Synthesis of some new biologically active thiadiazolotriazinones - Part II

Article abstract of DOI:10.1016/S0014-827X(99)00008-7

4-Amino-6-phenyl/methyl-3-mercapto-1,2,4-triazin-5(4H)-ones (1) are condensed with an aromatic carboxylic acid, aryloxyacetic acid or anilinoacetic acid (2), to yield 7-substituted-3-phenyl/methyl-4H-1,3,4-thiadiazolo-[2,3-c]-1,2,4-triazin-4-ones (3). Phosphorus oxychloride is used as a cyclizing agent. All the synthesized compounds are screened for their antibacterial activities against S. aureus, E. coli, P. aeruginosa and G. bacillus.

Full text of DOI:10.1016/S0014-827X(99)00008-7

Il Farmaco 54 (1999) 149–151
Synthesis of some new biologically active
thiadiazolotriazinones—Part IIꢀ
B. Shivarama Holla a,*, B.K. Sarojini a, K. Shridhara b, Georgy Antony c
a Mangalore Uni6ersity, Department of Post Graduate Studies and Research in Chemistry, Mangalagangothri 574 199, India
b Rallies Agrochemical Research Station, Plot No. 21 and 22 Phase II, Peenya, Bangalore 560 058, India
c Kasturba Medical College, Department of Microbiology, Mangalore 575 001, India
Abstract
4-Amino-6-phenyl/methyl-3-mercapto-1,2,4-triazin-5(4H)-ones (1) are condensed with an aromatic carboxylic acid, aryloxy-
acetic acid or anilinoacetic acid (2), to yield 7-substituted-3-phenyl/methyl-4H-1,3,4-thiadiazolo-[2,3-c]-1,2,4-triazin-4-ones (3).
Phosphorus oxychloride is used as a cyclizing agent. All the synthesized compounds are screened for their antibacterial activities
against S. aureus, E. coli, P. aeruginosa and G. bacillus. © 1999 Elsevier Science S.A. All rights reserved.
Keywords: Triazinones; Aryloxyacetic acids; Anilinoacetic acids; Thiadiazolotriazinones; Antibacterial activities
1. Introduction
zolotriazinones was confirmed by elemental analysis
and spectral studies.
In continuation of our studies on condensed hetero-
cycles [1], several 4-amino-6-phenyl/methyl-3-mercapto-
1,2,4-triazin-5(4H)-ones were prepared and condensed
with aryloxyacetic acids and anilinoacetic acids to yield
new thiadiazolotriazinones. All of these synthesized
thiadiazolotriazinones were screened for their antibacte-
rial activities. Results of these studies are discussed in
this paper.
All the newly synthesized compounds gave satisfac-
tory analyses for their nitrogen content. The formation
of these cyclized products was confirmed by recording
the proton magnetic resonance (PMR) spectra of some
of the selected compounds. The PMR spectrum of 3f
showed a sharp singlet at l 5.68, integrating two pro-
tons which is characteristic of –OCH2 protons of the
aryloxymethyl group. A singlet observed at l 2.54 was
due to the presence of the –CH3 group. The aromatic
protons resonated as a multiplet in the range l 7.27–
7.32. The PMR spectrum of 3j showed a singlet at l
5.65, integrating two protons due to the –OCH2 group.
The phenyl protons were observed as a multiplet in the
range l 7.53–7.58. Aromatic protons of the p-
chlorophenyl ring appeared as two doublets at l 7.47–
7.50 (J=9 Hz) and l 7.16–7.19 (J=9 Hz) respectively.
The disappearance of the singlet due to –SH protons at
l 13.8 of the parent triazinones in the cyclized products
3f and 3j confirmed the involvement of the –SH proton
in the condensation reaction.
2. Chemistry
Pyruvic acid and benzoylformic acid were allowed to
react with thiocarbohydrazide to yield 4-amino-3-mer-
capto-6-methyl/phenyl-1,2,4-triazin-5(4H)-ones (1) [2],
respectively. These triazinones were condensed with an
aromatic carboxylic acid, aryloxyacetic acid and anili-
noacetic acid in the presence of phosphorus oxychloride
to yield 7-substituted-3-phenyl/methyl-1,2,4-thiadiazolo-
[2,3-c]-1,2,4-triazin-4-ones. Aryloxyacetic acids and
anilinoacetic acids were prepared from the correspond-
ing phenols and anilines. Formation of these thiadia-
The mass spectrum of the product 3a showed a
molecular ion peak at m/z=278/280, which is consis-
tent with molecular formula C11H7ClN4OS. The molec-
ular ion underwent fragmentations with the loss of
carbon monoxide and produced an ion at m/z=250.
This ion underwent further fragmentation to give an
ꢀ Presented at the 34th Annual Convention of Chemists 1997,
December 17–20, University of Delhi, Delhi-110007, India.
* Corresponding author.
0014-827X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(99)00008-7

