Novel tetrahydropyrimidine-adamantane hybrids as anti-inflammatory agents: Synthesis, structure and biological evaluation

Article abstract of DOI:10.1007/s00044-015-1332-x

A series of novel (3-((3s,5s,7s)-adamantan-1-yl)-1-alkyl/aralkyl/aryl-1,2,3,4-tetrahydroyrimidin-5-yl)(aryl)methanones (5a-j) has been synthesized by the reaction of 1-aryl-3-(alkyl/aralkyl/aryl)aminoprop-2-en-1-ones 3a-j, 1-adamantanamine 4 and formaldehyde under thermal conditions. The structures of the products (5a-j) have been established with the help of spectral and analytical data. The stereochemistry of the products was established by X-ray crystallographic studies of a representative product (3-((3s,5s,7s)-adamantan-1-yl)-1-methyl-1,2,3,4-tetrahydropyrimidin-5-yl)(4-chlorophenyl) methanone (5g) of the series. The target adamantane-tetrahydropyrimidine hybrids 5a-j were evaluated for their anti-inflammatory activities as a result of which compounds 5e (R=C₆H₅CH₂, Ar=C₆H₅), 5i (R=CH₃, Ar=4-CH₃C₆H₄), 5j (R=C₆H₅CH₂, Ar=4-CH₃C₆H₄) and 5g (R=CH₃, Ar=4-ClC₆H₄) were found to exhibit excellent and promising anti-inflammatory activities.

Full text of DOI:10.1007/s00044-015-1332-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1332-x
ORIGINAL RESEARCH
Novel tetrahydropyrimidine–adamantane hybrids
as anti-inflammatory agents: synthesis, structure
and biological evaluation
•
Utpalparna Kalita Shunan Kaping
•
•
•
Revinus Nongkynrih Laishram Indira Singha
Jai Narain Vishwakarma
Received: 19 June 2014 / Accepted: 20 January 2015
Ó Springer Science+Business Media New York 2015
Abstract A series of novel (3-((3s,5s,7s)-adamantan-1-
yl)-1-alkyl/aralkyl/aryl-1,2,3,4-tetrahydroyrimidin-5-yl)
(aryl)methanones (5a–j) has been synthesized by the re-
action of 1-aryl-3-(alkyl/aralkyl/aryl)aminoprop-2-en-1-
ones 3a–j, 1-adamantanamine 4 and formaldehyde under
thermal conditions. The structures of the products (5a–j)
have been established with the help of spectral and ana-
lytical data. The stereochemistry of the products was
established by X-ray crystallographic studies of a repre-
sentative product (3-((3s,5s,7s)-adamantan-1-yl)-1-methyl-
1,2,3,4-tetrahydropyrimidin-5-yl)(4-chlorophenyl) metha-
none (5g) of the series. The target adamantane–tetrahy-
dropyrimidine hybrids 5a–j were evaluated for their anti-
inflammatory activities as a result of which compounds 5e
(R=C6H5CH2, Ar=C6H5), 5i (R=CH3, Ar=4-CH3C6H4), 5j
(R=C6H5CH2, Ar=4-CH3C6H4) and 5g (R=CH3, Ar=4-
ClC6H4) were found to exhibit excellent and promising
anti-inflammatory activities.
Keywords Tetrahydropyrimidine ꢀ Adamantanamine ꢀ
Anti-inflammatory ꢀ Enaminones ꢀ
Formylated acetophenones
Introduction
Tetrahydropyrimidines and their analogues have attracted
considerable attention because of their great pharmaco-
logical importance and biological activities such as an-
timicrobial (Elumalai et al., 2013; EL-Mahdy et al., 2013;
El-Fattah et al., 2010; Baldev et al., 2012; Chauhan et al.,
2012) and antimycobacterial activity (Elumalai et al.,
2013), COX-2 inhibitor (Lokwani et al., 2012), anti-
inflammatory (Dongarwar et al., 2011), antifungal (Gaffar
et al., 2012), antioxidant (Mansouri et al., 2012) and an-
ticancer (Desai et al., 2011). Keeping in view the biolo-
gical properties of these molecules, we have reported the
synthesis of novel 5-benzoyl-6-methylthio-1,2,3,4-tetrahy-
dropyrimidines (Benzoyl-THP-1) (Karim et al., 2003),
5-benzoyl-1,2,3,4-tetrahydropyrimidines (Benzoyl-THP-2)
(Chanda et al., 2004), bis-(5-benzoyl-1,2,3,4-tetrahy-
dropyrimidines) (Benzoyl-THP-3) (Dutta et al., 2005),
(1,2,3,4-tetrahydro-3-methyl-1-phenylpyrimidin-5-yl)
(pyridin-4-yl)methanone (4-Isonicotinoyl-THP-4) (Vish-
wakarma et al., 2009) and [3,30-(ethane-1,2-diyl)bis(1-
phenyl-1,2,3,4-tetrahydropyrimidine-5,3-diyl)]bis(pyridin-
4-ylmethanone) (4-Isonicotinoyl-THP-5) with antibacterial
property (Vishwakarma et al., 2009).
U. Kalita ꢀ S. Kaping ꢀ J. N. Vishwakarma (&)
Organic Research Lab., Department of Chemical Science,
Assam Don Bosco University, Guwahati 781017, Assam, India
e-mail: jnvishwakarma@rediffmail.com
R. Nongkynrih ꢀ L. I. Singha
Department of Biotechnology, St. Anthony’s College,
Shillong 793001, India
123

