Design, synthesis and antimycobacterial activity of some novel imidazo[1,2-c]pyrimidines

Article abstract of DOI:10.1016/j.ejmech.2009.04.002

Tuberculosis, due to its relentless nature, is now a major public health threat. The concomitant resurgence of TB with the MDR- or XDR-TB and HIV/AIDS pandemic has exposed the frailties of the current drug armatorium. Based on isosteric replacement and go

Full text of DOI:10.1016/j.ejmech.2009.04.002

European Journal of Medicinal Chemistry 44 (2009) 3837–3844
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis and antimycobacterial activity of some novel
imidazo[1,2-c]pyrimidines
,
b
Mahesh T. Chhabria a , Mitesh H. Jani
*
a Department of Pharmaceutical Chemistry, L. M. College of Pharmacy, Navrangpura, Ahmedabad 380 009, Gujarat, India
b K.B. Institute of Pharmaceutical Education and Research, Gh 6, Sector 23, Gandhinagar 382 023, Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Tuberculosis, due to its relentless nature, is now a major public health threat. The concomitant resur-
gence of TB with the MDR- or XDR-TB and HIV/AIDS pandemic has exposed the frailties of the current
drug armatorium. Based on isosteric replacement and good 3D structural similarity between PA-824,
a novel antimycobacterial agent undergoing clinical trials, and imidazo[1,2-c]pyrimidines, we have
designed novel imidazo[1,2-c]pyrimidines. The designed molecules were synthesized by nucleophilic
displacement of chloro group of various substituted 4-chloropyrimidines by ethanolamine followed by
cyclisation of these 4-(2-hydroxyethyl)aminopyrimidines to imidazo[1,2-c]pyrimidines in good yield. All
the compounds were screened for their antimycobacterial activity on Mycobacterium tuberculosis H37Rv
strain by 1% proportion method. Some of the synthesized compounds exhibited potent antimycobacterial
Received 20 January 2009
Received in revised form
29 March 2009
Accepted 2 April 2009
Available online 8 April 2009
Keywords:
Tuberculosis
Molecular modeling
Imidazo[1,2-c]pyrimidine
Antimycobacterial activity
activity with MIC values in the range of 2–20 mg/mL.
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
makes it a difficult therapeutic target [5–7]. In addition,
M. tuberculosis may be located in pulmonary cavities, empyema
pus, or solid caseous material, where penetration of antibiotics is
difficult or the pH is sufficiently low to inhibit the activity of most
antibiotics [8,9]. Although TB can be cured by an optimized
regimen comprising of various first line and second line drugs
[10,11], the emergence of MDR-TB and extremely drug resistant TB
(XDR-TB, first reported in November 2005 [12]) has created new
challenges to control and defeat the disease. The concomitant
resurgence of TB with the MDR- or XDR-TB and HIV/AIDS
pandemic has exposed the frailties of the current drug armato-
rium. All these suggest that there is an urgent need of new potent
therapeutic agents which can be effective against resistant strains
of mycobacteria.
PA-824, an imidazooxazine derivative [13] has generated
considerable excitement with its antitubercular potency and pres-
ently is undergoing clinical trials. It was thought of interest to
replace the oxazine ring of PA-824 with its bioisoster pyrimidine
ring (Fig. 1). Further, the 3D structural similarity between PA-824
and the designed imidazopyrimidines was checked by indirect type
of molecular modeling studies. Low r.m.s.d. (root mean square
distance) value suggested good 3D structural similarity between
the designed molecule and PA-824. This prompted us to synthesize
Tuberculosis (TB), caused by Mycobacterium tuberculosis, is
a disease rich in paradoxes. Currently, one third of the world
population is latently infected with TB bacteria [1]. Despite the
availability of the BCG vaccine and chemotherapy, TB still remains
a leading infectious disease globally, especially in Third World
countries. According to estimates of the World Health Organiza-
tion (WHO), TB is now the leading infectious cause of death
worldwide and there were an estimated 9.2 million new cases of
TB every year [1] (afflicting mostly the young and productive
adults). Because of relentless spread of TB throughout the world,
WHO took the unprecedented step of declaring TB a global
emergency in 1993 that has to be given prime importance [2]. The
problem has worsened primarily due to the growing human
immunodeficiency virus (HIV) epidemic and the emergence of
drug resistance [3,4]. There were an estimated 1.5 million deaths
from TB in HIV-negative people and 0.2 million among people
infected with HIV [1].
The approach to chemotherapy of TB is very different from that
for other bacterial infections. The organism has a long generation
time and a capacity for dormancy, when its low metabolic activity
a
series of ethyl 5-(un)substituted-7-(substituted amino)-2,3-
dihydroimidazo[1,2-c]pyrimidine-8-carboxylates and check its
antimycobacterial potential.
* Corresponding author. Tel.: þ91 79 26302746; fax: þ91 79 26304865.
E-mail address: mahesh.chhabria@rediffmail.com (M.T. Chhabria).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.04.002

3838
M.T. Chhabria, M.H. Jani / European Journal of Medicinal Chemistry 44 (2009) 3837–3844
vinyl amidines on reaction with dry hydrogen chloride gas get
O
N
NO2
cyclized to 4-chloropyrimidines (5, Scheme 2).
N
N
EtO
O
N
3. Results and discussion
N
HN
3.1. Molecular modeling
O
The 3D structural similarity between PA-824 and designed
series of imidazo[1,2-c]pyrimidines was checked by indirect type of
molecular modeling studies (Fig. 2). All the structures were
generated, energy minimized and superimposed using PC based
molecular modeling software ChemDraw Ultra (Version 11.0,
Cambridge Soft Corporation, USA). All geometries were fully opti-
mized by minimizing the energy with respect to geometrical vari-
F3CO
OCH3
PA-824
Compound 7i
Fig. 1. Structures of Compound 7i and PA-824.
ables without symmetry constraints, using
a 0.01 Kcal/mol
gradient. The r.m.s.d. observed was 0.202. The low r.m.s.d. value
suggested good 3D similarity between PA-824 and imida-
zo[1,2-c]pyrimidines which prompted us to synthesize some imi-
dazo[1,2-c]pyrimidine as novel potential antimycobacterial agents.
2. Chemistry
The most common method for synthesis of imidazo[1,2-c]pyr-
imidines is the condensation of 4-aminopyrimidine with -halo-
a
genated carbonyl compounds [14–28]. The 4-chloropyrimidines
can also be used for the preparation of imidazo[1,2-c]pyrimidine
[29–33]. Dihydroimidazo[1,2-c]pyrimidines have been prepared
3.2. Chemical synthesis
through the cyclization of the 4-
b-chloroethylaminopyrimidines
Various substituted 4-chloropyrimidines (5) were prepared
from vinyl amidines (4) using dry hydrogen chloride gas as catalyst
in 60–80% yield (Scheme 1). The 4-chloropyrimidines (5) were
refluxed with ethanolamine in ethanol for 30 min to 2 h to obtain
ethyl 4-(2-hydroxyethyl)amino-2-(un)substituted-6-(substituted
amino)pyrimidine-5-carboxylates (6), which on cyclization by
refluxing with phosphorous oxychloride in anhydrous toluene gave
fluorescent 2,3-dihydroimidazo[1,2-c]pyrimidines (7 and 8) in good
yield (Scheme 2, Table 1). All the synthesized compounds were
freely soluble in chloroform, dichloromethane, DMF, DMSO and
[29,34,35] and of 4- -diethoxyethylaminopyrimidines [18,36]
b-b
with phosphorus oxychloride.
