4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (34).
Yield 59%; mp 242–244°C; 1H NMR (400 MHz,
DMSO-d6): δ ppm: 2.31 (s, 3H, Ar-CH3), 2.38 (s, 3H,
Ar-CH3), 3.97 (s, 3H, Ar-OCH3), 6.60 (d, 1H,
J = 16.3 Hz, olefinic H near to pyrazole), 7.22–7.33 (m,
6H, ArH), 7.50–7.80 (m, 7H, olefinic H near to
pyrimidinone and ArH), 7.98–8.22 (m, 4H, ArH and
pyrazole ring H), 8.99 (s, 1H, ArH near to nitrogen); 13C
NMR (100 MHz, DMSO-d6): 21.9 (Ar-CH3), 23.1 (Ar-
CH3), 54.5 (Ar-OCH3), 107.1, 117.3, 120.1, 120.9, 121.3,
122.8, 123.6, 124.5, 125.0, 126.9, 127.5, 128.4, 130.5,
131.0, 132.7, 133.1, 134.0, 134.9, 135.9, 136.1, 137.1,
143.1, 148.4, 157.2, 163.9 (C═O); ES-MS m/z 525.6
[M + 1]. Anal. Calcd for C34H28N4O2. (524.6): C, 77.84;
H, 5.39; N, 10.68. Found C, 78.02; H, 5.39; N, 10.03.
2-{2-[3-(2,4-Dimethoxy-phenyl)-1-p-tolyl-1H-pyrazol-4-yl]-
vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (31).
Yield
1
52%; mp 237–239°C; H NMR (400 MHz, DMSO-d6):
δ ppm: 2.37 (s, 3H, Ar-CH3), 3.95 (s, 3H, Ar-OCH3),
3.99 (s, 3H, Ar-OCH3), 6.60 (d, 1H, J = 16 Hz, olefinic
H near to pyrazole), 7.00–7.25 (m, 5H, ArH), 7.45–7.60
(m, 5H, olefinic H near to pyrimidinone ArH), 7.80–8.00
(m, 3H, ArH), 8.20–8.34 (m, 5H, pyrazole ring H and
ArH), 8.90 (s, 1H, ArH near to nitrogen); 13C NMR
(100 MHz, DMSO-d6): 21.1 (Ar-CH3), 54.1 (Ar-OCH3),
54.9 (Ar-OCH3), 104.3, 116.3, 119.1, 120.2, 120.9, 121.7,
122.3, 122.9, 123.5, 124.3, 125.5, 126.2, 126.9, 127.1,
127.9, 130.8, 131.9, 132.5, 133.8, 134.7, 134.9 136.9,
137.2, 143.9, 148.9, 154.9, 157.0, 163.9 (C═O); ES-MS
m/z 541.3 [M + 1]. Anal. Calcd for C34H28N4O3. (540.6):
C, 75.40; H, 5.21; N, 10.36. Found C, 75.24; H, 5.09;
N, 10.79.
2-{2-[3-(2-Methoxy-4-Methyl-phenyl)-1-p-tolyl-1H-pyrazol-
4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (35).
Yield 67%; mp 234–236°C; mp1H NMR (400 MHz,
DMSO-d6): δ ppm: 2.27 (s, 3H, Ar-CH3), 2.31 (s, 3H,
Ar-CH3), 3.97 (s, 3H, Ar-OCH3), 6.60 (d, 1H, 16 Hz
olefinic H near to pyrazole), 7.20–7.45 (m, 6H, ArH and
olefinic H near to pyrimidinone), 7.60–7.85 (m, 4H,
ArH), 8.00–8.22 (m, 6H, ArH and pyrazole ring H), 8.99
(s, 1H, ArH near to nitrogen); 13C NMR (100 MHz,
DMSO-d6): 21.2 (Ar-CH3), 23.3 (Ar-CH3), 54.6 (Ar-
OCH3), 107.5, 118.3, 120.5, 120.9, 121.7, 122.9, 123.9,
124.4, 125.6, 126.9, 127.4, 128.9, 130.7, 131.4, 132.6,
2-{2-[3-(2,5-Dimethoxy-phenyl)-1-p-tolyl-1H-pyrazol-4-yl]-
vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (32).
