Synthesis and comparing the antibacterial activities of pyrimidine derivatives

Article abstract of DOI:10.1007/s12039-017-1228-z

A series of 10 derivatives of 5-(5-amino-1,3,4-thiadiazole-2-yl)-3,4-dihydro-6-methyl-4-phenyl-pyrimidin-2(1H)-one and 10 derivatives of 3,4-dihydro-5-(5-mercapto-4H-1,2,4-triazol-3-yl)-6-methyl-4-phenyl pyrimidin-2(1H)-one have been synthesized. Among th

Full text of DOI:10.1007/s12039-017-1228-z

c
J. Chem. Sci. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-017-1228-z
REGULAR ARTICLE
Synthesis and comparing the antibacterial activities of pyrimidine
derivatives
B ANDREWSa,b,c,∗, K KOMATHIc,d and S MOHANc,d
aPG and Research Department of Chemistry, Islamiah College, Vaniyambadi 635 752, India
bThiruvalluvar University, Vellore, Tamil Nadu, India
cPriyadarshini Engineering College, Vaniyambadi, Tamil Nadu, India
dAnna University, Chennai, Tamil Nadu, India
Email: bandrews2006@yahoo.com
MS received 29 July 2016; revised 23 September 2016; accepted 29 December 2016
Abstract. A series of 10 derivatives of 5-(5-amino-1,3,4-thiadiazole-2-yl)-3,4-dihydro-6-methyl-4-phenyl-
pyrimidin-2(1H)-one and 10 derivatives of 3,4-dihydro-5-(5-mercapto-4H-1,2,4-triazol-3-yl)-6-methyl-4-
phenyl pyrimidin-2(1H)-one have been synthesized. Among the synthesized derivatives, triazole substituted
compounds have shown higher antibacterial inhibition when compared to the thiadiazole derivatives. All the
structures of the newly synthesized compounds have been characterized by IR, 1H and 13C NMR, GC-MS and
CHN analysis. Most of the compounds have shown promising antibacterial activity when compared with the
standard drug ciprofloxacin.
Keywords. 5-amino thiadiazole; 5-amino triazole; hydrazine carbothioamide; pseudomonas aeruginosa;
staphylococcus aureus; escherichia coli.
1. Introduction
in vitro study of antibacterial activities by using three
different species namely, Pseudomonas aeruginosa
(Gram –ve), Staphylococcus aureus (Gram +ve) and
Escherichia coli (Gram –ve). The inhibition values are
compared with standard drug, ciprofloxacin. All the syn-
thesized compounds were characterized by using ele-
mental analysis, mass spectra, 1H and 13C NMR spectra.
The pyrimidine and its derivatives have a wide vari-
ety of applications in different fields, prominently for
biological treatment process,1 8 such as antitumor, anti-
cancer, anti-inflammatory, anti-hypertensive, antibac-
terial and antifungal agents, etc. The five-membered
heterocyclic ring substituted in pyrimidine derivatives
have moderate inhibition against the bacterial species.9
In order to improve the antibacterial activity, we have
synthesized twenty pyrimidine derivatives.
2. Experimental
Melting points were determined using open capillary
method and are uncorrected. The compounds are
checked for homogeneity by TLC on silica gel-G using
pet ether and ethyl acetate as eluent in 3:5 ratio. The IR
spectra were recorded on FT-IR THERMO NICOLET
AVATAR 370 spectrometer using KBr disc. The 1H and
13C NMR were recorded on Bruker Avance-III 400
MHz - NMR spectrometer using DMSO-d6. Elemental
analyses were recorded on elemental vario EL III
instrument. The mass spectra were recorded on Joel
GC-mate spectrometer. All the compounds gave satis-
factory micro analytical results.
The pyrimidine and its derivatives have been synthe-
sized by using various methods. In continuation of this
work, novel pyrimidine derivatives were synthesized by
using the reported procedure for the first step.10,11 These
pyrimidine derivatives have a large number of reactive
sites to produce the substituted derivatives.12 18
Herein, the reaction was carried out only in the 5th
position of the pyrimidine ring, because the ethanolic
group which is present in the position 5 is easily re-
moved by boiling in presence of catalyst and hydrazine
carbothioamide.19,20 The synthesized 10 derivatives of
5-(5-amino-1, 3, 4-thiadiazole-2-yl)-3,4-dihydro-6-me-
thyl-4-phenyl-pyrimidin-2(1H)-one and 10 derivatives
of 3,4-dihydro-5-(5-mercapto-4H-1,2,4-triazol-3-yl)-6-
methyl-4-phenylpyrimidin-2(1H)-one are subjected to
2.1 General Procedure
The synthesize 5-(hydrazine carbothioamide)-3,4-dihy-
dro-6-methyl-4-phenyl pyrimidin-2(1H)-one (Scheme 1)
∗For correspondence

