Novel simple efficient synthetic approach toward 6-substituted-2H-[1,2,4] triazolo[3,4-b][1,3,4]thiadiazole-3-thiones and first synthesis and biological evaluation of N-and S-β-D-glucosides of the[1,2,4]triazolo [3,4-b][1,3,4]thiadiazole ring system

Article abstract of DOI:10.1080/15257770701296978

Novel simple and efficient synthetic approach for the synthesis of 6-substituted-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thiones is described. Glucosidation of these novel bases with 2,3,4,6-tetra-O-acetyl- α-d-glucopyranosyl bromide followed by chr

Full text of DOI:10.1080/15257770701296978

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Novel Simple Efficient
Synthetic Approach Toward 6-
Substituted-2H-[1,2,4]Triazolo[3,4-
b][1,3,4]Thiadiazole-3-Thiones
and First Synthesis and Biological
Evaluation of N-and S-β-D-Glucosides
of the[1,2,4]Triazolo [3,4-b]
[1,3,4]Thiadiazole Ring System
Nasser S. A. M. Khalil a
a Regional Center for Food and Feed, Agricultural Research Center,
Giza, Egypt
Published online: 03 May 2007.
To cite this article: Nasser S. A. M. Khalil (2007) Novel Simple Efficient Synthetic Approach Toward 6-
Substituted-2H-[1,2,4]Triazolo[3,4-b][1,3,4]Thiadiazole-3-Thiones and First Synthesis and Biological
Evaluation of N-and S-β-D-Glucosides of the[1,2,4]Triazolo [3,4-b][1,3,4]Thiadiazole Ring System,
Nucleosides, Nucleotides and Nucleic Acids, 26:4, 347-359, DOI: 10.1080/15257770701296978
To link to this article: http://dx.doi.org/10.1080/15257770701296978
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Nucleosides, Nucleotides, and Nucleic Acids, 26:347–359, 2007
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701296978
NOVEL SIMPLE EFFICIENT SYNTHETIC APPROACH TOWARD
6-SUBSTITUTED-2H-[1,2,4]TRIAZOLO[3,4-b][1,3,4]THIADIAZOLE-3-
THIONES AND FIRST SYNTHESIS AND BIOLOGICAL EVALUATION
OF N- AND S-β-D-GLUCOSIDES OF THE[1,2,4]TRIAZOLO
[3,4-b][1,3,4]THIADIAZOLE RING SYSTEM
Nasser S. A. M. Khalil
Regional Center for Food and Feed, Agricultural Research
2
Center, Giza, Egypt
Novel simple and efficient synthetic approach for the synthesis of 6-substituted-2H-
2
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thiones is described. Glucosidation of these novel bases
with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide followed by chromatographic separation
gave the corresponding N- and S-ß-d-glucosides. The structure of these two regiosiomers was
established chemically and spectroscopically. Antimicrobial screening of two selected regioisomeric
compounds against Aspergillus fumigatus, Penicillium italicum, Syncephalastrum racemosum,
Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, and Es-
cherichia coli are compared.
Keywords
Synthesis;
glucosidation;
1,2,4-triazoles;
2H-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole-3-thiones; antimicrobial activity
INTRODUCTION
Various 1,2,4-triazoles have been reported to possess antibacterial, an-
tifungal, antiviral, antiinflammatory, antitubercular, anticonvulsant, antide-
pressant, antihypertensive, analgesic, hypoglycemic, herbicidal, and sedative
properties.[1–22] The 1,3,4-thiadiazoles exhibit broad spectrum of biological
activities, possibly due to the presence of toxophoric N-C-S moiety.[23]
They find applications as antibacterials, antitumor, and antiinflammatory
agents, pesticides, herbicides, dyes, lubricants, and analytical reagents.[24]
The 1,2,4-triazolo[3,4-b][1,3,4]-thiadiazole derivatives obtained by fusing
the bio-labile 1,2,4-triazole and 1,3,4-thiadiazole rings together, are reported
Received 27 November 2006; accepted 24 January 2007.
Address correspondence to Nasser S. A. M. Khalil, Regional Center for Food and Feed, Agricultural
Research Center, P.O. Box 588 Orman, Giza, Egypt. E-mail: nasserkhalil 23@hotmail.com
347

348
N. S. A. M. Khalil
to possess antibacterial, antifungal, antiinflammatory, CNS depressant,
hypocholesteremic, antiviral, analgesic, anthelmintic, herbicidal and plant
growth regulatory effects.[25]
Prompted by these observations and in continuation of our long-
standing interest in the preparation of bio-active molecules,[21,22,26–33] we
designed new simple efficient route for the synthesis of 6-substituted-
2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thiones. Also, we report here
the first synthetic approach of a series of novel 2-N - and 3-S-β-d-glucosyl-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles as well as a comparable antimicro-
bial activity of two selected regioisomers against Aspergillus fumigatus, Peni-
cillium italicum, Syncephalastrum racemosum, Candida albicans, Staphylococcus
aureus, Pseudomonas aeruginosa, Bacillus subtilis, and Escherichia coli.
RESULTS AND DISCUSSION
The only example found in the literature describing the synthesis of
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole ring system having an active NH
group in the 2-position or a possible tautomeric thiol group in the 3-position
was described by Potts and Huseby[34] through the reaction of (5-phenyl-
1,3,4-thiadiazol-2-yl)hydrazine with carbon disulfide (Equation (1)).
In the present work, we report a novel simple and efficient procedure
for the synthesis of 6-substituted-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-
3-thiones 2a–e, which in turn allowed us to an easier entry for the
first synthesis of N - and S-β-d-glucosides of the [1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole ring system. Thus, we found that 6-substituted-
2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thiones (2a–e) can be ob-
tained directly in excellent yields from the 4-amino-4H-[1,2,4]-triazole-3,
5-dithiol (3), by its cyclization with the appropriate carboxylic acid or acid
chloride in refluxing phosphoryl chloride (Scheme 1).
Glucosidation of compounds 2a–d with 1.2 molar equivalent
of 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide (4) gave
a
chromatographically separable mixture (45–59% overall yield) of
two products namely, 3-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosylthio)
-6-aryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (5a–d) and 2-(2,3,4,6-tetra-
O-acetyl-β-d-glucopyranosyl)-6-aryl-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadia-
zole-3-thiones (6a–d).
The S-β-d-configuration of compounds 5a–d and the N -β-d-
configuration of compounds 6a–d are supported based on spectroscopic

