Synthesis of some new fluorine containing thiadiazolotriazinones as potential antibacterial agents

Article abstract of DOI:10.1080/713744567

2,4-dichloro-5-fluorophenyl, 4-fluoro-3-(Phenoxy)phenyl, 4-fluorophenyl groups are known pharmacophores and can be used in the synthesis of new biologically active molecules. Therefore, 4-amino-6-arylmethyl-3-mercapto-1,2,4- triazin5(4H)-ones 1 are conden

Full text of DOI:10.1080/713744567

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of Some New Fluorine Containing
Thiadiazolotriazinones as Potential Antibacterial
Agents
B. Shivarama Holla a , K. Subrahmanya Bhat a & N. Suchetha Shetty b
a Mangalore University , Mangalagangotri, India
b Justice K. S. Hegde Medical Academy , Deralakatte, Mangalore, India
Published online: 27 Oct 2010.
To cite this article: B. Shivarama Holla , K. Subrahmanya Bhat & N. Suchetha Shetty (2003) Synthesis of Some New Fluorine
Containing Thiadiazolotriazinones as Potential Antibacterial Agents, Phosphorus, Sulfur, and Silicon and the Related Elements,
178:10, 2193-2199, DOI: 10.1080/713744567
To link to this article: http://dx.doi.org/10.1080/713744567
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Phosphorus, Sulfur, and Silicon, 178:2193–2199, 2003
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ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500390228864
SYNTHESIS OF SOME NEW FLUORINE
CONTAINING THIADIAZOLOTRIAZINONES
AS POTENTIAL ANTIBACTERIAL AGENTS
B. Shivarama Holla,a K. Subrahmanya Bhat,a
and N. Suchetha Shettyb
Mangalore University, Mangalagangotri, Indiaa and Justice
K. S. Hegde Medical Academy, Deralakatte, Mangalore, Indiab
(Received February 19, 2003; accepted April 24, 2003)
2,4-dichloro-5-fluorophenyl, 4-fluoro-3-(Phenoxy)phenyl, 4-fluorophen-
yl groups are known pharmacophores and can be used in the syn-
thesis of new biologically active molecules. Therefore, 4-amino-6-
arylmethyl-3-mercapto-1,2,4-triazin5(4H)-ones 1 are condensed with
3-phenoxy-4-fluoro-benzoic acid, 2,4-dichloro-5-fluorobenzoic acid, and
4-fluorobenzoic acid 2 to give 7-substituted-3-arylmethyl-4H-1,3,4-
thiadiazolo[2,3-c]-1,2,4-triazin-4-ones 3. Phosphorous oxychloride was
used as cyclizing agent. All the newly synthesized compounds 3a-l was
screened for their antibacterial activities. Most of them showed promis-
ing activity in the range of 10 µg/mL concentrations.
Keywords: Antibacterial activity; fluoroheterocycles; thiadiazolotriazi-
nones
Several thiadiazoles find important application in medicine, agricul-
ture, and industry. Triazinones also are used as effective herbicides
and fungicides.1–4 In continuation on our studies on the synthesis of
biologically active thiadiazolotriazinones5 and in an attempt to signifi-
cantly improve their antibacterial activity, we considered substitution
at C-7 position by fluorophenyl moieties. Our earlier attempt of modify-
ing the structure by halophenylfuranyl moiety significantly enhanced
their antibacterial activity.6 It has been reported that substitution of
hydrogen or methyl group in a biologically active unit by a fluorine
or trifluromethyl group enhances the biological activity.7 It was hoped
We would like to thank RSIC, IIT Madras for spectral data. KSB is thankful to
CSIR, New Delhi for the award of Junior Research Fellowship. We are also thankful
to Rallies India Ltd., Bangalore for gift sample of 4-fluoro-3-phenoxybenzaldehyde.
Address correspondence to B. S. Holla, Department of Chemistry, Mangalore Univer-
sity, Mangalagangotri-574199, India. E-mail: hollabs@yahoo.com
2193