B Andrews et al.
R
R1
O
C
CHO
H2N
NH2
+
O
Ethanol
+
Reflux
6 h
R1
H3CH2CO
H3C
NH
O
O
H2
R
R
C2H5O
C
C C CH3
N
H
X
1a
S
Reflux
10-12 h
R1
H2N NH
C
NH2
A
c
/
et
on
e
O
H
N
2a
H2N
N
H
NH
X = O, S
S
H3C
N
H
X
2g. R = Cl, R1 = H
2a. R = H, R1 = H
2b. R = Cl, R1 = H
2d. R = H, R1 = NO2
2h. R = N(CH3)2, R1 = H
2i. R = H, R1 = NO2
2j. R = OH, R1 = H
2e. R = OH, R1 = H
2f. R = H, R1 = H
2c. R = N(CH3)2, R1 = H
Scheme 1. Synthesis of 5-(hydrazine carbothioamide)-3,4-dihydro-6-methyl-4-phenyl pyrimidin-2 (1H)-one 2(a–j).
2(a–j), an equimolar mixture of compound 1a (2.61 g, DMSO-d6): δ 2.258 (s, 3H), 4.004 (s, 2H), 5.159 (d, J
0.01 mol) and thiosemicarbazide (0.91 g, 0.01 mol) in = 3.2 Hz, 1H), 7.227–7.347 (m, 5H), 7.701 (d, J = 2
acetone was refluxed for 10–12 h and allowed to cool. Hz, 1H), 9.151 (s, 1H). 13C NMR (400 MHz, DMSO-
The yellow crude solid was purified by recrystalliza- d6): δ 17.03, 59.15, 99.30,126.20, 127.20, 128.34,
tion from alcohol. M.p.: 139–141◦C. [Yield: 2.4 g, 82%] 144.82, 148.27, 152.10, 165.32. FT-IR (KBr, cm−1):
Analysis: Calculated (%) for C13H15O2N5S: C, 51.17; 3354, 3227, 3110 (NH), 3027 (Ar–H), 2976 (CH), 1689
H, 4.94; N, 22.50; S, 10.47. Found (%): C, 51.10; H, (C=O), 1460 (C=N), 1225 (C–S), 1378 (C–N), 1098
4.85; N, 22.24; S, 10.94. GCMS: m/z 305 [M+]. FT- (N–N). GCMS: m/z 287 [M+]. Analysis: Calculated
IR (KBr, cm−1): 3365, 3241, 3116 (NH), 3079 (Ar–H), (%) for C13H13ON5S: C, 54.38; H, 4.56; N, 24.39; S,
2978 (CH), 1724 (C=O), 1385 (C–N), 1219 (C=S), 11.13. Found (%): C, 54.35; H, 4.56; N, 24.64; S, 11.68.
1089 (N–N). 1H NMR (400 MHz, DMSO-d6): δ 2.251
(s, 3H), 5.152 (d, J = 3.2 Hz, 1H), 6.501 (s, 2H), 7.213–
2.3 General procedure for Synthesis of 3,4-dihydro-5-
7.336 (m, 5H), 7.702 (d, J = 2.8 Hz, 1H), 8.175 (d,
J = 6.4 Hz, 2H,), 9.149 (s, 1H). 13C NMR (400 MHz,
(5-mercapto-4H-1,2,4-triazol-3-yl)-6-methyl-4-phenyl
pyrimidin-2(1H)-one (Scheme 3) 4(a–j)
DMSO-d6): δ 17.72, 59.17, 99.33, 126.21, 127.23,
128.34, 148.25, 151.71, 152.16, 165.33, 178.40.
The carbothioamide 2a (3.05 g, 0.01 mol) was added
into (8 g in 100 mL) 8% NaOH; it was refluxed for 4 h.
The reaction mixture was cooled to room temperature
and acidified with dilute acetic acid, then filtered and
washed well with water and purified by recrystallization
from alcohol as shiny crystals. M.p.:119–121◦C, [Yield:
2.2 General procedure for synthesis of 5-(5-amino-1,
3, 4-thiadiazole-2-yl)-3, 4-dihydro-6-methyl-4-phenyl-
pyrimidin-2(1H)-one (Scheme 2), 3(a–j)
Hydrazine carbothioamide 2a (3.05 g, 0.01 mol) was 2.42 g; 80%]. 1H NMR (400 MHz, DMSO-d6): δ 2.304
dissolved in 5 mL conc. H2SO4. This solution was (s, 3H), 3.217 (s, 1H), 5.507 (d, J = 3.6 Hz, 1H), 6.975
stirred at RT and left overnight. It was then poured (s, 1H), 7.268–7.338 (m, 5H), 7.766 (d, J = 2.4 Hz,
in crushed ice. The resulting suspension was kept in 1H), 9.217 (s, 1H). 13C NMR (400 MHz, DMSO-d6):
ammoniacal water for 2 h, filtered and purified by δ 17.74, 59.14, 99.24, 126.22, 127.21, 128.33, 144.84,
recrystallization from alcohol as white crystals. M.p.: 148.29, 152.15, 155.11, 165.32. FT-IR (KBr, cm−1):
1
174–176◦C. [Yield: 2.7 g; 81%]. H NMR (400 MHz, 3423 (NH), 3027 (Ar–H), 2968 (CH), 2235 (SH),

