Synthesis and antiviral activity against tobacco mosaic virus and 3D-QSAR of α-substituted-1,2,3-thiadiazoleacetamides

Article abstract of DOI:10.1016/j.bmcl.2006.05.043

A series of α-substituted-1,2,3-thiadiazoleacetamides were prepared and tested in vitro against tobacco mosaic virus. The preliminary bioassays indicated that some of the new compounds are good as compared to the commercial pesticide Virus A at 500 mg/L,

Full text of DOI:10.1016/j.bmcl.2006.05.043

Bioorganic & Medicinal Chemistry Letters 16 (2006) 6107–6111
Synthesis and antiviral activity against tobacco mosaic virus
and 3D-QSAR of a-substituted-1,2,3-thiadiazoleacetamides
Wei-Guang Zhao,* Jian-Guo Wang, Zheng-Ming Li and Zhao Yang
National Pesticide Engineering Research Center (Tianjin), State Key Laboratory of Elmento-Organic Chemistry,
Nankai University, Tianjin 300071, PR China
Received 5 December 2005; revised 3 May 2006; accepted 16 May 2006
Available online 19 October 2006
Abstract—A series of a-substituted-1,2,3-thiadiazoleacetamides were prepared and tested in vitro against tobacco mosaic virus. The
preliminary bioassays indicated that some of the new compounds are good as compared to the commercial pesticide Virus A at
500 mg/L, and the activity was influenced by the nature of the substituents. 3D-QSAR models were established based on the anti-
viral activity of the compounds. It has also been found that some of the new compounds also exhibit significant anti-HBV activity in
human hepatoblastoma-derived liver Hep-G2 cells.
ꢀ 2006 Published by Elsevier Ltd.
Virus infections in plants cause a variety of detrimental
effects and often leave plants more susceptible to dam-
age by other pests and pathogens. Viruses and viroids
are responsible for a wide variety of plant diseases which
cause significant and costly crop losses annually. Some
viral diseases, for example, rice tungro, African cassava
mosaic, and tospoviruses, are estimated to cause annual
losses in excess of AUD$1 billion worldwide.1 The
tobacco mosaic virus (TMV) infects plants of commer-
cial importance including tobacco and related plants
such as tomato and pepper. While not lethal, TMV af-
fects the growth and productivity of these plants. Most
countermeasures, however, were an indirect means of
protection and technical methods of virus removal, such
as soil disinfection and insecticides.
could prevent mycelium from invading sideward healthy
cell (Fig. 1). We became interested in making 1,2,3-
thiadiazoleacetamides, analogues of three commercial
pesticides.
Herein, we reported a series of a-substituted 1,2,3-
thiadiazoleacetamides that have been found to possess
potent antiviral activity against tobacco mosaic virus.
In our previous paper, we reported the synthesis of
2-chloro-N-methyl-2-(1,2,3-thiadiazol-4-y)l-acetamide
(1).8 The N-acylhydrazone, which was easily prepared
from commercially available N-methyl-a-chloroacetoac-
etamide and ethyl carbazate in ethanol, was cyclized
with three equivalents of thionyl chloride at room tem-
perature to form a-chloro-N-methyl-1,2,3-thiadiazole-
4-acetamide (1) in accord with the Hurd-Mori reaction
conditions. The compound (1) reacted with substituted
phenols, substituted benzenethiols or mercapto hetero-
cyclic compounds in the presence of inorganic base to
yield a-substituted phenoxy(phensulfydryl)-N-methyl-
1,2,3-thiadiazole-4-acetamide (2–5,9 10–1310) as shown
In the investigation of new agrochemicals, we found
1,2,3-thiadiazole derivatives, which had good biological
activities,2–4 had received only limited attention, but
commercial pesticides containing 1,2,3-thiadiazole often
possess unique active mechanism. For example, TDZ,5 a
cotton defoliant, had been found to exhibit more signif-
icant plant growth regulative activity than 6-BA and
zeatin; BTH was the first commercial plant activator;6
Tiadinil possessed excellent fungicidal activity7 and
N
S
Me
Cl
O
Me
N
N
O
N
N
H
S
N
N
N
H
N
H
Keywords: 1,2,3-Thiadiazoleacetamide; Synthesis; TMV; Anti-HBV;
S
SMe
O
3D-QSAR.
*
TDZ
Tiadinil
BTH
Corresponding author. Fax: +00862223505948; e-mail: zwg@nankai.
edu.cn
Figure 1.