Yield
1
62%; mp 213–215°C; H NMR (400 MHz, DMSO-d6):
δ ppm: 2.33 (s, 3H, Ar-CH3), δ 3.97 (s, 3H, Ar-OCH3),
3.99 (s, 3H, Ar-OCH3), 6.70 (d, 1H, J = 15.4 Hz,
olefinic H near to pyrazole), 7.23–7.45 (m, 5H, olefinic
H near to pyrimidinone ArH), 7.55–7.60 (m, 5H, ArH),
7.80–8.00 (m, 4H, ArH), 8.20–8.34 (m, 3H, pyrazole
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Pyrido[1,2-a]pyrimidin-4-ones: Ligand-based Design, Synthesis, and Evaluation
as an Anti-inflammatory Agent
133.2, 134.1, 134.9, 135.9, 136.3, 137.5, 143.2, 148.2,
157.4, 163.9 (C═O); ES-MS m/z 525.6 [M + 1]. Anal.
Calcd for C34H28N4O2. (524.6): C, 77.84; H, 5.39; N,
10.68. Found C, 77.88; H, 5.09; N, 10.50.
2-{2-[3-(2-Methoxy-5-Methyl-phenyl)-1-p-tolyl-1H-pyrazol-
4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (36).
Yield 54%; mp 236–238°C; 1H NMR (400 MHz, DMSO-
d6): δ ppm: 2.33 (s, 3H, Ar-CH3), 2.37 (s, 3H, Ar-CH3),
3.97 (s, 3H, Ar-OCH3), 6.60 (d, 1H, J = 16 Hz, olefinic H
near to pyrazole), 7.00–7.20 (m, 3H, ArH), 7.25–7.40 (m,
5H, ArH and olefinic H near to pyrimidinone), 7.45–7.60
(m, 6H, ArH), 7.80–8.00 (m, 2H, ArH), 8.24 (s, 1H,
pyrazole ring H), 8.99 (s, 1H, ArH); 13C NMR (100 MHz,
DMSO-d6): 21.9 (Ar-CH3), 23.9 (Ar-CH3), 54.1 (Ar-
OCH3), 105.9, 117.1, 120.1, 120.9, 121.7, 122.9, 123.2,
124.3, 125.1, 126.1, 127.5, 128.9, 130.1, 131.4, 132.3,
133.6, 134.4, 134.1, 135.2, 136.6, 137.7, 143.5, 148.6,
157.9, 163.2 (C═O); ES-MS m/z 525.6 [M + 1]. Anal.
Calcd for C34H28N4O2. (524.6): C, 77.84; H, 5.39; N,
δ ppm: 2.27 (s, 3H, Ar-CH3), 2.31 (s, 3H, Ar-CH3), 3.97
(s, 3H, Ar-OCH3), 6.60 (d, 1H, J = 15.3 Hz, olefinic H
near to pyrazole), 7.00 (d, 1H, J = 8.05 Hz, ArH), 7.23–
7.35 (m, 6H, ArH), 7.45–7.60 (m, 4H, olefinic H near
to pyrimidinone and ArH); 7.80–7.89 (m, 5H, ArH),
8.22 (s, 1H, pyrazole ring H), 8.91 (s, 1H, ArH near to
nitrogen); 13C NMR (100 MHz, DMSO-d6): 21.1
(Ar-CH3), 23.2 (Ar-CH3), 54.9 (Ar-OCH3), 105.8, 117.2,
120.3, 120.8, 121.4, 122.2, 123.4, 124.4, 125.7, 126.2,
127.4, 128.6, 130.3, 131.9, 132.3, 133.5, 134.4, 134.1,
135.5, 136.7, 137.7, 143.6, 148.0, 157.9, 163.2 (C═O);
ES-MS m/z 525.6 [M + 1]. Anal. Calcd for C34H28N4O2.