150
B.S. Holla et al. / Il Farmaco 54 (1999) 149–151
ion at m/z=155 as a base peak. The mass spectrum of
3f showed a molecular ion peak at m/z=342/344/346
which was in accordance with the molecular formula
C12H8Cl2N4O2S. The molecular ion underwent frag-
mentation with the loss of carbon monoxide to yield an
ion at m/z=314. This ion underwent further fragmen-
tation with the loss of the aryloxy radical to produce an
ion at m/z=153. Compound 3j showed a molecular ion
peak at m/z=370/372 which confirmed the assigned
molecular formula C17H11ClN4O2S. The fragmentation
pattern of compound 3j was similar to that of 3f. The
mass spectrum of the product 3o did not show a
molecular ion peak; however, it showed an intense peak
at m/z=282 accounting for the loss of carbon monox-
ide and phenyl radical from the molecular ion.
recorded on a VG micromass mass spectrometer oper-
ating at 70 eV. Purity of the compound was checked by
TLC on silica gel plates using a benzene–methanol
(9:1) solvent system and iodine was used as visualizing
agent. Phenyl/methyl amino mercapto triazinones (1)
were prepared according to the method reported in the
literature [2].
3.1. General procedure for the preparation of
7-substituted-3-phenyl/methyl-1,3,4-thiadiazolo[2,3-c]-
1,2,4-triazin-4-ones (3a–o)
A mixture of triazinone (1, 10 mmol), substituted
carboxylic acid (2, 10 mmol) and phosphorus oxychlo-
ride (10 ml) was refluxed for about 5 h on a water bath.
Excess of phosphorus oxychloride was removed under
reduced pressure. The reaction mixture was cooled and
poured onto crushed ice (200 g). The resulting solid
product was filtered, washed with aqueous (2%) sodium
bicarbonate solution, followed by water. It was dried
and recrystallized from suitable solvents. The character-
ization data of thiadiazolotriazinones (3a–o) prepared
according to this method are given in Table 1.
3. Chemical experimental section
Melting points were taken in open capillaries and
were uncorrected. PMR spectra were recorded in
DMSO-d6 on a JEOL GX 400–400 MHz spectrometer
using TMS as an internal standard. Mass spectra were
Table 1
Analytical data of 7-substituted-3-methyl/phenyl-4H-1,2,4-thiadiazolo[2,3-c]1,2,4-triazin-4-one
Comp.
R
R1
Yield (%)
M.p. (°C)
Molecular formula
Analysis (%N)
Found
Calc.
3aa
3b
3c
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
2-Chlorophenyl
70
90
85
86
89
78
69
85
63
96
90
73
88
53
57
205–207
205–207
200–202
140–142
240–242
258–260
220–222
195–197
205–207
245–247
220–222
260–262
180–185
205–207
200–202
C11H7ClN4OS
C13H12N4O2S
19.88
19.20
19.21
18.50
17.29
16.25
22.78
19.50
21.48
15.50
14.30
13.53
18.50
16.50
18.56
20.10
19.44
19.44
18.18
17.39
16.37
22.80
19.94
21.54
15.53
14.58
13.86
18.98
16.94
18.87
4-Methyl-phenoxymethyl
2-Methyl-phenoxymethyl
4-Chloro-phenoxymethyl
4-Chloro-3-methyl-phenoxymethyl
2,3-Dichloro-phenoxymethyl
4-Chloro-anilinomethyl
C
13H12N4O2S
3d
3e
C12H9ClN4O2S
C13H11ClN4O2S
C12H8Cl2N4O2S
C12H10ClN5OS
C12H10BrN5OS
C12H9ClFN5OS
C17H11ClN4O2S
C18H13Cl2N4O2S
C17H10Cl2N4O2S
C17H12ClN5OS
C17H12BrN5OS
C17H11ClFNF5OS
3fb
3g
3h
3i
4-Bromo-anilinomethyl
3-Chloro-4-fluoro-anilinomethyl
4-Chloro-phenoxymethyl
4-Chloro-3-methyl-phenoxymethyl
2,3-Dichloro-phenoxymethyl
4-Chloro-anilinomethyl
3jc
3k
3l
3m
3n
3od
4-Bromo-anilinomethyl
3-Chloro-4-fluoro-anilinomethyl
a MS: m/z=278 [M+], m/z=280 [M+2], m/z=250 [M−CO]+
.
b MS: m/z=342 [M+], m/z=344 [M+2], m/z=346 [M+4], m/z=314 [M−CO], m/z=153 [M−CO-aryloxy radical]. PMR (DMSO-d6): l
5.6 (s, 2H, aryloxymethyl), l 2.5 (m, 3H, methyl protons), l 7.3 (m, 3H, aromatic protons).
c PMR (DMSO-d6): l 5.5 (s, 2H, aryloxymethyl), l 7.2 (m, 5H, aromatic protons), l 8.1 (d, 2H, J=9 Hz, aromatic protons), l 8.2 (d, 2H, J=9
Hz, aromatic protons).
d MS: m/z=282 [(M−CO)-phenyl radical]+, m/z=145 [C6H5ClFN]+
.