Med Chem Res
O
O
O
O
R1
R1
A
Ar
N
Ar
MeS
N
Ar
N
N
Ar
N
R
N
R
N
R
N
R
Benzoyl-THP-1
Benzoyl-THP-2
Benzoyl-THP-3
O
O
O
R1
A
N
N
N
N
N
N
N
R
N
R
N
R
4-Isonicotinoyl-THP-4
4-Isonicotinoyl-THP-5
Recently, Kshirsagar and Shanmugasundaram have re-
ported (2013) the synthesis of 1,2,3,4-tetrahydropyrimidine
derivatives containing carbamates and carbamides with
calcium channel blocking activity. However, to the best of
our knowledge, tetrahydropyrimidine derivatives contain-
ing adamantane moiety are unknown in the literature, and
hence, their biological properties remain unexplored. In
light of these findings, it was thought worthwhile to syn-
thesize molecular hybrids of 1,2,3,4-tetrahydropyrimidine
derivatives by incorporating adamantane moiety and to
evaluate their anti-inflammatory activities.
Results and discussion
A series of novel hitherto unreported hybrids containing
tetrahydropyrimidine and adamantane was synthesized.
The anti-inflammatory activities of the compounds were
evaluated, and their structures were elucidated by IR, NMR
and MS. X-ray crystallographic study for a particular
compound from the series was done for the final confir-
mation of the structures.
Chemistry
Inflammation is associated with many disease conditions
such as cancer (O’Byrne and Dalgleish, 2001), heart failure
(Gullestal et al., 2012), Parkinson’s disease (Przedborski,
2010), Alzheimer’s disease (Breitner, 1996) and other
diseases. At present, non-steroidal anti-inflammatory drugs
(NSAIDs) represent the most widely used drug in medic-
inal practice, and indeed, the use of this class of com-
pounds has increased dramatically during the recent years
among patients of all ages (Musu et al., 2011). In 1966,
amantadine, a derivative of adamantane, was approved in
the USA for use against A/H3N2 and subsequently for all
influenza A infection (Hayden, 2006; Leng et al., 2007).
New series of 5-(1-adamantyl)-1,3,4-thiadiazole deriva-
tives were synthesized and tested for their antimicrobial
and anti-inflammatory activities (Kadi et al., 2010). A
series of new adamantyl triazoles and related derivatives
was synthesized, the antimicrobial and anti-inflammatory
activities of these compounds were determined, and these
compounds show promising activities comparable to
known antibacterial, antifungal and anti-inflammatory
drugs (Al-Omar et al., 2010; Bredt and Snyder, 1994).
Prompted by this, we herein report the synthesis, structure
and anti-inflammatory activities of novel tetrahydropy-
rimidine–adamantane hybrids.
In order to synthesize the desired tetrahydropyrimidine–
adamantane hybrids, enaminones of type 3 derived from
acetophenone were required. Their synthesis could be
achieved by first reacting acetophenone 1a–c with DMF-
DMA following a previously reported procedure (Kalita
et al., 2014) to yield the formylated product 2a–c and then
converting 2a–c into 3a–j by a procedure (Kalita et al.,
2014) developed in our laboratory (Scheme 1).
Synthesis of the desired tetrahydropyrimidine–adaman-
tane hybrids was subsequently undertaken. Thus, when a
mixture of enaminone 3a, 1-adamantanamine and
formaldehyde (1:1:2) in methanol (4 ml) was heated at
reflux for 2.5 h, work up of the reaction mixture gave 5a in
88 % yields, the structure of which was proposed to be
(3-((3s,5s,7s)-adamantan-1-yl)-1-phenyl-1,2,3,4-tetrahy-
dropyrimidin-5-yl)(phenyl)methanone on the basis of
spectral and analytical data. The reaction conditions could
easily be extrapolated for the synthesis of 5b–j in 85–96 %
overall yields in 3–6 h (Scheme 1).
The structures of the products 5(a–j) (Table 1) were
established without any ambiguity. The infrared spectra
of 5a–j showed strong peaks in the region of 1,500 to
123

Med Chem Res
Scheme 1 Synthesis of tetrahydropyrimidine-adamantane hybrids 5(a–j)
1,630 cm-1 due to extensively delocalized double bonds
and carbonyl groups. The C–H stretching due to
adamantane gave characteristic bands close to 2,900 and
and Z = 4. The molecular graphic was performed using
ORTEP-3, and displacement ellipsoids are drawn at 30 %
probability level.
1
2,840 cm-1. In the H NMR spectra of 5a–j, the signals
due to aromatic protons appear between 6.80 and
7.56 ppm. The C6-H proton of the tetrahydropyrimidine
ring resonated as singlet close to 6.99 ppm in 5a, 5e, 5f,
5g and 5i, whereas it remains obscured by the aromatic
protons in 5b, 5c, 5d, 5h and 5j. The signals due to
benzylic CH2 protons in 5e and 5j appeared as singlet at
4.30 and 4.28 ppm, respectively. The CH2 protons at C-2
of the tetrahydropyrimidine ring appeared between 3.94
and 4.65 ppm, while those at C-4 gave their signals in
the range of 3.73–3.93 ppm. The three sets of protons of
adamantyl group resonated as three distinct multiplets in
ranges 1.64–1.73, 1.84–1.92 and 2.14–2.18 ppm. In the
13C NMR spectra of the tetrahydropyrimidines, the most
striking signal was due to carbonyl carbon (close to
190 ppm) and those due to adamantyl group carbon
atoms appearing in the ranges of 29.43–29.62,
36.05–36.19, 43.17–43.41 and 53.28–53.80 ppm. The
proposed cyclic structures for the tetrahydropyrimidines
are further supported by the absence of NH
(*12.00 ppm) and vinylic C–H (*6.00 ppm) proton
signals of the starting enaminones in the spectra of 5a–j.
The mass spectra of the products were in conformity
with the proposed structures.
Biological activities
Anti-inflammatory activity
Inhibition of FCA-induced paw edema
Compounds (5a–j) were tested for their in vivo anti-
inflammatory activities against FCA-induced paw edema in
mice. The test was performed to examine the ability of the
test compounds to reduce paw thickness after 24 h as
compared to the untreated inflamed mice. The results are
given in Table 2 which showed varying degrees of reduc-
tion in thickness. In general, 5g and 5d showed the highest
reduction, followed by 5i and 5e in decreasing order.
Nitric oxide level in the paw exudates
The anti-inflammatory activities of compounds 5a–j were
also determined by studying the level of NO in paw exu-
dates. The results of the NO level in paw exudates pre-
sented in Fig. 2 showed different levels of reduction in NO.
Mice treated with compound 5a showed highest reduction
in NO level followed by 5b, 5g and 5i.
Furthermore, the proposed structure of (3-((3s,5s,7s)-
adamantan-1-yl)-1-methyl-1,2,3,4-tetrahydropyrimidin-5-
yl)(4-chlorophenyl) methanone (5g) was unequivocally
confirmed by single-crystal X-ray crystallography (Fig. 1)
with CCDC no. 976466. The crystals of 5g suitable for
X-ray analysis were obtained by crystallization from
ethylacetate. The crystal belongs to monoclinic, space
Level of nitric oxide concentration in whole blood
Nitric oxide concentration in response to the test com-
pounds was also determined in blood (Fig. 3). The results
presented in Fig. 3 showed varying level of reduction in
NO concentration. Compound 5h showed highest reduction
followed by 5j and 5e. Compounds 5b, 5c, 5f and 5i
˚
group P2(1)/c with a = 14.1482 (4) A, b = 15.0308 (4) A,
˚
3
˚
˚
c = 9.1382 (2) A, b = 92.645 (1)°, V = 1,941.25 (9) A
123

Med Chem Res
Table 1 Synthesis of compounds 5a–j by reaction of enaminones 3 with 1-adamantanamine 4
Entry
1
Enaminone
4
Product
% yield (time, h)
88 (2.5 h)
2
96 (4 h)
3
85 (4 h)
4
86 (5 h)
123

Med Chem Res
Table 1 continued
Entry
5
Enaminone
4
Product
% yield (time, h)
90 (5 h)
6
92 (5 h)
7
94 (3 h)
8
90 (6 h)
9
96 (5 h)
123