(524.6): C, 77.84; H, 5.39; N, 10.68. Found C, 77.63; H,
5.40; N, 11.08.
2-{2-[3-(5-Methoxy-2-Methyl-phenyl)-1-p-tolyl-1H-pyrazol-
4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (40). Yield 59%;
1
mp 214–216°C; H NMR (400 MHz, DMSO-d6): δ ppm:
2.33 (s, 3H, Ar-CH3), 3.97 (s, 3H, Ar-OCH3), 3.99 (s, 3H,
Ar-OCH3), 6.80 (d, 1H, J = 16.20 Hz, olefinic H near to
pyrazole), 7.20–7.35 (m, 6H, ArH), 7.45–7.65 (m, 4H,
olefinic H near to pyrimidinone and ArH), 7.80–8.00 (m,
6H, ArH), 8.22 (s, 1H, pyrazole ring H). 8.99 (s, 1H, ArH
near to nitrogen); 13C NMR (100 MHz, DMSO-d6): 21.3
(Ar-CH3), 23.1 (Ar-CH3), 55.9 (Ar-OCH3), 107.8, 118.2,
119.2, 120.8, 121.9, 122.6, 123.5, 124.7, 125.6, 126.1,
127.7, 128.8, 130.9, 131.4, 132.3, 133.6, 134.1, 135.7,
136.8, 137.9, 143.7, 148.9, 157.9, 162.9 (C═O); ES-MS m/z
525.6 [M + 1]. Anal. Calcd for C34H28N4O2. (524.6): C,
10.68. Found C, 77.74; H, 5.94; N, 10.17.
2-{2-[3-(2-Methoxy-6-Methyl-phenyl)-1-p-tolyl-1H-pyrazol-
4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (37). Yield 64%;
mp 224–226 °C1H NMR (400 MHz, DMSO-d6): δ ppm:
2.38 (s, 3H, Ar-CH3), 2.39 (s, 3H, Ar-CH3), 3.97 (s, 3H,
Ar-OCH3), 6.60 (d, 1H, J = 15.8 Hz, Hz, ArH), 7.05 (d,
2H, ArH), 7.25–7.34 (m, 4H, ArH), 7.40–7.65 (m, 5H,
olefinic H near to pyrimidinone and ArH), 7.80–7.90 (m,
3H, ArH), 8.00 (d, 1H, J = 7.05 Hz, ArH), 8.23 (s, 1H,
pyrazole ring H), 8.99 (s, 1H, ArH); 13C NMR (100 MHz,
DMSO-d6): 21.1 (Ar-CH3), 23.1 (Ar-CH3), 54.2 (Ar-OCH3),
105.2, 117.7, 120.6, 120.4, 121.2, 122.4, 123.4, 124.3,
125.9, 126.4, 127.6, 128.9, 130.5, 131.7, 132.4, 133.6,
134.2, 134.4, 135.2, 137.7, 143.5, 148.6, 157.9, 163.6
(C═O); ES-MS m/z 525.6 [M + 1]. Anal. Calcd for
C34H28N4O2. (524.6): C, 77.84; H, 5.39; N, 10.68. Found
77.84; H, 5.39; N, 10.68. Found C, 78.01; H, 5.41; N, 10.82.
2-{2-[3-(6-Methoxy-2-Methyl-phenyl)-1-p-tolyl-1H-pyrazol-
4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (41). Yield
1
68%; mp 224–226°C; H NMR (400 MHz, DMSO-d6):
δ ppm: 2.34 (s, 3H, Ar-CH3), 2.38 (s, 3H, Ar-CH3),
3.99 (s, 3H, Ar-OCH3), 6.70 (d, 1H, J = 16 Hz, ArH),
7.00–7.35 (m, 7H, ArH), 7.45–7.65 (m, 5H, olefinic H
near to pyrazole and ArH), 7.80–8.00 (m, 4H, ArH),
8.29 (s, 1H, pyrazole ring H), 8.99 (s, 1H, ArH near to
nitrogen); 13C NMR (100 MHz, DMSO-d6): 21.9 (Ar-
CH3), 23.8 (Ar-CH3), 56.9 (Ar-OCH3), 108.1, 117.9,
119.2, 120.1, 121.7, 122.1, 123.4, 124.1, 125.1, 126.3,
127.0, 128.5, 130.1, 131.5, 132.4, 133.5, 134.6, 135.4,
136.7, 137.0, 143.3, 148.6, 157.0, 164.1 (C═O); ES-MS
m/z 525.6 [M + 1]. Anal. Calcd for C34H28N4O2.
