Synthesis and biological study of some novel 4-[5-(4,6-disubstituted-2- thiomethylpyrimidyl)-4'-amino-1,2,4- triazol-3'-yl] thioacetyl-3-arylsydnones

Article abstract of DOI:10.1080/10426500601161049

A series of 4-[5-(4,6-disubstituted-2-thiomethyl pyrimidyl)-4'-amino-1,2-4- triazol-3'-yl]thioacetyl-3-arylsydnones 7a-i were synthesized by the reaction of 5-(4,6-disubstituted-2-thiomethylpyrimidyl)-4-amino-3-mercapto-1,2-4-triazoles 3 with 3-aryl-4-bromoacetyl sydnones 6 in an ethanol medium. The newly synthesized compounds 7a-i were screened for their antibacterial activity against E. coli and Serratia marcesens and for antibacterial activity against Aspergillus niger and Pencillium. Most of the tested compounds showed significant antifungal activity particularly against Pencillium at 10-g/mL concentration comparable with that of the standard drug Flukanazole.

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Synthesis and Biological
Study of Some Novel 4-
[5-(4,6-Disubstituted-2-
thiomethylpyrimidyl)-4′-
amino-1,2,4- triazol-3′-yl]
thioacetyl-3-arylsydnones
Balakrishna Kalluraya a , B. Lingappa a b & Satheesh
Rai Nooji a
a Department of Studies in Chemistry , Mangalore
University , Mangalagangotri, India
b India and Strides Research and Specialty Chemicals
Ltd. , Mangalore, India
Published online: 29 Aug 2007.
To cite this article: Balakrishna Kalluraya , B. Lingappa & Satheesh Rai Nooji
(2007) Synthesis and Biological Study of Some Novel 4-[5-(4,6-Disubstituted-2-
thiomethylpyrimidyl)-4′-amino-1,2,4- triazol-3′-yl] thioacetyl-3-arylsydnones,
Phosphorus, Sulfur, and Silicon and the Related Elements, 182:6, 1393-1401, DOI:
10.1080/10426500601161049
To link to this article: http://dx.doi.org/10.1080/10426500601161049
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Phosphorus, Sulfur, and Silicon, 182:1393–1401, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601161049
Synthesis and Biological Study of Some Novel 4-[5-(4,6-
Disubstituted-2-thiomethylpyrimidyl)-4ꢀ-amino-1,2,4-
triazol-3ꢀ-yl] thioacetyl-3-arylsydnones
Balakrishna Kalluraya
Department of Studies in Chemistry, Mangalore University,
Mangalagangotri, India
B. Lingappa
Department of Studies in Chemistry, Mangalore University,
Mangalagangotri, India and Strides Research and Specialty Chemicals
Ltd., Mangalore, India
Satheesh Rai Nooji
Department of Studies in Chemistry, Mangalore University,
Mangalagangotri, India
A series of 4-[5-(4,6-disubstituted-2-thiomethyl pyrimidyl)-4ꢀ-amino-1,2-4-triazol-
3ꢀ-yl]thioacetyl-3-arylsydnones 7a–i were synthesized by the reaction of 5-(4,6-
disubstituted-2-thiomethylpyrimidyl)-4-amino-3-mercapto-1,2-4-triazoles 3 with 3-
aryl-4-bromoacetyl sydnones 6 in an ethanol medium. The newly synthesized com-
pounds 7a–i were screened for their antibacterial activity against E. coli and
Serratia marcesens and for antibacterial activity against Aspergillus niger and
Pencillium. Most of the tested compounds showed significant antifungal activity
particularly against Pencillium at 10-µg/mL concentration comparable with that
of the standard drug Flukanazole.
Keywords Biological activity; pyrimidine; sydnone; triazoles
Received October 5, 2006; accepted November 22, 2006.
The authors are thankful to the Head, Dept of Chemistry, Mangalore University,
for the IR and microanalysis, and the Head, Regional Sophisticated Instrumentation
Centre, Indian Institute of Sciences, Bangalore, for 1H NMR and masss spectral data.
The authors are also thankful to Dr. T. B. Karegoudar, Professor, Department of Studies
in Biochemistry, Gulbarga University, Gulbarga, Karnataka, India, for help in biological
screening.
Address correspondence to Balakrishna Kalluraya, Department of Studies in Chem-
istry, Mangalore University, Mangalagangotri, 574199 India. E-mail: bkalluraya 2001@
yahoo.com
1393

