Synthesis, in vitro antibacterial and antifungal evaluations of 2-amino-4-(1-naphthyl)-6-arylpyrimidines

Article abstract of DOI:10.1016/j.ejmech.2006.09.012

A series of 2-amino-4-(1-naphthyl)-6-arylpyrimidines have been synthesized and characterized by IR, NMR, MS, elemental analyses and evaluated for in vitro antibacterial and antifungal activities. Some of the compounds were found to be active against a limited panel of bacteria and fungi. In particular, compounds 4b and 4e were found to be the most effective analogs against the tested bacterial and fungal strains.

Full text of DOI:10.1016/j.ejmech.2006.09.012

European Journal of Medicinal Chemistry 42 (2007) 517e520
http://www.elsevier.com/locate/ejmech
Short communication
Synthesis, in vitro antibacterial and antifungal evaluations of
2-amino-4-(1-naphthyl)-6-arylpyrimidines
*
N. Ingarsal, G. Saravanan, P. Amutha, S. Nagarajan
Department of Chemistry, Annamalai University, Annamalainagar, Chidambaram, Tamil Nadu 608 002, India
Received 19 March 2006; received in revised form 22 September 2006; accepted 22 September 2006
Available online 3 November 2006
Abstract
A series of 2-amino-4-(1-naphthyl)-6-arylpyrimidines have been synthesized and characterized by IR, NMR, MS, elemental analyses and
evaluated for in vitro antibacterial and antifungal activities. Some of the compounds were found to be active against a limited panel of bacteria
and fungi. In particular, compounds 4b and 4e were found to be the most effective analogs against the tested bacterial and fungal strains.
Ó 2006 Elsevier Masson SAS. All rights reserved.
Keywords: 2-Aminopyrimidines; Synthesis; Antibacterial activity; Antifungal activity
1. Introduction
chloride in CCl4. The ClaiseneSchmidt condensation of equi-
molar quantities of 1-(1-naphthyl)ethanone with different
substituted benzaldehydes in the presence of alkali gives
1-(1-naphthyl)-3-arylprop-2-en-1-one 3. When 1-(1-naphthyl)-
3-arylprop-2-en-1-ones are refluxed with guanidine nitrate in
presence of alkali, 2-aminopyrimidines 4aei are formed
(Scheme 1).
Pyrimidine is the basic nucleus in nucleic acids and has
been associated with a number of biological activities [1].
Pyrimidines are well known to have a number of biological
and antimicrobial activities [2]. Its derivatives display a wide
range of pharmacological activities [3e7]. The various
methods of synthesis and reactions of aminopyrimidines are
reported [8e10]. Recently, we have reported the synthesis
and antibacterial activity of biphenyl, phenyl and thienyl
substituted 2-aminopyrimidines [11e12]. Based on the above
reports and in continuation of our research on the syntheses of
biologically active heterocyclic molecules, we report here the
synthesis of some naphthalene substituted 2-aminopyrimidines
and their antibacterial activity.
The IR spectra of the compound 4 displayed characteristic
absorption bands (cmꢀ1) in the regions 3150e3500 (NH
stretching), 1500e1575 (C]C stretching) and 1600e1650
(C]N stretching); this gives positive evidence for the forma-
tion of the compound. Elemental analysis data of the com-
pounds (calculated and found) are presented in Table 1.
1
The H NMR shows characteristic peaks at d (ppm) 5.2e
5.72 (2H, s, NH2), around 7.3 (H-5) and 7.0e8.5 (AreH).
13C NMR displays characteristic peaks at d (ppm) 168.5 (C-6),
108.8 (C-5), 165.9 (C-4), 163.6 (C-2), 137.1, 134.0 and 130.7
(ipso carbons).
2. Results and discussion
The compounds 4aei were evaluated for antibacterial and
antifungal activities against representative bacteriadStaphylo-
coccus aureus, Escherichia coli, Klebsiella pneumoniae, Pseu-
domonas aeruginosa and fungidTrichophyton tonsurans and
Microsporum gypseum. Activity was expressed as Minimum
Inhibitory Concentration (MIC), the lowest concentration of
the tested compound that resulted in no visible growth on
1-(1-Naphthyl)ethanone 2 is prepared by acetylation of
naphthalene 1 in the presence of anhydrous aluminium
* Corresponding author. Tel.: þ91 4144 221424; fax: þ91 4144 238080.
E-mail address: nagarajan.au@gmail.com (S. Nagarajan).
0223-5234/$ - see front matter Ó 2006 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.09.012