Med Chem Res
Table 1 continued
Entry
10
Enaminone
4
Product
% yield (time, h)
91 (4 h)
showed equal degrees of reduction, but compounds 5a, 5d
and 5g showed no reduction.
While most of the tested compounds showed some anti-
inflammatory properties, the above results led to the con-
clusion that compounds 5e, 5i, 5j and 5g have the highest
potential as anti-inflammatory agents.
Differential leukocyte count in blood
Anti-inflammatory activities of the ten compounds were
also studied by performing a differential leukocyte count in
blood smear. Most of the compounds resulted in lower
counts of both basophils and eosinophils or either basophils
or eosinophils as compared to control mice as given in
Fig. 4. The results reveal that blood from mice treated with
compounds 5e and 5j have lowest levels of these cells.
In this investigation, paw thickness was taken as a
physical parameter. From the results, it is clear that com-
pounds 5d, 5g, 5i and 5e exhibited the highest ability to
reduce paw edema after 24 h (Table 2), while the others
showed no reduction in paw thickness. NO is an effective
mediator of inflammation (Korhonen et al., 2005), and high
levels of NO have been reported in many physiological
processes including inflammatory response (Kang et al.,
2008). Therefore, the inflammatory activities of com-
pounds 5a–j were also studied by determining the level of
NO in paw exudates and whole blood. The results
demonstrated varying degrees of reduction both in paw
exudates and in whole blood. In paw exudates, compound
5a showed the highest reduction followed by 5b, 5g and 5i,
whereas compound 5h showed the highest reduction in NO
in blood and is followed by 5j and 5e. Differential leuko-
cytes count is another parameter which was studied in this
investigation. Leukocytes such as eosinophils and ba-
sophils are present at the site of inflammatory response and
are suggested to reduce inflammation caused by other
leukocytes (Spuy et al., 2010). The anti-inflammatory ac-
tivities of compounds 5a–j were also studied by performing
differential leukocytes count. As mentioned above, the
results indicated that mice treated with compound 5e and 5j
showed the lowest basophil and eosinophil counts (Fig. 4).
Experimental
Chemistry
Melting points were recorded by open capillary method
and are uncorrected. The IR spectra were recorded on a
Perkin-Elmer 983 spectrometer (Perkin-Elmer). 1H and 13
C
NMR spectra were recorded on a JEOL JNM-ECS 400
taking Me4Si as the internal standard in CDCl3. The X-ray
diffraction data were collected at 296 K with Mo Ka ra-
˚
diation (k = 0.71073 A) using a Bruker Nonius SMART
APEX II CCD diffractometer equipped with a graphite
monochromator. The structures were solved by direct
methods (SHELXS 97) and refined by full-matrix least-
squares based on F square. All calculations were carried
out using WinGX system version 1.80.05. All the non-
H-atoms were refined in the anisotropic approximation:
H-atoms were located at calculated positions. The electron
spray mass spectra were recorded on a THERMO Finnigan
LCQ Advantage max ion trap mass spectrometer. Ele-
mental analysis was performed on a Vario-EL III instru-
ment. Formylated acetophenones 2a–c was synthesized by
our previously reported procedure (Kalita et al., 2014).
General procedure for the synthesis of (3-((3s,5s,7s)-
adamantan-1-yl)-1-alkyl/aralkyl/aryl-1,2,3,4-
tetrahydropyrimidin-5-yl)(aryl)methanone (5a–j)
A mixture of 1-adamantanamine (1 mmol) and formalde-
hyde (2 mmol) in 1 ml of methanol was stirred at room
123

Med Chem Res
Table 2 Paw thickness of mice bearing FCA-induced paw edema followed by intraperitoneal administration of 50 mg/kg bw of test compounds
5a–j at different time intervals in comparison with untreated control
Treatment group
Time (h)
Paw edema
(mm)
Increase in paw
thickness from 0 h
Percentage increase/decrease
in paw thickness
Control
0
3.08
3.27
3.42
3.69
3.83
3.83
3.07
3.83
3.67
3.17
3.53
4.00
3.87
3.77
3.57
3.87
3.87
3.43
3.23
3.47
3.77
3.47
3.13
3.53
3.87
3.87
3.13
3.93
3.90
3.50
3.13
3.33
3.97
3.77
3.00
3.87
3.70
3.77
3.17
3.43
4.00
3.77
3.27
3.93
0.07
0.28
0.29
0.27
0.29
0.29
0.12
0.29
0.29
0.29
0.46
0.00
0.06
0.25
0.12
0.12
0.12
0.12
0.25
0.29
0.25
0.29
0.12
0.25
0.06
0.06
0.12
0.06
0.10
0.00
0.12
0.29
0.06
0.23
0.00
0.12
0.17
0.25
0.29
0.12
0.00
0.23
0.06
0.06
0
0.00
6.17
1
0.19
0.35
0.62
0
3
11.24
20.02
0.00
24
0
5a
5b
5c
5d
5e
5f
1
0
0.00
3
-0.77
0.00
0
-19.98
0.00
24
0
0.00
1
-0.5
-0.13
0.33
0
-13.64
-3.65
9.08
3
24
0
0.00
1
-0.10
-0.3
0.00
0
-2.59
-7.76
0.00
3
24
0
0.00
1
-0.43
-0.63
-0.40
0
-11.22
-16.40
-10.27
0.00
3
24
0
1
-0.3
-0.64
-0.24
0
-7.96
-16.98
-6.37
0.00
3
24
0
1
0
0.00
3
-0.73
0.07
0
-18.98
1.71
24
0
5g
5h
5i
0.00
1
-0.4
-0.77
-0.57
0
-10.26
-19.67
-14.54
0.00
3
24
0
1
-0.20
-0.97
-0.10
0
-5.04
-24.43
-2.52
0.00
3
24
0
1
0.07
-3.53
-0.27
0
1.81
3
-14.41
-7.22
0.00
24
0
5j
1
-0.23
-0.73
-0.07
-5.75
-18.25
-1.75
3
24
123