0960-894X/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2006.05.043

6108
W.-G. Zhao et al. / Bioorg. Med. Chem. Lett. 16 (2006) 6107–6111
in Schemes 1–3. No by-products are found in the reac-
tion of compounds 1 and phenols, because compound
1 is instable in alkali or heat condition. By controlling
reaction temperature, compounds (4, 5) could be easily
oxidized by hydrogen peroxide to afford sulfoxide (6,
711) or sulfone (8, 912). And sulfone (8, 9) was readily
obtained by the reaction of compound 4 and compound
5 with hydrogen peroxide, respectively.
activity was different with the substituents of phenyl
moiety and oxidation state of sulfur atom.
Having the same linker between 1,2,3-thiadiazole and
benzene ring, compounds that were substituted by solely
halogen atom at the 2- or 4-position of benzene ring had
significant potency against TMV, however if a com-
pound was substituted by two halogen atoms at both
2- and 5-position of benzene ring it had hardly any inhi-
bition. Replacement of halogen with electron-donating
group, such as methyl or methoxyl, also abolished
Table 1 summarizes the antiviral screening results of the
studied compounds. The results indicated the antiviral
N
S
N
O
N
S
N
O
R'
R
OH
Me
N
N
S
O
N
H
OH
Me
N
H
Me
O
N
H
O
R
Cl
1
2
3
R'
2a-i: R = H, R' = 4-Br, 4-I, 2-Br, H, 4-Me, 3-Me, 2-Cl; R = 2-Cl, R' = 5-Me; R = 3-Me,
R' = 4-Me;
Scheme 1.
Me
HN
N
S
N
O
O
Me
N
H
SO
OS
S
S
R
N
N
6
7
R'
Cl
Cl
Me
HN
N
S
SH
N
O
O
SH
Me
R'
R
N
H
N
S
O
N
Cl
S
S
Me
N
H
R
N
N
Cl
4
R'
1
5
Me
HN
N
S
N
O
O
4a-f, 6a-f, 8a-f: R = H, R' = 4-F, 4-Cl, 4-OMe, 2-F;
R = 2-Me, R' = 5-Me; R = 2-Cl, R' = 5-Cl;
4g: R = H, R' = NH2;
Me
N
H
SO2
O2S
S
N
R
N
8
9
Cl
R'
Scheme 2.
O
HN
S
Me
N
N
N
N
13
N
N
N
Me
NH
N
O
H
Et
Me
N
S
O
N
S
N
Me
N
N
S
O
N
S
N
N
N
H
N
Me
N
N
N
N
N
Me
O
S
S
Me
N
S
N
HS
N
SH
S
Me
H
Me
O
Cl
1
N S
N
Me
11
N
Me
N
N
N
Me
N
N
SH
10
N
Me
N
Et
O
Me
S
N
Me
N
N
H
N
N
N
N S
Me
12
Scheme 3.

W.-G. Zhao et al. / Bioorg. Med. Chem. Lett. 16 (2006) 6107–6111
Table 1. Antiviral activity against TMV at 500 mg/L
6109
Compound
R
R0
Inhibition (%)
2a
2c
2f
H
4-Br
2-Br
3-Me
2-Cl
64
44
5.5
53
56
44
33
42
37
0
H
H
2g
2h
3
H
2-Cl
5-Me
4a
4b
4d
4e
4f
H
4-F
H
4-Cl
2-F
Figure 2.
H
2-Me
2-Cl
H
5-Me
5-Cl
NH2
0
4g
5
15
35
58
11
31
19
0
We had noticed that the active compounds are race-
mates, the effect of optical activity on biological activity
will be studied in future research.
Virus A
6a
6b
6d
6e
7
H
4-F
H
4-Cl
2-F
Some compounds have also been found to exhibit signif-
icant anti-HBV activity in human hepatoblastoma-de-
rived liver Hep-G2 cells (2.2.15 cells). The inhibition
rate of compound 2h at 0.6 lmol/mL was 88.6% against
HBsAg and 15.5% against HBeAg. In contrast, that of
purine acyclic acyclovir at 0.4 lmol/mL was 52.9%
against HBsAg and 44.2% against HBeAg for compari-
son of their anti-HBV potency. In addition, it was found
that compound 2h could inhibit viral DNA synthesis
activity with an approximate IC50 of 400 lM. We postu-
lated the possible mode of anti-viral activity is inhibition
of virus replication. Further studies on anti-HBV activ-
ities of the title compounds are under investigation and
will be reported in due course.
H
2-Me
5-Me
20
19
0
8a
8c
8d
8e
9
H
4-F
H
4-OMe
2-F
5-Me
H
2-Me
82
12
51
35
5
11
12
13
42
antiviral activity. But if compound 2h was substituted by
o-Cl, m-Me in ring, it had good antiviral activity.