B.S. Holla et al. / Il Farmaco 54 (1999) 149–151
151
Table 2
All the compounds showed antibacterial activity
without very specific preference among the tested bacte-
rial strains (wide spectrum of action). The highest activ-
ity was shown by compounds 3b and 3d against G.
bacillus. This activity may be promising and stimulating
for further studies on this kind of compound.
Antibacterial activity data of thiadiazolotriazinones (minimum in-
hibitory concentration, mg/ml)
Comp.
S. aureus
E. coli
P. aeruginosa
G. bacillus
3a
3b
3c
12.5
12.5
6
6
6
6
12.5
12.5
6
12.5
3
6
3d
6
6
6
3
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
6
12.5
6
12.5
6
12.5
12.5
12.5
12.5
12.5
6
12.5
6
12.5
6
6
6
6
6
6
12.5
6
6
6
12.5
12.5
12.5
6
12.5
6
Acknowledgements
The authors thank the Head, RSIC, Punjab Univer-
sity, Chandigarh, and the Head, RSIC, IIT, Madras,
for providing elemental analyses, mass and NMR spec-
tra of the compounds reported herein. The authors are
also grateful to Dr. Shalini Shenoy for providing facili-
ties to carry out the antimicrobial screening studies.
6
6
12.5
12.5
12.5
12.5
12.5
6
12.5
12.5
12.5
6
12.5
6
3o
Furacin
12.5
6
12.5
12.5
References
3.2. Antibacterial acti6ity
[1] B.S. Holla, B.K. Sarojini, R. Gonsalves, Synthesis of some new
biologically active thiadiazolo triazinones, Farmaco 53 (1998)
395–398 and references cited therein.
[2] A. Dornow, H. Mengel, P. Marx, Preparation of new s-triazolo
[3,2-c]-as-triazines. Ber. 97 2173, (1964); Chem Abstr. 61 (1964)
11999d.
[3] R. Cruickshank, J.P. Marmion, R.H.A. Swain, Medical Microbi-
ology, vol. 11, Churchill Livingstone, London and New York,
1975, p. 190.
All the newly synthesized compounds were screened
for their in vitro antibacterial activity against G. bacil-
lus, P. aeruginosa, E. coli and S. aureus according to the
serial dilution technique [3]. Furacin was used as a
standard drug. The results of the screening studies are
given in Table 2.
.