Med Chem Res
Fig. 1 Single-crystal X-ray structure of 5g
CH-phenyl), 123.8 (CH-phenyl), 128.1 (2, CH-phenyl),
128.3 (2, CH-phenyl), 129.6 (2, CH-phenyl), 130.0 (Cq),
139.9 (Cq), 143.8 (Cq), 146.5 (C6-tetrahydropyrimidine),
193.3 (CO); Mass [ESI] m/z (%): 399 [MH]?. Anal. Calcd.
For C27H30N2O (398): C, 81.37; H, 7.59; N, 7.03. Found:
C, 81.48; H, 7.53; N, 7.00 %.
temperature for 5–10 min. To this was added a solution of
the enaminone (1 mmol) in 4 ml of methanol and the re-
sulting solution was refluxed for 2.5–6 h. On completion of
the reaction (monitored by TLC), methanol was distilled
off to give a gum. This gum, on trituration with hexane,
gave a solid which was collected by filtration. The practi-
cally pure product thus obtained in 85–96 % overall yields
were further purified by column chromatography (silica
gel, 20 % EtOAc-Hexane).
(3-((3s,5s,7s)-adamantan-1-yl)-1-(p-tolyl)-1,2,3,4-tetrahy-
dropyrimidin-5-yl)(phenyl)methanone (5b)
(3-((3s,5s,7s)-adamantan-1-yl)-1-phenyl-1,2,3,4-tetrahy-
O
N
N
dropyrimidin-5-yl)(phenyl) methanone (5a)
O
N
N
CH3
Yellow crystals from ethylacetate (96 %); m.p.
143–144 °C; IR (KBr) tmax 2,904 (Adamantane), 2,853
Yellow crystals from ethylacetate (88 %); m.p.
(Adamantane), 1,581 (CO) cm-1 1H NMR (400 MHz,
;
132–133 °C; IR (KBr) tmax 2,900 (Adamantane), 2,846
(Adamantane), 1,598 (CO) cm-1 1H NMR (400 MHz,
;
CDCl3) d ppm: 1.58–1.67 (m, 6H, Adamantane), 1.80–1.81
(m, 6H, Adamantane), 2.09 (s, 3H, Adamantane), 2.30 (s,
3H, CH3, phenyl), 3.93 (s, 2H, CH2, tetrahydropyrimidine),
4.61 (s, 2H, CH2, tetrahydropyrimidine), 6.84 (d, 2H,
J = 8.8 Hz, phenyl), 7.12 (d, 2H, J = 8.8 Hz, phenyl),
7.36–7.44 (m, 4H, 3H-phenyl, 1H-C6-tetrahydropyrim-
idine), 7.54 (d, 2H, J = 8 Hz, phenyl); 13C NMR
(400 MHz, CDCl3) d ppm: 20.7 (CH3-phenyl), 29.6 (3,
CH, Adaman-tane), 36.5 (3, CH2, Adamantane), 40.0
(3, CH2, Adamantane), 41.2 (Cq, Adamantane), 54.6
(CH2-tetrahydropyrimidine), 62.2 (CH2-tetrahydropyrim-
idine), 113.1 (CH-phenyl), 118.1 (2, CH-phenyl), 128.0 (2,
CDCl3) d ppm: 1.58–1.67 (m, 6H, Adamantane), 1.80–1.81
(m, 6H, Adamantane), 2.09 (s, 3H, Adamantane), 3.94 (s,
2H, CH2, tetrahydropyrimidine), 4.65 (s, 2H, CH2,
tetrahydropyrimidine), 6.94 (d, 2H, J = 8.8 Hz, phenyl),
7.07–7.1 (t, 1H, phenyl), 7.32 (d, 2H, J = 8.8 Hz, phenyl),
7.39–7.43 (m, 3H, phenyl), 7.48 (s, 1H, CH-C6-tetrahy-
dropyrimidine), 7.54–7.56 (m, 2H, phenyl); 13C NMR
(400 MHz, CDCl3) d ppm: 29.5 (3, CH, Adamantane), 36.4
(3, CH2, Adamantane), 40.0 (3, CH2, Adamantane), 41.3
(Cq, Adamantane), 54.7 (CH2-tetrahydropyrimidine), 62.0
(CH2-tetrahydropyrimidine), 113.7 (CH-phenyl), 118.1 (2,
123

Med Chem Res
CH-phenyl), 128.3 (2, CH-phenyl), 129.8 (2, CH-phenyl),
130.1 (Cq), 133.7 (Cq), 140.0 (Cq), 141.5 (Cq), 146.9 (C6-
tetrahydropyrimidine), 193.1 (CO); Mass [ESI] m/z (%):
413 [MH]?. Anal. Calcd. For C28H32N2O (412): C, 81.51;
H, 7.82; N, 6.79. Found: C, 81.45; H, 7.76; N, 6.75 %.
Yellow crystals from ethylacetate (86 %); m.p.
163–165 °C; IR (KBr) tmax 2,908 (Adamantane), 2,847
(Adamantane), 1,636 (CO) cm-1 1H NMR (400 MHz,
;
CDCl3) d ppm: 1.60–1.64 (m, 6H, Adamantane), 1.78–1.79
(m, 6H, Adamantane), 2.09 (s, 3H, Adamantane), 3.92 (s,
2H, CH2, tetrahydropyrimidine), 4.61 (s, 2H, CH2, te-
trahydropyrimidine), 6.80 (d, 2H, J = 8.8 Hz, phenyl),
7.41–7.43 (m, 6H, 5H- phenyl, 1H-C6-tetahydropy-
imidine), 7.54 (d, 2H, J = 8.8 Hz, phenyl); 13C NMR
(400 MHz, CDCl3) d ppm: 29.5 (3, CH, Adamantane), 36.4
(3, CH2, Adamantane), 40.0 (3, CH2, Adamantane), 41.2
(Cq, Adamantane), 54.7 (CH2-tetrahydropyrimidine), 61.9
(CH2-tetrahydropyrimidine), 114.5 (Cq), 116.5 (Cq), 119.4
(2, CH-phenyl), 128.1 (2, CH-phenyl), 128.3 (2, CH-phe-
nyl), 130.2 (CH-phenyl), 132.5 (2, CH-phenyl), 139.7 (Cq),
142.8 (Cq), 145.6 (C6-tetrahydropyrimidine), 193.3 (CO);
Mass [ESI] m/z (%): 477 [MH]?. Anal. Calcd. For
C27H29BrN2O (476): C, 67.92; H, 6.12; N, 5.87. Found: C,
68.06; H, 6.09; N, 5.90 %.
(3-((3s,5s,7s)-adamantan-1-yl)-1-(4-methoxyphenyl)-
1,2,3,4-tetrahydropyrimidin-5-yl)(phenyl) methanone
(5c)
O
N
N
OCH3
Yellow crystals from ethylacetate (85 %); m.p. 105–106 °C;
IR (KBr) tmax 2,906 (Adamantane), 2,846 (Adamantane),
1,627 (CO) cm-1; H NMR (400 MHz, CDCl3) d ppm:
1
(3-((3s,5s,7s)-adamantan-1-yl)-1-benzyl-1,2,3,4-tetrahy-
1.58–1.67 (m, 6H, Adamantane), 1.81–1.82 (m, 6H,
Adamantane), 2.09 (s, 3H, Adamantane), 3.77 (s, 3H, OCH3,
phenyl), 3.93 (s, 2H, CH2, tetrahydropyrimidine), 4.58 (s,
2H, CH2, tetrahydropyrimidine), 6.84–6.92 (m, 4H, 3H-
phenyl, 1H-C6-tetrahydopyrimidine), 7.36–7.42 (m, 4H,
phenyl), 7.52–7.54 (m, 2H, phenyl); 13C NMR (400 MHz,
CDCl3) d ppm: 29.6 (3, CH, Adamantane), 36.5 (3, CH2,
Adamantane), 40.0 (3, CH2, Adamantane), 41.2 (Cq,
Adamantane), 54.6 (CH2-tetrahydropyrimidine), 55.5
(OCH3-phenyl), 62.7 (CH2-tetrahydropyrimidine), 112.6
(Cq), 114.7 (2, CH-phenyl), 120.4 (2, CH-phenyl), 128.0 (2,
CH-phenyl), 128.2 (2, CH-phenyl), 129.8 (CH-phenyl),
137.6 (Cq), 140.1 (Cq), 147.3 (Cq), 156.5 (C6-tetrahy-
dropyrimidine), 192.9 (CO); Mass [ESI] m/z (%): 429
[MH]?. Anal. Calcd. For C28H32N2O2 (428): C, 78.47; H,
7.53; N, 6.54. Found: C, 78.55; H, 7.49; N, 6.51 %.
dropyrimidin-5-yl)(phenyl) methanone (5e)
O
N
N
Yellow crystals from ethylacetate (90 %); m.p. 153 °C; IR
(KBr) tmax 2,904 (Adamantane), 2,853 (Adamantane), 1,562
(CO) cm-1; 1H NMR (400 MHz, CDCl3) d ppm: 1.59–1.62
(m, 6H, Adamantane), 1.66–1.73 (m, 6H, Adamantane),
2.06 (s, 3H, Adamantane), 3.78 (s, 2H, CH2, benzyl), 3.99 (s,
2H, CH2, tetrahydropyrimidine), 4.30 (s, 2H, CH2, tetrahy-
dropyrimidine), 7.17 (s, 1H, CH-C6-tetrahydropyrimidine),
7.22 (d, 2H, J = 8.8 Hz, phenyl), 7.30–7.40 (m, 6H, phe-
nyl), 7.48–7.50 (m, 2H, phenyl); 13C NMR (400 MHz,
CDCl3) d 29.5 (3, CH, Adamantane), 36.5 (3, CH2,
Adamantane), 39.3 (3, CH2, Adamantane), 40.7 (Cq,
Adamantane), 54.2 (CH2-benzyl), 58.0 (CH2-tetrahydropy-
rimidine), 61.0 (CH2-tetrahydropyrimidine), 109.4 (CH-
phenyl), 127.4 (2, CH-phenyl), 127.9 (2, CH-phenyl), 128.0
(2, CH-phenyl), 128.1 (2, CH-phenyl), 128.9 (CH-phenyl),
129.4 (Cq), 135.8 (Cq), 140.1 (Cq), 151.4 (C6-tetrahy-
dropyrimidine), 192.0 (CO); Mass [ESI] m/z (%):
413[MH]?. Anal. Calcd. For C28H32N2O (412): C, 81.51; H,
7.82; N, 6.79. Found: C, 81.60; H, 7.76; N, 6.77 %.
(3-((3s,5s,7s)-adamantan-1-yl)-1-(4-bromophenyl)-1,2,3,4-
tetrahydropyrimidin-5-yl)(phenyl) methanone (5d)
O
N
N
Br
123