(524.6): C, 77.84; H, 5.39; N, 10.68. Found C, 78.00;
C, 78.00; H, 5.49; N, 10.87.
2-{2-[3-(3-Methoxy-2-Methyl-phenyl)-1-p-tolyl-1H-pyrazol-
4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (38).
Yield 68%; mp 222–224°C; 1H NMR (400 MHz,
DMSO-d6): δ ppm: 2.31 (s, 3H, Ar-CH3), δ 2.38 (s, 3H,
Ar-CH3), 3.97 (s, 3H, Ar-OCH3), 6.60 (d, 1H, J = 16 Hz,
ArH), 7.24–7.30 (m, 4H, ArH), 7.45–7.65 (m, 5H,
olefinic H near to pyrimidinone and ArH), 7.70 (m, 1H,
ArH), 7.80–8.10 (m, 6H, ArH), 8.23 (s, 1H, pyrazole ring
H), 8.99 (s, 1H, ArH near to nitrogen); 13C NMR
(100 MHz, DMSO-d6): 21.2 (Ar-CH3), 23.3 (Ar-CH3),
54.1 (Ar-OCH3), 106.1, 117.2, 120.5, 120.6, 121.1,
122.9, 123.2, 124.3, 125.1, 126.3, 127.8, 128.9, 130.5,
131.7, 132.3, 133.5, 134.1, 135.6, 136.6, 137.4, 143.9,
148.7, 157.1, 163.0 (C═O); ES-MS m/z 525.6 [M + 1].
Anal. Calcd for C34H28N4O2. (524.6): C, 77.84; H, 5.39;
H, 4.99; N, 10.97.
2-{2-[3-(2,3-Dimethyl-phenyl)-1-p-tolyl-1H-pyrazol-4-yl]-
vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (42).
Yield
1
53%; mp 238–240°C; H NMR (400 MHz, DMSO-d6): δ
ppm: 2.30 (s, 3H, Ar-CH3), 2.35–2.40 (d, 6H, 2 X
Ar-CH3), 6.65 (d, 1H, 16 Hz, olefinic H near to pyrazole),
7.20 (s, 1H, ArH), 7.25–7.35 (m, 6H, olefinic H near
to pyrimidinone and ArH), 7.65–8.00 (m, 5H, ArH),
8.20–8.35 (m, 4H, pyrazole ring H and ArH), 9.00 (s, 1H,
ArH near to nitrogen); 13C NMR (100 MHz, DMSO-d6):
21.9 (Ar-CH3), 22.3 (Ar-CH3), 23.8 (Ar-CH3), 106.5,
N, 10.68. Found C, 77.78; H, 5.88 N, 10.12.
2-{2-[3-(4-Methoxy-2-Methyl-phenyl)-1-p-tolyl-1H-pyrazol-
4-yl]-vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (39). Yield
1
54%; mp 217–219°C; H NMR (400 MHz, DMSO-d6):
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. B. Jadhav, S. Fatema, R. B. Patil, J. N. Sangshetti, and M. Farooqui
Vol 000
117.1, 119.1, 120.3, 121.1, 122.4, 123.8, 124.9, 125.2,
126.1, 127.1, 128.4, 130.4, 131.4, 132.2, 133.3, 134.5,
135.7, 136.1, 137.1, 143.2, 148.1, 164.1 (C═O); ES-MS
m/z 509.3 [M + 1]. Anal. Calcd for C34H28N4O. (508.6):
C, 80.29; H, 5.55; N, 11.02. Found C, 80.49; H, 5.40;
N, 10.90.
were used to carry in vitro COX-1/2 inhibitory
performance of synthesized analogues. Ovine COX-1 and
human recombinant COX-2 were used in this experiment.