Synthesis of biologically active biheterocyclic pyrimidine derivatives
R
R
R1
R1
Co
nc.
H S
O
N
2
4
O
N
H
N
H2N
H2N
NH
3
S
N
H
NH
NH
S
H3C
N
H
X
H3C
N
H
X
2a
3a
3g. R = Cl, R1 = H
X = O, S
3a. R = H, R1 = H
3b. R = Cl, R1 = H
3c. R = N(CH3)2, R1 = H
3d. R = H, R1 = NO3
3h. R = N(CH3)2, R1 = H
3e. R = OH, R1 = H
3f. R = H, R1 = H
3i. R = H, R1 = NO3
3j. R = OH, R1 = H
Scheme 2. Synthesis of 5-(5-amino-1, 3, 4-thiadiazole-2-yl)-3, 4-dihydro-6-methyl-4-phenyl pyrimidin-2(1H)-one 3(a–j).
R
R
R1
R1
N
N
NaOH
O
HS
H
N
N
H
H2N
NH
Reflux
4 h
N
H
NH
H3C
N
H
X
S
H3C
2a
N
H
X
4a
4g. R = Cl, R1 = H
X = O, S
4a. R = H, R1 = H
4b. R = Cl, R1 = H
4c. R = N(CH3)2, R1 = H
4d. R = H, R1 = NO3
4h. R = N(CH3)2, R1 = H
4e. R = OH, R1 = H
4f. R = H, R1 = H
4i. R = H, R1 = NO3
4j. R = OH, R1 = H
Scheme 3. Synthesis of 3,4-dihydro-5-(5-mercapto-4H-1,2,4-triazol-3-yl)-
6-methyl-4-phenyl pyrimidin-2(1H)-one 4(a–j).
or thiourea in the presence of mineral acid, followed
1654 (C=O), 1590 (C=N), 1373 (C–N), 1057 (N–N).
GCMS: m/z 287 [M+]. Analysis: Calculated (%) for
C13H13ON5S: C, 54.38; H, 4.56; N, 24.39; S, 11.13.
Found (%): C, 54.41; H, 4.22; N, 24.35; S, 11.53.
by Biginelli reaction. The structures of the synthesized
1
compounds were confirmed by IR, H and 13C NMR,
GC-MS and CHN analysis. Formation of 2a was con-
firmed by the presence of N–H stretching peaks at 3365,
3241 cm−1 and 3116 cm−1 and C=O stretching peaks at
1724 cm−1 in IR and singlet at δ 6.50 for NH2 group in
1H NMR spectrum.
3. Results and Discussion
Compounds 3(a–j) and 4(a–j) were synthesized as per
the Schemes 1, 2 and 3. The final compound 3a was
prepared by the reaction of hydrazine carbothioamide
Treatment of compound 2a with conc. H2SO4 and
NH3, furnished 5-(5-amino-1,3,4-thiadiazol-2-yl)-3,4-
dihydro-6-methyl-4-phenyl pyrimidin-2(1H)-one (3a).
2a, conc.H2SO4 and NH3, whereas 4a was prepared The structure of 3a was elucidated on the basis of
C-S linkage in the thiadiazole ring, which causes a
by refluxing hydrazine carbothioamide 2a with NaOH.
Hydrazine carbothioamide 2a was synthesized by reac-
tion of pyrimidine ethyl ester 1 with thiosemicarbazide
in acetone, followed by condensation reaction.
The pyrimidine ethyl ester 1a was prepared by the
reaction of benzaldehyde, ethylacetoacetate and urea
sharp absorption band at 1225 cm−1 in its IR spec-
1
trum. H NMR spectrum shows a singlet at δ 4.00
due to NH2 functional group of the compound 3a.
The mechanism for compounds 3(a–j) is shown in
Scheme 4.

