Synthesis and antitumor activity of new dihydropyridine thioglycosides and their corresponding dehydrogenated forms

Article abstract of DOI:10.1016/j.ejmech.2009.11.039

A number of a new pyridine thioglycosides were synthesized via reaction of piperidinium salts of dihydropyridinethiones with 2,3,4,6-tetra-O-acetyl-α-d-gluco- and galactopyranosyl bromide. The antitumor activities of the synthesized compounds were evaluated utilizing two different human cell lines. Some of the tested compounds showed high inhibition of human cell lines. The detailed synthesis, spectroscopic data and antitumor activities for the synthesized compounds were reported.

Full text of DOI:10.1016/j.ejmech.2009.11.039

European Journal of Medicinal Chemistry 45 (2010) 973–982
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antitumor activity of new dihydropyridine thioglycosides
and their corresponding dehydrogenated forms
*
Hebat-Allah S. Abbas , Wael A. El Sayed, Nahed M. Fathy
Photochemistry Department, National research center, Dokki, 12622 Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A number of a new pyridine thioglycosides were synthesized via reaction of piperidinium salts of
Received 25 February 2009
Received in revised form
13 November 2009
Accepted 20 November 2009
Available online 26 November 2009
dihydropyridinethiones with 2,3,4,6-tetra-O-acetyl-a-D-gluco- and galactopyranosyl bromide. The anti-
tumor activities of the synthesized compounds were evaluated utilizing two different human cell lines.
Some of the tested compounds showed high inhibition of human cell lines. The detailed synthesis,
spectroscopic data and antitumor activities for the synthesized compounds were reported.
Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords:
Piperidinium salts
1,4-Dihydropyridine thioglycosides
Pyridine thioglycosides
Antitumor activity
1. Introduction
inhibitors in the protein glycosylation process was reported [31]. In
view of the above facts and our interest [32,33] in the attachment of
The importance of the pyridine ring in the chemistry of biological
system has been greatly realized because of their presence as
substructure in many natural products of therapeutic importance,
involved in oxidation–reduction process. The potent biological
activity of various vitamins and drugs [1–4] is primarily contributed
by the presence of pyridine ring in their molecular make-up. The
pyridine ring is found in the skeleton of many compounds with
potent antibacterial, antifungal and anticancer properties [5,6]. Pyr-
idinethiones and related compounds exhibit a wide range of bio-
logical activity [7]. Among these activities antitumor and cytotoxic
activities of pyridinethiones [8–13] were described. Moreover,
a number of sulfur [14,15] containing pyridines are active antimi-
crobial agents and herbicides [16–18]. On the other hand, thio-
glycosides have received considerable attention, because they are
widely employed as biological inhibitors [19–22], inducers [23] and
ligands [24–26] for affinity chromatography for carbohydrate pro-
cessing-enzymes and proteins. Thiopyridyl glycosides were exten-
sively studied because of their potential activity as glycosyl donors
[27]. A number of novel synthesized functionalized pyridinethione
glycosides have been shown to exhibit antagonistic activity against
human carcinoma cells and HIV-virus [28–30]. Furthermore, the use
of dihydropyridine glycosides as P-glycoprotein (Pgp) substrates or
carbohydrate residues to heterocycles in order to find new biologi-
callyactive leads, we report here the synthesis and antitumor activity
of new thioglycoside derivatives of substituted dihydropyridine and
their corresponding dehydrogenated forms.
2. Results and discussion
2.1. Chemistry
In this investigation, we describe the synthesis of dihydropyr-
idine thioglycosides through the reaction of piperidinium salts of
dihydropyridine thiolates with 2,3,4,6-tetra-O-acetyl-
a-D-gluco- or
galactopyranosyl bromides. Thus, condensation of arylidene-
malononitriles 1a–e with thiocyanoacetamide or reaction of
aromatic aldehydes 2a–e with thiocyanoacetamide and malononi-
trile in ethanol containing piperidine at 40 ꢀC gave the corre-
sponding piperidinium salts of 1,4-dihydropyridin-2-thiones 3a–e
following reported procedure [34–36]. Treatment of piperidinium
salts 3a–e with concentrated hydrochloric acid afforded the corre-
sponding 1,4-dihydropyridin-2-thiol derivatives (30a–e). The IR
spectra of the thiols 30a–e showed characteristic absorption bands
at 2205–2228 cmꢁ1 corresponding to the CN groups and their 1H
NMR as well as mass spectra agreed with the assigned structures.
When the piperidinium salts 3a–ewere treated with2,3,4,6-tetra-
O-acetyl-
0
a-D-gluco- or galactopyranosyl bromide 4a,b in acetone at
* Corresponding author. Tel.: þ2 33 371010; fax: þ2 37601877.
E-mail address: hebanrc@yahoo.com (H.-A.S. Abbas).
ꢀC, the corresponding S-glucosides 5a–e or S-galactosides 5f–h
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.11.039

974
H.-A.S. Abbas et al. / European Journal of Medicinal Chemistry 45 (2010) 973–982
were obtained, respectively. The structuresof thethioglycosides 5a–h
were proved by means of their spectral data (IR, mass, 1H and 13C
NMR) and elemental analyses. The 1H NMR spectrum of 5c as
a representative example showed the anomeric proton asa doublet at
(P < 0.05) the life span of the animals as compared with control
group [animals injected with Human liver carcinoma cell line
(HEPG2) or Human cervix carcinoma cell line (HELA) alone]. There is
a gradual increase in life span using the prepared compounds. The
increase in life span was around 25%–69%. The standard reference
drug (Cisplatine 2 mg/kg body weight) exhibited 83% (P < 0.05)
increase in life span of the animals. All the animals in the HEPG2 or
HELA injected alone group were dead after 25 or 22 days, respec-
tively. Additionally, the obtained results clearly indicated the effect
of substituents in the aryl group on position-4 in the pyridine ring
on the antitumor activity.
The results of measurements of effect in treatment with tested
compounds on the survival of ascites tumor harboring mice inocu-
lated with (HEPG2) cells line (Table 1) revealed that compound 7e
was the most active exhibiting 69% increase in life span followed by
compounds 7h, 7g and 9c. Compounds 9b, 9e and 9f showed
moderate activity against the same tumor cell lines.
The results of antitumor measurements of tested compounds
with respect to the survival of ascites tumor harboring mice inoc-
ulated with (HELA) cells line (Table 1) showed that compounds 7e
having the highest activity with an increase in life span 55% fol-
lowed by compounds 9e and 9b. Compounds 9c, 8f, 9f, 8c, 7h and
7g showed moderate activity with 45–50% increase in life span.
Additionally, the antitumor activity observed for the substituted
pyridyl glucopyranosylthio derivative 7e indicated the importance
of both the free hydroxyl glucopyranosylthio and the p-methoxy
phenyl as well as the conformation of the hydroxyl group at C-4 in
the glucose ring, as the activity was reduced when the glucopyr-
anosylthio group was replaced by its corresponding O-acetylated
derivative 5e. Moreover, the activity of the substituted glucopyr-
anosylthio derivative was higher than its corresponding gal-
actopyranosylthio analog 7h.
0
0
0
d
5.76 ppmwith coupling constant J1 –2 ¼10.4 Hz indicating that H-1
is trance-dioxal to H-20. The other six glucose protons resonated at
3.80–5.30 ppm and the four acetyl groups appeared as four singlet
peaks at 2.03–2.16 ppm and NH2 group appeared as singlet at
5.99 ppm. In addition, its C, H, N analytical data revealed a molecular
formula C27H27BrN4SO9. The 13C NMR spectrum of 5c revealed the
presence of a signal at
80.62 ppm corresponding to the C-10 atom
and five signals appearing at 62.15, 67.90, 68.32, 69.7 and 74.53 that
d
d
d
d
d
were assigned to C-60, C-40, C-20, C-30 and C-50, respectively. The
attachment of the glycosyl residues to the sulfur rather than to the
nitrogen atom to give N-glucosides 6a–h has been supported by the
value of the chemical shift of the anomeric protons which other wise
should appearat a lower field. The anomeric proton of
having an adjacent C]S, was reported [32,37] to appear at higher
chemical shift ( 6.90–7.20 ppm) due to the anisotropic deshielding
b-N-glucosides
d
effect of the C]S. The absence of a peak corresponding to the C]S
group in the 13C NMR spectrum indicates that the attachment of the
sugar has taken place at the sulfur atom and not on the nitrogen atom
which also agreed with the mode of their preparation.
Treatment of the glycosides 5a–h with saturated solution of
ammonia in methanol at room temperature afforded the free
glucosides 7a–e and galactosides 7f–h. The 1H NMR spectrum of 7a
showed the anomeric proton as a doublet at
d
5.73 ppm with
-configuration.
The signals of the other six glucose protons appeared at 3.23–
4.14 ppm, while the signals observed at 4.73–5.25 ppm and dis-
0
0
coupling constant J1 –2 ¼ 10.4 Hz indicating the
b-D
d
d
appeared on rapid exchange with D2O were assigned as the four
hydroxyl groups. Furthermore, the C, H, N analytical data revealed
a molecular formula C19H20N4SO5 (Scheme 1)
Reaction of the piperidinium salts 3a–e with 2,3,4,6-tetra-O-
acetyl-a-D-gluco- or galactopyranosyl bromide 4a,b in dry acetone
On the other hand, the results of In vivo acute toxicity
measurements of synthesized compound with respect to ascites
tumor harboring mice inoculated with (HEPG2) cells (Fig. 1)
revealed that compound 5e exhibiting the highest LD50 with
150
mg/kg b.w. followed by compounds 9e, 9b and 7g among the
tested series of compounds. For the ascites tumor harboring mice
inoculated with (HELA) cells, compound 5e also showed the high-
est LD50 with 160 mg/kg b.w. followed by compounds 8e, 9f, 9e, 9c
and 7g with acute toxicities 120–135 mg/kg b.w.
at 30 ꢀC afforded the corresponding aromatized pyridine thio-
glucosides 8a–c and thiogalactosides 8d–f, respectively (Scheme
2). Compounds 8a–f could be also prepared by heating of dihy-
drothioglycosides 5a–c and 5f–h in ethanol for 5 min, which
underwent spontaneous auto-oxidation [38,39] to give the
aromatized thioglycosides 8a–f. The structures of the produced
S-glycosides were confirmed by their spectral and analytical data
which were in agreement with the assigned structures. The
formation of S-glycosides 8a–f rather than the corresponding N-
glycosides were proved by 13C NMR spectroscopy which revealed
the absence of the thione carbon (C]S) and the appearance of
a signal corresponding to the C–S carbon, whose chemical shift is
very close to that of the corresponding S-methyl derivative
[40,41].
3. Conclusion
From the results of antitumor activity and structure activity
relationship, it can be concluded that the effect of the substituent in
the aryl group placed at position 4 as well as the glycopyranosylthio
moiety in the pyridine ring was obvious. Thus, compound 7e with
free glucopyranosylthio and p-methoxy phenyl groups, was the
most active against both type of tumor (HEPG2 and HELA) cell lines.
Furthermore, all tested compound substituted with free glycopyr-
anosyl moieties showed higher activities than their corresponding
acetylated derivatives. Furthermore, compounds 9e and 9b con-
taining a 2-naphthayl moiety in their structures exhibited high
activity against ascites tumor HELA cell line. On the other hand, the
O-acetylated glucopyranosylthio derivative 5e showed the less
acute toxicity with respect to both type of tumor (HEPG2 and HELA)
cell lines.
Deacetylation of the thioglycosides 8a–f using saturated solu-
tion of methanolic ammonia at room temperature afforded the
free glycoside derivatives 9a–f. The 1H NMR spectrum of
compound 9c, as a representative example, showed the anomeric
proton as a doublet at
resonated at
d 5.80 ppm. The other six glucose protons
d
3.25–4.12 ppm. Its 13C NMR spectrum showed the
signal at
signals at
d
85.28 ppm corresponding to the C-10 atom and five
62.68–75.52 ppm were assigned as the sugar carbons in
d
addition to the signals of the pyridine ring carbons.
2.2. Antitumor activity
4. Experimental
The synthesized compounds were tested and evaluated for
inhibition using human liver carcinoma cell line (HEPG2) and
Human cervix carcinoma cell line (HELA). As shown in Table 1, the
administration of prepared compounds significantly increases
4.1. Chemistry
Melting points were determined on open glass capillaries using
an Electrothermal IA 9100 digital melting point apparatus

H.-A.S. Abbas et al. / European Journal of Medicinal Chemistry 45 (2010) 973–982
975
Scheme 1. Synthesis of dihydropyridine thioglycosides 5a–h and 7a–h.
(Shimadzu, Japan) and are uncorrected. IR spectra were recorded as
potassium bromide pellets on a Perkin–Elmer 1650 Spectropho-
tometer, National Research Centre, Cairo, Egypt. 1H NMR and 13C
NMR spectra were determined on a Jeol-Ex-300 NMR spectrometer
mixture was heated at 40 ꢀC with stirring for 3 h and then left to cool
to room temperature. After cooling, the solution of the resulting
piperidinium salt 3a–e was acidified with concentrated hydro-
chloric acid and the obtained precipitate was filtered off, washed
with distilled water and crystallized from ethanol to give 30a–e.
Method (B): A mixture of thiocyanoacetamide (1.0 g, 0.01 mol),
aromatic aldehyde 2a–e (0.01 mol) and malononitrile (0.66 g,
0.01 mol) in absolute ethanol (30 ml) containing piperidine (0.58 ml,
0.01 mol) was heated at 40 ꢀC with stirring for 3 h and then left to
cool at room temperature. After cooling, the solution of the resulting
piperidinium salt 3a–e was acidified with concentrated hydro-
chloric acid and the obtained precipitate was filtered off, washed
with distilled water and crystallized from ethanol to give 30a–e.
and chemical shifts were expressed as part per million; ppm (
d
values) against TMS as internal reference (Faculty of Science, Cairo
University, Cairo, Egypt). Mass spectra were recorded by 70 eV El Ms-
QP 1000 EX and FAB on a Kratos MS 50 spectrometer. Microanalyses
were operated using Mario Elmentar apparatus, Organic Micro-
analysis Unit, National Research Centre, Cairo, Egypt and the results
were within the accepted range of the calculated values. Antitumor
activity of the synthesized compounds was measured at the National
Cancer Institute, Cairo University, Cairo, Egypt.
4.1.1. General procedure for the synthesis of 2-amino-4-aryl-6-
mercapto 3,5-dicyano-1,4-dihydropyridines (30a–e)
Method (A): Piperidine (0.85 ml, 0.01 mol) was added to
a suspension of thiocyanoacetamide (1.0 g, 0.01 mol) and arylidene-
malononitrile 1a–e (0.01 mol) in absolute ethanol (30 ml) and the
4.1.1.1. 2-Amino-3,5-dicyano-6-mercapto-4-phenyl-1,4-dihydropyr-
idine (30a). Yield 2.03 g (80%) (brown powder): mp 126–127 ꢀC; IR
(KBr) nmax in cmꢁ1: 3319 (NH), 3232 (NH2), 2211 (CN), 2205 (CN);
1H NMR (CDCl3):
d
4.79 (s, 1H, pyridine H-4), 5.80 (s, 1H, NH), 7.67
(m, 3H, Ar-H), 7.90 (m, 2H, Ar-H), 8.51 (br, 2H, NH2), 9.65 (s, 1H, SH);

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H.-A.S. Abbas et al. / European Journal of Medicinal Chemistry 45 (2010) 973–982
4.1.1.2. 2-Amino-3,5-dicyano-6-mercapto-4-(naphthalen-2-yl)-1,4-
dihydropyridine (30b). Yield 2.46 g (81%) (brown powder): mp 141–
142 ꢀC; IR (KBr) nmax in cmꢁ1: 3311 (NH), 3218 (NH2), 2220 (CN),
2208 (CN); 1H NMR (CDCl3):
d 4.74 (s, 1H, pyridine H-4), 5.71 (s, 1H,
NH), 7.41 (m, 2H, Ar-H), 7.48 (d, 1H, J ¼ 8.5 Hz, Ar-H), 7.56 (d, 1H,
J ¼ 8.2 Hz, Ar-H)7.69 (d, 1H, J ¼ 8.2 Hz, Ar-H), 7.76 (s, 1H, Ar-H), 8.21
(d, 1H, J ¼ 8.5 Hz, Ar-H), 8.41 (br, 2H, NH2), 9.84 (s, 1H, SH); m/z
(%) ¼ 304 (84, [Mþ]). Anal. Calcd. for C17H12N4S: C, 67.08; H, 3.97; N,
18.41. Found: C, 67.10; H, 3.90; N, 18.50.
4.1.1.3. 2-Amino-3,5-dicyano-4-(4-bromophenyl)-6-mercapto-1,4-
dihydropyridine (30c). Yield 2.26 g (68%) (dark yellow powder): mp
132–133 ꢀC; IR (KBr) nmax in cmꢁ1: 3307 (NH), 3241 (NH2), 2218
(CN), 2208 (CN); 1H NMR (CDCl3):
d
4.81 (s, 1H, pyridine H-4), 5.62
(s, 1H, NH), 7.12 (d, 2H, J ¼ 7.8 Hz, Ar-H), 7.76 (d, 2H, J ¼ 7.8 Hz, Ar-
H), 8.54 (br, 2H, NH2), 9.80 (s, 1H, SH); 13C NMR (CDCl3):
76.37 (C-
d
4), 83.18 (C-5), 105.21 (C-3), 112.51 (CN), 115.17 (CN), 126.16–134.14
(Ar-6C), 158.08 (C-6), 158.82 (C-2)m/z (%) ¼ 333 (69, [Mþ]). Anal.
Calcd. for C13H9BrN4S: C, 46.86; H, 2.72; N,16.81. Found: C, 46.79; H,
2.74; N, 16.87.
4.1.1.4. 2-Amino-3,5-dicyano-6-mercapto-4-(4-nitrophenyl)-1,4-
dihydropyridine (30d). Yield 2.39 g (80%) (yellow powder): mp 125–
126 ꢀC; IR (KBr) nmax in cmꢁ1: 3318 (NH), 3236 (NH2), 2228 (CN),
2215 (CN); 1H NMR (CDCl3):
d
4.71 (s, 1H, pyridine H-4), 5.49 (s, 1H,
NH), 7.49 (d, 2H, J ¼ 7.8 Hz, Ar-H), 7.90 (d, 2H, J ¼ 7.8 Hz, Ar-H), 8.35
(br, 2H, NH2), 9.98 (s, 1H, SH); 13C NMR (CDCl3):
75.87 (C-4), 82.90
d
(C-5), 105.12 (C-3), 111.71 (CN), 114.18 (CN), 125.92–134.14 (Ar-6C),
158.02 (C-6), 158.69 (C-2); m/z (%) ¼ 299 (92, [Mþ]). Anal. Calcd. for
C13H9N5O2S: C, 52.17; H, 3.03; N, 23.40. Found: C, 52.10; H, 2.98; N,
23.32.
Scheme 2. Synthesis of pyridine thioglycosides 8a–f and 9a–f.
4.1.1.5. 2-Amino-3,5-dicyano-6-mercapto-4-(4-methoxyphenyl)-1,4-
dihydropyridine (30e). Yield 2.45 g (88%) (yellow powder): mp 129–
130 ꢀC; IR (KBr) nmax in cmꢁ1: 3309 (NH), 3229 (NH2), 2217 (CN),
13C NMR (CDCl3):
(CN), 114.42 (CN), 126.02–134.12 (Ar-6C), 158.05 (C-6), 159.11 (C-2);
m/z (%) ¼ 254 (77, [Mþ]). Anal. Calcd. for C13H10N4S: C, 61.40; H,
3.96; N, 22.03. Found: C, 61.34; H, 4.00; N, 22.10.
d 76.32 (C-4), 83.40 (C-5), 105.18 (C-3), 112.69
2210 (CN); 1H NMR (CDCl3):
d 3.81 (s, 3H, OCH3), 4.79 (s, 1H,
pyridine H-4), 5.50 (s, 1H, NH), 7.12 (d, 2H, J ¼ 7.8 Hz, Ar-H), 7.35 (d,
2H, J ¼ 7.8 Hz, Ar-H), 8.49 (br, 2H, NH2), 9.97 (s, 1H, SH); m/z
Table 1
Effect of treatment with different compounds on the survival of ascites tumor harboring mice inoculated with (HEPG2) or (HELA) cells line.
Conc. of compounds
g/kg b. w.)
Survival time
(days) HEPG2
% Increase in life span
of animals HEPG2
Survival time
(days) HELA
% Increase in life span
of animals HELA
(
m
Control
Cisplatine (2 mg/kg b. w.)
25.00 ꢂ 1.95
45.00 ꢂ 4.20a
28.00 ꢂ 2.30a
29.00 ꢂ 2.50a
30.00 ꢂ 1.90a
35.00 ꢂ 2.70a
33.00 ꢂ 2.20a
35.00 ꢂ 2.70a
29.00 ꢂ 2.30a
36.00 ꢂ 2.50a
37.00 ꢂ 1.90a
39.00 ꢂ 2.70a
38.00 ꢂ 2.70a
38.00 ꢂ 2.80a
36.00 ꢂ 2.50a
36.00 ꢂ 2.30a
32.00 ꢂ 1.90a
37.00 ꢂ 2.70a
36.00 ꢂ 2.70a
37.00 ꢂ 2.20a
38.00 ꢂ 2.30a
36.00 ꢂ 2.50a
36.00 ꢂ 2.70a
0
83
29
31
34
39
34
38
30
43
50
69
60
63
49
48
43
50
48
58
60
57
56
22.00 ꢂ 1.90
45.00 ꢂ 4.20a
28.00 ꢂ 2.30a
29.00 ꢂ 2.50a
27.00 ꢂ 1.90a
27.00 ꢂ 2.70a
29.00 ꢂ 2.20a
29.00 ꢂ 2.50a
29.00 ꢂ 2.20a
30.00 ꢂ 2.50a
35.00 ꢂ 1.90a
37.00 ꢂ 2.70a
36.00 ꢂ 2.70a
36.00 ꢂ 2.50a
34.00 ꢂ 2.50a
36.00 ꢂ 2.30a
33.00 ꢂ 1.90a
35.00 ꢂ 2.70a
36.00 ꢂ 1.90a
37.00 ꢂ 2.80a
37.00 ꢂ 2.30a
38.00 ꢂ 2.50a
36.00 ꢂ 2.70a
0
84
30
29
27
25
30
31
30
35
39
55
45
44
40
46
38
39
47
51
50
53
47
5a (10
5c (10
5d (10
5e (10
5f (10
5g (10
5h (10
7a (10
7b (10
7e (10
7g (10
7h (10
8b (10
8c (10
8d (10
8e (10
8f (10
9b (10
9c (10
9e (10
9f (10
m
m
m
m
m
m
m
m
m
m
m
m
m
m
m
m
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
m
m
m
m
m
g/kg b. w.)
Values are mean ꢂ SE.; n ¼ 10 mice.
a
P < 0.05 significant with respect to control.

H.-A.S. Abbas et al. / European Journal of Medicinal Chemistry 45 (2010) 973–982
977
180
160
140
120
100
80
LD50 (HEPG2)
LD50 (HELA )
60
40
20
0
5a 5c 5d 5e 5f 5g 5h 7a 7b 7e 7g 7h 8b 8c 8d 8e 8f 9b 9c 9e 9f
Compound
Fig. 1. Acute toxicity of synthesized compounds (LD50 mg/kg b.w.).
(%) ¼ 284 (84, [Mþ]). Anal. Calcd. for C14H12N4OS: C, 59.14; H, 4.25;
(C-50), 79.57 (C-4), 82.68 (C-10), 84.51 (C-5), 110.55 (C-3), 113.65
(CN),113.95 (CN),125.10–139.60 (Ar-10C),148.39 (C-2),159.01 (C-6),
169.14–170.83 (4C]O); MS (FAB): m/z (%) ¼ 634 (56, [Mþ]). Anal.
Calcd. for C31H30N4SO9: C, 58.67; H, 4.76; N, 8.83. Found: C, 58.66; H,
4.73; N, 8.80.
N, 19.70. Found: C, 59.22; H, 4.20; N, 19.65.
4.1.2. General procedure for the synthesis of 2-amino-4-aryl-3,5-
dicyano-6-(20,30,40,60-tetra-O-acetyl-10-thio-
b-D-gluco- or
galactopyranosyl)-1,4-dihydropyridines (5a–h)
The piperidinium salt 3a–e (0.01 mol) was dissolved in dry
acetone (5 ml), then 2,3,4,6-teta-O-acetyl- -gluco- or gal-
4.1.2.3. 2-Amino-4-(4-bromophenyl)-3,5-dicyano-6-(20,30,40,60-tetra-
a
-D
O-acetyl-10-thio-
b-D
-glucopyranosyl)-1,4-dihydropyridines (5c). Yield
4.58 g (69%) (Pale yellow powder): mp 215–217 ꢀC; [
¼ þ22.6 (c
2, CHCl3); IR (KBr) nmax in cmꢁ1: 3319 (NH), 3280 (NH2), 2214 (CN),
actopyranosyl bromide 4a,b (4.52 g, 0.011 mol) in dry acetone
(20 ml) was added at 0 ꢀC. The reaction mixture was stirred for 25–
30 h and the solvent was evaporated under reduced pressure. The
residue was washed with distilled water and the obtained crude
solid was filtered off, washed with distilled water and dried. The
pure product was extracted from the above solid with petroleum
ether (80–100). The petroleum ether extract was evaporated under
reduced pressure and the obtained solid was crystallized from
benzene to give the thioglycosides 5a–h.
a]
D
2218 (CN), 1759 (CO); 1H NMR (CDCl3):
d 2.03–2.16 (4s, 12H,
4CH3CO), 3.80 (dd, 1H, J ¼ 3.2 Hz, J ¼ 10.4 Hz, H-60), 3.89 (dd, 1H,
J ¼ 3.4 Hz, J ¼ 10.4 Hz, H-600), 4.07–4.30 (m, 3H, H-50, NH and
pyridine H-4), 5.08 (m, 1H, H-40), 5.24 (t, 1H, J ¼ 7.5 Hz, H-30), 5.30
(dd, 1H, J ¼ 7.5 Hz, J ¼ 10.4 Hz, H-20), 5.76 (d, 1H, J1 –2 ¼ 10.4 Hz, H-
10), 5.99 (s, 2H, NH2), 7.63 (d, 2H, J ¼ 7.8 Hz, Ar-2H), 7.66 (d, 2H,
0
0
J ¼ 7.8 Hz, Ar-2H); 13C NMR (CDCl3):
d 20.34–20.67 (4CH3CO), 62.15
(C-60), 67.9 (C-40), 68.32 (C-30), 69.7 (C-20), 74.53 (C-50), 78.39 (C-4),
80.62 (C-10), 83.33 (C-5), 106.53 (C-3), 114.26 (CN), 114.94 (CN),
126.09–134.5 (Ar-6C), 158.20 (C-2), 159.33 (C-6), 169.20–170.80
(4C]O); MS (FAB): m/z (%) ¼ 663 (42, [Mþ]). Anal. Calcd. for
C27H27BrN4SO9: C, 48.88; H, 4.10; N, 8.44. Found: C, 48.87; H, 4.08;
N, 8.47.
4.1.2.1. 2-Amino-3,5-dicyano-4-phenyl-6-(20,30,40,60-tetra-O-acetyl-
10-thio-
b-
D
-glucopyranosyl)-1,4-dihydropyridines (5a). Yield 4.27 g
(73%) (Pale yellow powder): mp 220–222 ꢀC; [
¼ þ26.4 (c 2,
CHCl3); IR (KBr) nmax in cmꢁ1: 3311 (NH), 3212 (NH2), 2214 (CN),
a
]
D
2201 (CN), 1765 (CO); 1H NMR (CDCl3):
d 1.90–2.12 (4s, 12H,
4CH3CO), 3.80 (dd, 1H, J ¼ 2.8 Hz, J ¼ 10.5 Hz, H-60), 3.94 (dd, 1H,
J ¼ 3.2 Hz, J ¼ 10.5 Hz, H-600), 4.08–4.23 (m, 3H, H-50, NH and
pyridine H-4), 5.12 (m, 1H, H-40), 5.24 (t, 1H, J ¼ 7.4 Hz, H-30), 5.30
4.1.2.4. 2-Amino-3,5-dicyano-4-(4-nitrophenyl)-6-(20,30,40,60-tetra-
O-acetyl-10-thio-
b
-
D
-glucopyranosyl)-1,4-dihydropyridines (5d). Yield
4.22g (67%) (Pale yellow powder): mp 230–232 ꢀC; [
¼ þ20.4 (c
2, CHCl3); IR (KBr) nmax in cmꢁ1: 3328 (NH), 3218 (NH2), 2216 (CN),
(dd, 1H, J ¼ 7.4 Hz, J ¼ 10.0, H-20), 5.75 (d, 1H, J1 –2 ¼ 10.0 Hz, H-10),
a]
D
0
0
5.80 (s, 2H, NH2), 7.61 (m, 3H, Ar-3H), 7.91 (m, 2H, Ar-2H); 13C NMR
(CDCl3):
d
20.39–20.69 (4CH3CO), 62.35 (C-60), 67.20 (C-40), 68.80
2220 (CN), 1763 (CO); 1H NMR (CDCl3):
d 2.06–2.13 (4s, 12H,
(C-30), 71.79 (C-20), 75.53 (C-50), 78.37 (C-4), 80.57 (C-10), 85.43 (C-
5), 106.66 (C-3), 114.21 (CN), 114.95 (CN), 126.19–134.54 (Ar-6C),
158.22 (C-2), 159.36 (C-6), 169.27–170.84 (4C]O); MS (FAB): m/z
(%) ¼ 584 (87, [Mþ]). Anal. Calcd. for C27H28N4SO9: C, 55.47; H, 4.83;
N, 9.58. Found: C, 55.40; H, 4.86; N, 9.52.
4CH3CO), 3.93 (dd, 1H, J ¼ 3.2 Hz, J ¼ 10.8 Hz, H-60), 4.05 (dd, 1H,
J ¼ 2.8 Hz, J ¼ 10.8 Hz, H-600), 4.10–4.32 (m, 3H, H-50, NH and
pyridine H-4), 5.13–5.40 (m, 2H, H-40, H-30), 5.40 (dd, 1H, J ¼ 7.6 Hz,
J ¼ 10. 4 Hz, H-20), 5.74 (d, 1H, J1 –2 ¼ 10.4 Hz, H-10), 6.02 (s, 2H,
0
0
NH2), 7.60 (d, 2H, J ¼ 7.8 Hz, Ar-2H), 8.4 (d, 2H, J ¼ 7.8 Hz, Ar-2H). 13
C
NMR (CDCl3):
d
20.24–20.63 (4CH3CO), 62.19 (C-60), 67.20 (C-40),
4.1.2.2. 2-Amino-3,5-dicyano-4-(naphthalen-2-yl)-6-(20,30,40,60-
68.45 (C-30), 70.55 (C-20), 75.52 (C-50), 78.21 (C-4), 80.53 (C-10),
82.98 (C-5), 106.55 (C-3), 114.65 (CN), 114.97 (CN), 126.14–134.58
(Ar-6C), 158.24 (C-2), 159.56 (C-6), 169.20–170.78 (4C]O); MS
(FAB): m/z (%) ¼ 629 (29, [Mþ]). Anal. Calcd. for C27H27N5SO11: C,
51.51; H, 4.32; N, 11.12. Found: C, 51.53; H, 4.29; N, 11.10.
tetra-O-acetyl-10-thio-
b-D-glucopyranosyl)-1,4-dihydropyridines
(5b). Yield 4.89 g (77%) (Pale yellow powder): mp 204–205 ꢀC;
[
a]
¼ þ32.8 (c 2, CHCl3); IR (KBr) nmax in cmꢁ1: 3330 (NH), 3260
D
(NH2), 2222 (CN), 2200 (CN), 1750 (CO); 1H NMR (CDCl3):
d 2.02–
2.34 (4s, 12H, 4CH3CO), 3.97 (dd, 1H, J ¼ 3.2 Hz, J ¼ 10.4 Hz, H-60),
4.09 (dd,1H, J ¼ 3.4 Hz, J ¼ 10.4 Hz, H-600), 4.13–4.28 (m, 3H, H-50, NH
and pyridine H-4), 5.10 (m, 1H, H-40), 5.20 (t, 1H, J ¼ 7.5 Hz, H-300),
4.1.2.5. 2-Amino-3,5-dicyano-4-(4-methoxyphenyl)-6-(20,30,40,60-
tetra-O-acetyl-10-thio-
b-D-glucopyranosyl)-1,4-dihydropyridines
5.39 (dd, 1H, J ¼ 7.5, 10.4 Hz, H-20), 5.78 (d, 1H, J1 –2 ¼ 10.4 Hz, H-1 ),
5.88 (s, 2H, NH2), 7.44 (m, 2H, Ar-H), 7.52 (d, 1H, J ¼ 8.5 Hz, Ar-H),
7.59 (d,1H, J ¼ 8.2 Hz, Ar-H), 7.72 (d,1H, J ¼ 8.2 Hz, Ar-H), 7.78 (s,1H,
(5e). Yield 3.63 g (59%) (Pale yellow powder): mp 189–190 ꢀC;
0
0
[a
]
¼ þ38.4 (c 2, CHCl3); IR (KBr) nmax in cmꢁ1: 3336 (NH), 3238
D
(NH2), 2220 (CN), 2200 (CN), 1759 (CO); 1H NMR (CDCl3)
d in ppm:
Ar-H), 8.20 (d, 1H, J ¼ 8.5 Hz, Ar-H); 13C NMR (CDCl3):
d
20.10–20.96
2.03–2.12 (4s, 12H, 4CH3CO), 3.83 (s, 1H, OCH3), 3.90 (dd, 1H,
J ¼ 3.2 Hz, J ¼ 10.4 Hz, H-60), 4.09 (dd, 1H, J ¼ 2.8 Hz, J ¼ 10.4 Hz, H-
(4CH3CO), 62.2 (C-60), 68.46 (C-40), 69.77 (C-30), 71.14 (C-20), 76.5

978
H.-A.S. Abbas et al. / European Journal of Medicinal Chemistry 45 (2010) 973–982
600), 4.13–4.24 (m, 3H, H-50, NH and pyridine H-4), 4.55 (t, 1H,
4.1.3. General procedure for the synthesis of 2-amino-4-aryl-3,5-
dicyano-6-(10-thio-
-glycopyranosyl)1,4-dihdropyridines 7a–h
J ¼ 8.8 Hz, H-40), 5.12 (dd, 1H, J ¼ 8.8 Hz, J ¼ 10.3 Hz, H-30), 5.34 (t,
b-D
1H, J ¼ 10.3 Hz, H-20), 5.76 (d, 1H, J1 –2 ¼ 10.3 Hz, H-10), 5.99 (s, 2H,
NH2), 7.03 (d, 2H, J ¼ 7.8 Hz, Ar-2H), 7.75 (d, 2H, J ¼ 7.8 Hz, Ar-2H);
To a solution of saturated mathanolic ammonia (20 ml), glucoside
5a–e or galactosides 5f–h (0.01 mol) was added at room tempera-
ture. The reaction mixture was stirred at the same temperature for
24 h, and then evaporated under reduced pressure. The residue was
treated with distilled water; the formed solid was filtered off,
washed with methanol and crystallized from methanol-DMF (4:1)
to give free glucosides 7a–e or free galactosides 7f–h, respectively.
0
0
13C NMR (CDCl3):
d 20.20–20.60 (4CH3CO), 55.35 (OCH3), 62.15 (C-
60), 67.25 (C-40), 68.55 (C-30), 70.59 (C-20), 75.68 (C-50), 76.69 (C-4),
81.99 (C-10), 82.41 (C-5), 106.40 (C-3), 114.62 (CN), 114.89 (CN),
126.15–134.63 (Ar-6C), 158.14 (C-2), 159.59 (C-6), 169.29–170.75
(4C]O); MS (FAB): m/z (%) ¼ 614 (47, [Mþ]). Anal. Calcd. for
C28H30N4SO10: C, 54.72; H, 4.92; N, 9.12. Found: C, 54.70; H, 4.90; N,
9.09.
4.1.3.1. 2-Amino-3,5-dicyano-4-phenyl-6-(10-thio-
anosyl)-1,4-dihdropyridines (7a). Yield 2.08 g (50%) (Pale yellow
powder): mp 188–189 ꢀC; [
¼ þ42.8 (c 1.5, MeOH); IR (KBr) nmax
in cmꢁ1: 3325-3270 (OH, NH, NH2), 2219 (CN), 2203 (CN); 1H NMR
b-D-glucopyr-
4.1.2.6. 2-Amino-3,5-dicyano-4-phenyl-6-(20,30,40,60-tetra-O-acetyl-
a]
D
10-thio-
b
-D
-galactopyranosyl)-1,4-dihydropyridines (5f). Yield 3.86 g
(66%) (Pale yellow powder): mp 186–188 ꢀC; [
¼ þ36.6 (c 2,
CHCl3); IR (KBr) nmax in cmꢁ1: 3335 (NH), 3218(NH2), 2211 (CN),
a]
(DMSO-d6): d
3.23 (m, 2H, H-60, H-600), 3.29 (m, 1H, H-50), 3.56
D
(m, 2H, H-40, H-30), 4.14 (dd, 1H, J ¼ 7.8 Hz, J ¼ 10.4 H-20), 4.73
(m, 1H, OH), 4.83 (s, 1H, pyridine H-4), 4.86 (t, 1H, J ¼ 4.6 Hz, OH),
5.13 (d, 1H, J ¼ 4.5 Hz, OH), 5.25 (t, 1H, J ¼ 4.8 Hz, OH), 5.73 (d, 1H,
2200 (CN), 1758 (CO); 1H NMR (CDCl3):
d 2.04–2.18 (4s, 12H,
4CH3CO), 3.67 (dd, 1H, J ¼ 2.8 Hz, J ¼ 10.5 Hz, H-60), 4.88 (dd, 1H,
J ¼ 3.2 Hz, J ¼ 10.5 Hz, H-600), 4.11 (m, 3H, H-50, NH and pyridine H-
4), 5.08 (m, 1H, H-40), 5.21 (t, 1H, J ¼ 7.4 Hz, H-30), 5.62 (dd, 1H,
J1 –2 ¼ 10.4 Hz, H-10), 6.24 (bs, 2H, NH2), 6.38 (bs, 1H, NH), 7.18
0
0
(m, 3H, Ar-3H), 7.45 (m, 2H, Ar-2H); 13C NMR (DMSO-d6):
d 61.25
J ¼ 7.8 Hz, J ¼ 10.2 Hz, H-20), 5.73 (d, 1H, J1 –2 ¼ 10.2 Hz, H-10), 5.79
(C-60), 66.20 (C-40), 68.20 (C-20), 73.30 (C-30), 75.50 (C-50), 77.17
(C-4), 81.57 (C-10), 82.93 (C-5), 106.02 (C-3), 115.11 (CN), 115.75
(CN), 126.29–137.44 (Ar-6C), 158.36 (C-2), 159.26 (C-6); MS (FAB):
m/z (%) ¼ 416 (37, [Mþ]). Anal. Calcd. for C19H20N4SO5: C, 54.80; H,
4.84; N, 13.45. Found: C, 54.85; H, 4.81; N, 13.40.
0
0
(s, 2H, NH2), 7.40 (m, 3H, Ar-3H), 7.80 (m, 2H, Ar-2H); 13C NMR
(CDCl3):
d
20.30–20.57 (4CH3CO), 62.23 (C-60), 67.88 (C-40), 68.31
(C-30), 71.72 (C-20), 75.63 (C-50), 77.24 (C-4), 80.62 (C-10), 81.59 (C-
5), 105.89 (C-3), 114.25 (CN), 114.94 (CN), 126.09–134.90 (Ar-6C),
158.24 (C-2), 159.36 (C-6), 169.20–170.70 (4C]O); MS (FAB): m/z
(%) ¼ 584 (41, [Mþ]). Anal. Calcd. for C27H28N4SO9: C, 55.47; H, 4.83;
N, 9.58. Found: C, 55.46; H, 4.81; N, 9.54.
4.1.3.2. 2-Amino-3,5-dicyano-4-(naphthalen-2-yl)-6-(10-thio-
-gluco-pyranosyl)-1,4-dihdro pyridines (7b). Yield 2.05 g (44%)
(Pale yellow powder): mp 193–194 ꢀC; [
¼ þ39.4 (c 1.5, MeOH);
IR (KBr) nmax in cmꢁ1: 3380-3310 (OH, NH and NH2), 2200 (CN),
2198 (CN); 1H NMR (DMSO-d6) in ppm: 3.25 (m, 2H, H-60, H-600),
b-
D
a
]
D
4.1.2.7. 2-Amino-3,5-dicyano-4-(naphthalen-2-yl)-6-(20,30,40,60-
tetra-O-acetyl-10-thio-
b
-
D
-galactopyranosyl)-1,4-dihydropyridines
d
(5g). Yield 4.38 g (69%) (Pale yellow powder): mp 213–215 ꢀC;
3.28 (m, 1H, H-50), 3.53 (m, 2H, H-40, H-30), 4.12 (dd, 1H, J ¼ 7.6 Hz,
J ¼ 10.2 Hz, H-20), 4.72 (d,1H, J ¼ 7.2 Hz, OH), 4.85 (s,1H, pyridine H-
4), 4.88 (t, 1H, J ¼ 4.6 Hz, OH), 5.11 (m, 1H, OH), 5.25 (t, 1H,
[
a
]
¼ þ34.8 (c 2, CHCl3); IR (KBr) nmax in cmꢁ1: 3320 (NH), 3240
D
(NH2), 2225 (CN), 2217 (CN), 1760 (CO); 1H NMR (CDCl3):
d 2.05–2.18
(4s, 12H, 4CH3CO), 3.97 (dd, 1H, J ¼ 3.2 Hz, J ¼ 10.4 Hz, H-60), 4.14
(dd,1H, J ¼ 2.4 Hz, J ¼ 10.4 Hz, H-600), 4.15–4.32 (m, 3H, H-50, NH and
pyridine H-4), 5.10 (m, 1H, H-40), 5.19 (t, 1H, J ¼ 8.2 Hz, H-30), 5.40
J ¼ 4.4 Hz, OH), 5.74 (d, 1H, J1 –2 ¼ 10.2 Hz, H-1 ), 6.25 (bs, 2H, NH2),
6.35 (bs, 1H, NH), 7.40 (m, 2H, Ar-H), 7.47 (d, 1H, J ¼ 8.5 Hz, Ar-H),
7.57 (d,1H, J ¼ 8.2 Hz, Ar-H), 7.67 (d,1H, J ¼ 8.2 Hz, Ar-H), 7.76 (s,1H,
0
0
0
(dd, 1H, J ¼ 8.2 Hz, J ¼ 10.4 Hz, H-20), 5.79 (d, 1H, J1 –2 ¼ 10.4 Hz, H-
10), 5.99 (s, 2H, NH2), 7.24 (m, 1H, Ar-H), 7.36 (d,1H, J ¼ 8.5 Hz, Ar-H),
7.47 (m, 1H, Ar-H), 7.66 (m, 1H, Ar-H), 7.79 (d, 1H, J ¼ 8.2 Hz, Ar-H),
7.92 (d, 1H, J ¼ 8.2 Hz, Ar-H), 8.25 (d, 1H, J ¼ 8.5 Hz, Ar-H), 13C NMR
Ar-H), 8.19 (d, 1H, J ¼ 8.5 Hz, Ar-H). 13C NMR (DMSO-d6):
d61.2
0
0
(C-60), 68.26 (C-40), 73.37 (C-20), 75.82 (C-30), 76.12 (C-50), 76.98.
(C-4), 80.58 (C-10), 82.65 (C-5), 110.41 (C-3), 113.32 (CN), 113.87
(CN), 125.10–140.60 (Ar-10C), 148.02 (C-2), 159.10 (C-6); MS (FAB):
m/z (%) ¼ 466 (22, [Mþ]). Anal. Calcd. for C23H22N4SO5: C, 59.22; H,
4.75; N, 12.01. Found: C, 59.20; H, 4.74; N, 11.96.
(CDCl3): d
20.10–20.96 (4CH3CO), 62.32 (C-60), 68.49 (C-40), 69.72 (C-
30), 70.79 (C-20), 76.90 (C-50), 75.57 (C-4), 81.68 (C-10), 83.55 (C-5),
110.65 (C-3), 113.61 (CN), 113.95 (CN), 125.10–139.60 (Ar-10C),
148.39 (C-2), 159.21 (C-6), 169.19–170.33 (4C]O); MS (FAB): m/z
(%) ¼ 634 (36, [Mþ]). Anal. Calcd. for C31H30N4SO9: C, 58.67; H, 4.76;
N, 8.83. Found: C, 58.70; H, 4.77; N, 8.81.
4.1.3.3. 2-Amino-4-(4-bromophenyl)-3,5-dicyano-6-(10-thio-
gluco-pyranosyl)-1,4-dihdropyridines (7c). Yield 2.48 g (50%) (Pale
yellow powder); mp 203–205 ꢀC; [
¼ þ32.8 (c 1.5, MeOH); IR
(KBr) nmax in cmꢁ1: 3316-3250 (OH, NH and NH2), 2224 (CN), 2220
b-D-
a
]
D
4.1.2.8. 2-Amino-3,5-dicyano-4-(4-methoxyphenyl)-6-(20,30,40,60-
(CN); 1H NMR (DMSO-d6) in ppm: 3.27 (m, 2H, H-60, H-600), 3.29
d
tetra-O-acetyl-10-thio-
b
-
D
-galactopyranosyl)-1,4-dihydropyridines
(m,1H, H-50), 3.52 (m,1H, H-40), 3.88 (m, 2H, H-30, H-20), 4.75 (d,1H,
(5h). Yield 4.36 (71%) (Pale yellow powder): mp 220–221 ꢀC;
J ¼ 6.8 Hz, OH), 4.86 (s,1H, pyridine H-4), 4.92 (t,1H, J ¼ 4.6 Hz, OH),
¼ þ40.4 (c 2, CHCl3); IR (KBr) nmax in cmꢁ1: 3324 (NH), 3214
5.13 (m, 1H, OH), 5.27 (t, 1H, J ¼ 4.4 Hz, OH), 5.73 (d, 1H, J1 –
0
[
a]
D
(NH2), 2221 (CN), 2208 (CN), 1751 (CO); 1H NMR (CDCl3):
d
2.04–
¼ 9.8 Hz H-10), 6.24 (bs, 2H, NH2), 6.34 (bs, 1H, NH), 7.29 (d, 2H,
20
2.12 (s, 12H, 4CH3CO), 3.98 (s, 3H, OCH3), 4.10 (dd, 1H, J ¼ 3.2 Hz,
J ¼ 11.2 Hz, H-60), 4.15 (dd, 1H, J ¼ 2.8 Hz, J ¼ 11.2 Hz, H-600), 4.24
(m, 3H, H-50, NH and pyridine H-4), 5.11 (m, 1H, H-40), 5.18 (t, 1H,
J ¼ 7.8 Hz, H-30), 5.040 (dd,1H, J ¼ 7.8 Hz, J ¼ 9.8 Hz, H-20), 5.78 (d,1H,
J ¼ 7.8 Hz, Ar-2H), 7.78 (d, 2H, J ¼ 7.8 Hz, Ar-2H); 13C NMR (DMSO-
d6):
d
62.19 (C-60), 67.28 (C-40), 68.25 (C-20), 73.50 (C-30), 75.51
(C-50), 77.69 (C-4), 80.53 (C-10), 81.38 (C-5), 106.55 (C-3), 114.65
(CN), 114.87 (CN), 126.14–134.58 (Ar-6C), 158.24 (C-2), 159.56 (C-6);
MS (FAB): m/z (%) ¼ 495 (32, [Mþ]). Anal. Calcd. for C19H19BrN4SO5:
C, 46.07; H, 3.87; N, 11.31. Found: C, 46.09; H, 3.88; N, 11.29.
0
0
J1 –2 ¼ 9.8 Hz, H-1 ), 5.84 (s, 2H, NH2), 6.99 (d, 2H, J ¼ 7.8 Hz, Ar-2H),
7.17 (d, 2H, J ¼ 7.8 Hz, Ar-2H). 13C NMR (CDCl3):
d 20.20–20.60
(4CH3CO), 55.3 (OCH3), 62.25 (C-60), 67.35 (C-40), 69.56 (C-30), 71.62
(C-20), 75.54 (C-50), 75.98 (C-4), 81.85 (C-10), 82.87 (C-5), 106.49 (C-
3), 114.52 (CN); 114.92 (CN), 126.35–134.23 (Ar-6C), 158.34 (C-2),
159.49 (C-6), 169.35–170.42 (4C]O); MS (FAB): m/z (%) ¼ 614 (50,
[Mþ]). Anal. Calcd. for C28H30N4SO10: C, 54.72; H, 4.92; N, 9.12.
Found: C, 54.76; H, 4.98; N, 9.11.
4.1.3.4. 2-Amino-3,5-dicyano-4-(4-nitrophenyl)-6-(10-thio-
gluco-pyranosyl)-1,4-dihdropyridines (7d). Yield 2.68 g (58%) (Pale
yellow powder): mp 218–219 ꢀC; [
¼ þ28.8 (c 1.5, MeOH); IR
(KBr) nmax in cmꢁ1: 3297-3235 (OH, NH and NH2), 2213 (CN), 2200
(CN); 1H NMR (DMSO-d6): 3.24 (m, 2H, H-60, H-600), 3.26 (m, 1H,
b-D-
a]
D
d

H.-A.S. Abbas et al. / European Journal of Medicinal Chemistry 45 (2010) 973–982
979
H-50), 3.52 (m, 1H, H-40), 3.87–4.14 (m, 2H, H-30, H-20), 4.75 (m, 1H,
IR (KBr) nmax in cmꢁ1: 3350-3268 (OH, NH and NH2), 2222 (CN),
2218 (CN); 1H NMR (DMSO-d6): 3.20 (m, 2H, H-60, H-600), 3.24 (m,
OH), 4.84 (t, 1H, J ¼ 4.6 Hz, OH), 4.84 (s, 1H, pyridine H-4), 5.14 (d,
d
1H, J ¼ 6.4 Hz, OH), 5.27 (t, 1H, J ¼ 5.8 Hz, OH), 5.72 (d, 1H, J1 –
1H, H-50), 3.47 (m,1H, H-40), 3.82 (s, 3H, OCH3), 3.85 (m, 2H, H-30, H-
20), 4.72 (t,1H, J ¼ 4.8 Hz, OH), 4.81 (t,1H, J ¼ 4.6 Hz, OH), 4.88 (s,1H,
pyridine H-4), 5.20 (m, 1H, OH), 5.26 (t, 1H, J ¼ 4.4 Hz, OH), 5.75 (d,
0
¼ 10.4 Hz, H-10), 6.22 (bs, 2H, NH2), 6.32 (bs, 1H, NH), 7.33 (d, 2H,
20
J ¼ 7.8 Hz, Ar-2H), 7.84 (d, 2H, J ¼ 7.8 Hz, Ar-2H); 13C NMR (DMSO-
d
63.56 (C-60), 68.08 (C-40), 69.14 (C-20), 73.56 (C-30), 75.45
1H, J1 –2 ¼ 10.4 Hz, H-10), 6.18 (bs, 2H, NH2), 6.35 (bs, 1H, NH), 7.31
(d, 2H, J ¼ 7.8 Hz, Ar-2H), 7.85 (d, 2H, J ¼ 7.8 Hz, Ar-2H). 13C NMR
0
0
d6):
(C-50), 77.69 (C-4), 80.53 (C-10), 81.38 (C-5), 106.10 (C-3), 114.21
(CN), 114.87 (CN), 126.14–131.58 (Ar-6C), 158.24 (C-2), 159.21 (C-6);
MS (FAB): m/z (%) ¼ 461 (39, [Mþ]). Anal. Calcd. for C19H19N5SO7: C,
49.45; H, 4.15; N, 15.18. Found: C, 49.43; H, 4.11; N, 15.20.
(DMSO-d6):
d
55.68 (OCH3), 64.66 (C-60), 67.08 (C-40), 71.34 (C-20),
73.46 (C-30), 75.05 (C-50), 76.89 (C-4), 80.13 (C-10), 81.42 (C-5),
106.95 (C-3), 114.05 (CN), 114.67 (CN), 129.40–132.30 (Ar-6C),
158.24 (C-2), 159.26 (C-6); MS (FAB): m/z (%) ¼ 446 (31, [Mþ]). Anal.
Calcd. for C20H22N4SO6: C, 53.80; H, 4.97; N, 12.55. Found: C, 53.85;
H, 4.95; N, 12.49.
4.1.3.5. 2-Amino-3,5-dicyano-4-(4-methoxyphenyl)-6-(10-thio-
gluco-pyranosyl)-1,4-dihdropyridines (7e). Yield 2.72 g (61%) (Pale
yellow powder): mp 230–231 ꢀC; [
¼ þ30.2 (c 1.5, MeOH); IR
(KBr) nmax in cmꢁ1: 3309-3224 (OH, NH and NH2), 2224 (CN), 2220
(CN); 1H NMR (DMSO-d6): 3.21 (m, 2H, H-60, H-600), 3.23 (m, 1H,
b-D-
a
]
D
4.1.4. General procedure for the synthesis of 2-amino-4-aryl-3,5-
dicyano-6-(20,30,40,60-tetra-O-acetyl-10-thio-
b-D-gluco- or
d
H-50), 3.49 (m, 1H, H-40), 3.80 (s, 3H, OCH3), 3.86–4.14 (m, 2H, H-30,
H-20), 4.73 (t, 1H, J ¼ 6.4 Hz, OH), 4.82 (t, 1H, J ¼ 4.6 Hz, OH), 4.89 (s,
1H, pyridine H-4), 5.12 (m, 1H, OH), 5.26 (t, 1H, J ¼ 4.4 Hz, OH), 5.72
galactopyranosyl) pyridines 8a–f
Method (A): The piperidinium salt of dihydropyridinethiones
3a–e (0.01 mol) was dissolved in dry acetone (5 ml) and a solution
(d, 1H, J1 –2 ¼ 9.8 Hz, H-10), 6.22 (bs, 2H, NH2), 6.36 (bs, 1H, NH),
7.28 (d, 2H, J ¼ 7.8 Hz, Ar-2H), 7.82 (d, 2H, J ¼ 7.8 Hz, Ar-2H); 13C
of2,3,4,6-teta-O-acetyl-a-D-gluco- or galactopyranosyl bromide 4a,b
0
0
(4.52g, 0.011 mol) in dry acetone (20 ml) was then added at 30 ꢀC.
The reaction mixture was stirred at 30 ꢀC for 18–20 h, the solvent was
evaporated under reduced pressure and the residue was solidified
with distilled water. The obtained crude solid was filtered off,
washed with distilled water and dried. The pure product was
extracted from the above solid with petroleum ether (80–100). The
petroleum ether part was evaporated under reduced pressure and
the solid product was crystallized from benzene to give the thio-
glycosides 8a–f.
NMR (DMSO-d6):
d
55.38 (OCH3), 64.16 (C-60), 68.08 (C-40), 69.14
(C-20), 73.56 (C-30), 75.45 (C-50), 76.69 (C-4), 80.53 (C-10), 81.42
(C-5), 106.55 (C-3), 114.15 (CN), 114.67 (CN), 129.44–132.36 (Ar-6C),
158.24 (C-2), 159.56 (C-6); MS (FAB): m/z (%) ¼ 446 (19, [Mþ]). Anal.
Calcd. for C20H22N4SO6: C, 53.56; H, 4.94; N, 12.49. Found: C, 53.55;
H, 4.92; N, 12.50.
4.1.3.6. 2-Amino-3,5-dicyano-4-phenyl-6-(10-thio-
anosyl)-1,4-dihdropyridines (7f). Yield 2.21 (53%) (Pale yellow
powder): mp 180–181 ꢀC; [
¼ þ28.6 (c 1.5, MeOH); IR (KBr) nmax
in mꢁ1: 3326-2166 (OH, NH and NH2), 2200 (CN), 2198 (CN); 1H
NMR (DMSO-d6):
3.22 (m, 2H, H-60, H-600), 3.27 (m, 1H, H-50), 3.53
b-D-galactopyr-
Method (B): A suspension of 1,4-dihdropyridines thioglycosides
5a–c, f–h (0.01 mol) in ethanol were refluxed with stirring for
5 min the resulting products were collected by filtration and
crystallized from benzene.
a
]
D
d
(m, 2H, H-40, H-30), 4.15 (dd, 1H, J ¼ 7.8 Hz, J ¼ 10.5 Hz, H-20), 4.76
(t, 1H, J ¼ 4.6 Hz, OH), 4.86 (t, 1H, J ¼ 4.6 Hz, OH), 4.90 (s, 1H,
pyridine H-4), 5.14 (m, 1H, OH), 5.27 (t, 1H, J ¼ 4.4 Hz, OH), 5.78
4.1.4.1. 2-Amino-3,5-dicyano-4-phenyl-6-(20,30,40,60-tetra-O-acetyl-
10-thio-
b
-D
-glucopyranosyl)pyridines (8a). Yield 3.79 g (65%) (Pale
yellow powder): mp 184–185 ꢀC; [
¼ þ24.9 (c 2, CHCl3); IR (KBr)
nmax in cmꢁ1: 3230 (NH2), 2229 (CN), 2215 (CN), 1758 (CO); 1H NMR
(d, 1H, J1 –2 ¼ 9.8 Hz, H-10), 6.34 (bs, 2H, NH2), 6.99 (m, 3H, Ar-3H),
a]
D
0
0
7.31 (m, 2H, Ar-2H); 13C NMR (DMSO-d6):
d
61.24 (C-60), 64.90
(C-40), 70.50 (C-20), 74.80 (C-30), 75.50 (C-50), 76.87 (C-4), 81.57
(C-10), 82.21 (C-5), 110.02 (C-3), 114.11 (CN), 114.85 (CN), 125.29–
137.44 (Ar-6C), 158.30 (C-2), 159.20 (C-6); MS (FAB): m/z (%) ¼ 416
(28, [Mþ]). Anal. Calcd. for C19H20N4SO5: C, 54.80; H, 4.84; N, 13.45.
Found: C, 54.85; H, 4.80; N, 13.48.
(CDCl3):
d
1.89–2.11 (4s, 12H, 4CH3CO), 3.86 (dd, 1H, J ¼ 2.8 Hz,
J ¼ 10.5 Hz, H-60), 4.14 (dd, 1H, J ¼ 3.6 Hz, J ¼ 10.5 Hz, H-600), 4.28
(m, 1H, H-50), 5.13 (m, 1H, H-40), 5.17 (dd, 1H, J ¼ 7.6 Hz, J ¼ 10.8, H-
30), 5.24 (t, 1H, J ¼ 10.2 Hz, H-20), 5.78 (d, 1H, J1 –2 ¼ 10.2 Hz, H-10),
0
0
6.23 (s, 2H, NH2), 6.87 (m, 3H, Ar-3H), 7.38 (m, 2H, Ar-2H); 13C NMR
(CDCl3):
d
21.54–22.07 (4CH3CO), 61.25 (C-60), 67.85 (C-40), 69.10
4.1.3.7. 2-Amino-3,5-dicyano-4-(4-naphthalen-2-yl)-6-(10-thio-
galacto-pyranosyl)-1,4-dihdropyridines (7g). Yield 2.47 g (53%) (Pale
yellow powder): mp 217–217 ꢀC; [
¼ þ32.6 (c 1.5, MeOH); IR
(KBr) nmax in cmꢁ1: 3298-3227 (OH, NH and NH2), 2205 (CN), 2201
b
-
D
-
(C-30), 71.90 (C-20), 75.43 (C-50), 85.32 (C-10), 106.36 (C-3), 112.39
(C-5), 121.78 (CN), 121.98 (CN), 126.42–132.80 (Ar-6C), 152.39 (C-4),
157.30 (C-6), 162.08 (C-2), 169.60–170.70 (4C]O); MS (FAB): m/z
(%) ¼ 582 (65, [Mþ]). Anal. Calcd. for C27H26N4SO9: C, 55.66; H, 4.50;
N, 9.62. Found: C, 55.62; H, 4.52; N, 9.59.
a
]
D
(CN); 1H NMR (DMSO-d6):
d
3.24 (m, 2H, H-60, H-600), 3.29 (m, 1H,
H-50), 3.55 (m, 1H, H-40), 3.93 (m, 2H, H-30, H-20), 4.79 (t, 1H, J ¼ 6.6
Hz, OH), 4.84 (t, 1H, J ¼ 4.6 Hz, OH), 4.87 (s, 1H, pyridine H-4), 5.16
4.1.4.2. 2-Amino-3,5-dicyano-4-(naphthalen-2-yl)-6-(20,30,40,60-tetra-
(m, 1H, OH), 5.29 (t, 1H, J ¼ 4.8 Hz, OH), 5.73 (d, 1H, J1 –2 ¼ 10.2 Hz,
H-10), 6.29 (bs, 2H, NH2), 6.37 (bs, 1H, NH), 7.22 (m, 1H, Ar-H), 7.34
(d, 1H, J ¼ 8.5 Hz, Ar-H), 7.45 (m, 1H, Ar-H), 7.54 (m, 1H, Ar-H), 7.55
(d, 1H, J ¼ 8.2 Hz, Ar-H), 7.86 (d, 1H, J ¼ 8.2 Hz, Ar-H), 8.25 (d, 1H,
O-acetyl-10-thio-
b
-
D
-glucopyranosyl)pyridines (8b). Yield 4.43
(70%) (Pale yellow powder): mp 173–174 ꢀC; [
¼ þ28.4 (c 2,
CHCl3); IR (KBr) nmax in cmꢁ1: 3210 (NH2), 2209 (CN), 2199 (CN),1748
g
0
0
a]
D
(CO); 1H NMR (CDCl3):
d 1.88–2.10 (4s, 12H, 4CH3CO), 3.89 (dd, 1H,
J ¼ 8.5 Hz, Ar-H). 13C NMR (CDCl3):
d
62.05 (C-60), 67.98 (C-40), 72.88
J ¼ 3.2 Hz, J ¼ 10.4 Hz, H-60), 4.12 (dd,1H, J ¼ 2.8 Hz, J ¼ 10.4 Hz, H-600),
(C-20); 75.12 (C-30), 75.33 (C-50), 75.98 (C-4), 79.88 (C-10), 83.14
(C-5), 111.81 (C-3), 112.45 (CN),114.24 (CN),123.12–144.62 (Ar-10C),
147.77 (C-2), 160.08 (C-6); MS (FAB): m/z (%) ¼ 466 (69, [Mþ]). Anal.
Calcd. for C23H22N4SO5: C, 59.22; H, 4.75; N, 12.01. Found: C, 59.23;
H, 4.70; N, 11.94.
4.30 (m,1H, H-50), 5.12 (m,1H, H-40), 5.18 (t,1H, J ¼ 7.8 Hz, H-30), 5.22
(dd,1H, J ¼ 7.8 Hz, J ¼ 10.4 Hz, H-20), 5.88 (d,1H, J1 –2 ¼10.4 Hz, H-1 ),
6.21 (s, 2H, NH2), 7.43 (m, 2H, Ar-H), 7.48 (d,1H, J ¼ 8.5 Hz, Ar-H), 7.55
(d,1H, J ¼ 8.2 Hz, Ar-H), 7.70 (d,1H, J ¼ 8.2 Hz, Ar-H), 7.78 (s,1H, Ar-H),
0
0
0
8.20 (d, 1H, J ¼ 8.5 Hz, Ar-H); 13C NMR (CDCl3):
d 20.19–20.97
(4CH3CO), 62.05 (C-60), 67.50 (C-40), 69.80 (C-30), 71.75 (C-20), 75.59
(C-50), 85.12 (C-10), 106.58 (C-3), 112.30 (C-5), 121.29 (CN), 121.80
(CN),126.39–132.50 (Ar-10C),152.12 (C-4),157.28 (C-6),161.81 (C-2),
169.20–171.20 (4C]O); MS (FAB): m/z (%) ¼ 632 (80, [Mþ]). Anal.
4.1.3.8. 2-Amino-3,5-dicyano-4-(4-methoxyphenyl)-6-(10-thio-
galacto-pyranosyl)-1,4-dihdropyridines (7h). Yield 2.05 (46%)
(Pale yellow powder): mp 200–201 ꢀC; [
¼ þ34.2 (c 1.5, MeOH);
b-D-
g
a]
D

980
H.-A.S. Abbas et al. / European Journal of Medicinal Chemistry 45 (2010) 973–982
Calcd. for C31H28N4SO9: C, 58.85; H, 4.46; N, 8.86. Found: C, 58.80; H,
4.45; N, 8.85.
68.97 (C-30), 70.72 (C-20), 75.53 (C-50), 85.25 (C-10), 106.71 (C-3),
121.98 (CN), 122.45 (CN), 114.21 (C-5), 126.69–132.58 (Ar-6C),
153.89 (C-4), 157.20 (C-6), 161.88 (C-2), 169.20–170.85 (4C]O); MS
(FAB): m/z (%) ¼ 612 (26, [Mþ]). Anal. Calcd. for C28H28N4SO10: C,
54.90; H, 4.61; N, 9.15. Found: C, 54.86; H, 4.58; N, 9.13.
4.1.4.3. 2-Amino-4-(4-bromophenyl)-3,5-dicyano-6-(20,30,40,60-tetra-
O-acetyl-10-thio-
b
-
D
-glucopyranosyl)pyridines (8c). Yield 5.16
(78%) (Pale yellow powder): mp 230–232 ꢀC; [
¼ þ23.2 (c 2,
CHCl3); IR (KBr) nmax in cmꢁ1: 3217 (NH2), 2225 (CN), 2222 (CN),
1752 (CO); 1H NMR (CDCl3):
1.98–2.15 (4S, 12H, 4CH3CO), 3.95
g
a
]
D
4.1.5. General procedure for the synthesis of 4-aryl-2-amino-3,5-
dicyano-6-(10-thio-
b-D-glycopyranosyl)pyridines 9a–f
d
(dd, 1H, J ¼ 3.2 Hz, J ¼ 10.8 Hz, H-60), 4.12 (dd, 1H, J ¼ 2.8 Hz,
J ¼ 10.8 Hz, H-600), 4.18 (m, 1H, H-50), 5.09 (t, 1H, J ¼ 8.4 Hz, H-40),
5.19 (t, 1H, J ¼ 8.4 Hz, H-30), 5.21 (dd, 1H, J ¼ 8.4 Hz, J ¼ 10.4 Hz,
To a solutionof saturated methanolic ammonia(20ml), glucoside
8a–c or galactosides 8d–f (0.01 mol) was added at room tempera-
ture. The reaction mixture was stirred at the same temperature for
24 h, and then evaporated under reduced pressure. The residue was
treated with distilled water; the formed solid was filtered off,
washed with methanol and crystallized from ethanol-DMF (4:1) to
give the free glucosides 9a–c or free galactosides 9d–f, respectively.
H-20), 5.98 (d, 1H, J1 –2 ¼ 10.4 Hz, H-10), 6.28 (s, 2H, NH2), 7.60 (d,
2H, J ¼ 7.8 Hz, Ar-2H), 7.98 (d, 2H, J ¼ 7.8 Hz, Ar-2H). 13C NMR
0
0
(CDCl3):
d
20.34–20.67 (4CH3CO), 62.15 (C-60), 67.90 (C-40), 69.30
(C-20), 70.70 (C-20), 75.53 (C-50), 76.39 (C-4), 84.05 (C-10), 106.50
(C-3), 120.20 (CN), 121.90 (CN), 114.30 (C-5), 126.09–132.50 (Ar-6C),
157.20 (C-6), 161.88 (C-2), 169.20–170.80 (4C]O); MS (FAB): m/z
(%) ¼ 661 (49, [Mþ]). Anal. Calcd. for C27H25BrN4SO9: C, 49.02; H,
3.81; N, 8.47. Found: C, 49.07; H, 3.82; N, 8.45.
4.1.5.1. 2-Amino-3,5-dicyano-4-phenyl-6-(10-thio-
b-D-glucopyr-
anosyl)-pyridines (9a). Yield 2.49 g (60%) (Pale yellow powder): mp
233–235 ꢀC; [
a
] ¼ þ28.0 (c 1.5, MeOH); IR (KBr) nmax in cmꢁ1: 3331
(OH and NH2), 2223 (CN), 2218 (CN); 1H NMR (DMSO-d6):
d 3.11 (m,
4.1.4.4. 2-Amino-3,5-dicyano-4-phenyl-6-(20,30,40,60-tetra-O-acetyl-
2H, H-60, H-600), 3.83 (m, 1H, H-50), 3.53–3.61 (m, 2H, H-30, H-40),
4.14 (dd, 1H, J ¼ 8.2 Hz, J ¼ 9.8 Hz, H-20), 4.75 (m, 1H, OH), 4.83 (t,
1H, J ¼ 4.6 Hz, OH), 5.12 (m, 1H, OH), 5.22 (t,1H, J ¼ 4.8 Hz, OH), 5.78
10-thio-
b
-D
-galactopyranosyl)pyridines (8d). Yield 3.96 g (68%) (Pale
yellow powder): mp 158–160 ꢀC; [
¼ þ38.4 (c 2, CHCl3); IR (KBr)
nmax in cmꢁ1: 3268 (NH2), 2214 (CN), 2200 (CN), 1760 (CO); 1H NMR
a
]
D
(d, 1H, J1 –2 ¼ 9.8 Hz, H-10), 6.23 (bs, 2H, NH2), 7.58 (m, 3H, Ar-3H),
0
0
(CDCl3):
d
2.13–2.26 (4s, 12H, 4CH3CO), 3.83 (dd, 1H, J ¼ 3.4 Hz,
8.10 (m, 2H, Ar-2H); 13C NMR (DMSO-d6): 62.05 (C-60), 67.74
d
J ¼ 11.2 Hz, H-60), 4.08 (dd, 1H, J ¼ 2.8 Hz, J ¼ 11.2 Hz, H-600), 4.11
(C-40), 72.85 (C-20), 73.55 (C-30), 75.50 (C-50), 85.22 (C-10), 106.58
(C-3), 114.30 (C-5), 122.29 (CN), 123.96 (CN), 126.39–132.50 (Ar-6C),
154.39 (C-4), 157.33 (C-6), 161.81 (C-2); MS (FAB): m/z (%) ¼ 414
(51, [Mþ]). Anal. Calcd. for C19H18N4SO5: C, 55.06; H, 4.38; N, 13.52.
Found: C, 55.01; H, 4.35; N, 13.54.
(m, 1H, H-50), 5.12 (m, 1H, H-40), 5.16 (t, 1H, J ¼ 8.8 Hz, H-30), 5.25
(dd, 1H, J ¼ 8.8 Hz, J ¼ 10.5, H-20), 5.89 (d, 1H, J1 –2 ¼ 10.5 Hz, H-1 ),
0
0
0
6.18 (s, 2H, NH2), 7.40 (m, 3H, Ar-3H), 7.75 (m, 2H, Ar-2H); 13C NMR
(CDCl3):
d
21.14–22.27 (4CH3CO), 62.25 (C-60), 68.05 (C-40), 68.50
(C-30), 70.90 (C-20), 75.03 (C-50), 85.32 (C-10), 107.06 (C-3), 114.49
(C-5),122.80 (CN),122.50 (CN),126.42–132.80 (Ar-6C),153.09 (C-4),
157.30 (C-6), 162.38 (C-2), 169.60–170.70 (4C]O); MS (FAB): m/z
(%) ¼ 582 (25, [Mþ]). Anal. Calcd. for C27H26N4SO9: C, 55.66; H, 4.50;
N, 9.62. Found: C, 55.62; H, 4.50; N, 9.67.
4.1.5.2. 2-Amino-3,5-dicyano-4-(naphthalen-2-yl)-6-(10-thio-
gluco-pyranosyl)pyridines (9b). Yield 2.51 g (54%) (Pale yellow
powder): mp 218–220 ꢀC; [
]D ¼ þ36.4 (c 1.5, MeOH); IR (KBr) nmax in
cmꢁ1: 3304 (OH and NH2), 2226 (CN), 2220 (CN); 1H NMR (DMSO-
b-D-
a
d6): d
3.28 (m, 2H, H-60, H-600), 3.31 (m, 1H, H-50), 3.51 (m, 1H, H-40),
4.1.4.5. 2-Amino-3,5-dicyano-4-(naphthalen-2-yl)-6-(20,30,40,60-tetra-
3.82 (m, 2H, H-30, H-20), 4.76 (m, 1H, OH), 4.87 (t, 1H, J ¼ 4.6 Hz, OH),
O-acetyl-10-thio-
b
-
D
-galactopyranosyl)pyridines (8e). Yield 4.93 g
(78%) (Pale yellow powder): mp 236–238 ꢀC; [
¼ þ40.2 (c 2,
CHCl3); IR (KBr) nmax in cmꢁ1: 3250 (NH2), 2218 (CN), 2209 (CN),1757
5.12 (m,1H, OH), 5.22(t,1H, J ¼ 4.4 Hz, OH), 5.78(d,1H, J1 –2 ¼10.2 Hz,
H-10), 6.32 (bs, 2H, NH2), 7.42 (m, 2H, Ar-H), 7.47 (d,1H, J ¼ 8.5 Hz, Ar-
H), 7.59 (d, 1H, J ¼ 8.2 Hz, Ar-H), 7.71 (d, 1H, J ¼ 8.2 Hz, Ar-H), 7.77 (s,
0
0
a]
D
(CO); 1H NMR (CDCl3):
d
1.92–2.12 (4s, 12H, 4CH3CO), 3.92 (dd, 1H,
1H, Ar-H), 8.21 (d, 1H, J ¼ 8.5 Hz, Ar-H); 13C NMR (DMSO-d6):
d 62.35
J ¼ 2.6 Hz, J ¼ 10.8 Hz, H-60), 4.14 (dd,1H, J ¼ 3.2 Hz, J ¼ 10.8 Hz, H-600),
(C-60), 67.74 (C-40), 72.65 (C-20), 73.55 (C-30), 75.12 (C-50), 85.20 (C-10),
106.58 (C-3), 114.24 (C-5); 122.29 (CN), 122.96 (CN), 126.30–133.50
(Ar-10C), 153.80 (C-4); 157.35 (C-6), 161.86 (C-2); MS (FAB): m/z
(%) ¼ 464 (63, [Mþ]). Anal. Calcd. for C23H20N4SO5: C, 59.47; H, 4.34;
N, 12.06. Found: C, 59.42; H, 4.35; N, 12.05.
4.28 (m,1H, H-50), 5.14 (m,1H, H-40), 5.18 (t,1H, J ¼ 8.4 Hz, H-30), 5.20
(dd,1H, J ¼ 8.4 Hz, J ¼ 10.4 Hz, H-20), 5.79 (d,1H, J1 –2 ¼10.4 Hz, H-1 ),
6.22 (s, 2H, NH2), 7.21 (m,1H, Ar-H), 7.35 (d,1H, J ¼ 8.5 Hz, Ar-H), 7.47
(m, 1H, Ar-H), 7.62 (m, 1H, Ar-H), 7.77 (d, 1H, J ¼ 8.2 Hz, Ar-H), 7.89
(d, 1H, J ¼ 8.2 Hz, Ar-H), 8.24 (d, 1H, J ¼ 8.5 Hz, Ar-H); 13C NMR
0
0
0
(CDCl3):
d
21.22–22.07 (4CH3CO), 62.05 (C-60), 67.34 (C-40), 68.24
4.1.5.3. 2-Amino-4-(4-bromophenyl)-3,5-dicyano-6-(10-thio-
gluco-pyranosyl)pyridines (9c). Yield 2.81 g (57%) (Pale yellow
powder): mp 203–205 ꢀC; [
¼ þ24.6 (c 1.5, MeOH); IR (KBr) nmax
in cmꢁ1: 3311 (OH and NH2), 2215 (CN), 2200 (CN); 1H NMR
b-D-
(C-30), 71.75 (C-20), 75.93 (C-50), 85.70 (C-10), 106.58 (C-3), 114.30
(C-5), 121.29 (CN),121.98 (CN),126.34–132.93 (Ar-10C), 152.24 (C-4),
157.58 (C-6), 161.81 (C-2), 169.52–171.35 (4C]O); MS (FAB): m/z
(%) ¼ 632 (72, [Mþ]). Anal. Calcd. for C31H28N4SO9: C, 58.85; H, 4.46;
N, 8.86. Found: C, 58.86; H, 4.44; N, 8.85.
a]
D
(DMSO-d6):
d
3.25 (m, 2H, H-60, H-600), 3.30 (m, 1H, H-50), 3.51 (m,
1H, H-40), 3.96–4.12 (m, 2H, H-30, H-20), 4.75 (m,1H, OH), 5.08 (t,1H,
J ¼ 4.6 Hz, OH), 5.18 (m, 1H, OH), 5.58 (t, 1H, J ¼ 4.4 Hz, OH), 5.80 (d,
4.1.4.6. 2-Amino-3,5-dicyano-4-(4-methoxyphenyl)-6-(20,30,40,60-
1H, J1 –2 ¼ 10.2 Hz, H-10), 6.33 (bs, 2H, NH2), 7.30 (d, 2H, J ¼ 8.5 Hz,
0
0
tetra-O-acetyl-10-thio-
b
-
D
-galactopyranosyl)pyridines (8f). Yield
4.72 g (77%) (Pale yellow powder): mp 193–194 ꢀC; [
¼ þ32.9 (c
2, CHCl3); IR (KBr) nmax in cmꢁ1: 3214 (NH2), 2211 (CN), 2200 (CN),
Ar-2H), 7.63 (d, 2H, J ¼ 8.5 Hz, Ar-2H); 13C NMR (DMSO-d6):
d 62.68
a
]
D
(C-60), 67.89 (C-40), 71.85 (C-20), 73.57 (C-30), 75.52 (C-50), 85.28
(C-10), 106.58 (C-3), 115.30 (C-5), 121.88 (CN), 122.22 (CN),
126.39–132.59 (Ar-6C), 154.43 (C-4), 157.30 (C-6), 161.81 (C-2); MS
(FAB): m/z (%) ¼ 493 (39, [Mþ]). Anal. Calcd. for C19H17BrN4SO5: C,
46.26; H, 3.47; N, 11.36. Found: C, 46.29; H, 3.45; N, 11.30.
1750 (CO); 1H NMR (CDCl3):
d 1.93–2.17 (4S, 12H, 4CH3CO), 3.91 (dd,
1H, J ¼ 3.2 Hz, J ¼ 11.2 Hz, H-60), 4.03 (s, 3H, OCH3), 4.13 (dd, 1H,
J ¼ 3.4 Hz, J ¼ 11.2 Hz, H-600), 4.28 (m, 1H, H-50), 5.12 (m, 1H, H-40),
5.14 (t, 1H, J ¼ 8.2 Hz, H-30), 5.24 (dd, 1H, J ¼ 8.6 Hz, J ¼ 10.4 Hz, H-
20), 5.91 (d, 1H, J1 –2 ¼ 10.4 Hz, H-10), 6.24 (s, 2H, NH2), 6.90 (d, 2H,
J ¼ 8.8 Hz, Ar-2H), 7.30 (d, 2H, J ¼ 8.8 Hz, Ar-2H); 13C NMR (CDCl3):
4.1.5.4. 2-Amino-3,5-dicyano-4-phenyl-6-(10-thio-
b-D-galactopyr-
0
0
anosyl)-pyridines (9d). Yield 2.40 g (58%) (Pale yellow powder): mp
d
20.29–20.69 (4CH3CO), 55.80 (OCH3), 62.15 (C-60), 67.90 (C-40),
235–236 ꢀC; [
a]
¼ þ20.2 (c 1.5, MeOH); IR (KBr) nmax in cmꢁ1: 3279
D

H.-A.S. Abbas et al. / European Journal of Medicinal Chemistry 45 (2010) 973–982
981
(OH and NH2), 2220 (CN), 2213 (CN); 1H NMR (DMSO-d6):
d 3.22 (m,
Table 2
In vivo acute toxicity of prepared compounds LD50
m
g/kg b.w.
LD50 mg/kg b.w. (HELA)
2H, H-60, H-600), 3.29 (m, 1H, H-50), 3.50–3.85 (m, 3H, H-40, H-30, H-
20), 4.75 (m, 1H, OH), 4.81 (t, 1H, J ¼ 4.6 Hz, OH), 5.17 (m, 1H, OH),
Compounds
LD50
mg/kg b.w. (HEPG2)
0
0
0
5.27 (t,1H, J ¼ 4.4 Hz, OH), 5.75 (d,1H, J1 –2 ¼ 10.2 Hz, H-1 ), 6.28 (bs,
5a
5c
5d
5e
5f
5g
5h
7a
7b
7e
7g
7h
8b
9c
8d
8e
8f
80
90
85
150
70
65
60
65
110
110
130
60
60
65
65
125
65
75
90
70
160
60
70
65
75
115
95
120
80
60
75
60
135
70
2H, NH2), 6.96 (m, 3H, Ar-3H), 7.29 (m, 2H, Ar-2H). 13C NMR (DMSO-
d6): d
62.17 (C-60), 67.70 (C-40), 70.87 (C-20), 73.55 (C-30), 75.55 (C-50),
85.26 (C-10), 106.59 (C-3), 114.12 (C-5), 120.29 (CN), 121.96 (CN),
126.99–132.70 (Ar-6C), 152.39 (C-4), 157.83 (C-6), 161.81 (C-2); MS
(FAB): m/z (%) ¼ 414 (47, [Mþ]). Anal. Calcd. for C19H18N4SO5: C,
55.06; H, 4.38; N, 13.52. Found: C, 55.01; H, 4.33; N, 13.55.
4.1.5.5. 2-Amino-3,5-dicyano-4-(naphthalen-2-yl)-6-(10-thio-
galacto-pyranosyl)pyridines (9e). Yield 3.16 g (68%) (Pale yellow
powder): mp 253–255 ꢀC; [
¼ þ32.2 (c 1.5, MeOH); IR (KBr) nmax
in cmꢁ1: 3310 (OH and NH2), 2210 (CN), 2200 (CN); 1H NMR
b-D-
a]
D
(DMSO-d6):
d
3.07 (m, 2H, H-60,600), 3.28 (m, 1H, H-50), 3.45 (m, 1H,
H-40), 3.90–4.02 (m, 2H, H-30, H-20), 4.72 (m, 1H, OH), 4.86 (t, 1H,
J ¼ 4.6 Hz, OH), 5.22 (m, 1H, OH), 5.38 (t, 1H, J ¼ 4.4 Hz, OH), 5.79
9b
9c
9e
9f
130
105
145
115
110
120
125
130
(d, 1H, J1 –2 ¼ 9.8 Hz, H-10), 6.34 (bs, 2H, NH2), 6.99 (m, 1H, Ar-H),
7.32 (d, 1H, J ¼ 8.5 Hz, Ar-H), 7.38 (m, 1H, Ar-H), 7.52 (m, 1H, Ar-H),
7.55 (d, 1H, J ¼ 8.2 Hz, Ar-H), 7.85 (d, 1H, J ¼ 8.2 Hz, Ar-H), 8.28
0
0
(d, 1H, J ¼ 8.5 Hz, Ar-H); 13C NMR (DMSO-d6):
d
62.05 (C-60), 67.79
(C-40), 71.85 (C-20), 73.05 (C-30), 75.10 (C-50), 85.27 (C-10), 106.58
(C-3), 114.30 (C-5), 122.29 (CN), 122.98 (CN), 127.39–132.80
(Ar-10C), 154.32 (C-4), 157.33 (C-6), 161.81 (C-2); MS (FAB): m/z
(%) ¼ 464 (60, [Mþ]). Anal. Calcd. for C23H20N4SO5: C, 59.47; H, 4.34;
N, 12.06. Found: C, 59.40; H, 4.31; N, 12.00.
(HELA) cells. After 24 h of tumor inoculation the prepared
compounds were administered i.p. at dose of 10 g/kg body weight
m
and continued for 10 consecutive days. The group administered
with vehicle alone (DMSO) was maintained as control. Cisplatine
(2 mg/kg body weight, i.p., for 10 days) was used as the standard
reference drug. The mortality rate was noted in each group and the
percent increase in life span (ILS) was calculated as described by
Ahluwalia et al. [42] and Joy et al. [43].
4.1.5.6. 2-Amino-3,5-dicyano-4-(4-methoxyphenyl)-6-(10-thio-
galacto-pyranosyl)pyridines (9f). Yield 2.36 g (53%) (Pale yellow
powder): mp 143–144 ꢀC; [
¼ þ26.8 (c 1.5, MeOH); IR (KBr) nmax
in cmꢁ1:3299 (OH and NH2), 2208 (CN), 2200 (2CN); 1H NMR
b-D-
a
]
D
(DMSO-d6): d
3.14 (m, 2H, H-60, H-600), 3.22 (m, 1H, H-50), 3.46–3.51
5.4. Assay of acute toxicity
(m, 2H, H-40, H-30), 3.80 (s, 3H, OCH3), 4.21 (dd, 1H, J ¼ 8.4 Hz,
J ¼ 9.8 Hz, H-20), 4.74 (m, 1H, OH), 4.82 (t, 1H, J ¼ 4.6 Hz, OH), 5.23
The acute toxicity of the prepared compounds was determined in
vivo according to Prieur et al. [44] and Ghosh [45]. Briefly, adult
Swiss albino mice fasted for 12 h were randomly divided into groups
of 10 per group. Each group was separately administrated once with
gradually doses of the compounds intraperitoneal (i.p.) in a value of
1 ml/kg body weight. Control animals received the vehicle alone.
The fasted mice in both test and control groups were then provided
with food and water immediately after the administration.
Mortality of the animals was observed up to two week post-treat-
ment. LD50 (the median lethal doses) of each extract was deter-
mined (the dose resulted in 50% mortality of the animals) (Table 2).
0
0
(m,1H, OH), 5.26 (t,1H, J ¼ 4.8 Hz, OH), 5.74 (d,1H, J1 –2 ¼ 9.8 Hz, H-
10), 6.38 (bs, 2H, NH2), 7.29 (d, 2H, J ¼ 7.8 Hz, Ar-2H), 7.88 (d, 2H,
J ¼ 7.8 Hz, Ar-2H). 13C NMR (DMSO-d6):
d
55.80 (OCH3), 62.10 (C-60),
67.90 (C-40), 72.11 (C-20), 73.69 (C-30), 75.03 (C-50), 85.25 (C-10),
106.01 (C-3), 115.30 (C-5), 122.98 (CN), 123.43 (CN), 126.69–132.58
(Ar-6C), 154.34 (C-4), 157.20 (C-6), 161.80 (C-2); MS (FAB): m/z
(%) ¼ 444 (54, [Mþ]). Anal. Calcd. for C20H20N4SO6: C, 54.05; H, 4.54;
N, 12.61. Found: C, 54.00; H, 4.50; N, 12.66.
5. Antitumor activity
5.1. Animals
5.5. Statistical analysis
Male Swiss albino mice (body weight 20 ꢂ 2 g). They were kept
for a week under environmentally controlled conditions (constant
temperature 25–27 ꢀC, with 12 h light/dark cycle) for one week
prior to starting the experiments, and they were provided with tap
water and commercial diets.
Values are recorded as mean ꢂ SE. The data were analyzed by
Student’s t-test; differences below the 0.5 level (P < 0.05) was
considered as statistically significant.
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