Each activity tube of the experiment kit was initially
filled with 10 μL of heme, 10 μL of COX-1 and COX-2,
and 950 μL of reaction buffer (0.1 M Tris-HCl, pH 8.0,
comprising 5 mM EDTA and 2 mM phenol). Similarly,
the inhibitory tubes were prepared by addition of all these
material along with addition of inhibitory compound with
final concertation of 100, 10, 0.1, 0.01, and 0.001 μM, so
that the final volume of the tube was adjusted to 1 mL.
The COX-1 and COX-2 inactivated enzyme tubes were
obtained after keeping these tubes in boiling water for a
few minutes. Once the tube incubated for 20 min at
37°C, the arachidonic acid was added in each tube and
initiated the reaction, hence incubated the tubes for
2–3 min at 37°C. Afterward, the reaction was quenched
by adding 1 M HCl (50 μL). The SnCl2 (100 μL) was
added to obtain PGF2a by the reduction of PGH2 thus
formed. PG antiserum was added to quantify the PG
generation in each tubes. As there is competition
2-{2-[3-(2,4-Dimethyl-phenyl)-1-p-tolyl-1H-pyrazol-4-yl]-
vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (43). Yield 55%;
1
mp 212–214°C; H NMR (400 MHz, DMSO-d6): δ ppm:
2.20 (s, 3H, Ar-CH3), 2.25–2.37 (d, 6H, 2 X Ar-CH3),
6.60 (d, 1H, 16 Hz, olefinic H near to pyrazole),
7.24–7.55 (m, 7H, olefinic H near to pyrimidinone ArH),
7.65–8.05 (m, 7H, ArH), 8.10–8.35 (m, 3H, pyrazole H
and ArH), 9.00 (s, 1H, ArH near to nitrogen); 13C NMR
(100 MHz, DMSO-d6): 21.2 (Ar-CH3), 22.4 (Ar-CH3),
23.9 (Ar-CH3), 108.5, 117.3, 119.4, 120.1, 121.2, 122.6,
123.4, 124.1, 125.5, 126.5, 127.5, 128.8, 130.9, 131.8,
132.1, 133.6, 134.1, 135.9, 136.2, 137.7, 143.1, 148.5,
163.9 (C═O); ES-MS m/z 509.3 [M + 1]. Anal. Calcd for
C34H28N4O. (508.6): C, 80.29; H, 5.55; N, 11.02. Found
C, 80.23; H, 5.35; N, 11.39.
2-{2-[3-(2,5-Dimethyl-phenyl)-1-p-tolyl-1H-pyrazol-4-yl]-
vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (44). Yield 74%;
between PG and prostaglandin
A conjugates (PG
tracers) for the limited amount PG antiserum as the
concertation of PG varies while the concentration of PG
tracers held constant, the concertation of PG tracers
binds to PG antiserum that is inversely proportional to
the concentration of PG in the tube. This rabbit
antiserum-P (either free or tracer) complex binds to a
mouse monoclonal antirabbit antibody that has been
previously attached to the tube. The plate is washed to
remove any unbound reagents, and then Ellman’s
reagent (which contains the substrate to AChe) is added
to the well. Typical yellow color was observed due to
this enzymatic actiivity, which was strongly observed
at 420 nm. The intensity of color was determined
spectrophotometrically. The intensity of color is
proportional to the amount of free PG traces bound to
the tube, which is inversely proportional to the amount
of free PG present in the tube during incubation
process. When there is an absorption at 420 nm
observed in 96-well plates, it indicates the presence of
higher level of PG in the tubes, which in turn shows
less inhibition of enzymes. These absorption values
of different tubes confirm the COX inhibitory activities
of synthesized compounds. With the help of GraphPad
PRISM, the IC50 value (concentration of test compound
responsible for 50% inhibition) of the test compound
was determine by plotting dose–response inhibition
curve.