Acknowledgments
The substitution of oxygen for sulfur represents an
example of an approach that is commonly known as
bioisostere. Exchange of the oxygen linker for sulfur
leads to a slight loss in activity. After sulfur was oxi-
dized, the bioassay indicated that the antiviral activity
of the thioether was slightly better than sulfoxide,
whereas worse than sulfone.
The authors are indebted to the National Natural
Science Foundation of China (20202003), and National
Basic Research Program of China (2003CB114400)
for financial support, and the National Center for
Drug Screening of China for their technical assistance
in performing the biological assays.
Based on the biological activity of the investigated com-
pounds, 3D-QSAR models were established within
SYBYL6.6 (Tripos Associates, St. Louis, MO) software
using CoMFA method. Compound 8d was utilized as a
template and conformational search was performed to
derive possible biological conformers of all investigated
compounds. The activity was expressed in terms of D13
by the formula
References and notes
1. Cooperative Research Centre for Tropical Plant Protec-
tion, <http://www.tpp.uq.edu.au/disease/viruses.htm/>.
2. Lowe, J. A.; Seeger, T. F.; Nagel, A. A.; Howard, H. R.;
Seymour, P. A.; Heym, J. H.; Ewing, F. E.; Newman, M.
E.; Schmidt, A. W.; Furman, J. S.; Vincent, L. A.;
Maloney, P. R.; Robinson, G. L.; Reynolds, L. S.; Vinick,
F. J. J. Med. Chem. 1991, 34, 1860.
D ¼ lg½a=ð100 ꢀ aÞꢁ ꢀ lg Mw
where a is percent inhibition and Mw is the molecular
weight of the tested compounds. The crossvalidated q2,
optimal components are 0.517 and 6, respectively. For
the steric contour map (Fig. 2a), a steric group in the
green region will enhance the activity of the compound
and a bulky group in the yellow region will decrease
the activity. For the electrostatic contour map
(Fig. 2b), a positive charged group in the blue region will
increase the activity and a negative charged substituent
in the red region will decrease the activity. These results
provide useful information for further optimization of
the compounds.
3. Thomas, E. W.; Nishizawa, E. E.; Zimmermann, D. C.;
Williams, D. J. J. Med. Chem. 1985, 28, 442.
4. Bowles, S. A.; Miller, A.; Whittaker, M. WO 9,315,047,
1993; Chem. Abstr. 1994, 120, 271175e.
5. Krueger, H. R.; Arndt, F.; Rush, R.; Schering A. G. DE
3,139,505, 1983; Chem. Abstr. 1983, 99, 53761z.
6. Kunz, W.; Schurter, R.; Maetzke, T. Pestic. Sci. 1997, 50,
275.
7. Tsubata, K.; Sanpei, O.; Tajima, S.; Takagi, K.; Uchik-
urohane, T.; Umetani, K. WO 99 23,084, 1999; Chem.
Abstr. 1999, 130, 311799b.
8. Zhao, W. G.; Li, Z. M.; Yang, Z. J. Heterocyclic Chem.
2003, 40, 925.

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W.-G. Zhao et al. / Bioorg. Med. Chem. Lett. 16 (2006) 6107–6111
9. Preparation of 2a. The compound 1 (0.69 g, 3.6 mmol)
6 h at room temperature. After removal of solvent, the
residue was washed with water (10 mL). The precipitate
was filtered off and purified by recrystallization from
ethanol to afford a white solid, mp: 126–127 ꢁC, yield 62%.
1H NMR (CDCl3): d 2.82 (d, J = 5.0 Hz, 3H, NCH3), 5.41
(s, 1H, CH), 6.90–7.34 (m, 5H, Ph+NH), 8.52 (s, 1H,
thiadiazole-H). Anal. Calcd for C11H10FN3OS2: C, 46.63;
H, 3.56; N, 14.83. Found: C, 46.77; H, 3.54; N, 14.81. MS
(12 eV): m/z 283 (M+, 27), 226 (83), 193 (22), 165 (52), 128
(77), 58 (100). IR (m, cmꢀ1): 3389, 3138, 2990, 1645, 1617,
1582, 1484, 1394, 1289, 1233, 1190, 1154; 4b: a white solid;
mp: 140–141 ꢁC, yield 52%, 1H NMR (CDCl3): d 2.84
(d,J = 5.0 Hz, 3H, NCH3), 5.42 (s, 1H, CH), 6.92 (br, 1H,
NH), 7.22–7.40 (m, 4H, Ph), 8.53 (s, 1H, thiadiazole-H).