1394
B. Kalluraya et al.
INTRODUCTION
The literature survey shows that a large number of simple, N-bridged,
nitrogen- and sulphur-containing heterocyclic compounds carrying a
pyrimidine moiety are found to be associated with diverse biological
activities. The chemistry of pyrimidine and its derivatives have been
studied for over a century due to their diverse biological activities.1−4
They possess antibacterial,5 antiviral,6 antitumor,7,8 antihypertensive,
and anti-inflammatory9,10 activities. Similarly, 1,2,4-trizoles and their
derivatives are found to be associated with diverse pharmacological
activities.11−13 The study of sydnones still remains a field of interest be-
cause of their electronic structure and also because of the varied types of
biological activity displayed by them. Interest in sydnone has also been
encouraged by the discovery that they exhibit various pharmacological
activities.14,15 Keeping in view of these observations, we decided to un-
dertake the synthesis of some novel heterocycles containing pyrimidine,
triazole, and sydnone moiety and to evaluate their biological activity.
The synthetic route followed for obtaining the title compound is out-
lined in Schemes 1, 2, and 3. Thus 4,6-disubstituted-2-thioprymidines
1 on reaction with chloro acetic acid in aqueous sodium hydroxide
followed by neutralization with hydrochloric acid gave the pyrimi-
dine thioaceticacid 2. Fusion of 2 with thiocabohydrazide gave 5-(4,
6-disubstituted-2-thiomethylpyrimidyl)-4-amino-3-mercapto-1,2-4-tria
zoles, 3a–c (Scheme 1). Reaction of 3 with bromoacetyl sydnones 6 in
an ethanol medium employing sodium acetate as a catalyst gave novel
4-[5-(4,6-disubstituted-2-thiomethylpyrimidyl)-4ꢀ-amino-1,2-4-triazol-
SCHEME 1

Triazol-Arylsydnones
1395
SCHEME 2
3ꢀ-yl]-thioacetyl-3-arylsydnone 7a–i (Scheme 3). Arylsydnones 4, when
reacted with acetic acid in the presence of P2O5 in benzene medium,16
gave 4-acetyl-3-arylsydnones 5. Bromination of 5 in chloroform medium
under irradiation by visible light17 gave 4-bromoacetyl-3-arylsydnones
6 (Scheme 2). 2-Thio-pyrimidine 1 and arylsydnones 4 were prepared
as per the literature procedure,18,19 respectively.
RESULTS AND DISCUSSION
The structures of the newly synthesized triazoles 3a–c and
4-[5-(4,6-disubstituted-2-thiomethyl pyrimidyl)-4ꢀ-amino-1,2-4-triazol-
3ꢀ-yl]-thioacetyl-3-arylsydnones 7a–i were established on the basis of
analytical and spectral data. The IR spectra of triazoles 3a–c showed ab-
sorption bands in the region 3290–3450 cm−1 characteristic of the NH2
group. The C H stretching band was observed in the region 2730–2790
cm−1. The C N absorption band was observed around 1600–1625 cm−1
.
1
In a typical example the H NMR spectra of triazole 3b showed a sin-
glet at δ 2.32 integrating for three protons of the methyl group. The
S CH2 protons came into resonance at δ 4.36. The NH2 protons ap-
peared as a singlet at δ 5.11. The 5-H and 6-H protons of pyrimidine
appeared as two doublets at δ 6.81 (J = 11 Hz) and δ 8.26 (J = 11 Hz),
each integrating for one proton. The SH proton appeared as a singlet
at δ 10.5. In the mass spectrum of this compound, the molecular ion
peak was observed at m/z 254 (Molecular Formula; C8H10N6S2), which
is also the base peak, thereby indicating the stability of the triazole.
When these triazoles 3 were reacted with 4-bromoacetyl-3-
arylsyndone 6 in an ethanol medium in the presence of sodium acetate
as a catalyst, we expected the formation of triazolothiadiazines 8. How-
ever, the reaction resulted in the formation of a novel series of mercap-
toacetyl derivatives of sydnones 7 with the elimination of a molecule
of HBr. All of our attempts to cyclize these compounds to triazoloth-
iadiazines 8 employing either acidic as well as basic catalysts failed,