2194
B. S. Holla et al.
that these compounds (Structure 3), would improve the antibacterial
activity due to the introduction of 2,4-dichloro-5-fluorophenyl, 4-fluoro-
3-(Phenoxy)-phenyl, and 4-fluorophenyl substitutions at position-7 of
thiadiazolotriazinones. Further it is known that incorporation of fluo-
rine atom in the ring modifies its properties by enhancing the solubility
and thermal stability.8–9
RESULTS AND DISCUSSION
For the present work four 6-arylmethyl-4-amino-3-mercapto-1,2,4-
triazin-6(4H)-ones (R = 4-chlorobenzyl, piperanylbenzyl, 2,4-dichloro-
benzyl) were prepared by condensing the respective azalac-
tones with thiocarbohydrazide or by reaction of arylpyruvic acid
with thiocarbohydrazide.10 The 6-tert-butyl-4-amino-3-mercapto-1,2,4-
triazin-5(4H)-one was obtained commercially used after recrystal-
lization from ethanol. The required 4-fluoro-3-phenoxy-benzoic acid
was prepared from its aldehyde by oxidation using hydrogen perox-
ide/acetic acid mixture. 2,4-Dichloro-5-fluorobenzoic acid was prepared
from 2,4-dichloro-5-fluoro acetophenone by haloform reaction, whereas
4-fluorobenzoic acid was obtained commercially. The triazinones
were then condensed with fluorine containing acids in the presence
of phosphorous oxychloride-acetonitrile/dry toluene to afford 7-
(substituted phenyl)-3-arylmethyl/tert-butyl-4H-1,3,4-thiadiazolo[2,3-
c]-1,2,4-triazin-4-ones in 75–90% yield. Formation of these thiadiazolo-
triazinones was confirmed by elemental analysis, IR, 1H NMR, and
mass spectral data. In the IR spectrum of compound 3b showed char-
acteristic absorptions at 3100(Ar CH str.), 2960(CH3 str.), 1680(C O
str.), 1445(C N str.), 1200(C O str.), 1110 (C F str.) in conformity with
1
the structure assigned. The H NMR spectrum showed a singlet at δ
1.5 integrating for 9 protons assigned to t-butyl group. The multiplets
observed in the range 7.3–7.9, integrating for 8 protons were due to
aromatic protons. The mass spectrum of compound showed molecular
ion peak at m/z 396, followed by fragment ion at m/z 381 due to loss of
methyl group from molecular ion. An intense peak observed at m/z 231

Thiadiazolotriazinones as Potential Antibacterial Agents
2195
was due to the formation of 4-fluoro-(3-phenoxy)-thiobenzoyl cation. A
peak at m/z 187 and 77 was assigned to 4-fluoro-(3-phenoxy)-phenyl
and phenyl cation respectively. The physical data of these compounds
are given in Table I. Spectral data for some of the compounds are given
in Table II.
Antibacterial Activity
All the newly synthesized compounds were screened for their in vitro
antibacterial activity against Escherichia coli, Pseudomonas aerugi-
nosa, Klebsiella sp, and staphylococcus aureus Smith according to serial
dilution technique.11 Nitrofurazone was used as the standard drug. All
the tested compounds (Table III) showed good to moderate antibacterial
activities against tested bacterial strains. It is interesting to note that
the compounds are selective against staphylococcus aureus and Kleb-
siella sp. However, none of the compounds are active against pathogenic
bacteria Pseudomonas aeruginosa at lesser than 50 µg/ml concentra-
tions. Comparing the antibacterial activities of these compounds with
our earlier work,5 it is evident that the introduction of fluorophenyl
moiety significantly enhanced the antibacterial activities.
EXPERIMENTAL
Melting points were taken in open capillary tubes and are uncor-
rected. The IR spectra in KBr disc were recorded on a Shimadzu FT IR
TABLE I Characterization Data of Thiadiazolotriazinones (3a-l)
Comp
no.
Yield
R
Rꢁ
M.P (◦C) (%)
Mol. form.
3a
3b
3c
3d
3e
3f
3g
3h
3i
C(CH3)3
C(CH3)3
C(CH3)3
4-Cl C6H4 CH2
4-Cl C6H4CH2
4-Cl C6H4 CH2
3,4-O2CH2 C6H3 CH2 4-F
3,4-O2CH2 C6H3 CH2 4-F-3-(OC6H5) 192–93
3,4-O2CH2 C6H3 CH2 2,4-Cl2-5-F
4-F
188–90
85 C14H13FN4OS
4-F-3-(OC6H5) 134–35
2,4-Cl2-5-F
4-F
4-F-3-(OC6H5) 184–85
2,4-Cl2-5-F
85 C20H17FN4O2S
80 C14H11Cl2FN4OS
90 C17H10ClFN4OS
78 C23H14ClFN4O2S
76 C17H8Cl3FN4OS
80 C18H11FN4O3S
75 C24H15FN4O4S
78 C18H9Cl2FN4O3S
82 C17H9Cl2FN4OS
80 C23H13Cl2FN4O2S
80 C17H7Cl4FN4OS
148–50
208–10
166–67
205–05
156–58
176–78
3j
3k
3l
2,4-Cl2 C6H3 CH2
2,4-Cl2 C6H3 CH2
2,4-Cl2 C6H3 CH2
4-F
4-F-3-(OC6H5) 142–44
2,4-Cl2-5-F 186–87
aCompounds showed satisfactory microanalysis.
bReported yields are after recrystallization.
cThe compounds were crystallized from ethanol + dioxan mixture.