Med Chem Res
(3-((3s,5s,7s)-adamantan-1-yl)-1-methyl-1,2,3,4-tetrahy-
Adamantane), 54.3 (CH2, tetrahydropyrimidine), 62.5
(CH2-tetrahydropyrimidine), 108.8 (Cq), 128.2 (2, CH-
phenyl), 129.5 (2, CH-phenyl), 135.2 (Cq), 138.9 (Cq),
151.6 (C6-tetrahydropyrimidine), 190.2 (CO); Mass [ESI]
m/z (%): 371 [MH]?. Anal. Calcd. For C22H27ClN2O
(370): C, 71.24; H, 7.34; N, 7.55. Found: C, 71.37; H, 7.29;
N, 7.58 %.
dropyrimidin-5-yl)(phenyl) methanone (5f)
O
N
N
(3-((3s,5s,7s)-adamantan-1-yl)-1-(p-tolyl)-1,2,3,4-tetrahy-
CH3
dropyrimidin-5-yl)(4-chlorophenyl) methanone (5h)
Yellow crystals from ethylacetate (92 %); m.p. 125–126 °C;
IR (KBr) tmax 2,899 (Adamantane), 2,839 (Adamantane),
O
1
1,626 (CO) cm-1; H NMR (400 MHz, CDCl3) d ppm:
N
1.62–1.71 (m, 6H, Adamantane), 1.83–1.84 (m, 6H,
Adamantane), 2.13 (s, 3H, Adamantane), 2.92 (s, 3H, CH3,
tetahydropyrimidine), 3.76 (s, 2H, CH2, tetrahydropyrim-
idine), 4.02 (s, 2H, CH2, tetrahydropyrimidine), 6.96 (s, 1H,
CH-C6-tetrahydropyrimidine), 7.35–7.40 (m, 3H, phenyl),
7.47 (d, 2H, J = 8.8 Hz, phenyl); 13C NMR (400 MHz,
CDCl3) d ppm: 29.6 (3, CH, Adamantane), 36.6 (3, CH2,
Adamantane), 39.4 (3, CH2, Adamantane), 40.3 (CH3, te-
tahydropyrimidine), 40.5 (Cq, Adamantane), 54.3 (CH2, te-
trahydropyrimidine), 62.5 (CH2-tetrahydropyrimidine),
108.9 (Cq), 127.9 (2, CH-phenyl), 128.0 (2, CH-phenyl),
129.3 (CH-phenyl), 140.6 (Cq), 151.7 (C6-tetrahydropy-
rimidine), 191.7 (CO); Mass [ESI] m/z (%): 337 [MH]?.
Anal. Calcd. For C22H28N2O (336): C, 78.53; H, 8.39; N,
8.33. Found: C, 78.59; H, 8.35; N, 8.30 %.
Cl
N
CH3
Yellow crystals from ethylacetate (90 %); m.p. 155–156 °C;
IR (KBr) tmax 2,904 (Adamantane), 2,832 (Adamantane),
1,572 (CO) cm-1; H NMR (400 MHz, CDCl3) d ppm:
1
1.58–1.71 (m, 6H, Adamantane), 1.79–1.80 (m, 6H,
Adamantane), 2.09 (s, 3H, Adamantane), 2.31 (s, 3H, CH3,
phenyl), 3.91 (s, 2H, CH2, tetrahydropyrimidine), 4.62 (s,
2H, CH2, tetrahydropyrimidine), 6.84 (d, 2H, J = 8.8 Hz,
phenyl), 7.12 (d, 2H, J = 8.8 Hz, phenyl), 7.35–7.39 (m,
3H, 2H- phenyl, 1H-C6-tetahydopyrimidine), 7.48 (d, 2H,
J = 8.8 Hz, phenyl); 13C NMR (400 MHz, CDCl3) d ppm:
13C NMR (400 MHz, CDCl3) d ppm: 20.7 (CH3-phenyl),
29.6 (3, CH, Adamantane), 36.5 (3, CH2, Adamantane), 40.1
(3, CH2, Adamantane), 41.2 (Cq, Adamantane), 54.7 (CH2-
tetrahydropyrimidine), 62.3 (CH2-tetrahydropyrimidine),
113.0 (Cq), 118.5 (2, CH-phenyl), 128.3 (2, CH-phenyl),
129.7 (2, CH-phenyl), 130.2 (2, CH-phenyl), 134.0 (Cq),
135.9 (Cq), 138.4 (Cq), 141.5 (Cq), 146.8 (C6-tetrahy-
dropyrimidine), 191.5 (CO); Mass [ESI] m/z (%): 447
[MH]?. Anal. Calcd. For C28H31ClN2O (446): C, 75.23; H,
6.99; N, 6.27. Found: C, 75.33; H, 6.95; N, 6.25 %.
(3-((3s,5s,7s)-adamantan-1-yl)-1-methyl-1,2,3,4-tetrahy-
dropyrimidin-5-yl)(4-chlorophenyl) methanone (5g)
O
N
Cl
N
CH3
Yellow crystals from ethylacetate (94 %); m.p. 163 °C; IR
(KBr) tmax 2,914 (Adamantane), 2,862 (Adamantane),
1
1,633 (CO) cm-1; H NMR (400 MHz, CDCl3) d ppm:
(3-((3s,5s,7s)-adamantan-1-yl)-1-methyl-1,2,3,4-tetrahy-
1.61–1.71 (m, 6H, Adamantane), 1.80–1.83 (m, 6H,
Adamantane), 2.13 (s, 3H, Adamantane), 2.94 (s, 3H, CH3,
tetahydropyrimidine), 3.73 (s, 2H, CH2, tetrahydropyrim-
idine), 4.03 (s, 2H, CH2, tetrahydropyrimidine), 6.93 (s,
1H, CH-C6-tetrahydropyrimidine), 7.34 (d, 2H,
dropyrimidin-5-yl)(p-tolyl) methanone (5i)
O
J = 8.8 Hz, phenyl), 7.41 (d, 2H, J = 8.8 Hz, phenyl); 13
C
N
NMR (400 MHz, CDCl3) d ppm: 29.5 (3, CH, Adaman-
tane), 36.5 (3, CH2, Adamantane), 39.4 (3, CH2,
Adamantane), 40.2 (CH3, tetahydropyrimidine), 40.7 (Cq,
CH3
N
CH3
123

Med Chem Res
Yellow crystals from ethylacetate (96 %); m.p. 115 °C; IR
(KBr) tmax 2,908 (Adamantane), 2,847 (Adamantane),
Biology
1
1,633 (CO) cm-1; H NMR (400 MHz, CDCl3) d ppm:
Anti-inflammatory activity
1.61–1.70 (m, 6H, Adamantane), 1.83–1.84 (m, 6H,
Adamantane), 2.12 (s, 3H, Adamantane), 2.37 (s, 3H, CH3,
phenyl) 2.92 (s, 3H, CH3, tetahydropyrimidine), 3.75 (s,
2H, CH2, tetrahydropyrimidine), 4.01 (s, 2H, CH2, te-
trahydropyrimidine), 6.99 (s, 1H, CH-C6-tetrahydropyrim-
idine), 7.17 (d, 2H, J = 8.8 Hz, phenyl), 7.38 (d, 2H,
J = 8.8 Hz, phenyl); 13C NMR (400 MHz, CDCl3) d ppm:
13C NMR (400 MHz, CDCl3) d ppm: 21.3 (CH3, phenyl),
29.6 (3, CH, Adamantane), 36.6 (3, CH2, Adamantane),
39.4 (3, CH2, Adamantane), 40.3 (CH3, tetahydropyrim-
idine), 40.5 (Cq, Adamantane), 54.3 (CH2, tetrahydropy-
rimidine), 62.5 (CH2-tetrahydropyrimidine), 109.0 (Cq),
128.2 (2, CH-phenyl), 128.6 (2, CH-phenyl), 137.8 (Cq),
139.4 (Cq), 151.4 (C6-tetrahydropyrimidine), 191.7 (CO);
Mass [ESI] m/z (%): 351 [MH]?. Anal. Calcd. For
C23H30N2O (350): C, 78.82; H, 8.63; N, 7.99. Found: C,
78.85; H, 8.57; N, 8.00 %.
Griess reagent system was purchased from Promega
(USA). Wright stain, anhydrous potassium dihydrogen
phosphate, potassium chloride, disodium hydrogen phos-
phate, sodium-EDTA and dimethyl sulfoxide were pro-
cured from HiMEDIA. Methanol used in our experiments
was purchased from Merck, and Fruend’s complete adju-
vant (FCA) was procured from Genei.
Methodology
Anti-inflammatory activities of the test compounds were
studied by measuring paw diameter, assay of NO con-
centration in blood and in paw exudates and by per-
forming a differential WBC count in mice carrying FCA-
induced paw edema and subsequently treating with test
compounds.
(3-((3s,5s,7s)-adamantan-1-yl)-1-benzyl-1,2,3,4-tetrahy-
Induction of paw edema The anti-inflammatory activities
of the test compounds were determined by following the
method of (Lai et al., 2009) with some modification. Swiss
Albino mice aged between 8 and 10 weeks of either sex
(three per group) maintained at controlled temperature with
12-h light/12-h dark conditions, provided with standard
mice feed and common tap drinking water were used in all
experiments. About 50 ll of the Fruend’s complete adju-
vant (FCA) was injected into the plantar side of left hind
paws of the mice (Winter et al., 1962). Paw diameter of the
FCA-induced edema of mice was measured at 0-, 1, 3 and
24 h after administration of the FCA by using a caliper.
Test compounds (dissolved in 10 % DMSO) at a dose of
50 mg/kg body weight were administered 1 h after FCA
dropyrimidin-5-yl)(p-tolyl)methanone (5j)
O
N
CH3
N
White crystals from ethylacetate (91 %); m.p.
131–132 °C; IR (KBr) tmax 2,904 (Adamantane), 2,832
(Adamantane), 1,561 (CO) cm-1 1H NMR (400 MHz,
;
CDCl3)
d ppm: 1.58–1.62 (m, 6H, Adamantane),
injection. The percentage increase/decrease in the paw
bꢁa
1.65–1.73 (m, 6H, Adamantane), 2.05 (s, 3H, Adaman-
tane), 2.37 (s, 2H, CH3, phenyl), 3.77 (s, 2H, CH2, ben-
zyl), 3.98 (s, 2H, CH2, tetrahydropyrimidine), 4.28 (s, 2H,
CH2, tetrahydropyrimidine), 7.18–7.19 (m, 5H, phenyl),
7.39–7.41 (m, 5H, 4H-phenyl, 1H-C6-tetrahydropyrim-
idine); 13C NMR (400 MHz, CDCl3) d ppm: 21.3 (CH3,
phenyl), 29.6 (3, CH, Adamantane), 36.5 (3, CH2,
Adamantane), 39.4 (3, CH2, Adamantane), 40.8 (Cq,
Adamantane), 54.2 (CH2, benzyl), 58.0 (CH2-tetrahy-
dropyrimidine), 61.0 (CH2-tetrahydropyrimidine), 109.4
(CH-phenyl), 127.4 (Cq), 128.0 (2, CH-phenyl), 128.3 (2,
CH-phenyl), 128.6 (2, CH-phenyl), 128.8 (2, CH-phenyl),
136.0 (Cq), 138.7 (Cq), 139.5 (Cq), 151.4 (C6-tetrahy-
dropyrimidine), 192.0 (CO); Mass [ESI] m/z (%): 427
[MH]?. Anal. Calcd. For C29H34N2O (426): C, 81.65; H,
8.03; N, 6.57. Found: C, 81.69; H, 7.98; N, 6.54 %.
edema is calculated by the formula
ꢂ 100 where ‘a’ is
a
the paw diameter at 0 h, and ‘b’ is the paw diameter at
different time intervals. After 24 h, blood was collected by
retro-orbital bleeding and used for estimating NO and
preparing blood smear. Mice were then killed by cervical
dislocation. The left hind paw tissue was excised, rinsed
with ice-cold normal saline and homogenized in 1 ml of
cold normal saline. The homogenate was then centrifuged
at 12,000 rpm for 5 min, and the supernatant thus obtained
was used for NO assay.
NO assay NO2- was measured by using the Griess re-
action. Three columns in the 96-well plates were desig-
nated for the nitrite standard reference curve. Six serial
twofold dilution of 100 lM nitrite solution (50 ll/well) in
123

Med Chem Res
Fig. 2 Concentration of the NO (in lM) in the paw exudates of
different treatment groups. Mice were injected with 50 ll of FCA in
plantar side of hind paw followed by intraperitoneal administration of
test compounds 5a–j (50 mg/kg bw) 1 h later. Mice were killed after
24 h following FCA injection, and the hind paw was excised and
homogenized in 1 ml normal saline. NO level was measured by using
the Griess reaction with standard nitrite reference curve. Each group
represents the mean S.E.M (n = 3). *P \ 0.05 statistical sig-
nificance compared with control (unpaired Student’s t test)
Fig. 3 Concentration of the NO in whole blood of the different
treatment groups. Paw edema was induced by injecting FCA in all
groups of mice. Mice were then given intraperitoneal injections of test
compounds 5a–j (50 mg/kg bw). Blood was collected by retro-orbital
bleeding, and the whole blood was used to measure the level of NO
by using the Griess reaction with standard nitrite reference curve.
Each group represents the mean S.E.M (n = 3) *P \ 0.05 statis-
tical significance compared with control (unpaired Student’s t test)
triplicate was performed to generate the nitrite standard
reference curve. Fifty microliters of experimental sample
was taken in triplicate in test wells. To all wells, 50 ll of
sulfanilamide solution was added and incubated for
5–10 min at room temperature protected from light.
Thereafter, 50 ll of the N-(1-napthyl)ethylenediamine di-
hydrochloride (NED) solution was dispensed to all wells.
The plate was incubated at room temperature for 5–10 min,
protected from light. A purple/magenta color begins to
form immediately. The absorbance was measured within
30 min at 520 nm.
The concentration of NO in experimental samples was
calculated from the standard curve obtained from above.
Differential WBC count The differential WBC count was
performed according to the method described by (Houwen,
2000). Blood film was prepared on glass slides by wedge
method and air-dried. The blood films were fixed for 30 s
123

Med Chem Res
Fig. 4 Percentage counts of different types of leukocytes in mice
treated with test compound in comparison with untreated control.
Mice were killed 24 h after FCA injection. Blood smear was
prepared, the slides were stained with Wright’s stain, and cells were
counted under a microscope
in absolute methanol. Slides were stained for 2 min with
Wright’s stain, and an aliquot of Sorensen’s buffer was
added and allowed to stand for 3 min. Slides were rinsed
with distilled water and air-dried. The prepared slides were
viewed under a microscope with 40X objective, and WBCs
were counted.
accessible starting materials in good to excellent yields.
The structures of these molecular hybrids have been
unambiguously established with help of IR, PMR, CMR,
MS and X-ray crystallography. These products 5a–j were
tested for their anti-inflammatory activities, and overall
data of all parameters reveal that compounds 5e, 5i, 5j and
5g possess excellent anti-inflammatory properties. It is
noteworthy that compounds 5e, 5i, 5j and 5g have either
bynzyl or methyl group in position 1 of the tetrahydropy-
rimidine ring, while the rest of the products bearing phenyl
group in position 1 of the ring exhibited poor anti-inflam-
matory properties. Further studies on this class of mole-
cules correlating substituents in tetrahydropyrimidine ring
Conclusion
The present paper describes an efficient strategy for the
synthesis of hitherto unreported 1,2,3,4-tetrahydropyrim-
idines containing adamantane moiety from easily
123