6-Substituted-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thiones
349
SCHEME 1 Synthesis of N - and S-glucosides of 6-aryl-[1,2,4]-triazolo[3,4-b][1,3,4] thiadiazoles.
evidences. Thus, the appearance of the anomeric protons of compounds
6a–d more downfield (δ 6.24–6.27) than those of compounds 5a–d (δ
5.31–5.34) is consistent with similar reported data for N -[21,22,26–32,35] and
S-glycosides,[21,22] and confirms their structures. Such downfield shifts in
N -glucosyl derivatives is readily explained by the anisotropic deshielding by
the C = S (similar downfield shifts of the anomeric proton by an adjacent
C = S was reported for pyrimidine[35] and 1,2,4-triazole[21,22] nucleosides).
The β-configuration of compounds 5a–d and 6a–d is assigned from the

350
N. S. A. M. Khalil
ꢁ
ꢁ
coupling constant values of their anomeric protons (J H-1 -H-2 = 9.0–9.9 Hz)
which are consistent with similar reported data.[21,22,26,27,29–32,35]
Glucosidation of compound 2e having an electron donating methyl
group in the 6- position revealed the same starting materials. Thus, it
is interesting to point out that the presence of an aromatic substituent
with its known electron withdrawing character in the 6-position of the
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole ring system increases the yield of
glucosidation with higher yields of the S-glucosides (31–45%) than their
regioisomeric N -glucosides (10–19%). The higher overall glucosidation
yield was noticed for compound 2d having the more electron withdrawing
NO2 group in the 4-postion of the phenyl ring.
Compounds 5a–d were alternatively synthesized in excellent yields
(83–88%) via glucosidation of 4-amino-4H-[1,2,4]-triazole-3,5-dithiol (3) to
give 5-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosylthio)-4-amino-2,4-dihydro-
[1,2,4]triazole-3-thione (7) as the sole product followed by its ring closure
using the appropriate aromatic acid or acid chloride in the presence of
phosphoryl chloride.
Deacetylation of compounds 5a and 6a via methanolic ammonia treat-
ment led to the formation of the free nucleosides 8 and 9, respectively
1
(Scheme 1). The H NMR data of the latter compounds revealed the ab-
sence of the acetyl protons at δ 1.91–2.15 and the appearance of the D2O ex-
changeable OH protons at δ 4.10–5.59. The IR data of compound 9 as a typi-
cal example showed also the absence of the acetyl carbonyl function at 1756
cm−1 and the appearance of the characteristic OH band at 3390 (br) cm−1.
Compounds 5c and 6c were evaluated for their antifungal and an-
tibacterial activities against Aspergillus fumigatus, Penicillium italicum, Syn-
cephalastrum racemosum, Candida albicans, Staphylococcus aureus, Pseudomonas
aeruginosa, Bacillus subtilis, and Escherichia coli. The inhibitory effects of the
tested compounds against the mentioned organisms are given in Table 1.
The inhibitory effect of S-β-d-glucoside 5c were studied in comparison with
similar effect due to N -β-d-glucoside 6c. Thus, compound 5c showed higher
inhibitory effect against Aspergillus fumigatus, Penicillium italicum, Staphylococ-
cus aureus, and Escherichia coli. Compound 6c showed higher inhibitory effect
against Pseudomonas aeruginosa at concentration 5.0 mg/mL.
CONCLUSION
The present work describes a novel simple efficient synthetic route to-
ward the 6-substituted-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thiones
as well as first access to the N - and S-β-d-glucosides of [1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole ring system with potential antimicrobial activities.
These compounds could serve as possible starting materials for further
synthetic transformations. It also expands the synthesis as well as the
utility of both base-modified and sugar-modified nucleosides of possible
application in the chemotherapy of cancer and viral infections.

6-Substituted-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thiones
351
TABLE 1 Antimicrobial activity of compounds 5c and 6c compared to standard antimicrobial
agents
Compound
5ca
6ca
St.b
Concentration (mg/mL)
Test organisms
1
2.5
5
1
2.5
5
1
2.5
5
Aspergillus fumigatus
Penicillium italicum
Syncephalastrum racemosum
Candida albicans
Staphylococcus aureus
Pseudomonas aeruginosa
Bacillus subtilis
0
0
0
0
0
0
0
+
0
+
0
+
+
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
+
0
++
++
+++ +++
+++ +++
+++ +++ +++
0
0
0
++
++
++
++
++
++
++
++
++
+
+
+
+
0
0
0
+++ +++
+++ +++
0
+
0
+
Escherichia coli
0
++
++
Note: The test was done using the diffusion agar technique. Inhibition values = 0.1–0.5 cm beyond
control = +; Inhibition values = 0.6–1.0 cm beyond control = ++; Inhibition values = 1.0–1.5 cm
beyond control = +++; 0 = Not detected.
a100 µL of each conc. was tested (5, 2.5, 1.0 mg/mL); well diameter = 0.6 cm.
bSt. = Reference standard; Chloramphenicol was used as a standard antibacterial agent and
Terbinafin was used as a standard antifungal agent.
EXPERIMENTAL
General
All melting points are uncorrected. IR spectra were recorded on
a Perkin-Elmer 1430 spectrometer. 1H NMR spectra were recorded at
300 MHz with a Varian Mercury 300 spectrometer. Elemental analyses were
carried out at the Micro Analytical Center, Cairo University, Giza, Egypt. An-
timicrobial screening of compounds 5c and 6c was carried out at the Medical
Mycology Laboratory, Regional Center for Mycology and Biotechnology, Al
Azhar University, Cairo, Egypt. The starting 4-amino-4H-[1,2,4]-triazole-3,5-
dithiol (3)[36] and 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide (4)[37]
were prepared as reported. TLC was performed on Fluka silica gel 60 F254
aluminum sheets, and products were detected using 254 nm light. Fluka
silica gel 60 (70–230 mesh) was used for column chromatography.
6-Substituted-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thiones
(2 a–e)
General procedure: A mixture of compound 3 (500 mg, 3.4 mmol) and
the appropriate carboxylic acid (3.4 mmol for the synthesis of compounds
2a,b,d,e) or acid chloride (3.4 mmol for the synthesis of compound 2c) in
phosphoryl chloride (5 mL) was heated at reflux temperature in an oil bath
for 8 hours. The excess of phosphoryl chloride was removed under reduced