Designed molecules were synthesized by nucleophilic displace-
ment of chloro group of 4-chloropyrimidines with ethanolamine
followed by cyclization in the presence of phosphorus oxychloride
(Scheme 1). The 4-chloropyrimidines (5) were synthesized by
cyclization of difficultly isolable vinyl amidine intermediate (4),
which was synthesized by condensation of substituted amidine (3)
with S,N-acetal (2) under controlled reaction conditions [37,38]. This
N
Cl
NHCH2CH2OH
N
EtOOC
EtOOC
EtOOC
N
(ii)
N
(i)
R1
R1
N
HN
R
R1
HN
R
N
N
HN
R
5
6
R =alkyl/aryl
7, R1 =H
8, R1 =Ph
Scheme 1. Synthesis of 2,3-dihydroimidazo[1,2-c]pyrimidines: (i) ethanolamine, EtOH, warm, 1/2–2 h; (ii) POCl3, C6H6, reflux, 6–8 h.
EtOOC
CN
N
EtOOC
CN
EtOOC
MeS
CN
NH
R1
NH2
R1
+ RNH2
+
H2N
HN
R
SMe
HN
R
SMe
1
2
3
4
R1 = H/Ph
R = alkyl/aryl
Dry HCl
Cl
EtOOC
N
HN
R
N
R1
5
Scheme 2. Synthesis of 4-chloropyrimidines.

M.T. Chhabria, M.H. Jani / European Journal of Medicinal Chemistry 44 (2009) 3837–3844
3839
be omitted [18,29–33]. However, no such increase of reactivity was
required in our reaction and the product could be isolated by
a smooth reaction. As C-5 position is occupied by carbethoxy group
the possible side reaction of alternative cyclization [21–23] could
also be eliminated. Moreover, as the hydroxyl group of amino-
ethanol is not sufficiently nucleophilic in nature to attack the car-
bethoxy group, the cyclization with the later cannot be expected
(Scheme 3). Thus, various 2,3-dihydroimidazo[1,2-c]pyrimidines
(7 and 8) were the only isolated products in the cyclocondensation
reaction with phosphorus oxychloride. The possible intermediate
10 was not isolated.
3.3. Antimycobacterial activity
In the present investigation, various 2,3-dihydroimidazo[1,2-
c]pyrimidines were evaluated for their antimycobacterial activity
against H37Rv strain of M. tuberculosis. The minimum inhibitory
concentration (MIC) was determined by the serial dilution tech-
nique on Lowenstein–Jensen (L–J) medium, added with Gruft
mycobacterial supplement [39]. Rifabutin and amikacin were used
as standards for antimycobacterial activity. Some of the compounds
exhibited remarkable activity against M. tuberculosis H37Rv strain
as indicated by their MIC values (Table 2). It was observed that the
compounds unsubstituted at C-5 have exhibited significant anti-
mycobacterial activity as compared to the other substitution.
Compounds 7c, 7d, 7g, 7i–k, 7o, 8h, 8j and 8m have shown potent
antimycobacterial activity after 21 days with MIC values in the
Fig. 2. 3D structure superimposition of compound 7i and PA-824.
methanol but insoluble in non-polar solvents like n-hexane. The
structures of the synthesized compounds were confirmed by IR,
MS, 1H NMR and elemental analysis.
It has been observed that the use of
better instead of -aminoalcohols in these reactions as the step
involving conversion of the -hydroxyalkylaminopyrimidine
b-halogenoalkylamines is
b
b
intermediate into corresponding cyclized b-chloro derivative can
range of 2–20
mg/mL. An interesting fact observed was that the
Table 1
compounds with para-substitution on the benzene ring at C-7 (7g,
7i, k, 7o, 8h, 8j and 8m) have shown potent activity after 21 days
(Table 2). However, compounds 7d and 7j were also found equally
active. Compounds 8d, 8f and 8i were failed to exhibit significant
effect on the mycobacteria.
Physical data of ethyl 5-(un)substituted-7-(substituted amino)-2,3-dihy-
droimidazo[1,2-c]pyrimidine-8-carboxylates.
N
EtO2C
N
Additionally, it was observed that in a group of compounds
without any substitution at C-5, substitution on the para-position
of the benzene ring at C-7 was influencing the antimycobacterial
activity significantly. The presence of electron-withdrawing
halogen atoms (7j–l and 7o) or methoxy group (7i) improved
potency. However, a methyl group (7g) was also equally permis-
sible at that position. Other substitutions on the benzene ring at C-7
decreased the antimycobacterial activity. Alkyl groups at C-7
remarkably reduce the potency of the test compounds.
R1
N
HN
R
Compound
R
R1
Mol. formula
M.P. (ꢁC)
Yielda (%)
7a
7b
7c
7d
7e
7f
7g
7h
7i
CH3
C2H5
C6H5CH2
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C10H14N4O2
C11H16N4O2
C16H18N4O2
C15H16N4O2
C16H18N4O2
C16H18N4O2
C16H18N4O2
C16H18N4O3
C16H18N4O3
C15H15FN4O2
C15H15FN4O2
C16H18F3N4O2
C15H15ClN4O2
C15H15ClN4O2
C15H15ClN4O2
C15H15BrN4O2
C16H18N4O2
C17H20N4O2
C22H22N4O2
C21H20N4O2
C22H22N4O2
C22H22N4O2
C22H22N4O3
C22H22N4O3
C21H19FN4O2
C21H19FN4O2
C21H19ClN4O2
C21H19ClN4O2
C21H19ClN4O2
C21H19BrN4O2
178–180
196–198
128–130
192–194
140–142
138–140
149–150
178–180
152–154
172–174
135–137
178–180
145–147
115–117
170–171
149–151
180–182
187–190
154–156
192–194
182–184
184–186
192–194
152–154
160–162
164–166
130–132
115–117
126–128
128–130
48
52
54
62
58
51
61
60
68
68
62
35
45
51
63
70
40
42
52
50
50
52
42
45
55
49
45
37
48
51
2-CH3–C6H4
3-CH3–C6H4
4-CH3–C6H4
2-CH3O–C6H4
4-CH3O–C6H4
2-F–C6H4
4-F–C6H4
3-CF3–C6H4
2-Cl–C6H4
3-Cl–C6H4
4-Cl–C6H4
4-Br–C6H4
CH3
The most potent compound 7i has exhibited MIC of 2 mg/mL
which is comparable to the MIC value of amikacin and less potent
than rifabutin. As per the reported MIC range of PA-824 (0.015–
0.25 mg/mL) [13], compound 7i has exhibited less potency.