Med Chem Res
Gullestal L, Ueland T, Vinge LE, Finsen A, Yndestad A, Aukrust P
(2012) Inflammatory cytokines in heart failure: mediators and
markers. Cardiology 122(1):23–35
and anti-inflammatory activities, with a view to improving
the biological properties, are currently in progress.
Hayden FG (2006) Antivirals for influenza: historical perspectives
and lessons learned. Antiviral Res 71(2–3):372–378
Houwen B (2000) Blood film preparation and staining procedures.
Lab Hematol 6(1):1–7
Kadi AA, Al-Abdulah ES, Shehata IA, Habib EE, Ibrahim TM, El-
Emam AA (2010) Synthesis, antimicrobial and anti-inflamma-
tory activities of novel 5-(1-adamantyl)-1,3,4-thiadiazole deriva-
tives. Eur J Med Chem 45(11):5006–5011
Kalita U, Kaping S, Nongkynrih R, Sunn M, Boiss I, Singha LI,
Vishwakarma JN (2014) Synthesis, structure elucidation and
anti-inflammatory/anti-cancer/anti-bacterial activities of novel
(Z)-3-adamantyl-1-aryl-prop/but-2-en-1-ones. Med Chem Res.
doi:10.1007/s00044-014-1086-x
Acknowledgments Authors wish to thank Rev. Fr. Dr. Stephen
Mavely, Vice Chancellor, Assam Don Bosco University, for provid-
ing infrastructure for the execution of this work. Authors also wish to
express their gratitude to IIT, Guwahati, Tezpur University, Tezpur,
SAIF-NEHU, Shillong and SAIF-CDRI, Lucknow, for providing
spectral and analytical data. Our thanks are also due to the Depart-
ment of Biotechnology (DBT), Government of India, for a research
grant. UK, SK & RN thank DBT-GOI for research fellowships.
References
Kang O-H, Chae H-S, Oh Y-C, Choi J-G, Lee Y-S, Jang H-J, Kim J-H,
Kim YC, Sohn DH, Park H, Kwon D-Y (2008) Anti-Nociceptive
and anti-inflammatory effects of Angelicae Dahuricae Radix
through inhibition of the expression of inducible nitric oxide
synthase and NO production. Am J Chin Med 36(5):913–928
Karim E, Kishore K, Vishwakarma JN (2003) A facile one-pot
synthesis of novel substituted 1,2,3,4-tetrahydropyrimidines.
J Heterocycl Chem 40(5):901–903
Korhonen R, Lahti A, Kankaanranta H, Moilanen E (2005) Nitric
oxide production and signaling in inflammation. Curr Drug
Targets Inflamm Allergy 4(4):471–479
Kshirsagar SS, Shanmugasundaram P (2013) Synthesis and calcium
channel blocking activity of 1,2,3,4-tetrahydropyrimidine
derivatives containing carbamates and carbamides. Int J Chem
Tech Res 5(6):2899–2912
Al-Omar MA, Al-Abdullah ES, Shehata IA, Habib EE, Ibrahim TM, El-
Emam AA (2010) Synthesis, antimicrobial and anti-inflammatory
activities of novel 5-(1-adamantyl)-4-arylideneamino-3-mercapto-
1,2,4-triazoles and related derivatives. Molecules 15(4):2526–2550
Baldev AD, Vyas KB, Patel KB, Nimavat KS (2012) Synthesis of
1,2,3,4-tetrahydropyrimidine derivatives as an antimicrobial
agent. J Chem Pharm Res 4(6):2972–2978
Bredt DS, Snyder SH (1994) Nitric oxide: a physiologic messenger
molecule. Annu Rev Biochem 63:175–195
Breitner JCS (1996) The role of anti-inflammatory drugs in preven-
tion and treatment of Alzheimer’s disease. Annu Rev Med
47:401–411
Chanda K, Dutta MC, Karim E, Vishwakarma JN (2004) A facile one-
pot synthesis of novel substituted 1,2,3,4-tetrahydropyrimidine,
part 2: synthesis of 1-(aralkyl/aryl)-3-(alkyl/aralkyl/aryl)-5-aroyl-
1,2,3,4-tetrahydropyrimidines. J Heterocycl Chem 41(4):627–631
Chauhan N, Nimavat K, Vyas K (2012) Synthesis, characterization
and biological screening of novel N-[2-chloro-4-(tri-
fluoromethyl)phenyl]-4-(substituted phenyl)-6-methyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxamide. Der Pharm Sin
3(4):394–399
Lai SC, Peng WH, Huang SC, Ho YL, Huang TH, Lai ZR, Chang YS
(2009) Analgesic and anti-inflammatory activities of methanol
extract from Desmodium triflorum DC in mice. Am J Chin Med
37(3):573–588
Leng SX, Xue QL, Tian J, Walston JD, Fried LP (2007) Inflammation
and frailty in older women. JAGS 55(6):864–871
Lokwani D, Shah R, Mokale S, Shastry P, Shinde D (2012)
Development of energetic pharmacophore for the designing of
1,2,3,4-tetrahydropyrimidine derivatives as selective cyclooxy-
genase-2 inhibitors. J Comput Aided Mol Des 26(3):267–277
Mansouri M, Movahedian A, Rostami M, Fassihi A (2012) Synthesis
and antioxidant evaluation of 4-(furan-2-yl)-6-methyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate esters. Res Pharm
Sci 7(4):257–264
Desai NC, Chhabaria MT, Dodiya A, Bhavsar AM, Baldaniya BB
(2011) Synthesis, characterization, anticancer activity, and
QSAR-studies of some new tetrahydropyrimidines. Med Chem
Res 20(8):1331–1339
Dongarwar AS, Wanjari BE, Nema MV, Katolkar PP, Turaskar AO,
Nimbekar TP (2011) Synthesis, anti-inflammatory and anti-
microbial activity of pyrimidine-5-carboxylate derivatives. Int J
Biomed Adv Res 2(6):188–197
Musu M, Finco G, Antonucci R, Polati E, Sanna D, Evangelista M,
Ribuffo D, Schweiger V, Fanos V (2011) Acute nephrotoxicity
of NSAID from foetus to adult. Eur Rev Med Pharmacol Sci
15(12):1461–1472
O’Byrne KJ, Dalgleish AG (2001) Chronic immune activation and
inflammation as the cause of malignancy. Br J Cancer 85(4):473–483
Przedborski S (2010) Inflammation and Parkinson’s disease patho-
genesis. Mov Disord 25(S1):S55–S57
van der Spuy WJ, Potgieter M, Pretorius E, Vieira WA (2010)
Differential leukocyte counts of SJL/J mice with dysferlinopathy
treated with resveratrol and coenzyme Q10. Scand J Lab Anim
Sci 37(2):93–99
Vishwakarma JN, Dutta MC, Chanda K, Das B, Laskar MA, Nongkhlaw
RL (2009) Synthesis and anti-bacterial activities of novel
5-isonicotinoyl-1,2,3,4-tetrahydropyrimidines and bis-(5-isonicoti-
noyl-1,2,3,4-tetrahydropyrimidines). ARKIVOC xiii:131–141
Winter CA, Risley EA, Nuss GW (1962) Carrageenan-induced edema
in hind paw of rat as an assay for anti-inflammatory drugs. Proc
Soc Exp Biol Med 111:544–547
Dutta MC, Chanda K, Vishwakarma JN (2005) A facile one-pot
synthesis of tetrahydropyrimidines part 3: synthesis of [alka-
nediylbis(3-alkyl/aralkyl/aryl-3,6-dihydropyrimidine-1,5(2H)-
diyl)bis(arylmethanones) and [1,4-phenylenebis(3-phenyl-3,6-
dihydropyrimidine-1,5(2H)-diyl)]bis(phenylmethanone). J Hete-
rocycl Chem 42(1):121–123
El-Fattah OA, Abbas EMH, Mohamed NA, Abd-Elmoez SI (2010)
Synthesis and evaluation of some tetrahydropyrimidine deriva-
tives as antimicrobial. Aust J Basic Appl Sci 4(1):27–36
EL-Mahdy K, El-Kazak A, Abdel-Megid M, Seada M, Farouka O
(2013) Synthesis, characterization and biological evaluation of
some new thieno[2,3-d]Pyrimidine derivatives. J Adv Chem
5(1):581–591
Elumalai K, Ali MA, Elumalai M, Eluri K, Srinivasan S (2013) Novel
isoniazid cyclocondensed 1,2,3,4-tetrahydropyrimidine deriva-
tives for treating infectious disease: a synthesis and in vitro
biological evaluation. J Acute Dis 2(4):316–321
Gaffar S, Nikalje A, Riyaz S, Yogesh B, Harish L (2012) Design,
synthesis and evaluation of novel indolyl pyrimidine carbohy-
drazides as antifungal agents. Curr Pharma Res 2(3):612–619
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