2196
B. S. Holla et al.
TABLE II Spectral Characterization Data of the Compounds (3b, 3i, and 3k)
Compd
no.
1H NMR
(δ, ppm)
IR (cm−1
)
Mass (EIMS, m/z)
3b
3100(Ar CH str.), 2960(CH3 1.5(s, 9H,
m/z: 396(M+), 381(M+ −15,
loss of methyl group),
231(4-fluoro-(3-phenoxy)-
thiobenzoyl cation),
183(4-fluoro-(3-phenoxy)-
phenyl cation), 77(phenyl
cation)
str.), 1680(C O str.),
1445(C N str.),
1200(C O str.), 1110
(C F str.)
C(CH3)3,
7.3–7.9(m, 8H,
Ar H)
3i
3150(Ar CH str.), 2965(CH2 4.1(s, 2H, CH2 ),
—
str.), 1680 (C O str.),
1445 (C N str.),
4.9(s, 2H,
O
CH2 O),
1240(C O str.), 1180(C
F
7.3–7.9(m, 5H,
str.), 1040/890(C Cl str.)
Ar H)
3k
3150(Ar CH str.), 2975(CH2 4.4(s, 2H, CH2 ), m/z: 463(M+ −35, loss of
str.), 1680(C O str.), 1460
7.2–7.9(m, 11H,
Ar H)
Chlorine), 231(4-fluoro-(3-
phenoxy)-thiobenzoyl
(C N str.), 1260(C
O
str.), 1180 (C F str.),
840/790 (C Cl str.)
cation), 77(phenyl cation)
aHigher Ar CH stretch may be due to the presence of fluorine in the ring.
bRecorded using DMSO-d6 or CDCl3 as solvents.
TABLE III Antibacterial Activity Data of Triazinothiadiazoles
(MIC in µg/ml) (3a-l)
Bacteria tested
Compd
no.
E. coli
P. aeruginosa
S. aureus
Klebsiella sps.
3a
—
—
50
50
20
20
20
20
20
10
10
10
—
—
—
4
4
200
100
100
200
100
100
50
50
50
20
50
3b
3c
3d
3e
3f
3g
3h
3i
10
20
10
10
20
10
10
10
20
10
—
100
100
100
—
50
50
3j
3k
3l
50
50
50
aIndicates the bacteria is resistant to the compounds at the maximum
tested concentration, i.e., at 200 µg/ml.
MIC = Minimum Inhibitory Concentration.

Thiadiazolotriazinones as Potential Antibacterial Agents
2197
spectrophotometer. 1H NMR spectra were recorded in CDCl3-DMSO-d6
on a Bruker AC-300F (300 MHz) NMR spectrometer using TMS as an
internal standard. The mass spectra were recorded on a JEOL-JMS
D-300 mass spectrometer operating at 70 eV. Purity of the compounds
was checked by thin layer chromatography (TLC) on silica gel plates
using a hexane: chloroform (4:1) solvent system. Iodine was used as the
visualizing agent. Triazinones were prepared according to literature
method.10
General Procedure for the Preparation
of 4-Fluoro-3-phenoxy Benzoic Acid
4-Fluoro-3-phenoxy benzaldehyde (0.01 mmol) in 10 ml of alcohol was
added excess hydrogen peroxide and catalytic amount of acetic acid.
The reaction mixture was refluxed on a water bath for 4 h. The excess
of solvent was distilled off. The reaction mixture was cooled, washed
with cold water, and the separated solid was filtered and dried. It was
recrystallized from ethanol. m.p. 126◦C, yield 100%.
General Procedure for the Preparation
of 2,4-Dichloro-5-fluorobenzoic Acid
2,4-Dichloro-5-fluoro acetophenone ( 0.01 mmol) was dissolved in
minimum amount of ethanol. To it excess of Sodium hydroxide solu-
tion (pH is maintained at 8–10) was added and chlorine gas was passed
for 6 h. The solution was made acidic. The separated solid was filtered,
washed with cold water and dried. Yield of 2,4-dichloro-5-fluorobenzoic
acid is nearly quantitative, m.p: 144◦C.
Preparation of 4-Amino-6-arylmethyl-3-mercapto-1,2,4-
triazin-5(4H)-ones 1
To a solution of thiocarbohydrazide (1.06 g, 0.01 mmol) in warm water
(30 ml) was added dropwise a solution of arylpyruvic acid (0.01 mmol) in
ethanol with stirring. The reaction mixture was stirred on a water bath
for 2 h. The solid product thus separated was filtered and recrystallized
from ethanol to give triazinones 1. Their physical data is in agreement
with the values reported by us earlier.10
General Procedure for the Preparation of 7-(Substituted
phenyl)-3-arylmethyl/tert-butyl-4H-1,3,4-thiadiazolo-
[2,3-c]-1,2,4-triazin-4-ones 3
To a mixture of triazinones (0.01 mmol), 4-fluoro-3-phenoxy
benzoic acid/2,4-Dichloro-5-fluorobenzoic acid/4-fluorobenzoic acid
(0.012 mmol) in 20 ml of dry Acetonitrile/toluene was added 50 ml
of phosphorous oxychloride was added drop wise. The mixture was

2198
B. S. Holla et al.
SCHEME 1 Condensation of triazinones 1 with fluorobenzoic acids 2.
refluxed on an oil bath for 6 h. Excess of phosphorous oxychloride was
removed by distillation under reduced pressure. The reaction mixture
was cooled and poured onto crushed ice. The resulting solid product
was filtered, washed with sodium bicarbonate solution (2%), followed
by cold water. It was dried and recrystallized from dioxan and ethanol
mixture. The yield and characterization data of thiadiazolotriazinones
prepared according to this method are given in Table I.
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Thiadiazolotriazinones as Potential Antibacterial Agents
2199
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