Antifungal activity of new 1,3,4-oxadiazolo[3,2-a]-s-triazine-5,7-diones and their 5-thioxo-7-ones

Article abstract of DOI:10.1021/jf990742f

N¹- and N³-(4-fluorophenyl) ureas (III a-e) were cyclocondensed with ethyl chloroformate and CS₂/ KOH to yield 2-aryl-6-(4-fluorophenyl)-1,3,4-oxadiazolo[3,2-a]-s-triazine-5,7-diones (IVa-e) and their 5-thioxo-7-ones (Va-e

Full text of DOI:10.1021/jf990742f

J. Agric. Food Chem. 2000, 48, 5465−5468
5465
An tifu n ga l Activity of New
1,3,4-oxa d ia zolo[3,2-a ]-s-tr ia zin e-5,7-d ion es a n d Th eir 5-th ioxo-7-on es
Atma R. Mishra* and Shailendra Singh
Department of Chemistry, Shri Durga J I Post Graduate College, Chandesar, Azamgarh (U.P.), India
Abdul Wahab
Department of Chemistry, S.N.P.G. College, Azamgarh (U.P.), India
N1- and N3-(4-fluorophenyl) ureas (III a -e) were cyclocondensed with ethyl chloroformate and CS2/
KOH to yield 2-aryl-6-(4-fluorophenyl)-1,3,4-oxadiazolo[3,2-a]-s-triazine-5,7-diones (IVa -e) and their
5-thioxo-7-ones (Va -e), respectively. The compounds III-V(a -e) have been compared with Dithane
M-45 for their fungitoxic action against A. niger and F. oxyporum, and the results have been
correlated with the structural features of the tested compounds.
Keyw or d s: A. niger; F. oxysporum; czapekas agar; DMSO-d6
presence of anhydrous sodium acetate. All five compounds
(Ia -e) have already been reported in the literature (Gibson,
1982; Gehlen and Moeckle, 1962; Hoggarth, 1949).
Eth yl-N-(5-a r yl-1,3,4-oxa d ia zol-2-yl)ca r ba m a tes (IIa -
e). To Ia (6.44 g, 0.04 mol) in pyridine (160 mL) was added
ethyl chloroformate (4.78 g, 0.044 mol) and triethylamine (10
mL), and the mixture was refluxed for 1 h. It was poured into
dilute HCl (320 mL, 50%; V/V), and the carbamate IIa thus
obtained was recrystallized from ethanol, yield 7.00 g (75%),
mp 205-207 °C. Found: C, 56.5; H, 4.7; N, 17.9. C11H11N3O3
requires C, 56.7; H, 4.7; N, 18.0%. IR: 1730 cm-1 υ CdO.
Compounds IIb-c were similarly prepared and were recrys-
tallized from ethanol.
N1- a n d N3-(4-flu or op h en yl)u r ea s (IIIa -e). An equimo-
lar mixture of II and 4-fluoroaniline in ethanol was refluxed
for 16 h and the solvent was distilled off. The residue was
washed with water and recrystallized from ethanol to furnish
the following III in 59-67% yield.
Many 1,3,4-oxadiazoles are associated with a broad
spectrum of pesticidal activity (Meek, 1972; Stachler
and Sachse, 1977; Rhone-Poulenc, 1962). Similarly,
many s-triazine derivatives have attained significance
in agriculture as herbicides and fungicides, including
Simazine (2-chloro-4,6-bis-(ethylamino)-s-triazine), Atra-
zine (2-chloro-4 ethylamino-6-isopropylamino-s-tria-
zine), and others. In 1955, Gysin and co-workers dis-
covered the phytotoxic and plant growth regulating
properties of a series of amino derivatives of triazines
(Gast et al., 1955, 1956). In view of these facts, and with
the hope of achieving pesticidal compounds of high
potency, we have fused the biolabile 1,3,4-oxadiazole
with s-triazine nuclei to probe how this combination
could enhance the pharmacological activity. Thus, the
title nitrogen-bridged heterocyclic systems bearing 5,7-
dione (IVa -e) or 7-one-5-thione functions have been
synthesized and evaluated for their antifungal activity.
Further, all of these compounds possess fluoroaryl
moiety which might be expected to enhance the fungi-
cidal action.
IIIa . mp 230-31°. Found: N, 18.6. C15H11FN4O2 requires
N, 18.8%. IR: 3290 (υ N-H), 1660 cm-1 (υ CdO).
IIIb. mp 225-27°. Found: N,16.9. C15H10ClFN4O2 requires
N, 16.8%. IR: 3300 (υ N-H), 1665 cm-1 (υ CdO).
IIIc-e were similarly prepared, recrystallized from ethanol,
and characterized.
2-Ar yl-6-(4-flu or op h en yl)-1,3,4-oxa d ia zolo [3,2-a ]-s-tr i-
a zin e-5,7-d ion es (IVa -e). To a solution of III (0.01 mol) in
pyridine (40 mL) was added ethyl chloroformate in an ice-bath.
The mixture was stirred at room temperature for 2 h and then
refluxed for 1 h. The contents were treated with 1N KOH (40
mL) and the product thus precipitated was recrystallized from
ethanol, yield 69-78%. The following compounds were pre-
pared.
The reaction sequence leading to the title compounds
is depicted in Scheme I. All of the compounds have been
evaluated for their general pesticidal activity, and two
compounds have been found to have positive antifungal
activity.
EXPERIMENTAL PROCEDURES
IVa . mp 241 °C. Found: C, 59.5; H, 2.6; N, 17.4. C16H9FN4O3
requires C, 59.7; H, 2.7; N, 17.3%. IR: 1705 cm-1 (υ CdO). H
All melting points were determined in open glass capillaries
and are reported uncorrected. Infrared spectra in KBr were
recorded on a Perkin-Elmer 157 infrared spectrophotometer.
1H NMR spectra were recorded on a EM-360 L (60 MHz) NMR
spectrometer in DMSO-d6 using TMS as an internal reference;
chemical shifts are expressed in δ (ppm). All the compounds
have given satisfactory elemental analytical results (C, H, and
N) and IR spectra.
1
NMR: 7.00-8.10 (9H, m, aromatic H).
The compounds thus synthesized are given in Table 1 with
their characterization data.
2-Ar yl-6-(4-flu or op h en y1)-5-th iox-1,3,4-oxa d ia zolo [3,2-
a ]-7-on es (Va -e). A mixture of IIIa (2.98 g, 0.01 mol), ethanol
(40 mL), and carbon disulfide (1.52 g, 0.02 mol) was refluxed
for 6 h and concentrated to a small volume. The contents were
poured into ice-cold water and acidified with dilute HCl to give
the desired product Va in 76% yield; mp 215-17 °C (EtOH).
Found: N, 15.8; S, 9.4%. C16H9FN4O2S requires N, 15.9; S 9.4%.
2-Am in o-5-a r yl-1,3,4-oxa d ia zoles (Ia -e). These com-
pounds were prepared by oxidative cyclization of aldehyde
semicarbazones with bromine in glacial acetic acid in the
10.1021/jf990742f CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/14/2000

5466 J. Agric. Food Chem., Vol. 48, No. 11, 2000
Mishra et al.
Sch em e 1
IR: 1695 (υ CdO), 1090 cm-1 (υ CdS); 1H NMR: 7.00-8.10
(9H, m, aromatic H).
for N-H were present at above δ9.0 and 13.0 ppm in
1
the H NMR spectra of their precursors III.
Other compounds (Vb-e) were similarly synthesized and
their characterization data are given in Table 1. Spectral data
for compounds IV-V (a -e) are given in Table 2. An tifu n ga l
Scr een in g. The compounds III-V(a -e) were screened for
their antifungal activity against A. niger and F. oxyporum for
poisoned food technique (Horsfall, 1945) at 1000, 100, and 10
ppm concentrations using Czapekas agar medium. Suspension
of the compounds in an acetone and water mixture (20:80, V/V)
was applied. A standard, commercial fungicide Dithane M-45,
was also tested under similar conditions for comparison, and
the results are summarized in Table 3.
Effect of Com p ou n d s of th e Typ e III-V on
Mycilia l Gr ow th of F u n gi. The antifungal activity
displayed by the compounds III-V(a -e) is summarized
in Table 3 at 1000, 100, and 10 ppm concentrations. Out
of these, compounds IVb, Vb, and Vc, at 1000 ppm,
exhibited fungitoxicity similar to that of Dithane M-45
against both of the fungi. However, activity of the
compounds decreased markedly at lower concentrations
(100 and 10 ppm) except IVb, Vb, and Vc, which
inhibited 42-45% growth of the fungal species even at
10 ppm.
RESULT AND DISCUSSION
Comparison of fungitoxicity of compounds IV(a -e)
with the corresponding V(a -e) clearly indicates that
the latter (containing >cdo and >cds functions to-
gether) are more active than the former (incorporating
only >cdo groups). This is in confirmity with the earlier
observations that the combination of >cdo and >cds
functions sometimes works better than either alone
(Horsfall and Rich, 1951). In general, the compounds
IV(a -e) and V(a -e) are more potent than their parent
ureas (IIIa -e). This might be attributed to the more
planar and compact structure (Singh et al., 1981;
Summer 1976; Chatt et al., 1956; Rothwell and Wain,
1963) of these compound condensed heterocycles than
Ch a r a cter iza tion of Test Com p ou n d s. All com-
pounds are reported in Table 1 and had satisfactory
elemental analyses. The structural assignments of the
1
compounds were based on their IR and H NMR spectra.
The IR spectra of the type III compounds characteristics
band in the region 3260-3300 and 1660-1675 cm-1
attributable to υN-H and υCdO, respectively. The
disappearance of these bands in the IR spectra of the
type IV and V compounds is comparable with their
assigned structure. Similarly, the absence of peaks
above δ8.00 ppm in the 1H NMR spectra of the com-
pounds IV and V supports their structures, as signals

Antifungal Activity of New 1,3,4-Oxadiazoles
J. Agric. Food Chem., Vol. 48, No. 11, 2000 5467
Ta ble 1. Yield , Meltin g P oin t, Molecu la r F or m u la s, a n d Elem en ta l An a lysis of Com p ou n d s III-V (a -e)
found (calculated), %
compound no.
R
yield (%)
65
mp (°C)
230
molecular formula
C15H11FN4O2
C
H
N
III
IV
V
a
C6H5
60.5
(60.4)
54.1
(54.0)
53.9
(54.0)
58.1
(58.2)
58.0
(58.2)
59.5
(59.7)
53.2
(53.0)
53.1
(53.0)
57.5
(57.6)
57.4
(57.6)
57.8
(57.9)
56.1
(56.0)
55.9
(56.0)
55.1
(55.0)
55.2
3.70
(3.69)
3.1
(3.0)
2.9
(3.0)
3.95
(3.96)
3.97
(3.96)
2.6
(2.7)
2.3
(2.2)
2.2
(2.2)
3.2
(3.0)
3.1
(3.0)
2.54
(2.55)
2.7
(2.6)
2.5
(2.6)
2.8
(2.9)
2.7
18.6
(18.8)
16.9
(16.8)
16.70
(16.8)
17.1
(17.0)
17.2
(17.0)
17.4
(17.3)
15.7
(15.6)
15.7
(15.6)
15.9
(15.8)
15.9
(15.8)
15.8
(15.9)
16.1
(16.0)
16.2
(16.0)
15.1
b
c
d
e
a
b
c
d
e
a
b
c
d
e
2-ClC6H4
4-ClC6H4
2-OMeC6H4
4-OMeC6H4
C6H5
62
66
59
67
69
70
73
75
78
76
82
84
81
86
227
225
210
215
241
250
248
246
245
216
198
228
235
243
C15H10ClFN4O2
C15H10ClFN4O2
C16H13FN4O3
C16H13FN4O3
C16H9FN4O3
2-ClC6H4
4-ClC6H4
2-OMeC6H4
4-OMeC6H4
C6H5
C16H8ClFN4O3
C16H8ClFN4O3
C17H11FN4O4
C17H11FN4O4
C16H9FN4O2S
C16H8ClFN4O2S
C16H8ClFN4O2S
C17H11FN4O3S
C17H11FN4O3S
2-ClC6H4
4-ClC6H4
2-OMeC6H4
4-OMeC6H4
(15.0)
15.2
(55.0)
(2.9)
(15.0)
Ta ble 2. Sp ectr a l Da ta of Com p ou n d s IV-V(a -e)
IR (KBr)‚Cm-1
CdO CdS
compound no.
1H NMR (DMSO-d6)
IV
a
b
c
d
e
a
b
c
d
e
1705
1710
1705
1715
1705
1695
1700
1705
1700
1695
-
-
-
-
7.00-8.10 (9 H, m, aromatic H)
7.00-8.00 (8 H, m, aromatic H)
6.90-8.00 (8 H, m, aromatic H)
3.76 (3 H, s, OCH3), 6.95-7.50 (8 H, m, aromatic H)
3.78 (3 H, s, OCH3), 7.00-7.80 (8 H, m, aromatic H)
7.00-8.10 (9 H, m, aromatic H)
7.20-8.20 (8 H, m, aromatic H)
7.10-8.10 (8 H, m, aromatic H)
3.76 (3 H, s, OCH3), 6.90-7.00 (8 H, m, aromatic H)
3.80 (3 H, s, OCH3), 7.00-8.00 (8 H, m, aromatic H)
-
V
1090
1095
1100
1090
1100
Ta ble 3. F u n gicid a l Scr een in g Resu lts of Com p ou n d s III-Va
A. niger
F. oxysporum
compound
1000 ppm
100 ppm
10 ppm
1000 ppm
100 ppm
10 ppm
III
IV
V
a
b
c
d
e
a
b
c
d
e
a
b
c
d
e
68
70
75
68
71
82
97
88
78
80
92
98
98
94
93
100
37
42
45
41
44
38
51
48
46
49
53
58
56
50
49
85
17
22
23
20
21
29
40
36
32
33
42
45
44
43
42
68
6
67
72
66
70
80
96
87
76
78
91
98
97
92
91
100
37
40
41
38
43
38
49
47
44
48
53
58
56
49
48
80
17
20
18
20
20
26
38
35
30
32
41
45
44
42
41
67
Dith a n e M-45
a
Average inhibition of fungal growth (%) at stated concentration (mg/liter)-1
.

5468 J. Agric. Food Chem., Vol. 48, No. 11, 2000
Mishra et al.
Gehlen, H.; Moeckle, K. J ustus Liebigs Ann. Chem. 1962, 651,
133-136; Chem. Abstr. 1962, 57, 3424.
Gibson, M. S. Tetrahedron 1962, 18, 1377-1380.
Hoggarth, E. J . Chem. Soc. 1949, 1918-1923.
Horsfall, J . G. Bot. Rev. 1945, 11, 357.
their precursors, as well as to the presence of an
additional >CdO or >CdS group (Horsfall and Rich,
1951).
All of the compounds were more active against A.
niger than against F. oxysporium, but the difference was
marginal.
Horsfall, J . G.; Rich. S. Cont boyce Thompson Inst. 1951, 16,
361.
Meek, W. S. U.S. Patent 3641045, 1972; Chem. Abstr. 1972,
76, 126991.
ACKNOWLEDGMENT
Rhone-Poulenc, S. A. Br. Patent, 110500, 1962; Chem. Abstr.
Rothwell, K.; Wain, R. L. Ann. Appl. Biol. 1963, 51, 161.
Singh, S.; Yadava, L. D. S.; Singh, H. Indian J . Chem. 1981,
20B, 518.
Stachler, G.; Sachse, B. German Offen. 541388, 1977; Chem.
Abstr. 1977, 87, 23292.
We are thankful to the Principal and Head of the
Department of Chemistry, S.N.P.G. College, for provid-
ing laboratory facilities, and the Director, C.D.R.I.,
Lucknow for recording the IR and NMR spectra.
LITERATURE CITED
Summer, L. A. Tetrahedron 1976, 32, 615.
Chatt, J .; Duncanson, L. A.; Venanzi, L. M. Nature 1956, 177,
1042.
Gast, A.; Kunsli, E.; Gysin, H. Experientia 1955, 11, 107.
Gast, A.; Knusli, A.; Gysin, H. Experientia 1956, 12, 146.
Received for review J uly 7, 1999. Accepted J uly 1, 2000.
J F990742F