7j
7k
7l
7m
7n
7o
7p
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
4. Conclusion
Synthesis and antimycobacterial activity of certain novel imi-
dazo[1,2-c]pyrimidines have been carried out. Some of the
synthesized compounds showed significant activity against
M. tuberculosis H37Rv strain. Compounds 7g, 7i, 7j, 7k, 7o, 8h and
8j have exhibited potent antimycobacterial activity as indicated by
C2H5
C6H5CH2
C6H5
2-CH3–C6H4
4-CH3–C6H4
2-CH3O–C6H4
4-CH3O–C6H4
2-F–C6H4
4-F–C6H4
2-Cl–C6H4
3-Cl–C6H4
4-Cl–C6H4
4-Br–C6H4
their low MIC values (ꢀ5
mg/mL). Thus the present investigation
suggests that the bioisosteric replacement of imidazooxazine ring
of PA-824 with fused imidazopyrimidine can result into promising
compounds with good antimycobacterial potential. In comparison
with the antibiotics commonly used in the therapy, test compounds
were found significantly potent, forcing us to explore the potential
of the projected series to be developed as promising candidates for
antimycobacterial therapy to treat various clinical conditions
associated with multiple infectious diseases and drug resistant TB.
8m
8n
a
All the compounds were recrystallized from dichloromethane–n-hexane.

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M.T. Chhabria, M.H. Jani / European Journal of Medicinal Chemistry 44 (2009) 3837–3844
OH
O
Cl
N
O
HN
NH
O
POCl3
NH2CH2CH2OH
EtO
N
N
EtO
N
O
R1
HN
R
R1
HN
R
N
HN
N
R1
R
5
6
9
POCl3
Cl
O
O
HN
N
N
EtO
N
EtO
N
HN
R
R1
HN
R
N
R1
7, 8
10
Scheme 3. Cyclization of 4-(2-hydroxyethyl)aminopyrimidines.
5. Experimental
Spectrophotometer (Vmax in cmꢃ1). 1H NMR spectra were recorded
in DMSO-d6/CDCl3 on a Bruker Evance 400 MHz Spectrophotom-
eter using TMS as internal standard. Chemical shift values are
5.1. General
reported in ppm downfield on
d scale. Mass spectra were recorded
Melting points were determined in open capillaries using
microprocessor based melting point apparatus, Model VMP-D
(Veego India Ltd., Mumbai, India) and are uncorrected. Purity of the
compounds synthesized was checked by thin layer chromatog-
raphy (TLC) performed on microscopic slides, 2 ꢂ 7.5 cm, coated
with silica gel G as stationary phase and the spots were visualized
by exposure to iodine vapors or in the UV light. IR spectra were
recorded using KBr on 8400S Shimadzu Fourier Transform
on Perkin–Elmer LC-MS PE Sciex API/65 Spectrophotometer. The
elemental analyses were done on Elementar Vario EL III Carlo Erba
1108 and were in well accordance with the structures assigned to
the compounds.
Synthetic grade chemicals procured from SD fine Chemicals,
Baroda, India, were used for the synthesis of the target compounds,
only after purification. All the starting materials were prepared
according to the literature procedures with some minor modifica-
tions. General synthetic procedures used for the preparation of the
target compounds 7a–p and 8a–n are as follows:
Table 2
Antimycobacterial activity of ethyl 5-(un)substituted-7-(substituted amino)-2,3-
dihydroimidazo[1,2-c]pyrimidine-8-carboxylates.
5.2. General method for synthesis of ethyl 4-(2-
hydroxyethyl)amino-2-(un)substituted-6-(substituted
amino)pyrimidine-5-carboxylate (6)
Compound
MIC (mg/mL)
14th Day
21st Day
30th Day
7a
7b
7c
>200
>200
20
>200
>200
20
>200
>200
100
A mixture of ethyl 4-chloro-2-(substituted amino)pyrimidine-5-
carboxylate [38] (0.01 mol) and ethanolamine (0.61 g, 0.01 mol)
was refluxed in ethanol (40 mL) for 30 min to 2 h. The completion
of reaction was monitored through TLC. After the completion of
reaction, the reaction content was poured into ice–water mixture
with constant stirring. The content was allowed to stand at 20 ꢁC
overnight and the solid crystals obtained were filtered, washed
with cold water, dried and recrystallized from ethanol–water
mixture (50:50).
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
8a
8b
8c
8d
8e
8f
8g
20
20
50
>200
>200
5
>200
2
>200
>200
5
>200
2
>200
>200
50
>200
20
50
20
>200
>200
>200
20
5
5
5
5
100
>200
>200
5
100
>200
>200
5
5.2.1. Ethyl 4-(2-hydroxyethyl)amino-6-phenylaminopyrimidine-5-
carboxylate (6d)
50
50
100
IR (KBr, cmꢃ1): 3367 (OH), 3226 (NH), 1680 (C]O); 1H NMR
>200
>200
>200
50
100
100
>200
5
>200
>200
>200
50
100
100
>200
5
>200
>200
>200
100
>200
>200
>200
50
(CDCl3,
d
ppm): 1.33–1.41 (t, 3H, OCH2CH3, J ¼ 7.04 Hz); 4.28–4.31
(t, 2H, NHCH2CH2, J ¼ 7.68 Hz); 4.65–4.67(t, 2H, NHCH2CH2,
J ¼ 7.68 Hz); 4.68–4.72 (q, 2H, OCH2CH3, J ¼ 14.12 Hz); 5.35–5.42 (b,
1H, NHCH2CH2); 7.20–7.36 (m, 5H, NHArH); 8.11–8.23 (t, 1H, OH,
J ¼ 5.24 Hz); 8.46 (s, 1H, NCHN); 11.38 (s, 1H, NHAr); MS: m/z 302
(Mþ), 303 (M þ 1); Anal. calcd for C15H18N4O3: C, 59.60; H, 5.96; N,
18.54; Found: C, 59.88; H, 6.12; N, 18.62.
8h
8i
8j
>200
5
>200
5
>200
20
8k
8l
8m
8n
Rifabutin
Amikacin
>200
>200
20
100
0.05
2
>200
>200
20
100
0.05
2
>200
>200
50
>200
0.05
2
5.2.2. Ethyl 4-(2-hydroxyethyl)amino-6-(4-
methylphenyl)aminopyrimidine-5-carboxylate (6g)
IR (KBr, cmꢃ1): 3375 (OH), 3234 (NH), 1674 (C]O); 1H NMR
(CDCl3/DMSO-d6,
d ppm): 1.29 (s, 3H, ArCH3); 1.32–1.41 (t, 3H,
OCH2CH3, J ¼ 7.04 Hz); 4.12–4.24 (t, 2H, NHCH2CH2, J ¼ 7.68 Hz);

M.T. Chhabria, M.H. Jani / European Journal of Medicinal Chemistry 44 (2009) 3837–3844
3841
4.42–4.55 (t, 2H, NHCH2CH2, J ¼ 7.68 Hz); 4.65–4.75 (q, 2H,
OCH2CH3, J ¼ 14.12 Hz); 5.66–5.79 (b,1H, NHCH2CH2); 6.89–7.17 (m,
4H, NHArH); 8.10–8.22 (t, 1H, OH, J ¼ 5.24 Hz); 8.31 (s, 1H, NCHN);
11.45 (s, 1H, NHAr); MS: m/z 316 (Mþ), 317 (M þ 1); Anal. calcd for
C16H20N4O3: C, 60.76; H, 6.33; N, 17.72; Found: C, 60.42; H, 6.41; N,
17.63.