Anal. Calcd for C11H10ClN3OS2: C, 44.07; H, 3.36; N,
14.02. Found: C, 43.94; H, 3.41; N, 13.88; 4c: a white
solid; mp: 110–111 ꢁC, yield 74%. 1H NMR (CDCl3): d
2.81 (d, J = 4.5 Hz, 3H, NCH3), d 3.73 (s, 3H, CH3), 5.30
(s, 1H, CH), 6.84 (br, 1H, NH), 6.72–7.23 (m, 4H, Ph),
8.40 (s, 1H, thiadiazole-H). Anal. Calcd for C12H13-
N3O2S2: C, 48.79; H, 4.44; N, 14.23. Found: C, 48.82; H,
4.44; N, 14.18; 4d: a white solid; mp: 135–137 ꢁC, yield
68%. 1H NMR (CDCl3): d 2.84 (d, J = 4.2 Hz, 3H,
NCH3), 5.49 (s, 1H, CH), 6.96 (br, 1H, NH), 7.05–7.33
(m, 4H, Ph), 8.57 (s, 1H, thiadiazole-H). Anal. Calcd for
C11H10FN3OS2: C, 46.63; H, 3.56; N, 14.83. Found: C,
46.56; H, 3.55; N, 14.68; 4e: a white solid; mp: 139–140 ꢁC,
was added to a mixture of sodium hydroxide (0.16 g,
4 mmol), 4-bromophenol (0.69 g, 4 mmol), and methanol
(15 mL). The reaction mixture was stirred for 48 h at room
temperature. After removal of solvent, the residue was
chromatographed on silica gel column eluting with ethyl
acetate/petroleum ether (1/3) to give pure 2a, a white solid;
1
mp: 140–142 ꢁC, yield 46%. H NMR (CDCl3): d 2.91 (d,
J = 4.8 Hz, 3H, NCH3), 6.12 (s, 1H, CH), 6.85–7.39 (q,
4H, Ar-H), 6.93 (br, 1H, NH), 8.63 (s, 1H, thiadiazole-H).
Anal. Calcd for C11H10BrN3O2S: C, 40.26; H, 3.07; N,
12.80; Found: C, 40.41; H, 2.77; N, 12.61. MS (12 eV): m/z
329 (M+, 13, 81Br), 327 (M+, 13, 79Br), 272 (7), 270 (8), 174
(29), 172 (31), 128 (100). IR (m, cmꢀ1): 3405, 3145, 1662,
1580, 1486, 1443, 1412, 1297, 1229; 2b: a white solid; mp:
157–158 ꢁC, yield 23%. 1H NMR (CDCl3): d 2.91 (d,
J = 4.8 Hz, 3H, NCH3), 6.12 (s, 1H, CH), 6.74–7.57 (m,
4H, Ar-H), 6.92 (br, 1H, NH), 8.62 (s, 1H, thiadiazole-H).
Anal. Calcd for C11H10IN3O2S: C, 35.21; H, 2.69; N,
11.20. Found: C, 35.08; H, 2.55; N, 11.29; 2c: a white
solid; mp: 148–149 ꢁC, yield 39%. 1H NMR (CDCl3): d
2.95 (d, J = 5.0 Hz, 3H, NCH3), 6.24 (s, 1H, CH), 6.91–
7.58 (m, 4H, Ar-H), 7.28 (br, 1H, NH), 8.63 (s, 1H,
thiadiazole-H). Anal. Calcd for C11H10BrN3O2S: C, 40.26;
H, 3.07 N, 12.80. Found: C, 40.29; H, 3.08; N, 12.90; 2d: a
white solid; mp: 140–141 ꢁC, yield 29%. 1H NMR
(CDCl3):d 2.91 (d, J = 5.0 Hz, 3H, NCH3), 6.16 (s, 1H,
CH), 6.95–7.30 (m, 5H, Ar-H), 6.98 (br, 1H, NH), 8.62 (s,
1H, thiadiazole-H). Anal. Calcd for C11H11N3O2S: C,
53.00; H, 4.45; N, 16.86. Found: C, 53.18; H, 4.46; N,
16.60; 2e: a white solid; mp: 130–132 ꢁC, yield 15%. 1H
NMR (CDCl3): d 2.26 (s, 3H, CH3), 2.92 (d, J = 5.0 Hz,
3H, NCH3), 6.11 (s, 1H, CH), 6.84–7.08 (m, 4H, Ar-H),
6.02 (br, 1H, NH), 8.59 (s, 1H, thiadiazole-H). Anal.
Calcd for C12H13N3O2S: C, 54.74; H, 4.98; N, 15.96.