B Andrews et al.
R
R
R1
R1
O
H+
H
N
OH
H2N
H
N
N
H
NH
H2N
N
H
NH
S
H3C
N
H
O
S
H3C
N
H
O
2a
R
R
R1
R1
H
N
OH
N
OH
H
N
H2N
NH
S
H2N
N
H
NH
S
N
H
O
H3C
N
H
O
H3C
R
-H2O
R1
N
N
3a
NH
H2N
S
N
H
O
H3C
Scheme 4. Mechanism of 5-(5-amino-1, 3, 4-thiadiazole-2-yl)-3, 4-dihydro-
6-methyl-4-phenyl pyrimidin-2(1 H)-one 3(a–j).
1
drug. Most of the synthesized compounds showed mod-
erate to good inhibition at a concentration of 10 μg/mL.
The IR and H NMR spectral data reveal that the
carbonyl absorption band at 1689 cm−1 of NH–CO–
NH group, N–N stretching band at 1098 cm−1, aliphatic
C–H and aromatic C–H stretching at 2976 cm−1 and
3027 cm−1, in the pyrimidine compound 3a. Mass spec-
trum also supports the proposed structure by the pres-
ence of molecular ion peak at m/z 287 M+.
3.1 Antibacterial studies
The newly synthesized pyrimidine derivatives were
screened for their antibacterial activity in vitro against
pseudomonas aeruginosa, staphylococcus aureus and
escherichia coli, using agar well disk diffusion method.
The test compounds were dissolved in DMSO to get a
solution of 10 μg/mL concentration. The inhibition
zones were measured in millimeters at the end of an
incubation period of 18 h at 37◦C. Ciprofloxacin was
used as a standard drug and the results are shown in
Tables 1 and 2. The investigation of antibacterial screen-
ing data reveals that, all the tested compounds show
moderate to good inhibition at 10 μg/mL concentration.
The structure of (4a) was elucidated on the basis
of C–N linkage in the triazole ring, which causes an
absorption band at 1373 cm−1 in its IR spectrum. H
1
NMR spectrum shows a singlet at δ 3.21 due to SH
functional group of compound 4a. The IR and 1H NMR
spectral data reveal that the carbonyl absorption band
at 1654 cm−1 of NH–CO–NH group, N–N stretching
band at 1053 cm−1, aliphatic C–H and aromatic C–H
stretching at 2968 cm−1 and 3027 cm−1, in the group of
pyrimidine compound (4a). Molecular ion peak at m/z
287 M+ in the mass spectrum also supports the pro-
posed structure. The mechanism of compounds 4(a–j)
is shown in Scheme 5.
3.2 Comparison of anti bacterial activity
All these compounds were screened for antibacte-
rial activity by pseudomonas aeruginosa (Gram –ve),
staphylococcus aureus (Gram +ve) and escherichia
coli (Gram –ve). Ciprofloxacin was used as standard
Comparison of antibacterial activity for all the syn-
thesised compounds are shown in Figures S1–S3 (in
Supplementray Information). Based on the comparative

Synthesis of biologically active biheterocyclic pyrimidine derivatives
R
R
R 1
R 1
O
O
H
N
H
N
H
N
O H -
-H 2
H
N H
H N
N
H
H N
N
H
O
S
S
O
N
H
C H 3
2 a
O
N
H
C H 3
R
R
R 1
R 1
O
O
H
N
H
N
N
N H
N
H
N H
H N
H N
S H
S
O
N
H
C H 3
O
N
H
C H 3
R
R
R 1
R 1
N
S H
N H
N
H N
N
O H
H N
O H
C H 3
S H
H N
N
O
N
H
O
N
H
C H 3
R
-O H
R 1
N
S H
N
N H
H N
4 a
O
N
H
C H 3
Scheme 5. Mechanism of 3,4-dihydro-5-(5-mercapto-4H-1,2,4-triazol-3-
yl)-6-methyl-4-phenyl pyrimidin-2(1H)-one 4(a–j).
Table 1. Antibacterial activity of compounds 3(a–j).
Pseudomonas
Staphylococcus
Escherichia coli
Compound
aeruginosa (mm)
aureus (mm)
(mm)
Control (DMSO)
0
6
5
5
5
14
5
0
7
7
8
5
16
5
0
7
8
9
8
18
6
3a
3b
3c
3d
3e
3f
3g
3h
3i
7
5
5
10
10
5
8
7
6
10
14
3j
11

B Andrews et al.
Table 2. Antibacterial activity of compounds 4(a–j).
Pseudomonas
aeruginosa (mm)
Staphylococcus
aureus (mm)
Escherichia coli
Compound
(mm)
Control (DMSO)
0
7
9
5
5
20
7
23
8
10
8
0
8
12
7
0
8
11
7
4a
4b
4c
4d
4e
4f
4g
4h
4i
7
5
14
12
8
6
10
10
10
12
14
15
12
9
4j
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Supplementary Information (SI)
All additional information pertaining to characterization of
the compounds using FT-IR spectra (Figures S1 to S10 and
S31 to S40), 1H NMR spectra (Figures S11 to S20 and S41 to
S50), 13C NMR spectra (Figures S21 to S30 and S51 to S60),
antibacterial screening data (Tables S1, S2) and antibacterial
activities comparative diagram (Figure S1, S2 and S3) are
given in the supporting information available at www.ias.ac.
in/chemsci.
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Department of Chemistry, Islamiah College, Vaniyambadi,
Vellore district, Tamil Nadu, India for constant encourage-
ment and providing necessary facilities.
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