352
N. S. A. M. Khalil
pressure, the formed residue was diluted with ice-water mixture, and the
whole mixture stirred at room temperature for 1 hour. The precipitated
solid products were filtered, washed several times with water, dried at room
temperature, and recrystallized from N ,N -dimethylformamide.
6-Phenyl-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thione (2a). Yield
749 mg (94%); pale yellow crystals, m.p. 238–240◦C. IR: 3433, 3074, 3020,
1597, 1512, 1450, 1373, 1315, 1246, 1184, 1157, 1076, 1003, 953, 771, 687,
640, 609, 478; 1H NMR (DMSO-d6) δ 7.52 (tt, 2H, J = 1.8, 7.5 Hz, ArH), 7.65
(tt, 1H, J = 1.8, 7.5 Hz, ArH), 7.87 (td, 2H, J = 1.8, 7.5 Hz, ArH), 8.28 (s,
1H, D2O exchangeable NH). Anal. Calcd for C9H6N4S2 (234.3): C, 46.14;
H, 2.58; N, 23.91; S, 27.37. Found: C, 46.18; H, 2.61; N, 24.20; S, 27.24.
6-(4-Aminophenyl)-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thione
(2b). Yield 831 mg (98%); yellow crystals, m.p. >324◦C. IR: 3356, 3220,
3069, 1595, 1508, 1406, 1370, 1317, 1244, 1180, 1095, 1013, 975, 904,
1
844, 761, 694, 632, 523; H NMR; (DMSO-d6) δ 6.4–6.8 (br s, 2H, D2O
exchangeable NH2), 7.75 (d, 2H, J = 8.7 Hz, ArH), 7.94 (d, 2H, J = 8.7 Hz,
ArH), 10.42 (br s, 1H, D2O exchangeable NH), Anal. Calcd for C9H7N5S2
(249.3): C, 43.36; H, 2.83; N, 28.09; S, 25.72. Found: C, 43.30; H, 2.77; N,
28.15; S, 25.91.
6-(4-Chlorophenyl)-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thione
(2c). Yield 895 mg (98%); colorless crystals, m.p. 260–262◦C. IR: 3425, 3070,
3024, 1593, 1570, 1516, 1455, 1396, 1369, 1311, 1246, 1188, 1092, 1014, 953,
833, 798, 714, 679, 606, 498, 471, 420; 1H NMR (DMSO-d6) δ 7.62 (td, 2H,
J = 1.9, 8.7 Hz, ArH), 7.90 (td, 2H, J = 1.9, 8.7 Hz, ArH). Anal. Calcd for
C9H5ClN4S2 (268.7): C, 40.22; H, 1.88; N, 20.85; S, 23.86. Found: C, 40.27;
H, 1.84; N, 20.77; S, 23.94.
6-(4-Nitrophenyl)-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thione
(2d). Yield 902 mg (95%); orange yellow crystals, m.p. 244–246◦C. IR: 3437,
3036, 1605, 1524, 1454, 1350, 1315, 1250, 1084, 1003, 957, 852, 752, 687,
1
602, 455, 417; H NMR (DMSO-d6) δ 8.17 (dd, 2H, J = 2.1, 9.0 Hz, ArH),
8.35 (dd, 2H, J = 2.1, 8.7 Hz, ArH). Anal. Calcd for C9H5N5O2S2 (279.3):
C, 38.70; H, 1.80; N, 25.07; S, 22.96. Found: C, 38.88; H, 1.84; N, 25.18; S,
22.93.
6-Methyl-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thione (2e). Yield
252 mg (43%); pale crystals, m.p. 254–256◦C. IR: 3421, 2924, 2859, 1624,
1539, 1458, 1427, 1385, 1200, 1169, 991, 810, 652, 617, 544, 528, 471, 447,
1
417; H NMR (DMSO-d6) δ 2.71 (s, 3 H, CH3). Anal. Calcd for C4H4N4S2
(172.2): C, 27.90; H, 2.34; N, 32.53; S, 37.23. Found: C, 27.98; H, 2.21; N,
32.44; S, 37.19.
5-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosylthio)-4-amino-2,4-dihydro-
[1,2,4]triazole-3-thione (7). To a solution of compound 3 (311 mg, 2.1
mmol) in N ,N -dimethylformamide (2.5 mL) and triethylamine (0.36 mL,
2.6 mmol) was added 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide (4)

6-Substituted-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thiones
353
(1.07 g, 2.6 mmol) and the reaction mixture was stirred overnight. The
next day, the reaction mixture was diluted with ice-water mixture and the
formed precipitate was collected by filtration, washed several times with
water, and dried at room temperature. The precipitate was extracted with
dichloromethane, the solution was concentrated and the residue subjected
to silica gel (70–230 mesh) column chromatography. Compound 7 was
eluted with 70% ethyl acetate/petroleum ether (b.p. 40–60◦C) → 80%
ethyl acetate/petroleum ether (b.p. 40–60◦C) and recrystallized from
ethanol to give 663 mg (66%) of colorless crystals, m.p. 176–178◦C (Rf =
0.62, determined on TLC aluminum sheets using ethyl acetate/petroleum
ether (b.p. 40–60◦C) [60:40, v/v] as a developing system). IR: 3309, 3178,
2946, 1752, 1618, 1511, 1457, 1436, 1373, 1237, 1057, 1040, 950, 912, 818,
1
725, 671, 627, 601, 560, 488, 461, 428; H NMR (DMSO-d6) δ 1.94, 1.98,
ꢁ
ꢁ
ꢁ
ꢁꢁ
1.99, 2.07 (4 s, 12H, CH3CO), 3.99 (dd, 1H, J H-6 -H-5 = 2.1Hz, J H-6 -H-6
=
12.6 Hz, H-6ꢁ), 4.05 (ddd, 1H, J H-5 -H-6 = 2.1Hz, J H-5 -H-6 = 4.8 Hz, J H-5 -H-4
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁ
= 9.6 Hz, H-5ꢁ), 4.11 (dd, 1H, J H-6 -H-5 = 4.8 Hz, J H-6 -H-6 = 12.6 Hz, H-6ꢁꢁ),
ꢁꢁ
ꢁ
ꢁꢁ
ꢁ
4.95 (t, 1H, J H-4 -H-3 = 9.6 Hz, J H-4 -H-5 = 9.6 Hz, H-4ꢁ), 5.07 (t, 1H, J H-3 -H-2
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
= 9.3 Hz, J H-3 -H-4 = 9.6 Hz, H-3ꢁ), 5.38 (t, 1H, J H-2 -H-1 = 9.9 Hz, J H-2 -H-3
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
= 9.3 Hz, H-2ꢁ), 5.57 (d, 1H, J H-1 -H-2 = 9.9 Hz, H-1ꢁ), 5.58 (s, 2H, D2O
exchangeable NH2), 13.88 (s, 1H, D2O exchangeable NH). Anal. Calcd
for C16H22N4O9S2 (478.5): C, 40.16; H, 4.63; N, 11.71; S, 13.40. Found: C,
40.08; H, 4.52; N, 11.74; S, 13.56.
ꢁ
ꢁ
General Procedures for the Synthesis of Compounds 5a–d
and 6a–d
A) To a solution of each of compounds 2a–d (2.1 mmol) in N ,N -
dimethylformamide (2.5 mL) and triethylamine (0.36 mL, 2.6 mmol) was
added 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide (4) (1.07 g, 2.6
mmol) and the reaction mixture was stirred overnight. The next day, the
reaction mixture was diluted with ice-water mixture and the formed precip-
itate was collected by filtration, washed several times with water, and dried
at room temperature. The precipitate was extracted with dichloromethane,
the solution was concentrated, and the residue subjected to silica gel
(70–230 mesh) column chromatography. Compounds 6a–d were eluted
first with 50% ethyl acetate/petroleum ether (b.p. 40–60◦C) → 70% ethyl
acetate/petroleum ether (b.p. 40–60◦C), followed by compounds 5a–d with
80% ethyl acetate/petroleum ether (b.p. 40–60◦C) → 10% methanol/ethyl
acetate. The chromatographically separated crude products were recrys-
tallized from dichloromethane/petroleum ether (b.p. 40–60◦C). Rf values
of the latter compounds were determined on TLC aluminum sheets using
ethyl acetate/petroleum ether (b.p. 40–60◦C) [60:40, v/v] as a developing
system.

354
N. S. A. M. Khalil
B) A mixture of compound 7 (478 mg, 1.0 mmol) and the appropriate
carboxylic acid (1 mmol; for the synthesis of compounds 5a, b, d) or
acid chloride (1 mmol for the synthesis of compound 5c) in phosphoryl
chloride (2 mL) was heated at reflux temperature in an oil bath for 8 hours.
The excess of phosphoryl chloride was removed under reduced pressure
and the formed residue was extracted with dichloromethane, washed with
KOH solution (0.1 M, 2 × 100 mL) then water (4 × 100 mL), and dried
(Na2SO4). The solvent was then removed under reduced pressure and the
formed residue was recrystallized from dichloromethane/petroleum ether
(b.p. 40–60◦C). Rf values of the latter compounds were determined on
TLC aluminum sheets using ethyl acetate/petroleum ether (b.p. 40–60◦C)
[60:40, v/v] as a developing system.
3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosylthio)-6-phenyl-[1,2,4]triazo-
lo[3,4-b][1,3,4]thiadiazole (5a). Yield 439 mg (37%, A), 497 mg (88%, B);
yellow crystals, m.p. 154–156◦C (Rf = 0.65). IR; 3054, 2925, 2713, 1747,
1603, 1444, 1413, 1376, 1352, 1311, 1267, 1189, 1158, 1096, 1028, 970, 817,
1
758, 703, 637, 593, 530; H NMR (CDCl3) δ 1.91 (s, 3 H, CH3CO), 1.97
ꢁ
ꢁ
(s, 6 H, CH3CO), 2.05 (s, 3 H, CH3CO), 3.74 (ddd, 1H, J H-5 -H-6 = 2.1Hz,
J H-5 -H-6 = 4.8 Hz, J H-5 -H-4 = 10.2Hz, H-5ꢁ), 4.02 (dd, 1H, J H-6 -H-5 = 2.1Hz,
ꢁ
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁ
J H-6 -H-6 = 12.3 Hz, H-6ꢁ), 4.16 (dd, 1H, J H-6 -H-5 = 4.8 Hz, J H-6 -H-6 = 12.3
ꢁ
ꢁꢁ
ꢁꢁ
ꢁ
ꢁꢁ
ꢁ
Hz, H-6ꢁꢁ), 5.07 (t, 1H, J H-4 -H-3 = 9.6 Hz, J H-4 -H-5 = 10.2Hz, H-4ꢁ), 5.15 (t,
ꢁ
ꢁ
ꢁ
ꢁ
1H, J H-3 -H-2 = 9.3 Hz, J H-3 -H-4 = 9.6 Hz, H-3ꢁ), 5.24 (t, 1H, J H-2 -H-1 = 9.9
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
Hz, J H-2 -H-3 = 9.3 Hz, H-2ꢁ), 5.33 (d, 1H, J H-1 -H-2 = 9.9 Hz, H-1ꢁ), 7.49 (t,
2H, J = 8.7 Hz, ArH), 7.54 (t, 1H, J = 8.7 Hz, ArH), 7.84 (dd, 2H, J = 1.8,
8.7 Hz, ArH). Anal. Calcd for C23H24N4O9S2 (564.6): C, 48.93; H, 4.28; N,
9.92; S, 11.36. Found: C, 49.11; H, 4.21; N, 10.10; S, 11.22.
ꢁ
ꢁ
ꢁ
ꢁ
3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosylthio)-6-(4-aminophenyl)-[1,
2,4]triazolo[3,4-b][1,3,4]thiadiazole (5b). Yield 426 mg (35%, A), 498 mg
(86%, B); yellow crystals, m.p. 130–132◦C (Rf = 0.11). IR: 3375, 3229, 3033,
2943, 1751, 1628, 1605, 1497, 1458, 1373, 1311, 1227, 1180, 1038, 949,
1
914, 833, 756, 690, 667, 602, 513, 482, 447, 417; H NMR (CDCl3) δ 1.92
(s, 3 H, CH3CO), 1.97 (s, 6 H, CH3CO), 2.04 (s, 3 H, CH3CO), 3.51 (br,
ꢁ
ꢁ
ꢁ
ꢁꢁ
2H, D2O exchangeable NH2), 3.73 (ddd, 1H, J H-5 -H-6 = 2.1Hz, J H-5 -H-6
= 4.8 Hz, J H-5 -H-4 = 9.9 Hz, H-5ꢁ), 4.02 (d, 1H, J H-6 -H-6 = 12.3 Hz, H-6ꢁ),
ꢁ
ꢁ
ꢁ
ꢁꢁ
4.16 (dd, 1H, J H-6 -H-5 = 4.8 Hz, J H-6 -H-6 = 12.3 Hz, H-6ꢁꢁ), 5.07 (t, 1H,
ꢁꢁ
ꢁ
ꢁꢁ
ꢁ
J H-4 -H-3 = 9.6 Hz, J H-4 -H-5 = 9.9 Hz, H-4ꢁ), 5.17 (t, 1H, J H-3 -H-2 = 9.3 Hz,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
J H-3 -H-4 = 9.6 Hz, H-3ꢁ), 5.24 (t, 1H, J H-2 -H-1 = 9.9 Hz, J H-2 -H-3 = 9.3 Hz,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
H-2ꢁ), 5.31 (d, 1H, J H-1 -H-2 = 9.9 Hz, H-1ꢁ), 6.68 (d, 2H, J = 8.7 Hz, ArH),
7.60 (d, 2H, J = 8.7 Hz, ArH). Anal. Calcd for C23H25N5O9S2 (579.6): C,
47.66; H, 4.35; N, 12.08; S, 11.06. Found: C, 47.74; H, 4.48; N, 12.14; S,
11.01.
ꢁ
ꢁ
3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosylthio)-6-(4-chlorophenyl)-[1,
2,4]triazolo[3,4-b][1,3,4]thiadiazole (5c). Yield 390 mg (31%, A), 497 mg
(83%, B); yellow crystals, m.p. 108–110◦C (Rf = 0.72). IR: 3033, 2942, 1749,

6-Substituted-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thiones
355
1642, 1597, 1571, 1467, 1381, 1225, 1036, 957, 917, 828, 682, 603, 495, 473;
1H NMR (CDCl3) δ 1.93, 1.97, 1.98, 2.05 (4s, 12H, CH3CO), 3.75 (ddd, 1H,
J H-5 -H-6 = 2.1Hz, J H-5 -H-6 = 4.8 Hz, J H-5 -H-4 = 9.9 Hz, H-5ꢁ), 4.03 (dd, 1H,
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁ
J H-6 -H-5 = 2.1Hz, J H-6 -H-6 = 12.6 Hz, H-6ꢁ), 4.16 (dd, 1H, J H-6 -H-5 = 4.8
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁꢁ
ꢁ
Hz, J H-6 -H-6 = 12.6 Hz, H-6ꢁꢁ), 5.07 (t, 1H, J H-4 -H-3 = 9.6 Hz, J H-4 -H-5 = 9.9
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
Hz, H-4ꢁ), 5.15 (t, 1H, J H-3 -H-2 = 9.3 Hz, J H-3 -H-4 = 9.6 Hz, H-3ꢁ), 5.24 (t,
ꢁ
ꢁ
ꢁ
ꢁ
1H, J H-2 -H-1 = 9.9 Hz, J H-2 -H-3 = 9.3 Hz, H-2ꢁ), 5.34 (d, 1H, J H-1 -H-2 = 9.9
Hz, H-1ꢁ), 7.49 (td, 2H, J = 2.1, 8.7 Hz, ArH), 7.81 (td, 2H, J = 2.1, 8.7 Hz,
ArH). Anal. Calcd for C23H23ClN4O9S2 (599.0): C, 46.12; H, 3.87; N, 9.35;
S, 10.71. Found: C, 46.08; H, 3.90; N, 9.21; S, 10.70.
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosylthio)-6-(4-nitrophenyl)-[1,2,
4]triazolo[3,4-b][1,3,4]thiadiazole (5d). Yield 576 mg (45%, A), 536 mg
(88%, B); yellow crystals, m.p. 178–180◦C (Rf = 0.14). IR: 3040, 2943, 2889,
2854, 1743, 1605, 1527, 1454, 1373, 1346, 1300, 1223, 1092, 1034, 984, 953,
914, 856, 795, 752, 717, 687, 644, 617, 598, 536, 459, 432; 1H NMR (CDCl3)
δ 1.91 (s, 3 H, CH3CO), 1.960 (s, 3 H, CH3CO), 1.963 (s, 3 H, CH3CO),
ꢁ
ꢁ
ꢁ
ꢁꢁ
2.04 (s, 3 H, CH3CO), 3.75 (ddd, 1H, J H-5 -H-6 = 2.1Hz, J H-5 -H-6 = 4.8 Hz,
J H-5 -H-4 = 10.2Hz, H-5ꢁ), 4.02 (dd, 1H, J H-6 -H-5 = 2.1Hz, J H-6 -H-6 = 12.6 Hz,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
H-6ꢁ), 4.13 (dd, 1H, J H-6 -H-5 = 4.8 Hz, J H-6 -H-6 = 12.6 Hz, H-6ꢁꢁ), 5.06 (t,
ꢁꢁ
ꢁ
ꢁꢁ
ꢁ
1H, J H-4 -H-3 = 9.9 Hz, J H-4 -H-5 = 10.2Hz, H-4ꢁ), 5.14 (t, 1H, J H-3 -H-2 = 9.0
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
Hz, J H-3 -H-4 = 9.9 Hz, H-3ꢁ), 5.24 (t, 1H, J H-2 -H-1 = 9.9 Hz, J H-2 -H-3 = 9.0
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
Hz, H-2ꢁ), 5.33 (d, 1H, J H-1 -H-2 = 9.9 Hz, H-1ꢁ), 8.09 (td, 2H, J = 2.1, 9.0 Hz,
ArH), 8.36 (td, 2H, J = 2.1, 9.0 Hz, ArH). Anal. Calcd for C23H23N5O11S2
(609.6): C, 45.32; H, 3.80; N, 11.49; S, 10.52. Found: C, 45.19; H, 3.96; N,
11.39; S, 10.47.
ꢁ
ꢁ
2- (2, 3, 4, 6-Tetra - O-acetyl-β -D -glucopyranosyl)-6-phenyl-2H-[1,2,4]tria-
zolo[3,4-b][1,3,4]thiadiazole-3-thione (6a). Yield 119 mg (10%, A); yellow
crystals, m.p. 188–190◦C. IR: 2921, 2853, 1756, 1552, 1525, 1446, 1395,
1
1323, 1232, 1036, 1004, 923, 761, 688, 601; H NMR (CDCl3) δ 1.92, 2.02,
ꢁ
ꢁ
ꢁ
ꢁꢁ
2.07, 2.15 (4 s, 12H, CH3CO), 4.02 (ddd, 1H, J H-5 -H-6 = 2.1Hz, J H-5 -H-6
=
4.8 Hz, J H-5 -H-4 = 9.9 Hz, H-5ꢁ), 4.15 (dd, 1H, J H-6 -H-5 = 2.1Hz, J H-6 -H-6
=
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
12.6 Hz, H-6ꢁ), 4.31 (dd, 1H, J H-6 -H-5 = 4.8 Hz, J H-6 -H-6 = 12.6 Hz, H-6ꢁꢁ),
ꢁꢁ
ꢁ
ꢁꢁ
ꢁ
5.23 (t, 1H, J H-4 -H-3 = 9.3 Hz, J H-4 -H-5 = 9.9 Hz, H-4ꢁ), 5.43 (t, 1H, J H-3 -H-2
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
= 9.6 Hz, J H-3 -H-4 = 9.3 Hz, H-3ꢁ), 5.72 (t, 1H, J H-2 -H-1 = 9.3 Hz, J H-2 -H-3
=
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
9.6 Hz, H-2ꢁ), 6.27 (d, 1H, J H-1 -H-2 = 9.3 Hz, H-1ꢁ), 7.55 (m, 3 H, ArH), 7.90
(td, 2H, J = 1.6, 7.5 Hz, ArH). Anal. Calcd for C23H24N4O9S2 (564.6): C,
48.93; H, 4.28; N, 9.92; S, 11.36. Found: C, 49.09; H, 4.19; N, 9.89; S, 11.39.
2- (2,3,4,6-Tetra-O-acetyl -β-D-glucopyranosyl)-6-(4-aminophenyl)-2H- [1,
2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thione (6b). Yield 231 mg (19%, A);
yellow crystals, m.p. 116–118◦C, with shrinkage at 90◦C (Rf = 0.5). IR: 3483,
3381, 3029, 2957, 1751, 1607, 1496, 1371, 1229, 1037, 913, 834, 601, 421;
1HN MR (CDCl3) δ 1.90, 2.04, 2.05, 2.14 (4 s, 12H, CH3CO), 4.01 (ddd,
ꢁ
ꢁ
1H, J H-5 -H-6 = 2.1Hz, J H-5 -H-6 = 4.8 Hz, J H-5 -H-4 = 9.9 Hz, H-5ꢁ), 4.14 (dd,
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁ

356
N. S. A. M. Khalil
1H, J H-6 -H-5 = 2.1Hz, J H-6 -H-6 = 12.6 Hz, H-6ꢁ), 4.29 (dd, 1H, J H-6 -H-5
ꢁ
=
=
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁꢁ
ꢁ
4.8 Hz, J H-6 -H-6 = 12.6 Hz, H-6ꢁꢁ), 5.22 (t, 1H, J H-4 -H-3 = 9.3 Hz, J H-4 -H-5
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁ
9.9 Hz, H-4ꢁ), 5.42 (t, 1H, J H-3 -H-2 = 9.6 Hz, J H-3 -H-4 = 9.3 Hz, H-3ꢁ), 5.43
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
(s, 2H, D2O exchangeable NH2), 5.51 (t, 1H, J H-2 -H-1 = 9.3 Hz, J H-2 -H-3
=
9.6 Hz, H-2ꢁ), 6.25 (d, 1H, J H-1 -H-2 = 9.3 Hz, H-1ꢁ), 6.67 (d, 2H, J = 8.7 Hz,
ArH), 7.64 (d, 2H, J = 8.7 Hz, ArH). Anal. Calcd for C23H25N5O9S2 (579.6):
C, 47.66; H, 4.35; N, 12.08; S, 11.06. Found: C, 47.57; H, 4.28; N, 12.12; S,
11.01.
ꢁ
ꢁ
2-(2, 3,4,6-Tetra-O-acetyl-β- Dglucopyranosyl)-6-(4-chlorophenyl)-2H- [1,
2,4] triazolo[ 3,4-b] [1,3,4]thiadiazole-3-thione (6c). Yield 176 mg (14%, A);
yellow crystals, m.p. 84–86◦C (Rf = 0.83). IR: 3091, 2962, 2930, 2848, 2420,
2108, 1750, 1595, 1551, 1524, 1485, 1370, 1225, 1158, 1090, 1036, 1002,
953, 925, 833, 795, 758, 726, 683, 648, 599, 523, 496, 460; 1H NMR (CDCl3)
ꢁ
ꢁ
δ 1.93, 2.06, 2.07, 2.15 (4 s, 12H, CH3CO), 4.02 (ddd, 1H, J H-5 -H-6 = 2.1Hz,
J H-5 -H-6 = 4.8 Hz, J H-5 -H-4 = 9.9 Hz, H-5ꢁ), 4.15 (dd, 1H, J H-6 -H-5 = 2.1Hz,
ꢁ
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁ
J H-6 -H-6 = 12.6 Hz, H-6ꢁ), 4.31 (dd, 1H, J H-6 -H-5 = 4.8 Hz, J H-6 -H-6 = 12.6
ꢁ
ꢁꢁ
ꢁꢁ
ꢁ
ꢁꢁ
ꢁ
Hz, H-6ꢁꢁ), 5.23 (t, 1H, J H-4 -H-3 = 9.6 Hz, J H-4 -H-5 = 9.9 Hz, H-4ꢁ), 5.43
ꢁ
ꢁ
ꢁ
ꢁ
(t, 1H, J H-3 -H-2 = 9.3 Hz, J H-3 -H-4 = 9.6 Hz, H-3ꢁ), 5.72 (t, 1H, J H-2 -H-1
=
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
J H-2 -H-3 = 9.3 Hz, H-2ꢁ), 6.27 (d, 1H, J H-1 -H-2 = 9.3 Hz, H-1ꢁ), 7.51 (td, 2H,
J = 2.1, 8.7 Hz, ArH), 7.85 (td, 2H, J = 2.1, 8.7 Hz, ArH). Anal. Calcd for
C23H23ClN4O9S2 (599.0): C, 46.12; H, 3.87; N, 9.35; S, 10.71. Found: C,
45.98; H, 3.88; N, 9.26; S, 10.85.
ꢁ
ꢁ
ꢁ
ꢁ
2-(2, 3, 4, 6-Tetra- O -acetyl-β -D -glucopyranosyl)-6-(4-nitrophenyl) -2H-[1,
2,4]triazolo[3, 4-b] [1,3,4]thiadiazole-3-thione (6d). Yield 179 mg (14%, A);
yellow crystals, m.p. 178–180◦C(Rf = 0.64). IR; 3104, 3074, 2928, 2846,
1751, 1605, 1532, 1486, 1454, 1373, 1348, 1228, 1038, 1004, 955, 924, 854,
1
794, 752, 724, 687, 637, 599; H NMR (CDCl3) δ 1.90, 2.00, 2.04, 2.13 (4s,
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁ
12H, CH3CO), 4.02 (ddd, 1H, J H-5 -H-6 = 2.1Hz, J H-5 -H-6 = 4.8 Hz, J H-5 -H-4
= 10.2Hz, H-5ꢁ), 4.14 (dd, 1H, J H-6 -H-5 = 2.1Hz, J H-6 -H-6 = 12.6 Hz, H-6ꢁ),
ꢁ
ꢁ
ꢁ
ꢁꢁ
4.29 (dd, 1H, J H-6 -H-5 = 4.8 Hz, J H-6 -H-6 = 12.6 Hz, H-6ꢁꢁ), 5.21 (t, 1H,
ꢁꢁ
ꢁ
ꢁꢁ
ꢁ
J H-4 -H-3 = 9.6 Hz, J H-4 -H-5 = 10.2Hz, H-4ꢁ), 5.42 (t, 1H, J H-3 -H-2 = 9.3 Hz,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
J H-3 -H-4 = 9.6 Hz, H-3ꢁ), 5.68 (t, 1H, J H-2 -H-1 = 9.0 Hz, J H-2 -H-3 = 9.3 Hz,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
H-2ꢁ), 6.24 (d, 1H, J H-1 -H-2 = 9.0 Hz, H-1ꢁ), 8.10 (dd, 2H, J = 1.8, 8.7 Hz,
ArH), 8.37 (dd, 2H, J = 1.8, 8.7 Hz, ArH). Anal. Calcd for C23H23N5O11S2
(609.6): C, 45.32; H, 3.80; N, 11.49; S, 10.52. Found: C, 45.28; H, 3.79; N,
11.63; S, 10.49.
ꢁ
ꢁ
Deacetylation of Compounds 5a and 6a
General procedure: Dry gaseous ammonia was passed through a solution
of each of compounds 5a and 6a (1 mmol) in dry methanol (10 mL) for
about 1 hour with cooling and stirring then the reaction mixture was stirred
at room temperature over night. The resulting mixture was then concen-
trated at reduced pressure to afford a solid residue which was washed several

6-Substituted-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thiones
357
times via boiling in chloroform (100 mL) and decantation. The residue
was dried at room temperature, column chromatographed (chloroform
→ 20% methanol/chloroform), and recrystallized from methanol to give
colorless crystals of compounds 8 and 9. Rf values of the latter compounds
were determined using TLC aluminum sheets using chloroform/methanol
(80:20, v/v) as a developing system.
3-(β-D-glucopyranosylthio)-6-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadi-
azole (8). Yield 277 mg (75%); colorless crystals, m.p. 144–146◦C (Rf =
0.49). 1H NMR (DMSO-d6) δ 3.14–3.59 (m, 6 H, H-2ꢁ, H-3ꢁ, H-4ꢁ, H-5ꢁ, H-6ꢁ,
H-6ꢁꢁ), 4.10 (d, 1H, J = 3.9 Hz, D2O-exchangeable OH), 5.03 (br s, 1H
D2O-exchangeable OH), 5.14 (d, 1H, J H-1 -H-2 = 9.0 Hz, H-1ꢁ), 5.18 (br d,
1H, J = 6.9 Hz, D2O-exchangeable OH), 5.59 (br s, 1H, D2O-exchangeable
OH), 7.57–7.70 (m, 3 H, ArH), 7.97 (d, 2H, J = 7.5 Hz, ArH). Anal. Calcd
for C15H16N4O5S2 (396.4): C, 45.45; H, 4.07; N, 14.13; S, 16.18. Found: C,
44.51; H, 4.13; N, 14.02; S, 16.22.
ꢁ
ꢁ
2-β-D-Glucopyranosyl)-6-phenyl-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadia-
zole-3-thione (9). Yield 314 mg (85%); colorless crystals, m.p. 276–278◦C (Rf
= 0.75). IR: 3390 (br), 3059, 2914, 2863, 1569, 1533, 1475, 1446, 1394, 1317,
1288, 1260, 1078, 1055, 941, 893, 858, 761, 690, 599; 1H NMR (DMSO-d6) δ
3.28–4.36 (m, 6 H, H-2ꢁ, H-3ꢁ, H-4ꢁ, H-5ꢁ, H-6ꢁ, 6ꢁꢁ), 4.68 (t, 1H, J OH-H-6 = 5.4
ꢁ
Hz, J OH-H-6 = 5.7 Hz, D2O-exchangeable 6ꢁ-OH), 5.12 (d, 1H, J = 5.4 Hz
ꢁꢁ
D2O-exchangeable OH), 5.24 (d, 1H, J = 5.1Hz D2O-exchangeable OH),
ꢁ
ꢁ
5.48 (d, 1H, J = 5.4 Hz, D2O-exchangeable OH), 5.84 (d, 1H, J H-1 -H-2 = 9.0
Hz, H-1ꢁ), 7.57–7.66 (m, 3 H, ArH), 7.90 (t, 1H, J = 7.5 Hz, ArH), 8.00 (dd,
1H, J = 1.2, 7.5 Hz, ArH). Anal. Calcd for C15H16N4O5S2 (396.4): C, 45.45;
H, 4.07; N, 14.13; S, 16.18. Found: C, 44.31; H, 4.03; N, 14.17; S, 16.35.
REFERENCES
1. Jones, D.H.; Slack, R.; Squires, S.; Wooldridge, K.R.H. Antiviral chemotherapy. I. The activity of
pyridine and quinoline derivatives against neurovaccina in mice. J. Med. Chem.1965, 8, 676–680.
2. Goswami, B.N.; Kataky, J.C.S.; Baruah, J.N. Synthesis and antibacterial activity of 1-(2,4-
dichlorobenzoyl)-4-substituted thiosemicarbazides, 1,2,4-triazoles and their methyl derivatives.
J. Heterocycl. Chem. 1984, 21, 1225–1229.
3. Holla, B.S.; Kalluraya, B.; Sridhar, K.R. Synthesis of 4-(5-nitro-2-furfurylidene)amino-3-mercapto-5-
(substituted)-1,2,4-triazoles as possible antibacterial agents. Curr. Sci. 1987, 56, 236–238.
4. Holla, B.S.; Poojary, K.N.; Kalluraya, B.; Gowda, P.V. Synthesis, characterisation and antifungal
activity of some N -bridged heterocycles derived from 3-(3-bromo-4-methoxyphenyl)-4-amino-5-
mercapto-1,2,4-triazole. Farmaco 1996, 51, 793–799.
5. Abdou, N.A.; Amin, F.M. Synthesis and biological activity of certain 5-mercapto-3-(3-pyridyl)-4H-
1,2,4-triazole derivatives. Mansoura J. Pharm. Sci. 1990, 6, 25–29.
6. Mishra, R.K.; Tewari, R.K.; Srivastava, S.K.; Bahel, S.C. Synthesis and antifungal activity of
some 1,4-disubstitued-thiosemicarbazides, 2,5-disubstituted-1,3,4-thiadiazoles and 3,4-disubstituted-
5-mercapto-1,2,4-triazoles. J. Indian Chem. Soc. 1991, 68, 110–112.
7. Unangst, P.C.; Shurum, G.P.; Connor, D.T.; Dyer, R.D.; Schrier, D.J. Novel 1,2,4-oxadiazoles and 1,2,4-
thiadiazoles as dual 5-lipoxygenase and cyclooxygenase inhibitors. J. Med. Chem. 1992, 35, 3691–3698.
8. Mullican, M.D.; Wilson, M.W.; Connor, D.T.; Kostlan, C.R.; Schrier, D.J.; Dyer, R.D. Design of 5-
(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3,4-thiadiazoles, -1,3,4-oxadiazoles, and -1,2,4-triazoles as orally
active, nonulcerogenic antiinflammatory agents. J. Med. Chem. 1993, 36, 1090–1099.

358
N. S. A. M. Khalil
9. Sugden, J.K.; Yoloye, T.O. Medicinal applications of indole derivatives. Pharm. Acta Helv. 1978, 53,
65–92.
10. Shams El-Dine, Sh.A.; Hazzaa, A.A.B. Synthesis of compounds with potential fungicidal activity.
Pharmazie 1974, 29, 761–763.
11. Misato, T.; Ko, K.; Honma, Y.; Konno, K.; Taniyama, E. 1,3,4-thiadiazole derivatives as fungicides.
Jpn. Kokai Tokkyo Koho 77 25,028, 1977; Chem. Abstr. 1977, 87, 147054 a.
12. Cansiz, A.; Servi, S.; Koparir, M.; Altintas, M.; Digrak, M. Synthesis and biological activities of some
Mannich bases of 5-(2-furyl)-1,2,4-triazole-3-thiones. J. Chem. Soc. Pak. 2001, 23, 237–240.
13. Stillings, M.R.; Welbourn, A.P.; Walter, D.S. Substituted 1,3,4-thiadiazoles with anticonvulsant activity.
2. Aminoalkyl derivatives. J. Med. Chem. 1986, 29, 2280–2284.
14. Kane, J.M.; Dudley, M.W.; Sorensen, S.M.; Miller, F.P. 2,4-Dihydro-3H-1,2,4-triazole-3-thiones as
potential antidepressant agents. J. Med. Chem. 1988, 31, 1253–1258.
15. George, T.; Mehta, D.V.; Tahilramani R.; David, J.; Talwalker, P.K. Synthesis of some s-triazoles with
potential analgesic and antiinflammatory activities. J. Med. Chem. 1971, 14, 335–338.
16. Srivastava, U.; Khan, R.H.; Bahel, S.C. Synthesis of fungicidal 1,2,4-triazoles and related compounds.
Bokin Bobai. 1979, 7, T414–T417.
17. Rudnicka, W.; Osmailowska, Z. Cyanoalkylation of 4-amino-1,2,4-triazol-3-thione. Acta Pol. Pharm.
1979, 36, 411–419.
18. Shu-Qing, K.; Sun-Yung, T.; Ki, T.; Hung-Shan, C. Wei Sheng Wu Hsueh Pao 1980, 20, 208–212.
19. Singh, H.; Yadav, L.D.S.; Bhattacharya, B.K. Synthesis of some new bis(1,2,4-triazol-3-yl) disulfides,
sulfides and sulfones as potential pestcides. J. Indian Chem. Soc. 1979, 56, 1013–1016.
20. Gall, M.; Lahti, R.A.; Rudzik, A.D.; Duchamp, D.J.; Chidester, C.; Scahill, T. Novel anxiolytic agents
derived from .alpha.-amino-.alpha.-phenyl-o-tolyl-4H-triazoles and –imidazoles. J. Med. Chem. 1978,
21, 542–548.
21. Khalil, N.S.A.M. Efficient synthesis, structure, and antimicrobial activity of some novel N - and S-β-D-
glucosides of 5-pyridin-3-yl-1,2,4-triazoles. Carbohydr. Res. 2006, 341, 2187–2199.
22. Abbas, A.A.; Khalil, N.S.A.M. Synthesis of some new 1,3/ or 1,4-bis(glucopyranosyl-1,2,4-triazol-5-
ylthio)propanes/ or butanes as potential antimicrobial agents. Nucleosides Nucleotides Nucleic Acids
2005, 24, 1353–1372.
23. Omar, A.M.E.; Aboul Wafa, O.M. Synthesis and in vitro antimicrobial and antifungal properties of
some novel 1,3,4-thiadiazole and s-triazolo[3,4-b][1,3,4]thiadiazole derivatives. J. Heterocycl. Chem.
1986, 23, 1339–1341.
24. Kurtzer, F. In Advances in Heterocyclic Chemistry, eds. A.R. Katritzky, A.J. Boulton, A.J. Academic Press,
New York, 1965, vol. 5, p. 165.
25. Zhang, Z.Y.; Sun, X.W. s-Triazolo[3,4-b]-1,3,4-thiadiazole derivatives. Heterocycles 1998, 48, 561–584.
26. Khalil, N.S.A.M.; Mansour, A.K.; Eid, M.M. Synthesis of some novel 6-benzyl(or substituted benzyl)-
2-β-D-glucopyranosyl-1,2,4-triazolo[4,3-b][1,2,4]triazines as potential antimicrobial chemotherapeu-
tics. Nucleosides Nucleotides Nucleic Acids 2004, 23, 1889–1910.
27. Khalil, N.S.A.M. Synthesis of some novel N -ribosyl-1,2,4-triazin-6(1H)-/ones or thiones as poten-
tial antibacterial and antifungal chemotherapeutics. Nucleosides Nucleotides Nucleic Acids 2005, 24,
111–120.
28. Khalil, N.S.A.M. Synthesis of novel α-l-arabinopyranosides of β-lactams with potential antimicrobial
activity. Nucleosides Nucleotides Nucleic Acids 2005, 24, 1277–1287.
29. Mansour, A.K.; Eid, M.M.; Khalil, N.S.A.M. Selective synthesis and reactions of 6-substituted-2-β-
galactosyl-1,2,4-triazines of potential anticancer activity. Nucleosides Nucleotides Nucleic Acids 2003, 22,
21–44.
30. Mansour, A.K.; Eid, M.M.; Khalil, N.S.A.M. Synthesis of some new 2-α-l-arabinopyranosyl-1,2,4-
triazines as potential antitumor chemotherapeutics. Nucleosides Nucleotides Nucleic Acids 2003, 22,
1805–1823.
31. Mansour, A.K.; Eid, M.M.; Khalil, N.S.A.M. Synthesis of some N -galactosides of 3-aryl-5-benzyl (or
substituted benzyl)-1,2,4-triazin-6(1H)-/ones or thiones of expected biological activity. Nucleosides
Nucleotides Nucleic Acids 2003, 22, 1825–1833.
32. Mansour, A.K.; Ibrahim, Y.A.; Khalil, N.S.A.M. Selective synthesis and structure of 6-arylvinyl-2- and
4- glucosyl-1,2,4-triazines of expected interesting biological activity. Nucleosides Nucleotides 1999, 18,
2265–2283.

6-Substituted-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thiones
359
33. Mansour, A.K.; Eid, M.M.; and Khalil, N.S.A.M. Synthesis and reactions of some new heterocyclic
carbohydrazides and related compounds as potential anticancer agents. Molecules 2003, 8, 744–755.
34. Potts, K.T.; Huseby, R.M. 1,2,4-Triazoles. XVI. Derivatives of the s-triazolo[3,4-b][1,3,4]thiadiazole
ring system. J. Org. Chem. 1966, 31, 3528–3531.
35. Cleve, G.; Hoyer, G.A.; Schulz, G.; Vorbru¨ggen, H. Synthesis of nucleosides. VIII. NMR and CD
spectra of pyrimidine nucleosides and their 2-thio analogs. Chem. Ber. 1973, 106, 3062–3072.
36. Sandstrom, J. Cyclizations of thiocarbohydrazide and its monohydrazones. III. Reactions with carbon
disulfide in pyridine. Acta Chem. Scand. 1961, 15, 1295–1302.
37. Furniss, B.S.; Hannaford, A.J.; Smith, P.W.G.; Tatchell, A.R.; eds. Vogel’s Textbook of Practical Organic
Chemistry, Longman Group UK, Ltd., England, 1989, 5th ed., p. 647.