Found: C, 54.46; H, 4.97; N, 15.97; 2f: a white solid; mp:
1
yield 68%. H NMR (CDCl3): d 2.24 (s, 3H, CH3), d 2.27
(s, 3H, CH3), d 2.84 (d, J = 4.7 Hz, 3H, NCH3), 5.34 (s,
1H, CH), 6.88 (br, 1H, NH), 6.92–7.15 (m, 3H, Ph), 8.46
(s, 1H, thiadiazole-H). Anal. Calcd for C13H15N3OS2: C,
53.22; H, 5.15; N, 14.32. Found: C, 53.08; H, 4.98; N,
14.14; 4f: a white solid; mp: 170–172 ꢁC, yield 45%. 1H
NMR (CDCl3): d 2.82 (d, J = 4.4 Hz, 3H, NCH3), 5.48 (s,
1H, CH), 7.04 (br, 1H, NH), 7.14–7.32 (m, 3H, Ph), 8.58
(s, 1H, thiadiazole-H). Anal. Calcd for C11H9Cl2N3OS2:
C, 39.53; H, 2.71; N, 12.57. Found: C, 39.26; H, 2.93; N,
12.78; 4g: a white solid; mp: 139–141 ꢁC, yield 77%. 1H
NMR (CDCl3): d 2.88 (d, J = 4.8 Hz, 3H, NCH3), 2.76
(br, 2H, NH2), 5.30 (s, 1H, CH), 6.92 (br, 1H, NH), 6.55–
7.14 (m, 4H, Ph), 8.43 (s, 1H, thiadiazole-H). Anal. Calcd
for C11H12N4OS2: C, 47.12; H, 4.31; N, 19.98. Found: C,
47.25; H, 4.20; N, 19.90; 5: a white solid; mp: 143–144 ꢁC,
1
127–128 ꢁC, yield 38%. H NMR (CDCl3): d 2.29 (s, 3H,
CH3), 2.91 (d, J = 5.1 Hz, 3H, NCH3), 6.15 (s, 1H, CH),
6.80–7.14 (m, 4H, Ar-H), 6.98 (br, 1H, NH), 8.61 (s, 1H,
thiadiazole-H). Anal. Calcd for C12H13N3O2S: C, 5474; H,
4.98; N, 15.96. Found: C, 54.68; H, 4.70; N, 15.95; 2g: a
white solid; mp: 118–119 ꢁC, yield 27%. 1H NMR
(CDCl3): d 2.89 (d, J = 4.6 Hz, 3H, NCH3), 6.16 (s, 1H,
CH), 6.88–7.23 (m, 5H, Ar-H+NH), 8.66 (s, 1H, thiadia-
zole-H). Anal. Calcd for C11H10ClN3O2S: C, 46.56; H,
3.55; N, 14.81. Found: C, 46.39; H, 3.30; N, 14.86; 2h: a
white solid; mp: 134–135 ꢁC, yield 25%. 1H NMR
(CDCl3):d 2.89 (s, 3H, CH3), 2.91 (d, J =5.0 Hz, 3H,
NCH3), 6.11 (s, 1H, CH), 6.74–7.24 (m, 3H, Ar-H), 6.98
(br, 1H, NH), 8.62 (s, 1H, thiadiazole-H). Anal. Calcd for
C12H12ClN3O2S: C, 48.40; H, 4.06; N, 14.11. Found: C,
48.54; H, 3.91; N, 13.90. MS (12 eV): m/z 299 (M+, 12,
37Cl), 297 (M+, 34, 35Cl), 242 (4), 240 (11), 142 (100), 128
(82). IR (m, cmꢀ1): 3393, 3088, 1668, 1621, 1559, 1481,
1409, 1306, 1235, 1171; 2i: a white solid; mp: 116–117 ꢁC,
yield 63%. 1H NMR (CDCl3): d 2.15 (s, 3H, CH3), 2.18 (s,
3H, CH3), 2.91 (d, J = 4.6 Hz, 3H, NCH3), 6.11(s, 1H,
CH), 6.71–7.02 (m, 5H, Ar-H+NH), 8.60 (s, 1H, thiadia-
zole-H). Anal. Calcd for C13H15N3O2S: C, 56.30; H, 5.45;
N, 15.15. Found: C, 56.20; H, 5.54; N, 15.06; 3: a white
solid; mp: 172–173 ꢁC, yield 27%; 1H NMR (CDCl3): 2.94
(d, J = 4.80 Hz, 3H, NCH3), 6.33 (s, 1H, CH), 7.04 (br,
1H, NH), 7.20–7.79 (m, 7H, naphthalene-H), 8.62 (s, 1H,
thiadiazole-H). Anal. Calcd for C15H13N3O2S: C, 60.18;
H, 4.38; N, 14.04. Found: C, 60.07; H, 4.31; N, 13.86.
Preparation of 4a. The 4-fluorobenzenethiol (1.02 g,
8.0 mmol) was added to a mixture of potassium carbonate
(1.4 g, 10 mmol), the compound 1 (1.53 g, 4.0 mmol), and
acetonitrile (20 mL). The reaction mixture was stirred for
1
yield 64%. H NMR (CDCl3): d 2.80 (d, J = 4.8 Hz, 3H,
NCH3), 3.75, 3.79 (q, AB, 2H, CH2), 5.30 (s, 1H, CH),
6.84 (br, 1H, NH), 6.72–7.23 (m, 4H, Ph), 8.40 (s, 1H,
thiadiazole-H). Anal. Calcd for C11H9Cl2N3OS2: C, 45.93;
H, 3.85; N, 13.39. Found: C, 45.71; H, 3.63; N, 13.36.
10. Preparation of 10: The 5-(5-ethyl-2-methyl-2H-pyrazol-3-
yl)-1,3,4-oxadiazole-2-thiol (0.66 g, 2.9 mmol) was added
to a mixture of potassium carbonate (0.42 g, 2.9 mmol),
the compound 1 (0.55 g, 2.9 mmol), and acetonitrile
(20 mL). The reaction mixture was stirred for 6 h at room
temperature. After removal of solvent, the residue was
washed with water (10 mL). The precipitate was filtered off
and purified by recrystallization from ethanol to give a
white solid, mp: 165–167 ꢁC, yield 15%. 1H NMR
(CDCl3): d 1.23 (t, J = 6.9 Hz, 3H, CH3), 2.64 (q,
J = 7.2 Hz, 2H, CH2), 2.89 (d, 3H, NCH3), 4.16 (s, 3H,
pyrazole-CH3), 6.26 (s, 1H, CH), 6.57 (s, 1H, pyrazole-H),
7.14 (br, 1H, NH), 8.96 (s, 1H, thiadiazole-H). Anal.
Calcd for C13H15N7O2S2: C, 42.73; H, 4.14; N, 26.83.
Found: C, 42.63; H, 3.95; N, 26.69; 11: a white solid; mp:
162–164 ꢁC, yield 40%. 1H NMR (acetone-d6): d2.47 (s,
3H, SCH3), 2.59 (s, 3H, pyrazole-CH3), 3.31 (s, 3H,
NCH3), 3.83 (s, 3H, pyrazole-CH3), 6.25 (s, 1H, CH), 9.16
(s, 1H, thiadiazole-H). Anal. Calcd for C13H15N7OS4: C,
37.75; H, 3.66; N, 23.71. Found: C, 37.89; H, 3.12; N,
23.81. MS (70 eV): 413 (M+, 14), 258 (39), 185 (40), 58

W.-G. Zhao et al. / Bioorg. Med. Chem. Lett. 16 (2006) 6107–6111
6111
(99), 56 (100); 12: a white solid; mp: 232–234 ꢁC, yield
44%. 1H NMR (acetone-d6): 2.49 (s, 6H, 2· CH3), 2.64 (s,
3H, NCH3), 6.31 (s, 1H, CH), 7.12 (s, 1H, pyrimidne-H),
8.64 (br, 1H, NH), 9.15 (s, 1H, thiadiazole-H). Anal.
Calcd for C12H13N7OS2: C, 42.97; H, 3.91; N, 29.23.
Found: C, 42.83; H, 3.70; N, 29.54. Preparation of 13: The
1,2,4-triazol (0.10 g, 1.4 mmol) was added to a mixture of
potassium carbonate (0.20 g, 1.4 mmol), the compound 1
(0.20 g, 1.0 mmol), and acetonitrile (10 mL). The reaction
mixture was stirred for 48 h at room temperature. After
removal of solvent, the residue was washed with water
(10 mL). The precipitate was filtered off and subjected to
silica gel column chromatography to give a white solid,
mp: 168–170 ꢁC, yield 36%. 1H NMR (CDCl3): 2.90 (d,
J = 4.4 Hz, 3H, NCH3), 6.77 (s, 1H, CH), 6.88 (br, 1H,
NH), 8.06 (s, 1H, triazole-H), 8.42 (s, 1H, triazole-H), 8.74
(s, 1H, thiadiazole-H).