1396

Triazol-Arylsydnones
1397
mainly due to the sensitivity of the sydnone ring toward acids and bases.
The IR spectra of compounds 7 showed absorption bands at 3100–3400
cm−1 characteristic of the NH2 group. The absorption band at 1760–
1780 cm−1 is characteristic of the sydnone carbonyl group, and the ab-
sorption peak around 1660–1685 cm−1 is due to the carbonyl group of
the thioacetyl moiety. In the 1H NMR spectrum of 7f, the methyl protons
attached to the pyrimidyl group appeared as a singlet at δ 2.4 integrat-
ing for three protons. The OCH3 protons came into resonance at δ 3.9.
The S CH2 protons appeared as a singlet at δ 4.5. The singlet at δ 4.65
integrating for two protons was assigned for the S CH2 C CO pro-
tons. The NH2 protons appeared as a broad singlet at δ 5.9. The signal
due to ortho protons of p-anisyl and the pyrimidine 5H protons mingled
together and appeared as a multiplet in the region δ 7.1–7.2 integrat-
ing for three protons. The meta-protons of the p-anisyl group appeared
as a doublet at δ 7.53, and the pyrimidine —6H proton appeared as a
doublet at δ 8.6 integrating for one proton. Further, the mass spectrum
of 7f showed the molecular ion peak at m/z 487 (M++1) consistent with
the molecular formula (C19H18N8S2O4), and the cluster of isotope peaks
due to S34 were also observed at m/z 489 and 491 respectively. Similarly,
the spectral details of few other selected compounds are presented in
Table II.
EXPERIMENTAL
Melting points were determined in open capillary tubes and are uncor-
rected. IR spectra (cm−1) were recorded on a Perkin Elmer 577 spec-
trophotometer in KBr pellets. 1H NMR spectra were recorded on a
Perkin Elmer (Model RB-12) spectrometer using TMS as an internal
standard (chemical shifts are reported in δ scale). Mass spectrum was
recorded on LC/MS (API 3000, Applied Biosystems, Agilent, USA) oper-
ating at 70 eV. C H N analysis was carried out on a Vairo-EL (Elementa)
model. Purity of the compounds was checked by TLC on silica gel plates.
Substituted-pyrimidne-2-thioaceticacid 2
2-chloro acetic acid (9.5 g, 0.1 mol) was taken in a round-bottom flask,
and 50 mL water was added, cooled, and neutralized by adding a
solution of saturated sodium carbonate. A solution of substituted-2-
thiopyrimidine (0.1 mol) 1 in aq. sodium hydroxide (8.0 g, 0.2 mol) was
added slowly at 15–20◦C and stirred at room temperature for 3–4 h. The
reaction was monitored by TLC. The contents were cooled and acidified
to pH 2–4 using hydrochloric acid. The resulting solids that separated
were filtered, washed with water, dried, and recrystallized from ethanol.

1398
B. Kalluraya et al.
5-(4,6-Disubtituted-pyrimidine-2-thiomethyl)-4-amino-3-
mercapto-1,2,4-triazole 3
Substitued-pyrimidine-2-thioaceticacid (0.02 mol) 2 and thiocarbohy-
drazide (2.12 gm, 0.02 mol) were taken in a round-bottom flask and
heated under stirring in an oil bath to form a clear solution. Completion
of the reaction was monitored by TLC. The contents were cooled to room
temperature diluted with water. The solid that separated was filtered,
washed with saturated sodium bicarbonate solution, and dried. Further
purification was done by recrystallization from ethanol (Scheme 1). The
compounds prepared as per this procedure are listed in Table I.
TABLE I Characterization Data of Newly Synthesized
5-(4,6-disubstituted-2-thiomethyl Pyrimidyl)-4-amino-3-mercapto-
1,2,4-triazoles (3a–c) and 4-[5-(4,6-disubstituted-2-thiomethyl
Pyrimidyl)-4ꢀ-amino-1,2-4-triazol-3ꢀ-yl]-thioacetyl-3ꢀ-arylsydnones 7a–i
Analysis (%)
Found (Calculated)
Compound
No.
m.p.◦C
(Yield %) (Mol. Weight)
Mol. Formula
R
R1
H
R2
—
C
H
N
3a
3b
3c
7a
7b
7c
7d
7e
7f
H
112–114
(74)
C7H8N6S2
(240)
35.09
(35.00) (3.33)
37.72 3.90
3.32
34.98
(35)
33.03
CH3
H
—
—
116–120
(78)
C8H10N6S2
(254)
(37.79) (3.93) (33.07)
40.19 4.45 31.30
(40.23) (4.47) (31.34)
3.14 25.35
(46.15) (3.16) (25.33)
167–169 C18H16N8O3S2 47.40 3.52 24.51
(65) (456) (47.36) (3.50) (24.56)
190–94 C18H16N8O4S2 45.81 3.35 23.68
(74) (472) (45.76) (3.39) (23.72)
160–164 C18H16N8O3S2 47.30 3.52 24.61
(75) (456) (47.36) (3.50) (24.56)
188–190 C19H18N8O3S2 48.55 3.80 23.79
(80) (470) (48.51) (3.82) (23.82)
OCH3 198–200 C19H18N8O4S2 46.91 3.68 23.08
(85) (486) (46.87) (3.70) (23.04)
158–162 C19H18N8O3S2 48.56 3.79 23.77
(80) (470) (48.51) (3.82) (23.82)
172–176 C20H20N8O3S2 49.55 4.15 23.18
(82) (484) (49.58) (4.13) (23.14)
CH3 CH3 OCH3 194–197 C20H20N8O4S2 48.05 3.98 22.36
(78) (500) (48.00) (4.00) (22.40)
CH3 CH3
154–158
(75)
C9H12N6S2
(268)
H
H
H
H
H
H
H
H
H
158–160 C17H14N8O3S2 46.10
(75) (442)
CH3
OCH3
H
H
CH3
CH3
CH3
CH3
7g
7h
7i
CH3 CH3‘
CH3 CH3
H
CH3