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N. Ingarsal et al. / European Journal of Medicinal Chemistry 42 (2007) 517e520
CH3COCl
AlCl3
COCH3
1
2
NaOH
ArCHO
CH
CH
X
NH
C
HNO3
C
O
NH2
H2N
NaOH/EtOH
X
3a-i
4a -H
4b 4-F
4c 2-Cl
4d 3-Cl
N
N
4e 4-Cl
4f 2-OCH3
4g 4-OCH3
4h 3-NO2
4i 4-NO2
NH2
4a-i
Scheme 1.
the plate. As can be seen in Table 2, although not as active as
the standard ampicillin, 4aei were generally found to be more
active against K. pneumoniae and P. aeruginosa than the other
organisms in the testing panel. In particular, the 4-fluoro (4b)
and 4-chloro (4e) analogs had the best overall antibacterial
profile. Table 2 also contains results of antifungal activity tests
of 4aei where, miconazole was used as the standard. Again,
compounds 4b and 4e were more active than the other analogs
in the series. Although the rest of the compounds showed vary-
ing degrees of inhibition none were as effective as miconazole.
Among the three chloro isomers 4-chloro (4e) was more effec-
tive than the 2- or 3-chloro substituted compounds. Thus the
nature and position of the substituent have strong influence
on the spectrum and extent of antibacterial and antifungal
activities.
3. Experimental
Meltingpoints are determined in an open capillary and are un-
corrected. 1H NMR, 13C NMR and SEFT spectra were recorded
on Brucker (AMX-400) using CDCl3 as solvent. TMS was used
as internal reference for 1H NMR, 13C NMR and SEFT spectra.
Mass spectra were recorded on a CLASS-5000 mass spectrome-
ter with an ion source temperature of 200 ꢁC. Elemental analyses
were done on Vario EL, CHNOS elemental analyzer.
3.1. Procedure for preparation of
1-(1-naphthyl)ethanone
A mixture of 41.9 g (38 ml, 0.53 mol) of acetyl chloride
and 100 ml of carbon tetrachloride was taken in a round
Table 1
Physical and analytical data of 4aei
Compounds
Melting point
(ꢁC)
Yield
(%)
Molecular formula
Elemental analysis
Carbon, found (calcd) %
Hydrogen, found (calcd) %
Nitrogen, found (calcd) %
4a
4b
4c
4d
4e
4f
80e82
121e122
76e78
60
54
55
45
60
60
65
75
75
C
C
20H15N3
20H14N3F
80.60 (80.78)
77.61 (76.17)
72.99 (72.39)
72.87 (72.39)
72.80 (72.39)
77.18 (77.04)
77.87 (77.04)
70.35 (70.17)
70.66 (70.17)
5.12 (5.08)
4.84 (4.47)
4.83 (4.45)
4.75 (4.25)
4.43 (4.25)
5.63 (5.23)
5.73 (5.23)
4.77 (4.62)
4.61 (4.52)
14.23 (14.13)
13.72 (13.32)
12.88 (12.66)
12.96 (12.66)
12.81 (12.66)
13.00 (12.83)
13.02 (12.83)
16.98 (16.87)
16.50 (16.37)
C20H14N3Cl
20H14N3Cl
109e111
116e118
79e80
C
C20H14N3Cl
C21H17N3O
C21H17N3O
4g
4h
4i
136e138
163e165
195e197
C20H14N4O2
C20H14N4O2

N. Ingarsal et al. / European Journal of Medicinal Chemistry 42 (2007) 517e520
519
Table 2
In vitro antibacterial and antifungal activities of 4aei and their standard (MIC mg mlꢀ1
)
Compound
S. aureus
E. coli
K. pneumoniae
P. aeruginosa
T. tonsurans
M. gypseum
4a
4b
>60
7.30
40
42
8.10
>60
41
5.50
2.55
5.38
6.38
19.8
8.22
9.31
14.28
15.35
1.80
NT
6.59
5.45
25
25
2.20
25
25
5.90
25
25
4c
4d
6.40
7.42
39
4e
12.30
>60
>60
29.10
25.65
1
13.50
36
21.90
9.18
2.80
25
25
5.55
25
25
4f
4g
>60
19.50
16.65
1.65
NT
10.21
18.21
11.92
1.80
4h
4i
25
25
25
25
Ampicillin
Miconazole
NT
0.20
NT
0.20
NT
NT
NT: not tested.
bottom flask. About 70 g (0.52 mol) of powdered dry AlCl3
was added slowly to the vigorously stirred above mixture.
The mixture becomes warm and then cooled to 20 ꢁC. A solu-
tion of naphthalene (32 g, 0.25 mol) in 100 ml of CCl4 was
added and hydrogen chloride was evolved. The mixture was
warmed to 30 ꢁC for 30 min. The resulting mixture was de-
composed with ice and concentrated hydrochloric acid. The
product was separated and the crude was distilled under re-
duced pressure.
3.3.2. 2-Amino-4-(1-naphthyl)-6-(4-fluorophenyl)
pyrimidine (4b)
1H NMR, d (ppm) 5.34 (2H, s, NH2), 7.26 (1H, s, H-5),
6.97e8.21 (AreH). 13C NMR, d (ppm) 168.13 (C-6), 108.07
(C-5), 165.36 (C-4), 163.47 (C-2), 137.23, 133.98, 129.65,
130.79 (quaternary carbons), 125.28e128.77 (AreC).
3.3.3. 2-Amino-4-(1-naphthyl)-6-(2-chlorophenyl)
pyrimidine (4c)
1H NMR, d (ppm) 5.66 (2H, s, NH2), 6.96e8.29 (AreH),
singlet for H-5 proton is merged with other aromatic protons.
13C NMR, d (ppm) 167.70 (C-6), 109.11 (C-5), 165.52 (C-4),
163.36 (C-2), 137.60, 136.33, 138.86, 133.98 and 133.83 (qua-
ternary carbons), 124.36e132.29 (AreC).
3.2. General procedure for preparation of
1-(1-naphthyl)-3-arylprop-2-en-1-ones (3aei)
A solution of substituted benzaldehyde (0.01 mol) and 1-(1-
naphthyl)ethanone (0.01 mol) in 65% aqueous ethanol (60 ml)
containing sodium hydroxide (0.5 g) was heated over a water
bath for 2 h. The solution was then cooled. The product thus
obtained was filtered and recrystallised from ethanol.
3.3.4. 2-Amino-4-(1-naphthyl)-6-(3-chlorophenyl)
pyrimidine (4d)
1H NMR, d (ppm) 5.32 (2H, s, NH2), 7.30 (1H, s, H-5),
6.83e8.19 (AreH). 13C NMR, d (ppm) 168.73 (C-6), 108.65
(C-5), 164.28 (C-4), 163.41 (C-2), 139.27, 137.46, 136.66,
134.94, 134.09 (quaternary carbons), 123.47e134.02 (AreC).
3.3. General procedure for preparation of 2-amino-4-
(1-naphthyl)-6-arylpyrimidine (4aei)
A
mixture of 1-(1-naphthyl)-3-aryl-prop-2-en-1-one
3.3.5. 2-Amino-4-(1-naphthyl)-6-(4-chlorophenyl)
pyrimidine (4e)
(0.01 mol) and guanidine nitrate (0.01 mol) in ethanol
(75 ml) was refluxed, while a solution of sodium hydroxide
(0.5 mol) in water (10 ml) was added portion wise for 2 h. Re-
fluxing was continued for further 10 h and the mixture was
poured into ice cold water. The formed solid was separated
by filtration. The 2-aminopyrimidines are purified from the
solid mixture by column chromatography using benzene and
ethyl acetate mixture as eluting solvent.
1H NMR, d (ppm) 5.2 (2H, s, NH2), 7.2e8.1 (AreH), the
singlet for H-5 proton is merged with aromatic protons. 13C
NMR, d (ppm) 162.27 (C-6), 109.17 (C-5), 161.20 (C-4),
157.86 (C-2), 137.30, 152.3, 140.3, 134.5, 133.7, 130.6 (qua-
ternary carbons), 124.4e129.8 (AreC).
3.3.6. 2-Amino-4-(1-naphthyl)-6-(2-methoxyphenyl)
pyrimidine (4f)
3.3.1. 2-Amino-4-(1-naphthyl)-6-(phenyl)pyrimidine (4a)
1H NMR, d (ppm) 5.72 (2H, s, NH2), 7.32 (1H, s, H-5),
7.30e8.25 (AreH). 13C NMR (100.6 MHz, CDCl3), d (ppm)
168.50 (C-6), 108.83 (C-5), 165.91 (C-4), 163.65 (C-2),
137.65, 137.10, 134.01 and 130.78 (quaternary carbons),
124.35e130.62 (AreC).
1H NMR, d (ppm) 5.63 (2H, s, NH2), 3.84 (3H, s, OCH3),
6.97e8.34 (AreH), singlet of H-5 proton is merged in aro-
matic region. 13C NMR, d (ppm) 166.97 (C-6), 111.67 (C-
5), 164.50 (C-4), 157.86 (C-2), 137.30, 137.02, 132.35,
134.04 (quaternary carbons), 122.61e131.32 (AreC),
55.72(eOCH3).

520
N. Ingarsal et al. / European Journal of Medicinal Chemistry 42 (2007) 517e520
3.3.7. 2-Amino-4-(1-naphthyl)-6-(4-methoxyphenyl)
pyrimidine (4g)
medium of Sabouraud (Difco), transferred to 3.5 ml nutrient
broth (NB, Himedia) and incubated for 3e5 days at 25 ꢁC.
At the end of the incubation period these strains were trans-
ferred into screw-capped bottles containing sterilized beads
and shaken for 4e5 min in a vortex. The suspensions of the
cultures were adjusted to have an absorbance degree of 0.5
at 500 nm in the spectrophotometer. Eight different dilutions
of the test compounds were prepared in microplates by serial
dilutions from top to bottom. Then all the wells except the pos-
itive control were filled with 10 ml of the standardized strains.
These plates were incubated at 25 ꢁC for 7 days. The mini-
mum concentration at which no growth was observed was
taken as the MIC value.
1H NMR, d (ppm) 5.41 (2H, s, NH2), 7.26 (1H, s, H-5), 6.98e
8.22 (AreH), 3.86 (3H, s, OCH3). 13C NMR, d (ppm) 168.21
(C-6), 108.10 (C-5), 163.47 (C-4), 161.87 (C-2), 137.26,
133.99, 130.78, 129.98 (quaternary carbons), 125.28e129.64
(AreC), 55.42 (eOCH3), Mþ 327, 77 (100).
3.3.8. 2-Amino-4-(1-naphthyl)-6-(3-nitrophenyl)
pyrimidine (4h)
1H NMR, d (ppm) 5.2 (2H, s, NH2), 7.2e8.5 (AreH), the
singlet for H-5 proton may be merged with the aromatic pro-
tons. 13C NMR, d (ppm) 163.0 (C-6), 108.7 (C-5), 163.4 (C-4),
169.5 (C-2), 148.9, 136.5, 139.3, 134.0, 130.6 (quaternary car-
bons), 122.2e129.7 (AreC), Mþ 342, 77 (100).
Acknowledgements
3.3.9. 2-Amino-4-(1-naphthyl)-6-(4-nitrophenyl)pyrimidine
(4i)
Authors are thankful to NMR Research Center, Indian In-
stitute of Science, Bangalore for NMR spectral measurements.
1H NMR, d (ppm) 5.3 (2H, s, NH2), 7.3e8.4 (AreH), the
singlet for H-5 proton is merged with aromatic protons. 13C
NMR, d (ppm) 163.1 (C-6), 109.2 (C-5), 163.5 (C-4), 169.4
(C-2), 149.1, 136.5, 139.3, 134.0, 130.5 (quaternary carbons),
123.9e128.6 (AreC).
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3.4. Microbiology
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