37.52; H, 2.81; N, 12.29;7: a white solid; mp: 126–129 ꢁC,
1
yield 53%. H NMR (CDCl3): d 2.88 (d, J = 4.2 Hz, 3H,
NCH3), 3.88, 3.92 (q, AB, 2H, CH2), 5.23 (s, 1H, CH),
6.96 (br, 1H, NH), 7.15–7.36 (m, 4H, Ph), 8.79 (s, 1H,
thiadiazole-H). Anal. Calcd for C11H9Cl2N3O2S2: C,
43.70; H, 3.67; N, 12.74. Found: C, 43.66; H, 3.39; N,
12.50. IR (m, cmꢀ1): 3301, 3130, 2961, 1664, 1559, 1489,
1406, 1286, 1231, 1032.
12. Preparation of 8a. To a solution of the compound 4a (4.8 g,
1.7 mmol) in glacial acetic acid (10 mL) was added
dropwise 30% hydrogen peroxide (0.4 g, 3.5 mmol). The
mixture was stirred for 6 h at 80 ꢁC and poured over water
(20 mL). The precipitate was filtered off and purified by
recrystallization from ethanol to give a white solid, mp:
156–158 ꢁC, yield 92%. 1H NMR (CDCl3): d 2.91 (d,
J = 4.8 Hz, 3H, NCH3), 5.99 (s, 1H, CH), 7.13–7.66 (m,
5H, Ph+NH), 8.92 (s, 1H, thiadiazole-H). Anal. Calcd for
C11H10FN3O3S2: C, 41.90; H, 3.20; N, 13.33. Found: C,
41.66; H, 3.14; N, 13.17. MS (12 eV): 251 (10), 194 (11), 128
(100), 58 (83). IR (m, cmꢀ1): 3384, 3181, 2931, 1683, 1585,
1509, 1410, 1318, 1233, 1146; 8b: a white solid; mp: 196–
198 ꢁC, yield 87%. 1H NMR (acetone-d6): d 2.93 (d,
J = 4.8 Hz, 3H, NCH3), 5.88 (s, 1H, CH), 7.07 (br, 1H,
NH), 7.28–7.60 (m, 4H, Ph), 8.90 (s, 1H, thiadiazole-H).
Anal. Calcd for C11H10ClN3O3S2: C, 39.82; H, 3.04; N,
12.66. Found: C, 39.63; H, 3.10; N, 12.44. MS (12 eV): 267
(5.8), 210 (8.4), 128 (48), 58 (100); 8c: a white solid; mp:
11. Preparation of 6a. To a solution of the compound 4a
(4.8 g, 1.7 mmol) in glacial acetic acid (10 mL) was added
dropwise 30% hydrogen peroxide (0.4 g, 3.5 mmol). The
mixture was stirred for 24 h at room temperature and
poured into water (20 mL). The precipitate was filtered off
and purified by recrystallization from ethanol to give a
white solid, mp: 157.5–159 ꢁC, yield 51%. 1H NMR
(CDCl3): d 2.86 (d, J = 5.0 Hz, 3H, NCH3), 5.44 (s, 1H,
CH), 6.96 (br, 1H, NH), 7.05–7.34 (m, 4H, Ph), 8.65 (s,
1H, thiadiazole-H). Anal. Calcd for C11H10FN3O2S2: C,
44.14; H, 3.37; N, 14.04. Found: C, 44.16; H, 3.17; N,
1
178–179 ꢁC, yield 94%. H NMR (CDCl3): d 2.93 (s, 3H,
1
13.85. ; 6b: a white solid; mp: 126–129 ꢁC, yield 62%. H
NCH3), d 3.83 (s, 3H, CH3), 5.94 (s, 1H, CH), 7.17 (br, 1H,
NH), 6.86–7.51 (m, 4H, Ph), 8.90 (s, 1H, thiadiazole-H).
Anal. Calcd for C12H13N3O4S2: C, 44.02; H, 4.00; N, 12.84.