Triazol-Arylsydnones
1399
TABLE II Selected 1H NMR (δ, ppm) (CDCl3) and MS m/z of the
Compounds
3c. 5-(4,6-Dimethyl-pyrimidine-2-thiomethyl)-4-amino-3-mercapto-1,2,4-triazole
δ, 2.45 (s, 6H, 2 × CH3), 4.5 (s, 2H, S CH2), 4.9 (s, 2H, NH2), 6.75 (s, 1H, pyrimidine-5H)
and 10.5 (s, 1H, SH). Mass: m/z, 269 (M++1) consistent with the molecular
formula C9H12N6S2.
7d. 4-[5-(4-methyl-2-thiomethylpyrimidyl)-4ꢀ-amino-1,2-4-triazol-3ꢀ-yl]-thioacetyl-3-(p-
phenyl) sydnone.
δ, 2.41 (s, 3H, Pyrimidine-CH3), 3.91 (s, 2H, S CH2), 4.68 (s, 2H, S CH2
C O),
5.12 (s, 2H, NH2), 6.80 (d, 1H, pyrimidine-5H), 7.0–7.82 (m, 5H, Ar H) and 8.20
(d, 1H, pyrimidine-6H). Mass: m/z, 457(M++1) consistent with the molecular formula
C18H16N8O3S2.
7e. 4-[5-(4-methyl-2-thiomethylpyrimidyl)-4ꢀ-amino-1,2-4-triazol-3ꢀ-yl]-thioacetyl-3-(p-
tolyl) sydnone
δ, 1.66 (s, 3H, Ar CH3), 2.43 (s, 3H, Pyrimidine-CH3), 3.92 (s, 2H, S CH2), 4.64 (s,
2H, S CH2
C O), 5.1 (s, 2H, NH2), 6.85 (d, 1H, pyrimidine-5H) 7.1 (d, 2H, ortho-
protons of p-tolyl) 7.26 (d, 2H meta-protons of p-tolyl) and 8.26 (d, 1H, pyrimidine-
6H). Mass: m/z, 471(M++1) consistent with the molecular formula C19H18N8O3S2.
7g. 4-[5-(4,6-Dimethyl-2-thiomethylpyrimidyl)-4ꢀ-amino-1,2-4-triazol-3ꢀ-yl]-thioacetyl-
3-(p-phenyl) sydnone
δ, 2.23 (s, 6H, 2 × CH3 of Pyrimidine), 4.43 (s, 2H, S CH2), 4.54 (s, 2H, S CH2
C O),
4.9 (s, 2H, NH2), 6.76 (s, 1H, pyrimidine-5H) and 7.2–7.76 (m, 5H, Ar H). Mass: m/z,
471 (M++1) consistent with the molecular formula C19H18N8O3S2.
7h. 4-[5-(4,6-Dimethyl-2-thiomethylpyrimidyl)-4ꢀ-amino-1,2-4-triazol-3ꢀ-yl]-thioacetyl-
3-(p-tolyl) sydnone
δ, 1.86 (s, 3H, Ar CH3), 2.22 (s, 6H, 2 × CH3 of Pyrimidine), 4.4 (s, 2H, S CH2),
4.53 (s, 2H, S CH2
C O), 4.9 (s, 2H, NH2), 6.61 (s, 1H, pyrimidine-5H) 7.15 (d, 2H,
ortho-protons of p-tolyl) and 7.25 (d, 2H meta-protons of p-tolyl). Mass: m/z, 485
(M++1) consistent with the molecular formula C20H20N8O3S2.
7i. 4-[5-(4,6-Dimethyl-2-thiomethylpyrimidyl)-4ꢀ-amino-1,2-4-triazol-3ꢀ-yl]-thioacetyl-3-
(p-anisyl) sydnone
δ, 2.24 (s, 6H, 2 × CH3 of Pyrimidine), 3.89 (s, 3H, OCH3), 4.52 (s, 2H, S CH2), 4.65
(s, 2H, S CH2
C O), 5.7 (s, 2H, NH2), 7.25 (d, 2H, ortho-protons of p-anisyl) and
7.54 (d, 2H meta-protons of p-anisyl), 6.66 (s, 1H, pyrimidine-5H). Mass: m/z,
501(M++1), consistent with the molecular formula C20H20N8O4S2.
4-[5-(4,6-Disubstituted-2-thiomethylpyrimidyl)-4ꢀ-amino-1,2-4-
triazol-3ꢀ-yl]-thioacetyl-3-arylsydnone 7
A
solution of 5-substituted-4-amino-3-mercapto-1,2,4-triazole
3
(0.01 mol) and appropriate bromoacetyl sydnones 6 (0.01 mol) in
ethanol (20 mL) and sodium acetate (0.86 g, 0.001 mol) was refluxed on
a water bath for 2–3 h. Completion of the reaction was monitored by
TLC. On cooling the contents to room temperature, the solid mass that
separated was collected by filtration and recrystallized from ethanol
(Scheme 3). The compounds prepared as per this procedure are listed
in Table I.

1400
B. Kalluraya et al.
TABLE III Antibacterial Activity of Compounds 7 at 10-µg/mL
Concentration (Diameter of Zone of Inhibition in mm)
Compound No.
E. coli
Serratia marcesens
7a
7b
7c
7d
7e
7f
7g
7h
23
16
19
15
11
22
19
10
15
25
12
17
11
15
13
15
10
14
14
19
7i
Tetracyclin (Std.)
Antibacterial Activity
The newly synthesized compounds were screened for their antibacte-
rial activity in vitro against Gram-positive bacteria E. coli and Gram-
negative bacteria Serratia marcesens by the disk diffusion method.20
The test compounds were dissolved in N,N-dimethylformamide (DMF)
to obtain a solution of 10-µg/mL concentration. The inhibition zones
of microbial growth produced by different compounds were measured
in millimeters at the end of an incubation period of 48 h at 37◦C. DMF
alone showed no inhibition zone. Tetracyclin was employed as the refer-
ence standard (10 µg) to evaluate the potency of the tested compounds.
The results are illustrated in Table III.
TABLE IV Antifungal Activity of Compounds 7 at 10-µg/mL
Concentration (Diameter of Zone of Inhibition in mm)
Compound No.
Aspergillus niger
Pencillium
7a
7b
7c
7d
7e
7f
7g
7h
17
22
21
15
15
24
24
19
21
25
22
25
22
21
16
18
22
18
29
22
7i
Flukanozole (Std.)

Triazol-Arylsydnones
1401
Antifungal Activity
Newly synthesized compounds were also screened for their antifungal
activity against two species of fungi, Aspergillus niger and Pencillium,
using the disk diffusion method.20 The test compounds were dissolved
in DMF to get a solution of 10-µg/mL concentration. The inhibition
zones were measured in millimeters at the end of an incubation period
of 48 h at 37◦C. Flukanozole was used as a reference standard, and the
results were shown in Table IV. Most of the tested compounds showed
significant antifungal activity comparable with that of the standard
drug Flukanozole.
CONCLUSION
A new series of pyrimidine- and sydnone-bearing triazoles were re-
ported with a view to evaluate their biological activity. However, the
testing results indicated that they are more potent antifungal agents
comparable with the standard drug Flukanazole.
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