(Mþ), 299 (M þ 1); Anal. calcd for C16H18N4O2: C, 64.41; H, 6.08; N,
18.78; Found: C, 64.31; H, 6.02; N, 18.34.
5.3.4. Ethyl 7-(phenylamino)-2,3-dihydroimidazo
[1,2-c]pyrimidine-8-carboxylate (7d)
IR (KBr, cmꢃ1): 3305 (NH), 1676 (C]O); 1H NMR (DMSO-d6/
CDCl3,
d
ppm): 1.47–1.51 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 4.28–
5.2.3. Ethyl 4-(2-hydroxyethyl)amino-6-(4-
4.31 (t, 2H, ]NCH2CH2N–, J ¼ 8.08 Hz); 4.65–4.67 (t, 2H,
]NCH2CH2N–, J ¼ 8.08 Hz); 4.68–4.72 (q, 2H, –CO2CH2CH3,
J ¼ 14.12 Hz); 7.20–7.36 (m, 5H, NHArH); 8.46 (s, 1H, NCHN); 11.38
(s, 1H, NHAr), MS: m/z 284 (Mþ), 285 (M þ 1); Anal. calcd for
C15H16N4O2: C, 63.37; H, 5.67; N, 19.71; Found: C, 63.78; H, 5.25; N,
19.55.
methoxyphenyl)aminopyrimidine-5-carboxylate (6i)
IR (KBr, cmꢃ1): 3377 (OH), 3226 (NH), 1672 (C]O); 1H NMR
(CDCl3/DMSO-d6,
d
ppm): 1.35–1.47 (t, 3H, OCH2CH3, J ¼ 7.04 Hz);
3.80 (s, 3H, ArOCH3); 4.28–4.35 (t, 2H, NHCH2CH2, J ¼ 7.68 Hz);
4.62–4.67 (t, 2H, NHCH2CH2, J ¼ 7.68 Hz); 4.71–4.78 (q, 2H,
OCH2CH3, J ¼ 14.12 Hz); 5.37–5.47 (b,1H, NHCH2CH2); 7.08–7.32 (m,
4H, NHArH); 8.15–8.28 (t, 1H, OH, J ¼ 5.24 Hz); 8.52 (s, 1H, NCHN);
11.45 (s, 1H, NHAr); MS: m/z 332 (Mþ), 333 (M þ 1); Anal. calcd for
C16H20N4O4: C, 57.83; H, 6.02; N, 16.87; Found: C, 58.02; H, 6.30; N,
17.03.
5.3.5. Ethyl 7-[(2-methylphenyl)amino]-2,3-dihydroimidazo
[1,2-c]pyrimidine-8-carboxylate (7e)
IR (KBr, cmꢃ1): 3307 (NH), 1641 (C]O); 1H NMR (DMSO-d6/
CDCl3,
d
ppm): 1.41–1.50 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 2.43 (s,
3H, ArCH3); 4.28–4.31 (t, 2H, ]NCH2CH2N–, J ¼ 8.08 Hz); 4.63–4.67
(t, 2H, ]NCH2CH2N–, J ¼ 8.08 Hz); 4.68–4.72 (q, 2H, –CO2CH2CH3,
J ¼ 14.12 Hz); 7.21–7.35 (m, 4H, NHArH); 8.49 (s, 1H, NCHN); 11.35
(s, 1H, NHAr), MS: m/z 298 (Mþ), 299 (M þ 1); Anal. calcd for
C16H18N4O2: C, 64.41; H, 6.08; N, 18.78; Found: C, 64.38; H, 5.89; N,
18.62.
5.3. General method for synthesis of ethyl 2-(un)substituted-7-
(substituted amino)-2,3-dihydoimidazo[1,2-c]pyrimidine-8-
carboxylate (7a–p and 8a–n)
To
a
solution of ethyl 4-(2-hydroxyethyl)amino-2-(un)
amino)pyrimidine-5-carboxylate
substituted-6-(substituted
(0.01 mol) in anhydrous toluene (40 mL), was added phosphorous
oxychloride (1.68 g, 0.01 mol) and the resultant reaction mixture
was refluxed for 6–8 h. The excess of solvent was removed under
reduced pressure to obtain sticky mass, which was poured into ice–
water mixture with constant stirring. It was allowed to stand for 6 h
at room temperature and neutralized with saturated solution of
sodium bicarbonate. The solid product obtained was washed with
cold water, dried and recrystallized from dichloromethane–n-
hexane.
5.3.6. Ethyl 7-[(3-methylphenyl)amino]-2,3-dihydroimidazo
[1,2-c]pyrimidine-8-carboxylate (7f)
IR (KBr, cmꢃ1): 3394 (NH), 1668 (C]O); 1H NMR (CDCl3,
d ppm):
1.48–1.52 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 3.81 (s, 3H, ArCH3);
4.27–4.32 (t, 2H, ]NCH2CH2N–, J ¼ 9.08 Hz); 4.49–4.54 (t, 2H,
]NCH2CH2N–, J ¼ 9.08 Hz); 4.65–4.71 (q, 2H, –CO2CH2CH3,
J ¼ 14.12 Hz); 7.41–7.71 (m, 4H, NHArH); 10.01 (s, 1H, NCHN); 11.49
(s, 1H, NHAr), MS: m/z 298 (Mþ), 299 (M þ 1); Anal. calcd for
C16H18N4O2: C, 64.41; H, 6.08; N, 18.78; Found: C, 63.99; H, 5.72; N,
18.35.
5.3.1. Ethyl 7-(methylamino)-2,3-dihydroimidazo
[1,2-c]pyrimidine-8-carboxylate (7a)
5.3.7. Ethyl 7-[(4-methylphenyl)amino]-2,3-dihydroimidazo
[1,2-c]pyrimidine-8-carboxylate (7g)
IR (KBr, cmꢃ1): 3375 (NH), 1676 (C]O); 1H NMR (DMSO-d6/
CDCl3,
d
ppm): 1.30–1.34 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 2.23–
IR (KBr, cmꢃ1): 3300 (NH), 1680 (C]O); 1H NMR (DMSO-d6/
2.27 (d, 3H, NHCH3, J ¼ 6.25 Hz); 3.49–3.59 (b, 1H, NHCH3); 3.90–
3.95 (t, 2H, ]NCH2CH2N–, J ¼ 7.68 Hz); 4.06–4.11 (t, 2H,
]NCH2CH2N–, J ¼ 7.68 Hz); 4.34–4.40 (q, 2H, –CO2CH2CH3,
J ¼ 14.68 Hz); 7.87 (s, 1H, NCHN), MS: m/z 222 (Mþ), 223 (M þ 1);
Anal. calcd for C10H14N4O2: C, 54.04; H, 6.35; N, 25.21; Found: C,
53.73; H, 6.49; N, 25.07.
CDCl3,
d
ppm): 1.47–1.51 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 2.37
(s, 3H, ArCH3); 4.28–4.31 (t, 2H, ]NCH2CH2N–, J ¼ 8.08 Hz); 4.65–
4.67 (t, 2H, ]NCH2CH2N–, J ¼ 8.08 Hz); 4.68–4.72 (q, 2H,
–CO2CH2CH3, J ¼ 14.12 Hz); 7.20–7.36 (m, 4H, NHArH); 8.46 (s, 1H,
NCHN); 11.38 (s, 1H, NHAr), MS: m/z 298 (Mþ), 299 (M þ 1); Anal.
calcd for C16H18N4O2: C, 64.41; H, 6.08; N, 18.78; Found: C, 64.18; H,
5.76; N, 18.70.
5.3.2. Ethyl 7-(ethylamino)-2,3-dihydroimidazo[1,2-c]pyrimidine-
8-carboxylate (7b)
5.3.8. Ethyl 7-[(2-methoxyphenyl)amino]-2,3-dihydroimidazo
[1,2-c]pyrimidine-8-carboxylate (7h)
IR (KBr, cmꢃ1): 3360 (NH), 1680 (C]O); 1H NMR (DMSO-d6/
CDCl3,
d
ppm): 1.21–1.26 (t, 3H, NHCH2CH3, J ¼ 7.06 Hz); 1.32–1.40
IR (KBr, cmꢃ1): 3300 (NH), 1680 (C]O); 1H NMR (DMSO-d6,
(t, 3H, –CO2CH2CH3, J ¼ 7.68 Hz); 2.23–2.37 (m, 2H, NHCH2CH3);
3.49–3.59 (b, 1H, NHC2H5); 3.90–3.95 (t, 2H, ]NCH2CH2N–,
J ¼ 7.68 Hz); 4.06–4.11 (t, 2H, ]NCH2CH2N–, J ¼ 7.68 Hz); 4.34–4.40
(q, 2H, –CO2CH2CH3, J ¼ 14.68 Hz); 7.87 (s, 1H, NCHN), MS: m/z 236
(Mþ), 237 (M þ 1); Anal. calcd for C11H16N4O2: C, 55.92; H, 6.83; N,
23.71; Found: C, 55.78; H, 6.98; N, 23.75.
d
ppm): 1.35–1.41 (t, 3H, OCH2CH3, J ¼ 7.04 Hz); 2.13 (s, 3H,
ArOCH3); 3.92–3.98 (t, 2H, ]NCH2CH2N–, J ¼ 8.08 Hz); 4.04–4.12
(t, 2H, ]NCH2CH2N–, J ¼ 8.08 Hz); 4.41–4.47 (q, 2H, OCH2CH3,
J ¼ 14.12 Hz); 7.12–7.29 (m, 4H, NHArH); 7.72(s, 1H, NCHN); 11.35–
11.42 (s, 1H, NHAr); MS: m/z 314 (Mþ), 315 (M þ 1); Anal. calcd for
C16H18N4O3: C, 61.13; H, 5.77; N, 17.82; Found: C, 61.55; H, 5.38; N,
17.81.
5.3.3. Ethyl 7-(benzylamino)-2,3-dihydroimidazo
[1,2-c]pyrimidine-8-carboxylate (7c)
5.3.9. Ethyl 7-[(4-methoxyphenyl)amino]-2,3-dihydroimidazo
[1,2-c]pyrimidine-8-carboxylate (7i)
IR (KBr, cmꢃ1): 3361 (NH), 1680 (C]O); 1H NMR (DMSO-d6/
CDCl3,
d
ppm): 1.36–1.40 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 3.90–
IR (KBr, cmꢃ1): 3336 (NH), 1645 (C]O); 1H NMR (DMSO-d6/
3.95 (t, 2H, ]NCH2CH2N–, J ¼ 9.08 Hz); 4.06–4.11 (t, 2H,
]NCH2CH2N–, J ¼ 9.08 Hz); 4.34–4.40 (q, 2H, –CO2CH2CH3,
J ¼ 14.16 Hz); 4.73–4.75 (d, 2H, NHCH2Ar); 7.24–7.35 (m, 5H,
CH2ArH); 7.73 (s, 1H, NCHN); 10.09 (b, 1H, NHCH2Ar), MS: m/z 298
CDCl3,
d
ppm): 1.41–1.47 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 3.82
(s, 3H, ArOCH3); 3.92–3.98 (t, 2H, ]NCH2CH2N–, J ¼ 8.08 Hz); 4.08–
4.12 (t, 2H, ]NCH2CH2N–, J ¼ 8.08 Hz); 4.40–4.45 (q, 2H,
–CO2CH2CH3, J ¼ 14.12 Hz); 7.27–7.32 (m, 4H, NHArH); 7.73 (s, 1H,

3842
M.T. Chhabria, M.H. Jani / European Journal of Medicinal Chemistry 44 (2009) 3837–3844
NCHN); 11.35–11.42 (s, 1H, NHAr), MS: m/z 314 (Mþ), 315 (M þ 1);
Anal. calcd for C16H18N4O3: C, 61.13; H, 5.77; N, 17.82; Found: C,
60.82; H, 5.81; N, 17.59.
(s, 1H, NHAr), MS: m/z 363 (Mþ), 365 (M þ 2); Anal. calcd for
C15H15BrN4O2: C, 49.60; H, 4.16; N, 15.43. Found: C, 49.36; H, 3.78;
N, 14.98.
5.3.10. Ethyl 7-[(4-fluorophenyl)amino]-2,3-dihydroimidazo[1,2-
c]pyrimidine-8-carboxylate (7k)
5.3.16. Ethyl 7-(methylamino)-5-phenyl-2,3-dihydroimidazo[1,2-
c]pyrimidine-8-carboxylate (8a)
IR (KBr, cmꢃ1): 3292 (NH), 1678 (C]O); 1H NMR (DMSO-d6/
IR (KBr, cmꢃ1): 3228 (NH), 1672 (C]O); 1H NMR (DMSO-d6/
CDCl3,
d
ppm): 1.29–1.37 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 3.85–
CDCl3,
d
ppm): 1.23–1.28 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 1.49–
3.92 (t, 2H, ]NCH2CH2N–, J ¼ 8.08 Hz); 3.99–4.10 (t, 2H,
]NCH2CH2N–, J ¼ 8.08 Hz); 4.35–4.47 (q, 2H, –CO2CH2CH3,
J ¼ 14.12 Hz); 7.59–7.76 (m, 4H, NHArH); 8.21 (s, 1H, NCHN); 11.21(s,
1H, NHAr), MS: m/z 302 (Mþ), 303 (M þ 1); Anal. calcd for
C15H15FN4O2: C, 59.60; H, 5.00; N,18.53; Found: C, 59.67; H, 5.01; N,
18.45.
1.54 (d, 3H, NHCH3); 3.40–3.48 (b, 1H, NHCH3); 3.51–3.55 (q, 2H,
–CO2CH2CH3, J ¼ 14.08 Hz); 3.97–4.02 (t, 2H, ]NCH2CH2N–,
J ¼ 7.68 Hz); 4.22–4.29 (t, 2H, ]NCH2CH2N–, J ¼ 7.68 Hz); 7.40–7.48
(m, 5H, ArH), MS: m/z 298 (Mþ), 299 (M þ 1); Anal. calcd for
C16H18N4O2: C, 64.41; H, 6.08; N, 18.78; Found: C, 64.22; H, 6.02; N,
18.51.
5.3.11. Ethyl 7-[(3-trifluoromethylphenyl)amino]-2,3-
dihydroimidazo[1,2-c]pyrimidine-8-carboxylate (7l)
IR (KBr, cmꢃ1): 3361 (NH), 1689 (C]O); 1H NMR (DMSO-d6/
5.3.17. Ethyl 7-(ethylamino)-5-phenyl-2,3-dihydroimidazo[1,2-
c]pyrimidine-8-carboxylate (8b)
IR (KBr, cmꢃ1): 3340 (NH), 1695 (C]O); 1H NMR (CDCl3/DMSO-
CDCl3,
d
ppm): 1.41–1.47 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 3.92–
d6,
d
): 1.11–1.15 (t, 3H, NHCH2CH3, J ¼ 7.06 Hz); 1.29–1.31 (t, 3H,
4.01 (t, 2H, ]NCH2CH2N–, J ¼ 8.08 Hz); 4.08–4.15 (t, 2H,
]NCH2CH2N–, J ¼ 8.08 Hz); 4.45–4.52 (q, 2H, –CO2CH2CH3,
J ¼ 14.12 Hz); 6.92–7.08 (m, 4H, ArH); 8.47 (s, 1H, NCHN); 11.68 (s,
1H, NHAr), MS: m/z 352 (Mþ); Anal. calcd for C16H15F3N4O2: C,
54.55; H, 4.29; N, 15.90; Found: C, 54.11; H, 3.99; N, 15.52.
OCH2CH3, J ¼ 7.04 Hz); 3.21–3.26 (m, 2H, NHCH2CH3); 3.31–3.36 (b,
1H, NHC2H5); 3.97–4.02 (t, 2H, ]NCH2CH2N–, J ¼ 7.68 Hz); 4.22–
4.29 (t, 2H, ]NCH2CH2N–, J ¼ 7.68 Hz); 4.51–4.55 (q, 2H, OCH2CH3,
J ¼ 14.08 Hz); 7.49–7.59 (m, 5H, ArH); MS: m/z 312 (Mþ), 313
(M þ 1); Anal. calcd for C17H20N4O2: C, 65.37; H, 6.45; N, 17.94;
Found: C, 65.04; H, 6.25; N, 17.83.
5.3.12. Ethyl 7-[(2-chlorophenyl)amino]-2,3-dihydroimidazo[1,2-
c]pyrimidine-8-carboxylate (7m)
5.3.18. Ethyl 7-(benzylamino)-5-phenyl-2,3-dihydroimidazo[1,2-
c]pyrimidine-8-carboxylate (8c)
IR (KBr, cmꢃ1): 3394 (NH), 1668 (C]O); 1H NMR (DMSO-d6/
CDCl3,
d
ppm): 1.21–1.34 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 3.67–
IR (KBr, cmꢃ1): 3240 (NH), 1680 (C]O); 1H NMR (DMSO-d6/
3.85 (t, 2H, ]NCH2CH2N–, J ¼ 8.08 Hz); 3.93–4.00 (t, 2H,
]NCH2CH2N–, J ¼ 8.08 Hz); 4.26–4.32 (q, 2H, –CO2CH2CH3,
J ¼ 14.12 Hz); 7.39–7.51 (m, 4H, NHArH); 8.13 (s, 1H, NCHN); 11.19 (s,
1H, NHAr), MS: m/z 318 (Mþ), 320 (M þ 2); Anal. calcd for
C15H15ClN4O2: C, 56.52; H, 4.74; N, 17.58; Found: C, 56.24; H, 4.51;
N, 17.50.
CDCl3,
d
ppm): 1.19–1.22 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 3.22–
3.29 (b, 1H, NHCH2Ar); 4.17–4.22 (t, 2H, ]NCH2CH2N–,
J ¼ 7.68 Hz); 4.55–4.60 (t, 2H, ]NCH2CH2N–, J ¼ 7.68 Hz); 4.63–
4.68 (q, 2H, –CO2CH2CH3, J ¼ 14.08 Hz); 4.72–4.77 (d, 2H,
NHCH2Ar, J ¼ 6.24 Hz); 7.23–7.41 (m, 5H, CH2ArH); 7.56–7.79 (m,
5H, ArH), MS: m/z 374 (Mþ), 375 (M þ 1); Anal. calcd for
C22H22N4O2: C, 70.57; H, 5.92; N, 14.96; Found: C, 70.27; H, 5.63;
N, 15.23.
5.3.13. Ethyl 7-[(3-chlorophenyl)amino]-2,3-dihydroimidazo[1,2-
c]pyrimidine-8-carboxylate (7n)
IR (KBr, cmꢃ1): 3365 (NH), 1676 (C]O); 1H NMR (DMSO-d6/
5.3.19. Ethyl 7-(phenylamino)-5-phenyl-2,3-dihydroimidazo[1,2-
c]pyrimidine-8-carboxylate (8d)
CDCl3,
d
ppm): 1.28–1.39 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 3.62–
3.80 (t, 2H, ]NCH2CH2N–, J ¼ 8.08 Hz); 3.95–4.08 (t, 2H,
]NCH2CH2N–, J ¼ 8.08 Hz); 4.31–4.45 (q, 2H, –CO2CH2CH3,
J ¼ 14.12 Hz); 7.31–7.52 (m, 4H, NHArH); 8.25 (s, 1H, NCHN); 11.20
(s, 1H, NHAr), MS: m/z 318 (Mþ), 320 (M þ 2); Anal. calcd for
C15H15ClN4O2: C, 56.52; H, 4.74; N, 17.58; Found: C, 56.24; H, 4.42;
N, 17.19.
IR (KBr, cmꢃ1): 3215 (NH), 1677 (C]O); 1H NMR (DMSO-d6/
CDCl3,
d
ppm): 1.49–1.52 (t, 3H, –CO2CH2CH3, J ¼ 7.06 Hz); 4.17–
4.22 (t, 2H, ]NCH2CH2N–, J ¼ 9.68 Hz); 4.58–4.62 (t, 2H,
]NCH2CH2N–, J ¼ 9.68 Hz); 4.63–4.68 (q, 2H, –CO2CH2CH3,
J ¼ 14.08 Hz); 7.23–7.41 (m, 5H, ArH); 7.55–7.79 (m, 5H, NHArH);
11.42(s, 1H, NHAr), MS: m/z 360 (Mþ), 361 (M þ 1); Anal. calcd for
C21H20N4O2: C, 69.98; H, 5.59; N, 15.55; Found: C, 69.71; H, 5.48; N,
15.82.
5.3.14. Ethyl 7-[(4-chlorophenyl)amino]-2,3-dihydroimidazo[1,2-
c]pyrimidine-8-carboxylate (7o)
IR (KBr, cmꢃ1): 3304 (NH), 1653 (C]O); 1H NMR (DMSO-d6/
5.3.20. Ethyl 7-[(2-methylphenyl)amino]-5-phenyl-2,3-
dihydroimidazo[1,2-c]pyrimidine-8-carboxylate (8e)
CDCl3,
d
ppm): 1.20–1.31 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 3.67–
3.85 (t, 2H, ]NCH2CH2N–, J ¼ 8.08 Hz); 3.92–4.01 (t, 2H,
]NCH2CH2N–, J ¼ 8.08 Hz); 4.35–4.47 (q, 2H, –CO2CH2CH3,
J ¼ 14.12 Hz); 7.35–7.50 (m, 4H, NHArH); 8.15 (s, 1H, NCHN); 11.25
(s, 1H, NHAr), MS: m/z 318 (Mþ), 320 (M þ 2); Anal. calcd for
C15H15ClN4O2: C, 56.52; H, 4.74; N, 17.58; Found: C, 56.61; H, 4.59;
N, 17.24.
IR (KBr, cmꢃ1): 3302 (NH), 1676 (C]O); 1H NMR (DMSO-d6/
CDCl3,
d
ppm): 1.42–1.46 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 1.88 (s,
3H, ArCH3); 3.95–3.99 (t, 2H, ]NCH2CH2N–, J ¼ 10.80 Hz); 4.05–
4.08 (t, 2H, ]NCH2CH2N–, J ¼ 10.80 Hz); 4.45–4.51 (q, 2H,
–CO2CH2CH3, J ¼ 14.24 Hz); 6.86–7.01 (m, 4H, NHArH); 7.49–7.67
(m, 5H, Ar–H); 11.81 (s, 1H, NHAr), MS: m/z 374 (Mþ), 375 (M þ 1);
Anal. calcd for C22H22N4O2: C, 70.57; H, 5.92; N, 14.96; Found: C,
70.35; H, 5.57; N, 14.73.
5.3.15. Ethyl 7-[(4-bromophenyl)amino]-2,3-dihydroimidazo[1,2-
c]pyrimidine-8-carboxylate (7p)
IR (KBr, cmꢃ1): 3400 (NH), 1680 (C]O); 1H NMR (DMSO-d6/
5.3.21. Ethyl 7-[(4-methylphenyl)amino]-5-phenyl-2,3-
dihydroimidazo[1,2-c]pyrimidine-8-carboxylate (8f)
CDCl3,
d
ppm): 1.21–1.34 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 3.77–
3.84 (t, 2H, ]NCH2CH2N–, J ¼ 8.08 Hz); 3.93–4.00 (t, 2H,
]NCH2CH2N–, J ¼ 8.08 Hz); 4.16–4.27 (q, 2H, –CO2CH2CH3,
J ¼ 14.12 Hz); 7.39–7.51 (m, 4H, NHArH); 8.09 (s, 1H, NCHN); 11.17
IR (KBr, cmꢃ1): 3334 (NH), 1645 (C]O); 1H NMR (DMSO-d6/
CDCl3,
d
ppm): 1.50–1.54 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 2.35 (s, 3H,
ArCH3); 4.28–4.33 (t, 2H, ]NCH2CH2N–, J ¼ 10.56 Hz); 4.53–4.58

M.T. Chhabria, M.H. Jani / European Journal of Medicinal Chemistry 44 (2009) 3837–3844
3843
(t, 2H, ]NCH2CH2N–, J ¼ 10.56 Hz); 4.70–4.75 (q, 2H, –CO2CH2CH3,
J ¼ 14.12 Hz); 7.16–7.43 (m, 4H, NHArH); 7.55–7.75 (m, 5H, ArH);
11.50 (s, 1H, NHAr), MS: m/z 374 (Mþ), 375 (M þ 1); Anal. calcd
for C22H22N4O2: C, 70.57; H, 5.92; N, 14.96; Found: C, 70.55; H, 5.97;
N, 14.75.
]NCH2CH2N–, J ¼ 8.88 Hz); 4.62–4.70 (q, 2H, –CO2CH2CH3,
J ¼ 14.24 Hz); 7.21–7.45 (m, 5H, ArH); 7.55–7.71 (m, 4H, NHArH);
11.52 (s, 1H, NHAr), MS: m/z 395 (Mþ), 397 (M þ 2), 396 (M þ 1);
Anal. calcd for C21H19ClN4O2: C, 63.88; H, 4.85; N, 14.19; Found: C,
63.58; H, 4.56; N, 14.01.
5.3.22. Ethyl 7-[(2-methoxyphenyl)amino]-5-phenyl-2,3-
dihydroimidazo[1,2-c]pyrimidine-8-carboxylate (8g)
5.3.28. Ethyl 7-[(4-chlorophenyl)amino]-5-phenyl-2,3-
dihydroimidazo[1,2-c]pyrimidine-8-carboxylate (8m)
IR (KBr, cmꢃ1): 3361 (NH), 1670 (C]O); 1H NMR (DMSO-d6/
IR (KBr, cmꢃ1): 3352 (NH), 1668 (C]O); 1H NMR (CDCl3/DMSO-
d6,
d
ppm): 1.48–1.52 (t, 3H, OCH2CH3, J ¼ 7.04 Hz); 3.80 (s, 3H,
CDCl3,
d
ppm): 1.49–1.52 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 4.17–
ArOCH3); 4.27–4.32 (t, 2H, ]NCH2CH2N–, J ¼ 10.56 Hz); 4.49–4.54
(t, 2H, ]NCH2CH2N–, J ¼ 10.56 Hz); 4.65–4.71 (q, 2H, OCH2CH3,
J ¼ 14.12 Hz); 7.41–7.44 (m, 4H, NHArH); 7.54–7.72 (m, 5H, ArH);
11.42 (s, 1H, NHAr); MS: m/z 390 (Mþ), 391 (M þ 1); Anal. calcd for
C22H22N4O3: C, 67.68; H, 5.68; N, 14.35; Found: C, 67.65; H, 5.52; N,
13.98.
4.22 (t, 2H, ]NCH2CH2N–, J ¼ 8.88 Hz); 4.55–4.59 (t, 2H,
]NCH2CH2N–, J ¼ 8.88 Hz); 4.62–4.69 (q, 2H, –CO2CH2CH3,
J ¼ 14.24 Hz); 7.23–7.41 (m, 5H, ArH); 7.51–7.69 (m, 4H, NHArH);
11.51 (s, 1H, NHAr), MS: m/z 395 (Mþ), 397 (M þ 2), 396 (M þ 1);
Anal. calcd for C21H19ClN4O2: C, 63.88; H, 4.85; N, 14.19; Found: C,
63.95; H, 4.89; N, 14.22.
5.3.23. Ethyl 7-[(4-methoxyphenyl)amino]-5-phenyl-2,3-
dihydroimidazo[1,2-c]pyrimidine-8-carboxylate (8h)
5.3.29. Ethyl 7-[(4-bromophenyl)amino]-5-phenyl-2,3-
dihydroimidazo[1,2-c]pyrimidine-8-carboxylate (8n)
IR (KBr, cmꢃ1): 3315 (NH), 1676 (C]O); 1H NMR (CDCl3/DMSO-
IR (KBr, cmꢃ1): 3380 (NH), 1666 (C]O); 1H NMR (DMSO-d6/
d6,
d
ppm): 1.45–1.52 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 3.08 (s, 3H,
CDCl3,
d
ppm): 1.39–1.42 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 4.28–
ArOCH3); 3.97–4.02 (t, 2H, ]NCH2CH2N–, J ¼ 10.56 Hz); 4.39–4.45
(t, 2H, ]NCH2CH2N–, J ¼ 10.56 Hz); 4.61–4.67 (q, 2H, –CO2CH2CH3,
J ¼ 14.12 Hz); 7.35–7.49 (m, 4H, NHArH); 7.55v7.67 (m, 5H, ArH);
11.55 (s, 1H, NHAr), MS: m/z 390 (Mþ), 391 (M þ 1); Anal. calcd for
C22H22N4O3: C, 67.68; H, 5.68; N, 14.35; Found: C, 67.39; H, 5.25; N,
14.21.
4.31 (t, 2H, ]NCH2CH2N–, J ¼ 8.88 Hz); 4.58–4.62 (t, 2H,
]NCH2CH2N–, J ¼ 8.88 Hz); 4.68–4.72 (q, 2H, –CO2CH2CH3,
J ¼ 14.24 Hz); 7.35–7.48 (m, 5H, ArH); 7.55–7.79 (m, 4H, NHArH);
11.45 (s, 1H, NHAr), MS: m/z 439 (Mþ), 441 (M þ 2), 440 (M þ 1);
Anal. calcd for C21H19BrN4O2: C, 57.41; H, 4.36; N, 12.75; Found: C,
57.49; H, 4.41; N, 12.86.
5.3.24. Ethyl 7-[(2-fluorophenyl)amino]-5-phenyl-2,3-
dihydroimidazo[1,2-c]pyrimidine-8-carboxylate (8i)
5.4. Antimycobacterial activity
IR (KBr, cmꢃ1): 3226 (NH), 1647 (C]O); 1H NMR (DMSO-d6/
CDCl3,
d
ppm): 1.42–1.46 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 3.94–
All the test compounds were evaluated against M. tuberculosis
H37Rv strain. The sensitivity testing for M. tuberculosis H37Rv
strain was performed by 1% proportion method [39]. The MIC
values were determined by the serial dilution technique using L–J
medium, added with Gruft mycobacterial supplement. M. tuber-
culosis H37Rv strain was obtained from New Delhi TB Centre, New
Delhi and was maintained on L–J medium at 37 ꢁC. All experiments
were performed in triplicate. The MIC values were obtained from
the lowest concentration where the tubes remained clear indi-
cating complete inhibition of the bacterial growth at that concen-
tration. The MIC values for antimycobacterial activity are presented
in Table 2.
The inoculum was prepared from master culture by transferring
several spadesful of growth to a sterilized screw cap bottle con-
taining 6–8 glass beads and 3 mL of Tween-albumin liquid medium
(Middlebrook 7H9) and the content of the bottle was homogenized.
Large particles were allowed to settle and the supernatant
suspension was withdrawn. The suspension was adjusted to 3 ꢂ108
CFU using McFarland turbidity standard (incubation at 37 ꢁC for 7
days) and the number of CFU per mL of the final inoculum was
confirmed by plating serial dilutions on L–J medium. The
compounds were dissolved in DMSO to prepare a solution of 3 mg/
mL so that when 1 mL of this stock solution is diluted to 15 mL,
4.00 (t, 2H, ]NCH2CH2N–, J ¼ 8.88 Hz); 4.06–4.11 (t, 2H,
]NCH2CH2N–, J ¼ 8.88 Hz); 4.45–4.51 (q, 2H, –CO2CH2CH3,
J ¼ 14.24 Hz); 7.01–7.10 (m, 5H, ArH); 7.47–7.66 (m, 3H, NHArH);
11.68 (s, 1H, NHAr), MS: m/z 378 (Mþ), 379 (M þ 1); Anal. calcd for
C21H19FN4O2: C, 66.66; H, 5.06; N,14.81; Found: C, 66.62; H, 4.86; N,
14.54.
5.3.25. Ethyl 7-[(4-fluorophenyl)amino]-5-phenyl-2,3-
dihydroimidazo[1,2-c]pyrimidine-8-carboxylate (8j)
IR (KBr, cmꢃ1): 3348 (NH), 1658 (C]O); 1H NMR (CDCl3/DMSO-
d6,
d
ppm): 1.41–1.50 (t, 3H, OCH2CH3, J ¼ 7.04 Hz); 4.01–4.11 (t, 2H,
]NCH2CH2N–, J ¼ 8.88 Hz); 4.15–4.22 (t, 2H, ]NCH2CH2N–,
J ¼ 8.88 Hz); 4.42–4.52 (q, 2H, OCH2CH3, J ¼ 14.24 Hz); 7.21–7.41
(m, 5H, ArH); 7.48–7.55 (m, 4H, NHArH); 11.72 (s,1H, NHAr); MS: m/
z 378 (Mþ), 379 (M þ 1); Anal. calcd for C21H19FN4O2: C, 66.66; H,
5.06; N, 14.81; Found: C, 66.75; H, 5.14; N, 14.88.
5.3.26. Ethyl 7-[(2-chlorophenyl)amino]-5-phenyl-2,3-
dihydroimidazo[1,2-c]pyrimidine-8-carboxylate (8k)
IR (KBr, cmꢃ1): 3375 (NH), 1678 (C]O); 1H NMR (CDCl3/DMSO-
d6,
d
ppm): 1.32–1.37 (t, 3H, OCH2CH3, J ¼ 7.04 Hz); 4.17–4.22 (t, 2H,
]NCH2CH2N–, J ¼ 8.88 Hz); 4.58–4.62 (t, 2H, ]NCH2CH2N–,
J ¼ 8.88 Hz); 4.63–4.68 (q, 2H, OCH2CH3, J ¼ 14.24 Hz); 7.23–7.41
(m, 5H, ArH); 7.55–7.79 (m, 4H, NHArH); 11.37 (s, 1H, NHAr); MS:
m/z 395 (Mþ), 397 (M þ 2), 396 (M þ 1); Anal. calcd for
C21H19ClN4O2: C, 63.88; H, 4.85; N, 14.19; Found: C, 63.97; H, 4.82;
N, 13.83.
a final concentration of 200
obtained. From this, a series of consecutive double fold dilutions
(100, 50, 20,10, 5, 2 g/mL) was prepared for all the compounds and
mg/mL in the culture medium is
m
tested against M. tuberculosis H37Rv strain. M. tuberculosis H37Rv
culture inoculum (0.1 mL), as prepared above was added in L–J
medium slants (15 mL) previously containing a specified concen-
tration of the test compounds. Rifabutin and amikacin were used as
standard drugs. The inoculated L–J medium slants were incubated
at 37 ꢁC for 30 days and results were observed at 14th, 21st and
30th day for the growth of mycobacteria. MIC values were deter-
mined for H37Rv strain of M. tuberculosis as described above.
5.3.27. Ethyl 7-[(3-chlorophenyl)amino]-5-phenyl-2,3-
dihydroimidazo[1,2-c]pyrimidine-8-carboxylate (8l)
IR (KBr, cmꢃ1): 3274 (NH), 1660 (C]O); 1H NMR (DMSO-d6/
CDCl3,
d
ppm): 1.41–1.52 (t, 3H, –CO2CH2CH3, J ¼ 7.04 Hz); 4.11–
4.23 (t, 2H, ]NCH2CH2N–, J ¼ 8.88 Hz); 4.45–4.51 (t, 2H,

3844
M.T. Chhabria, M.H. Jani / European Journal of Medicinal Chemistry 44 (2009) 3837–3844
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