Found: C, 44.04; H, 3.91; N, 12.86; 8d: a white solid; mp:
147–148.5 ꢁC, yield 76%. 1H NMR (CDCl3): d 2.93 (d,
J = 4.4 Hz, 3H, NCH3), 6.15 (s, 1H, CH), 7.11-7.63 (m,
5H, Ph+NH), 8.69 (s, 1H, thiadiazole-H). Anal. Calcd for
C11H10FN3O3S2: C, 41.90; H, 3.20; N, 13.33. Found: C,
41.66; H, 3.03; N, 13.28; 8e: a white solid; mp: 176–178 ꢁC,
yield 63%. 1H NMR (CDCl3): d 2.21 (s, 3H, CH3), d 2.55 (s,
3H, CH3), d 2.94 (d, J = 4.7 Hz, 3H, NCH3), 5.91 (s, 1H,
CH), 7.12–7.29 (m, 4H, Ph+NH), 8.89 (s, 1H, thiadiazole-
H). Anal. Calcd for C13H15N3O3S2: C, 47.98; H, 4.65; N,
12.91. Found: C, 47.74; H, 4.40; N, 12.91; 8f: a white solid;
NMR (acetone-d6): d 3.30 (s, 3H, NCH3), 5.69 (s, 1H,
CH), 6.92 (br, 1H, NH), 7.31–7.52 (m, 4H, Ph), 9.15 (s,
1H, thiadiazole-H). Anal. Calcd for C11H10ClN3O2S2: C,
41.84; H, 3.19; N, 13.31. Found: C, 41.54; H, 3.04; N,
13.09. IR (m, cmꢀ1): 3391, 3163, 2929, 1689, 1556, 1472,
1399, 1279, 1046; 6c: a white solid; mp: 163–165 ꢁC, yield
38%. 1H NMR (CDCl3): d 2.90 (s, J = 4.5 Hz, 3H, NCH3),
d 3.81 (s, 3H, CH3), 5.46 (s, 1H, CH), 6.84–7.21 (m, 5H,
Ph+NH), 8.56 (s, 1H, thiadiazole-H). Anal. Calcd for
C12H13N3O3S2: C, 46.29; H, 4.21; N, 13.49. Found: C,
46.16; H, 4.16; N, 13.42; 6d: a white solid; mp: 170–172 ꢁC,
1
yield 72%. H NMR (CDCl3): d 2.94 (d, J = 4.5 Hz, 3H,
NCH3), 5.62 (s, 1H, CH), 6.80 (br, 1H, NH), 7.07–7.44 (m,
4H, Ph), 8.69 (s, 1H, thiadiazole-H). Anal. Calcd for
C11H10FN3O2S2: C, 44.14; H, 3.37; N, 14.04. Found: C,
44.00; H, 3.38; N, 13.85. MS (70 eV): m/z 299 (M+, 0.35),
156 (6.0), 144 (57), 143 (24), 128 (67), 58 (100); 6e: a white
solid; mp: 160–161.5 yield 94%. 1H NMR (CDCl3): d 2.24
(s, 3H, CH3), d 2.27 (s, 3H, CH3), d 2.84 (d, J = 4.7 Hz,
3H, NCH3), 5.44 (s, 1H, CH), 6.88 (br, 1H, NH), 6.92–
7.15 (m, 3H, Ph), 8.46 (s, 1H, thiadiazole-H). Anal. Calcd
for C13H15N3O2S2: C, 50.46; H, 4.89; N, 13.58. Found: C,
50.38; H, 4.90; N, 13.46; 6f: a white solid; mp: 170–172 ꢁC,
1
mp: 172–174 ꢁC, yield 53%. H NMR (CDCl3): d 2.95 (d,
J = 4.2 Hz, 3H, NCH3), 6.42 (s, 1H, CH), 7.06 (br, 1H,
NH), 7.10–7.62(m, 3H, Ph), 9.07 (s, 1H, thiadiazole-H).
Anal. Calcd for C11H9Cl2N3O3S2: C, 36.07; H, 2.48; N,
11.47. Found: C, 36.14; H, 2.48; N, 11.44; 9: a white solid;
1
mp: 161–163 ꢁC, yield 66%. H NMR (CDCl3): d 2.87 (d,
J = 4.2 Hz, 3H, NCH3), 4.28, 4.40 (q, AB, 2H, CH2), 5.63
(s, 1H, CH), 7.12 (br, 1H, NH), 7.21–7.42 (m, 4H, Ph), 8.79
(s, 1H, thiadiazole-H). Anal. Calcd for C11H9Cl2N3O3S2:
C, 41.68; H, 3.50; N, 12.15. Found: C, 41.40; H, 3.75; N,
12.39. IR (m, cmꢀ1): 3352, 3124, 1664, 1590, 1527, 1488,
1420, 1332, 1131.
1
yield 57%. H NMR (CDCl3): d 2.85 (d, J = 4.6 Hz, 3H,
NCH3), 5.38 (s, 1H, CH), 6.95 (br, 1H, NH), 7.07–7.37(m,
3H, Ph), 8.75 (s, 1H, thiadiazole-H). Anal. Calcd for
C11H9Cl2N3O2S2: C, 37.72; H, 2.59; N, 12.00. Found: C,
13. Zou, X. J.; Jin, G. Y.; Zhang, Z. X. J. Food Agric. Chem.
2002, 50, 1451.