mp 218–220°C; 1H NMR (400 MHz, DMSO-d6): δ
ppm: 2.21 (s, 3H, Ar-CH3), 2.39 (d, 3H, Ar-CH3), 2.42
(s, 3H, Ar-CH3), 6.80 (d, 1H, J = 16 Hz, olefinic
H near to pyrazole), 7.00 (s, 1H, ArH), 7.24–7.60
(m, 10H, olefinic H near to pyrimidinone and ArH),
7.80–8.00 (m, 5H, ArH), 8.29 (s, 1H, pyrazole ring H),
8.95 (s, 1H ArH near to nitrogen); 13C NMR
(100 MHz, DMSO-d6): 21.2 (Ar-CH3), 22.5 (Ar-CH3),
23.0 (Ar-CH3), 107.6, 117.9, 119.1, 120.1, 121.6, 122.2,
123.5, 124.4, 125.5, 126.9, 127.1, 128.3, 130.8, 131.7,
132.4, 133.7, 134.2, 135.1, 136.1, 137.2, 143.4, 148.7,
163.2 (C═O); ES-MS m/z 509.3 [M + 1]. Anal. Calcd
for C34H28N4O. (508.6): C, 80.29; H, 5.55; N, 11.02.
Found C, 80.34; H, 5.60; N, 11.04.
2-{2-[3-(2,6-Dimethyl-phenyl)-1-p-tolyl-1H-pyrazol-4-yl]-
vinyl}-3-phenyl-pyrido[1,2-a]pyrimidin-4-one (45). Yield 59%;
1
mp 227–229°C; H NMR (400 MHz, DMSO-d6): δ ppm:
2.22 (s, 3H, Ar-CH3), 2.35 (d, 3H, Ar-CH3), 2.42 (s, 3H,
Ar-CH3), 6.60 (d, 1H, J = 16 Hz, olefinic H near to
pyrazole), 7.22–7.55 (m, 7H, olefinic
H near to
pyrimidinone and ArH), 7.60–8.00 (m, 4H, ArH), 8.10–
8.16 (m, 5H, ArH), 8.21 (s, 1H, pyrazole rng H), 8.95
(s, 1H, ArH); 13C NMR (100 MHz, DMSO-d6): 21.6
(Ar-CH3), 22.9 (Ar-CH3), 23.0 (Ar-CH3), 107.1, 117.29,
119.0, 120.1, 121.4, 122.1, 123.1, 124.1, 125.3, 126.9,
127.3, 128.1, 130.3, 131.4, 132.1, 133.4, 134.1, 135.3,
136.5, 137.8, 143.7, 148.9, 163.1 (C═O); ES-MS m/z
509.3 [M + 1]. Anal. Calcd for C34H28N4O. (508.6): C,
80.29; H, 5.55; N, 11.02. Found C, 80.30; H, 5.84; N, 10.84.
In vivo anti-inflammatory activity study.
Carrageenan-
induced rat paw edema method was used to determine
in vivo anti-inflammatory activities of selected
compounds. In this experiment, three different sets of rats
of either sex were prepared, one set for standard
Biology. COX-1/COX-2 inhibitory screening assay. The
“COX inhibitor screening assay” kits with 96-well plates
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Pyrido[1,2-a]pyrimidin-4-ones: Ligand-based Design, Synthesis, and Evaluation
as an Anti-inflammatory Agent
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ðVt ꢀ VcÞ
ꢀ ðVt ꢀ VcÞtested compound
ðcVonttrꢀol VcÞcontrol X 100
% Inhibition ¼
Wherein Vt = Volumes of oedema at particular time and Vc
= Volume oedema at zero time.
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Acknowledgments. We acknowledge the management of Dr.
Rafiq Zakaria College for Women and Maulana Azad College
for their constant encouragement.
SUPPORTING INFORMATION
REFERENCES AND NOTES
Additional Supporting Information may be found online
in the supporting information tab for this article.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet