Synthesis and antitumor activity of new substituted mercapto-1,2,4-triazine derivatives, their thioglycosides, and acyclic thioglycoside analogs

Article abstract of DOI:10.1002/jhet.1022

New 1,2,4-triazine and their derived thioglycoside derivatives were synthesized from 5,6-diphenyl-1,2,4-triazine-3-thiol. Furthermore, the corresponding acyclic thioglycoside analogs were synthesized from the corresponding mercapto derivatives and acyclic

Full text of DOI:10.1002/jhet.1022

January 2013
Synthesis and Antitumor Activity of New Substituted Mercapto-
1,2,4-Triazine Derivatives, Their Thioglycosides, and Acyclic
Thioglycoside Analogs
129
*
Ibrahim F. Nassar
Faculty of Education, Ain Shams University, Abassia, Cairo, Egypt
*
E-mail: ibrahimnassar72@yahoo.com
Received March 31, 2011
DOI 10.1002/jhet.1022
View this article online at wileyonlinelibrary.com.
New 1,2,4-triazine and their derived thioglycoside derivatives were synthesized from 5,6-diphenyl-1,2,4-
triazine-3-thiol. Furthermore, the corresponding acyclic thioglycoside analogs were synthesized from the
corresponding mercapto derivatives and acyclic oxygenated alkyl halides. The newly synthesized
compounds were evaluated for their antitumor activity and some of them showed high inhibition activities.
J. Heterocyclic Chem., 50, 129 (2013).
INTRODUCTION
[19] properties have been cited in the scientific literature.
In addition, 6-azaisocytosine (e.g., 3-amino-1,2,4-triazin-
5(2H)-one), an isosteric isomer of 6-azacytosine and
6-azauracil, is of great biological interest because of
its resistance to deaminase, while azaribine the well-known
antiviral drug is structurally associated with the 1,2,4-
triazine moiety [20]. Various condensed 1,2,4-triazines
found applications as pharmaceuticals, herbicides,
pesticides, and dyes [21–26]. The 1,2,4-triazine core is a
versatile synthetic platform to access a wide range of
condensed heterocyclic ring systems via intramolecular
Diels-Alder reactions with a vast array of dienophiles. In
addition, the triazine ring system is a key component of
commercial dyes, herbicides, insecticides, and more
recently, pharmaceutical compositions [27]. Many 1,2,4-
triazines have been screened in vitro supporting their
anticancer activities [28]. Owing to the above facts and my
interest in the attachment of carbohydrate moieties to newly
synthesized heterocycles [29,30], the aim of the present
article is the synthesis of new 1,2,4-triazine derivatives,
and their thioglycoside and acyclic S-thioglycoside analogs
in an ongoing search for new biologically active leads with
potential antitumor activity.
The structural diversity and biological importance of
nitrogen containing heterocycles have made them attrac-
tive synthetic targets. Substituted 1,2,4-triazines represent
an important class of nitrogen containing heterocycles.
1,2,4-Triazines and their derivatives occupy a pivotal
position in modern medicinal chemistry because of their
high-potential for biological activity [1]. The 1,2,4-triazine
ring is a prominent structural motif found in numerous
natural and synthetic biologically active compounds. For
example, the well-known antiviral drug azaribine is
structurally based on the 1,2,4 triazine scaffold [1], 2].
They have been reported to possess a broad spectrum of bi-
ological activities, including antifungal [3], [4], anti-HIV
[5], anticancer [6], antiinflammatory [7], analgesic [8],
and antihypertensive activities [9]. Besides this, triazines
were used as herbicides, pesticides, and dyes [10,11]. Cer-
tain azanucleosides(6-azacytosine, 6-azauracil), structur-
ally based on the 1,2,4-triazine nucleus, have displayed
an impressive array of biological activities, among which
antitumor [12,13], antiviral [14,15], antimicrobial [16],
antiinflammatory [17], antimalarial [18], and antifungal
© 2013 HeteroCorporation

130
I. F. Nassar
Vol 50
Scheme 1
RESULTS AND DISCUSSION
The starting compound 5,6-diphenyl-1,2,4-triazine-3-
thiol (1) was synthesized according to a previously reported
procedure [31]. When compound 1 was alkylated with
chloroethylmethylether in DMF and in presence of potas-
sium carbonate at room temperature, 3-(2-methoxyethyl)thio
derivative 2 was formed in 80% yield. Its 1H NMR spectrum
showed the signal of the OCH3 group at δ 3.82 ppm in
addition to the CH2 signals each as triplet at δ 4.22 and
4.86 ppm. When the thiol derivative 1 was allowed to react
with chloroacetonitrile under the same reaction conditions
2-(5,6-diphenyl-1,2,4-triazin-3-ylthio)acetonitrile (3) was
formed. Its IR spectrum revealed the presence of a character-
istic absorption band at 2204 cm−1 for the CN group and its
1H NMR spectrum agreed with the assigned structure.
Reaction of the thiol 1 with 2-(2-chloroethoxy)ethanol under
reflux in ethanol in presence of potassium hydroxide
afforded 2-(2-(5,6-diphenyl-1,2,4-triazin-3-ylthio)ethoxy)
ethanol (4), which was acylated by means of acetic
anhydride to produce the corresponding O-acetyl derivative
5. The IR spectrum of 4 showed the absorption band for
the hydroxyl group at 3359 cm−1, which disappeared in the
corresponding spectrum of 5 and instead an absorption band
1
for the carbonyl group appeared. In addition, the H NMR
spectrum of the acetyl derivative 5 revealed the presence of
the acetyl methyl signal at δ 2.11 ppm (see Experimental sec-
tion) (Scheme 1).
deacetylated thioglycoside derivative 10 was obtained in
73.9% yield. Its structure was confirmed by IR, NMR,
and elemental analysis which agreed with the assigned
structure (see Experimental section).
Refluxing compound 1 with thiocarbohydrazide in
absolute ethanol afforded thiocarbohydrazide derivative
6, which was reacted with benzoin in glacial acetic acid
to afford 4-(5,6-diphenyl-1,2,4-triazin-3-ylamino)-5,6-
diphenyl-4,5-dihydro-1,2,4-triazine-3(2H)-thione (7) [32].
On the other hand, reaction of thiocarbohydrazide deriv-
ative 6 with phenacyl bromide in NaOH solution at reflux
temperature afforded the corresponding derivative 11 with
1
Its H NMR spectrum showed the signals of the aromatic
1
two 1,2,4-triazine rings in its structure. Its H NMR spec-
protons corresponding to four phenyl groups in the range
δ 7.21–7.85 ppm. Reaction of the latter thione 7 with
2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (8)
gave the corresponding acetylated thioglycoside derivative
trum showed signals corresponding to the CH2 group in
the dihydro 1,2,4-triazine ring at δ 5.25 ppm in addition
to the aromatic protons signals for three phenyl groups.
When compound 11 was reacted with 2,3,4,6-tetra-O-
acetyl-α-D-glucopyranosyl bromide (8) it gave the
corresponding acetylated thioglycoside derivative 12. The
1H NMR spectrum showed the acetyl methyl signals at δ
1.87–2.11 ppm in addition to the signals corresponding to
the sugar protons signals at δ 4.04–5.74 ppm. The chemical
shift value as well as the coupling constant of the anomeric
proton indicated the thioglucosidic β-configuration. Treat-
ment of the thioglucoside 12 with methanolic ammonia
at 0°C produced the deacetylated thioglycoside derivative
13. Its IR spectrum showed the hydroxyl absorption
bands at 3466–3447 cm−1 and its 1H NMR spectrum
showed signals for the hydroxyl groups and the aromatic
protons which agreed with the assigned structure, see
Experimental section (Scheme 2).
9. The IR spectrum of the produced acetylated glucoside
1
showed the C
¼
O absorption bands at 1737 cm−1. The H
NMR spectrum of the glucoside 9 showed signals
corresponding to the acetyl–methyl signals and the sugar
protons in addition to the aromatic protons. The anomeric
proton appeared at δ 5.75 ppm with coupling constants J
= 10.2 indicating the β-orientation of the thioglycosidic
bond. The anomeric proton of β-N-glucosides having an
adjacent C S, was reported [33–37] to appear at higher
¼
chemical shift because of the anisotropic deshielding effect
of the CS. The 13C NMR spectra of 9 showed a signal at δ
88.95 ppm corresponding to the anomeric C-1 that also
confirmed the β-configuration. The absence of a peak
corresponding to the C S group indicates that the attach-
¼
ment of the sugar has taken place at the sulfur atom and
not on the nitrogen atom. When compound 9 was treated
with methanolic ammonia at 0°C, the corresponding
Antitumor activity. The Antitumor activity of the newly
synthesized compounds was investigated against Ehrlich
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2013
Synthesis and Antitumor Activity of New Substituted Mercapto-1,2,4-Triazine
Derivatives, Their Thioglycosides, and Acyclic Thioglycoside Analogs
131
Scheme 2
Ascites Carcinoma cells (EAC). These cells were
maintained by weekly intraperitoneal transplantation of
2.5 × 106 cells in female Swiss albino mice. The tumor is
characterized by a moderately rapid growth, which kills
the mice in about 20 days due to the distal metastasis.
EAC is of mammary origin; since spontaneous breast
cancer served as the original tumor from which an ascites
variant was obtained [38].
Cytotoxicity assay. Ascites fluid was withdrawn under
aseptic conditions (ultraviolet laminar flow system) from
the peritoneal cavity of tumor bearing mice by needle
aspiration after 7 days of EAC cells inoculation. To
adjust the number of EAC cells/mL, tumor cells obtained
were diluted several times with normal saline. EAC
viable cells were counted by trypan blue exclusion
method where, 10 μL trypan blue (0.05%) was mixed
with 10 μL of the cell suspension. Within 5 min, the
mixture was spread onto haemocytometer, covered with a
cover slip and then the cells were examined under
microscope. Dead cells are blue stained but viable cells
are not. Cell suspension was adjusted to contain 2.5 ×
106 viable cells/mL.
EAC cells, RPMI medium, drugs, and DMSO were
added in sterile test tubes according to trypan blue exclu-
sion method [39]. The cells were incubated for 1 and 24
h at 37°C under a constant over lay of 5% CO2. EAC via-
ble cells were counted by trypan blue exclusion using hae-
mocytometer as mentioned earlier. The cell surviving
fraction was calculated from the relation T/C; where, T
and C represent the number of viable cells in a unit volume
and the number of total (viable + dead) cells in the same
unit volume, respectively.
The in vitro studies. The effects of the newly synthesized
compounds were assessed on the viability of EAC cells
using trypan blue exclusion test. The antitumor efficacy
of the compounds against ESC cell lines was
demonstrated compared to doxorubicin. The obtained
results revealed that compounds 2, 4, 6, 10, 12, and 13
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

132
I. F. Nassar
Vol 50
Table 1
were the most active derivatives among the series of tested
compounds and affected the EAC cell viability on a dose
dependent manner whereas other compounds exhibited
little or no activity. The effective dose calculated as IC50,
which correspond to the compound concentration resulted
in 50% mortality in the total cells count and presented in
Table 1. The 1,2,4-triazine derivatives 13 and 4 displayed
the highest activity with IC50 values 40, and 42 μg/mL,
respectively followed by compound 12.
The IC50 (μg/mL) of synthesized compounds.
Compound
IC50 (μg/mL)
2
4
6
10
12
13
57
42
54
56
49
40
38
Doxorubicin
From the antitumor activity results and structure activity
relationship, it could be concluded that the attachment of
glucopyranosyl sugar moiety to the substituted 1,2,4-
triazine-3-thiol ring system resulted in higher activities.
Furthermore, the 1,2,4-triazinyl thioglycoside with the free
hydroxyl glucopyranosyl sugar moiety revealed higher ac-
tivity than the corresponding acetylated analogs. More-
over, the [(glucopyranosyl)thio]-6-phenyl-1,2,4-triazine
derivative displayed higher inhibition activity than the
corresponding [(glucopyranosyl)thio]-5,6-diphenyl-1,2,4-
triazine derivatives. The attachment of acyclic oxygenated
hydroxyalkyl group to the 1,2,4-triazinyl thiol moiety
revealed higher inhibition activity.
mL) was added. The solid that formed was filtered off, and
recrystallized from ethanol as yellow crystals, 2.2 g (72.3%),
mp 125–127°C; IR (KBr) ν: 3050 (CH), 2204 (CN), 1612
(C
CH2), 7.26 (m, 3H, Ar
Ar H), 7.59 (d, 1H, J = 7.4 Hz, Ar
¼
N) cm1; 1H NMR (DMSO-d6, 300 MHz): δ 4.54 (s, 2H,
ꢀ
H), 7.34 (m, 2H, Ar
ꢀ
H), 7.44 (m, 2H,
ꢀ
ꢀH), 7.72 (m, 2H, Ar
ꢀH).
Anal. Calcd. for C17H12N4S: C, 67.08; H, 3.97; N, 18.41.
Found: C, 67.0; H, 4.0; N, 18.44.
2-(2-(5,6-Diphenyl-1,2,4-triazin-3-ylthio)ethoxy)ethanol
(4). To a solution of 1 (2.65 g, 10 mmol) and potassium hydroxide
(0.0112 g, 20 mmol) in EtOH (20 mL), was added 2-(2-
(chloroethoxy)ethanol (10 mmol). The solution was heated at
reflux temperature for 3 h, the solvent was removed under
reduced pressure and the solid that formed was filtered off, and
EXPERIMENTAL
recrystallized from ethylacetate as white crystals, 2.0 g (56.58%),
Melting points were determined with a kofler block apparatus
and are uncorrected. The IR spectra were recorded on a perkin-
Elmer model 1720 FTIR spectrometer for KBr disc. NMR spectra
were recorded on a varian Gemini 200 NMR Spectrometer at 300
MHz for 1H and 75 MHz for 13C or on a brucker Ac-250 FT spec-
1
mp 130–132°C. IR (KBr) ν: 3359 (OH), 1614 (C
¼
N) cm1; H
NMR (DMSO-d6, 300 MHz): δ 3.79 (t, 2H, J = 6.2 Hz, CH2),
4.24 (t, 2H, J = 5.6 Hz, CH2), 4.57 (m, 2H, CH2), 4.79 (t, 1H, J
= 6.8 Hz, OH), 5.14 (t, 2H, J = 6.2 Hz, CH2), 7.29 (m, 3H,
1
trometer at 250 MHz for H and at 62.9 MHz for 13C. Chemical
Ar
J = 7.4 Hz, Ar
75 MHz): δ 41.25, 48.15, 52.82, 54.29 (4CH2), 128.63–158.29
(15Ar C). Anal. Calcd. for C19H19N3O2S: C, 64.57; H, 5.42; N,
ꢀ
H), 7.41 (m, 2H, Ar
ꢀ
H), 7.46 (m, 2H, Ar
ꢀ
H), 7.61 (d, 1H,
ꢀH), 7.82 (m, 2H, Ar
ꢀ
H); 13C NMR (DMSO-d6,
shifts were reported in δ scale (ppm) relative to TMS as a standard
and the coupling constants J values are given in Hz. The progress
of the reactions was monitored by TLC using aluminum silica gel
plates 60 F245. Elemental analyses were performed at the Micro-
analytical data centre at Faculty of science, Cairo University,
Egypt. The antitumor activity investigation of the synthesized
compounds was carried out at the laboratory of biochemistry, ra-
diation research and technology center, Cairo, Egypt.
ꢀ
11.89.Found: C, 65.0; H, 5.52; N, 12.0.
2-(2-(5,6-Diphenyl-1,2,4-triazin-3-ylthio)ethoxy)ethyl acetate
(5). Compound 4 (0.01 mmol) in acetic anhydride (10 mL), was
refluxed for 2 h, and the solvent was removed under reduced
pressure. The solid that formed was filtered off, and recrystallized
3-(2-Methoxyethylthio)-5,6-diphenyl-1,2,4-triazine (2). To a
solution of 5,6-diphenyl-1,2,4-triazin-3-thiol 1 (2.65 g, 10 mmol)
and potassium carbonate (1.38 g, 10 mmol) in DMF (20 mL), was
added chloroethylmethylether (20 mmol). The solution was
stirred at room temperature for 5 h, the solvent was removed
under reduced pressure and water (100 mL) was added, and the
solid that formed was filtered off, and recrystallized from
ethanol as yellow crystals, 2.6 g (80.4%), mp 120–122°C; IR
from ethanol as white crystals, 2.8 g (70.8%); mp 145–147°C; IR
1
(KBr) ν: 1735 (C
300 MHz): δ 2.11 (s, 3H, CH3), 3.82 (t, 2H, J = 6.2 Hz, CH2),
4.25 (t, 2H, J = 5.6 Hz, CH2), 4.57 (t, 2H, J = 6.2 Hz, CH2),
¼
O), 1614 (C
¼
N) cm1; H NMR (DMSO-d6,
5.16 (t, 2H, J = 5.6 Hz, CH2), 7.25 (m, 3H, Ar
2H, Ar H), 7.52 (m, 2H, Ar H), 7.69 (d, 1H, J = 7.4 Hz,
Ar H), 7.85 (m, 2H, Ar H). Anal. Calcd. for C21H21N3O3S: C,
ꢀ
H), 7.40 (m,
ꢀ
ꢀ
ꢀ
ꢀ
63.78; H, 5.35; N, 10.63. Found: C, 63.55; H, 5.65; N, 10.39.
N′-(5,6-Diphenyl-1,2,4-triazin-3-yl)thiocarbohydrazide (6).
A solution of 5,6-diphenyl-1,2,4-triazin-3-thiol 1 (2.65 g, 10
mmol) and thiocarbohydrazide (1.06 g, 0.01 mmol) in ethanol
(20 mL) was refluxed for 4 h. The solution was allowed to cool
at room temperature, the solid that formed was filtered off and
recrystallized from benzene as white crystals, 2.6 g (77.06%);
(KBr) ν: 3055 (CH), 1611 (C
300 MHz): δ 3.82 (s, 3H, OCH3), 4.22 (t, 2H, J = 5.4 Hz,
CH2), 4.86 (t, 2H, J = 5.4 Hz, CH2), 7.29 (m, 3H, Ar H), 7.38
(m, 2H, Ar H), 7.44 (m, 2H, Ar H), 7.60 (d, 1H, J = 7.4 Hz,
Ar H), 7.75 (m, 2H, Ar H). Anal. Calcd. for C18H17N3OS:
¼
N) cm1; 1H NMR (DMSO-d6,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
C, 66.85; H, 5.3; N, 12.99. Found: C, 66.57; H, 5.35; N, 12.77.
2-(5,6-Diphenyl-1,2,4-triazin-3-ylthio)acetonitrile (3). To a
solution of 1 (2.65 g, 10 mmol) and potassium carbonate (1.38
g, 10 mmol) in DMF (20 mL), was added chloroacetonitrile (20
mmol). The solution was stirred at room temperature for 8 h,
the solvent was removed under reduced pressure and water (100
mp 130–132°C; IR (KBr) ν: 3348–3217 (NH2 and NH), 1610
1
(C
¼
N) cm1; H NMR (DMSO-d6, 300 MHz): δ 5.71 (bs, 1H,
NH), 5.91 (bs, 2H, NH2), 6.07 (m, 1H, NH), 6.14 (m, 1H, NH),
7.20 (m, 3H, Ar H), 7.33 (m, 2H, Ar H), 7.40 (m, 2H,
H), 7.74 (m, 2H, Ar H).
ꢀ
ꢀ
Ar
ꢀ
H), 7.52 (d, 1H, J = 7.4 Hz, Ar
ꢀ
ꢀ
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2013
Synthesis and Antitumor Activity of New Substituted Mercapto-1,2,4-Triazine
Derivatives, Their Thioglycosides, and Acyclic Thioglycoside Analogs
133
Anal. Calcd. for C16H15N7S: C, 56.96; H, 4.48; N, 29.06. Found:
C, 56.95; H, 4.50; N, 29.0.
4-(5,6-Diphenyl-1,2,4-triazin-3-ylamino)-6-phenyl-4,5-
dihydro-1,2,4-triazine3(2H)-thione (11).
A solution of
4-(5,6-Diphenyl-1,2,4-triazin-3-ylamino)-5,6-diphenyl-
4,5-dihydro-1,2,4-triazine-3(2H)-thione (7). A solution of
thiocarbohydrazide derivative 6 (0.01 mmol) and benzoin
(2.1 g 0.01 mmol) in glacial acetic acid (30 mL) was heated at
reflux temperature for 3 h. The solution was allowed to cool
and poured onto ice-cold water. The solid that formed was
filtered off and recrystallized from ethylacetate as white
crystals, 2.9 g (56.46%); mp 120–122°C; IR (KBr) ν: 3072
thiocarbohydrazide derivative 6 (3.37g 0.01 mmol) and phenacyl
bromide (1.99 g, 0.01 mmol) in (10%) NaOH solution (50 mL)
was heated at reflux temperature for 6 h. The solution was
allowed to cool and acidified with (10%) HCl solution, the solid
that formed was filtered off and recrystallized from ethanol as
white crystals, 2.7 g (61.71%); m.p 95–97°C. IR (KBr) ν: 3072
(CH), 1610 (C
(s, 1H, CH2), 5.73 (bs, 1H, NH), 7.21 (m, 3H, Ar
(m, 2H, Ar H), 7.48–7.52 (m, 3H, Ar H), 7.64–7.72 (m, 3H,
Ar H), 7.80 (m, 2H, Ar H), 7.85 (m, 2H, Ar H), 12.36 (s, 1H,
¼
N) cm1; 1H NMR (DMSO-d6, 300 MHz): δ 5.21
H), 7.35
ꢀ
(CH), 1610 (C
¼
N) cm1; 1H NMR (DMSO-d6, 300 MHz): δ
ꢀ
ꢀ
5.29 (s, 1H, triazine H-5), 5.71 (bs, 1H, NH), 7.21 (m, 3H,
ꢀ
ꢀ
ꢀ
Ar
Ar
ꢀ
H), 7.33–7.45 (m, 5H, Ar
H), 7.64–7.72 (m, 4H, Ar H), 7.79 (m, 2H, Ar
H), 12.28 (s, 1H, NH); 13C NMR (DMSO-d6, 75
ꢀ
H), 7.48–7.59 (m, 4H,
NH). Anal. Calcd. for C24H19N7S: C, 65.88; H, 4.38; N, 22.41.
ꢀ
ꢀ
ꢀH), 7.85
Found: C, 65.80; H, 4.60; N, 22.50.
(m, 2H, Ar
ꢀ
N-{3-[(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)thio]-
6-phenyl-1,2,4-triazin-4(5H)-yl}-5,6-diphenyl-1,2,4-triazin-3-
amine (12). To a solution of the thione 11 (5 mmol) in aqueous
potassium hydroxide [(0.28 g, 5 mmol) in distilled water
(15 mL] was added a solution of 2,3,4,6-tetra-O-acetyl-α-D-
glucopyranosyl bromide (8) (5 mmol) in acetone (20 mL).
The reaction mixture was stirred at room temperature for 8 h.
The solvent was evaporated under reduced pressure at 40°C
and the residue was washed with distilled water to remove
potassium bromide formed. The product was dried, and
recrystallized from ethanol as a yellow solid, 2.0 g (52.13%);
MHz): δ 57.18 (triazine C-5), 128.23–158.11 (27Ar-C +
triazine C-3,6), 172.81 (C S). Anal. Calcd. for C30H23N7S:
¼
C, 70.15; H, 4.51; N, 19.09. Found: C, 70.0; H, 4.50; N, 19.0.
N-{3-[(2,3,4,6-Tetra-O-acetyl-ß-D-glucopyranosyl)thio]-
5,6-diphenyl-1,2,4-triazin-4(5H)-yl}-5,6-diphenyl-1,2,4-triazin-
3-amine (9). To a solution of the thione 7 (5 mmol) in aqueous
potassium hydroxide [(0.28 g, 5 mmol) in distilled water
(15 mL)] was added a solution of 2,3,4,6-tetra-O-acetyl-α-D-
glucopyranosyl bromide (8) (5 mmol) in acetone (20 mL). The
reaction mixture was stirred at room temperature for 8 h. The
solvent was evaporated under reduced pressure at 40°C and
the residue was washed with distilled water to remove
potassium bromide formed. The product was dried, and
recrystallized from ethanol as yellow solid, 3.0 g (71.1%); mp
mp 103–105°C. IR (KBr) ν: 1736 (C
¼
O), 1612 (C
N) cm1;
¼
1H NMR (DMSO-d6, 300 MHz): δ 1.87, 1.93, 2.05, 2.11
(4s, 12H, 4CH3), 4.04 (m, 1H, H-5′), 4.11 (dd, J = 11.4 Hz,
J = 2.8 Hz, 1H, H-6′), 4.15 (dd, J = 11.4, 3.2 Hz, 1H, H-6′′),
4.90 (t, J = 9.3 Hz, 1H, H-4′), 5.16 (dd, J = 9.6 Hz, J = 9.3
Hz, 1H, H-3′), 5.25 (s, 2H, CH2), 5.32 (t, J = 9.6 Hz, 1H,
H-2′), 5.70 (bs, 1H, NH), 5.74 (d, J1′,2′ = 10.2 Hz, 1H, H-1′),
98–100°C; IR (KBr) ν: 1737 (C
¼
O), 1610 (C
N) cm1; 1H
¼
NMR (DMSO-d6, 300 MHz): δ 1.86, 1.91, 2.04, 2.11 (4s,
12H, 4CH3), 4.05 (m, 1H, H-5′), 4.12 (dd, J = 11.4 Hz, J =
2.8 Hz, 1H, H-6′), 4.16 (dd, J = 11.4, 3.2 Hz, 1H, H-6′′), 4.91
(t, J = 9.3 Hz, 1H, H-4′), 5.18 (dd, J = 9.6 Hz, J = 9.3 Hz, 1H,
H-3′), 5.29 (s, 1H, triazine H-5), 5.36 (t, J = 9.6 Hz, 1H, H-2′),
5.71 (bs, 1H, NH), 5.75 (d, J1′,2′ = 10.2 Hz, 1H, H-1′), 7.23 (m,
7.25 (m, 3H, Ar
3H, Ar H), 7.65–7.72 (m, 3H, Ar
Ar H), 7.86 (m, 2H, Ar
H); 13C NMR (DMSO-d6, 75
ꢀ
H), 7.36 (m, 2H, Ar
ꢀ
H), 7.50–7.55 (m,
H), 7.80 (m, 2H,
ꢀ
ꢀ
ꢀ
ꢀ
MHz): δ 19.34, 19.51, 20.19, 20.27 (4CH3), 56.94 (triazine
C-5), 62.89 (C-6′), 64.37 (C-4′), 68.69 (C-3′), 70.44 (C-2′),
72.81 (C-5′), 89.16 (C-1′), 129.20–158.58 (21Ar-C + triazine
3H, Ar
Ar H), 7.64–7.74 (m, 4H, Ar
(m, 2H, Ar
H); 13C NMR (DMSO-d6, 75 MHz): δ 19.32,
ꢀ
H), 7.35–7.46 (m, 5H, Ar
ꢀ
H), 7.52–7.64 (m, 4H,
ꢀ
ꢀH), 7.81 (m, 2H, Ar
ꢀH), 7.86
ꢀ
C-3,6), 169.58, 170.02, 170.54, 170.60 (4C O). Anal.
¼
19.50, 20.18, 20.27 (4CH3), 57.24 (triazine C-5), 62.88 (C-6′),
64.37 (C-4′), 68.65 (C-3′), 70.39 (C-2′), 72.82 (C-5′), 88.95 (C-
1′), 129.22–160.51 (27Ar-C + triazine C-3,6), 169.71, 170.15,
Calcd. for C38H37N7O9S: C, 59.44; H, 4.86; N, 12.77.
Found: C, 59.09; H, 4.90; N, 12.56.
N-{3-[(ß-D-Glucopyranosyl)thio]-6-phenyl-1,2,4-triazin-
4(5H)-yl}-5,6-diphenyl-1,2,4-triazin-3-amine (13). Dry gaseous
ammonia was passed through a solution of the acetylated
thioglycosides 12 (5 mmol) in dry methanol (15 mL) at 0°C
for 1 h, and the mixture was stirred at 0°C for about 6 h. The
solvent was evaporated under reduced pressure at 40°C to give
a solid residue, which was recrystallized from ethanol as a
170.52, 170.80 (4C O). Anal. Calcd. for C44H41N7O9S: C,
¼
62.62; H, 4.90; N, 11.62. Found: C, 62.55; H, 4.90; N, 11.80.
N-{3-[(β-D-Glucopyranosyl)thio]-5,6-diphenyl-1,2,4-triazin-
4(5H)-yl}-5,6-diphenyl-1,2,4-triazin-3-amine (10). Dry gaseous
ammonia was passed through a solution of the acetylated
thioglycoside 9 (5 mmol) in dry methanol (15 mL) at 0°C for
1 h, and the mixture was stirred at 0°C for about 6 h. The
solvent was evaporated under reduced pressure at 40°C to
give a solid residue, which was recrystallized from ethanol as
yellow solid, 2.5 g (83.4%); mp 100–102°C. IR (KBr) ν:
1
3466–3447 (OH), 1615 (C
¼
N) cm1; H NMR (DMSO-d6, 300
MHz): δ 3.45 (m, 2H, H-6′,6′′), 3.49 (m, 1H, H-5′), 3.94 (m,
2H, H-3′,4′), 4.31 (t, J = 9.4 Hz, 1H, H-2′), 4.74 (t, J = 6.2,
1H, OH), 4.84 (d, J = 6.4 Hz, 1H, OH), 5.23 (m, 1H, OH),
5.29 (m, 1H, OH), 5.22 (s, 2H, CH2), 5.75 (bs, 1H, NH),
a yellow solid, 2.5 g (73.9%); m.p 95–97°C. IR (KBr) ν:
1
3470–3450 (OH), 1610 (C
¼
N) cm1; H NMR (DMSO-d6, 300
MHz): δ 3.43 (m, 2H, H-6′,6′′), 3.48 (m, 1H, H-5′), 3.92
(m, 2H, H-3′,4′), 4.31 (t, J = 9.4 Hz, 1H, H-2′), 4.75 (t, J = 6.2,
1H, OH), 4.85 (d, J = 6.4 Hz, 1H, OH), 5.21 (m, 1H, OH), 5.25
(m, 1H, OH), 5.33 (s, 1H, triazine H-5), 5.74 (bs, 1H, NH),
5.81 (d, J1′,2′ = 10.2 Hz, 1H, H-1′), 7.24 (m, 3H, Ar
7.35–7.39 (m, 3H, Ar H), 7.56 (m, 2H, Ar H), 7.72–7.76
(m, 3H, Ar H), 7.84 (m, 2H, Ar H), 7.89 (m, 2H, Ar H);
ꢀ
H),
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
13C NMR (DMSO-d6, 75 MHz): δ, 57.74 (triazine C-5), 61.25
(C-6′), 64.08 (C-4′), 68.730 (C-3′), 71.33 (C-2′), 73.14 (C-5′),
90.02 (C-1′), 130.11–159.88 (21Ar-C + triazine C-3,6). Anal.
Calcd. for C30H29N7O5S: C, 60.09; H, 4.87; N, 16.35. Found:
C, 60.01; H, 4.80; N, 16.28.
5.80 (d, J1′,2′ = 10.2 Hz, 1H, H-1′), 7.24 (m, 3H, Ar
7.35–7.49 (m, 5H, Ar H), 7.54–7.68 (m, 4H, Ar H), 7.70–
7.75 (m, 4H, Ar H), 7.81 (m, 2H, Ar H), 7.88 (m, 2H,
Ar H). Anal. Calcd. for C36H33N7O5S: C, 63.99; H, 4.92; N,
14.51. Found: C, 63.85; H, 4.90; N, 14.50.
ꢀH),
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

134
I. F. Nassar
Vol 50
[17] Mitchel, W. L.; Hill, M. L.; Newtons, R. H.; Ravenscroft, P.;
Scopes, D. K. J Heterocycl Chem 1984, 21, 697.
[18] Salahuddin, N. A.; El-Barbary, A. A.; Abdo, N. I. Polym Adv
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Acknowledgments. Supply of Ehrlich Ascites Carcinoma Cells
(EAC) by National Cancer Institute (NCI) and performance of
biological evaluation by the laboratory of biochemistry,
radiation research and technology center, Cairo, Egypt, Cairo
University, Egypt are gratefully acknowledged.
[21] El-Gendy, Z.; Morsy, J. M.; Allimony, H. A.; Abdel-Monem
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[22] Erickson, J. G. Chem Heterocycl Compd 1956, 10, 44.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet