Synthesis and anti-inflammatory activities of some novel S-pyridyl glycosides derivatives

Article abstract of DOI:10.1080/10426500802059885

A series of some new acetylated S-glycosides of pyridine-2-thione derivatives, including D-glucose, D-galactose, D-xylose and L-arabinose derivatives were synthesized. Oxidation of some formed S-glycosides derivatives with H2O2 afforded the corresponding sulfones. S-Alkylation of pyridine-2-thione derivatives was performed to furnish the S-acyclo deazauridine derivatives. The entire tested compound showed potent anti-inflammatory activity were potent against edema and in the same time inhibited the prostaglandine formation. It is work mention that all the tested compounds showed high safety margin. The structures of the new synthesized compounds have been proved by IR, 1HNMR, mass spectra and elemental analysis. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500802059885

This article was downloaded by: [Gazi University]
On: 04 October 2014, At: 04:22
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Phosphorus, Sulfur, and Silicon
and the Related Elements
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Synthesis and Anti-
Inflammatory Activities
of Some Novel S-Pyridyl
Glycosides Derivatives
Nagy M. Khalifa a , Mostafa M. Ramla b , Abd El-Galil
E. Amr c & Mohamed M. Abdulla d
a Medicinal Chemistry Department , National
Research Center , Dokki, Cairo, Egypt
b Chemistry of Natural and Microbial Prod. Depart. ,
National Research Center , Dokki, Cairo, Egypt
c Applied Organic Chemistry Department , National
Research Center , Dokki, Cairo, Egypt
d Research Units, Hi-Care Pharmaceutical Co. ,
Cairo, Egypt
Published online: 03 Nov 2008.
To cite this article: Nagy M. Khalifa , Mostafa M. Ramla , Abd El-Galil E. Amr &
Mohamed M. Abdulla (2008) Synthesis and Anti-Inflammatory Activities of Some Novel
S-Pyridyl Glycosides Derivatives, Phosphorus, Sulfur, and Silicon and the Related
Elements, 183:12, 3046-3062
To link to this article: http://dx.doi.org/10.1080/10426500802059885
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,

or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur, and Silicon, 183:3046–3062, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802059885
Synthesis and Anti-Inflammatory Activities
of Some Novel S-Pyridyl Glycosides Derivatives
Nagy M. Khalifa,1 Mostafa M. Ramla,2 Abd El-Galil E.
Amr,3 and Mohamed M. Abdulla4
1Medicinal Chemistry Department, National Research Center, Dokki,
Cairo, Egypt
2Chemistry of Natural and Microbial Prod. Depart., National Research
Center, Dokki, Cairo, Egypt
3Applied Organic Chemistry Department, National Research Center,
Dokki, Cairo, Egypt
4Research Units, Hi-Care Pharmaceutical Co., Cairo, Egypt
A series of some new acetylated S-glycosides of pyridine-2-thione derivatives, includ-
ing D-glucose, D-galactose, D-xylose and L-arabinose derivatives were synthesized.
Oxidation of some formed S-glycosides derivatives with H2O2 afforded the corre-
sponding sulfones. S-Alkylation of pyridine-2-thione derivatives was performed to
furnish the S-acyclo deazauridine derivatives. The entire tested compound showed
potent anti-inflammatory activity were potent against edema and in the same time
inhibited the prostaglandine formation. It is work mention that all the tested com-
pounds showed high safety margin. The structures of the new synthesized com-
pounds have been proved by IR, 1 HNMR, mass spectra and elemental analysis.
Keywords Anti-inflammatory activity; glycoside derivatives; 5,6,7,8- Tetrahydronaph-
thalene
INTRODUCTION
3-Deazauridine and 3-deazacytidine were found to exert marked in-
hibitory effects on the growth of neoplastic and bacterial culture1 and
also have antiviral against RNA viruses.2Also 3-deazauridine was ac-
tive against L1210 leukemia cells in vivo.3 3-Deazauridine is a potent
inhibitor of CTP synthetase (phosphocholine cytidyltransferase). Deaza
UTP is a competitive inhibitor of this enzyme with respect to UTP.
Deaza UTP is an inhibitor of ribonucleotide reductase activity. The net
Received 10 October 2007; accepted 16 March 2008.
Address correspondence to Mostafa M. Ramla, Chemistry of Natural and Microbial
Prod. Depart., National Research Center, Dokki, Cairo, Egypt. E-mail: mostafa ramla@
yahoo.com
3046

Some Novel S-Pyridyl Glycosides Derivatives
3047
result of the inhibition at these sites is that the cells become deficient
in cytidine and deoxycytidine nucleotides, causing inhibition of both
RNA and DNA synthesis.4,5 The importance of such compounds, as in-
termediates for the synthesis of the biologically active deazafolic acid
and 3-deazapyrimidine nucleosides ring system6,7prompted our inter-
est in the synthesis and chemistry of this class of compounds. Recently,
some new chiral heterocyclic compounds containing pyridine moiety
have been reported as anticancer and anti-inflammatory.8,9 On the
other hand, tetrahydronaphthalene incorporated in heterocyclic sys-
tems with a wide spectrum of biological activities are known.10−14 As
part of our program of research on the synthesis new uridine and deaza-
uridine glycosides,15−18 we have herein synthesized some new pyridine
S-glycoside derivatives for their evaluation anti-inflammatory activity.
RESULTS AND DISCUSSION
Chemistry
In this study, the synthesis of some new acetylated glycosides
of 2-thioxo-3-deazapyrimidine utilizing pyridine-2(1H)-thione 1 as
starting materials. Thione derivatives 1 were prepared by the
reaction of 6-acetyl-5,6,7,8-tetrahydronaphthalene with arylidenecyan-
othioacetamide in presence of ammonium acetate according literature
method19. Compound 1 readily reacted with tetra-O-acetyl-α-D-
glucopyranosyl bromide 2 or with tetra-O-acetyl-α-D-galactopyranosyl
bromide 3 in the presence of potassium hydroxide in acetone to yield the
corresponding S-glucosides 4a–c and S-galactosides 5a–c, respectively
(Scheme 1).
Also, reaction of 1 with freshly prepared 2,3,4-tri-O-acetyl-α-D-
xylopyranosyl bromide 6 or with 2,3,4-tri-O-acetyl-β-L-arabinopyran-
osyl bromide 7 in the presence of potassium hydroxide in acetone gave
S-xylosides 8a–c and S-arabinosides 9a–c, respectively (Scheme 2).
Thin layer chromatography indicated that a single unique compound
was produced, and the structures were demonstrated by the elemental
analyses and the spectral data. Evidence for the attachment of the
sugar moiety to the 2-position was obtained by oxidation of the thio
galactosides 5a–c with hydrogen peroxide in acetic acid,20 which was
yielded the corresponding sulphones 10a–c as illustrated in Scheme 3.
One the other hand, compound 1c can be coupled with differ-
ent classes of acyclic sugar halides namely chloromethylethylether,
chloromethylmethylsulfide, and 3-bromo-1-propanol 11a–c in the
presence of sodium hydride in dry acetonitrile to give a series of some
pyridine acyclonucleoside analogues 12a–c (Scheme 4).

3048
N. M. Khalifa et al.
SCHEME 1
SCHEME 2

Some Novel S-Pyridyl Glycosides Derivatives
3049
SCHEME 3
SCHEME 4

3050
N. M. Khalifa et al.
The chemical formulas of the prepared compounds were elucidated
1
with correct elemental analyses and by IR, HNMR, 13CNMR as well
as mass spectra. The IR spectra of 4a–c, 5a–c, 8a–c, and 9a–c are
characterized by the absence of νas NH and νas SH at 3220−3340 cm−1
and by stretching vibration frequencies of the acetate carbonyl in the
−1
1
1765−1730 cm
region. The HNMR spectral data and their assign-
ments are shown below. All synthesized compounds, 4a–c, 5a–c, 8a–c,
and 9a–c exist predominantly in a chair like configuration and confor-
mation as shown in Schemes 1 and 2. In general, the anomeric proton
(H-1ꢀ ) of aldopyranosyl halides21 and acetylated 1-thioaldopyranoses22
resonate at relatively lower field than other sugar ring protons. The
structures of the synthesized acetylated S-glycopyranosyl derivatives
showed the anomeric protons which appear as doublets with large cou-
pling constants at C1 and C2 of the carbohydrate residue, correspond-
ing to the diaxial orientation of H-1ꢀ and H-2ꢀ protons which indicates
the presence of only β-configuration in the (D) conformation of com-
pounds 4a–c, 5a–c, and 8a–c, and the α- configuration in the (L) con-
formation of compounds 9a–c. Compound 5c serves as an example,
the anomeric proton appear as a doublet at δ 5.83 ppm with spin-spin
coupling constant equal to 9.97 Hz, which corresponds to the diaxial
orientation of H-1ꢀ and H-2ꢀ protons indicating the presence of only
β-configuration. The other six protons of the galactopyranosyl ring res-
onates at δ 4.12−5.63 ppm region. The remaining four acetoxy groups
appear as four singlets at δ 1.89, 1.96, 1.99, and 2.17 ppm. The 13CNMR
spectrum was characterized by a signal at δ 93.1 ppm corresponding to
C-1ꢀ atom of the β-D-galactopyranose. Four signals appear at δ 169.1,
169.6, 169.7, and 169.9 ppm due to the four acetoxy carbonyl carbon
atoms of the sugar moiety, with four additional signals at δ 20.1, 20.2,
20.5, and 20.7 ppm attributed to acetoxy methyl carbons and five sig-
nals at δ 61.3, 67.5, 67.9, 69.7 and 71.1 ppm assigned as C-6ꢀ, C-4ꢀ,
C-2ꢀ, C-3ꢀ, and C-5ꢀ of galactose, respectively, The nitrile carbon of the
pyridine thione appears at 118.1 ppm.
Pharmacological Screening
Anti-Inflammatory Potency
Initially the acute toxicity of the compounds was assayed via the
determination of their LD50. All the compounds except 5b were inter-
R
estingly less toxic than Valdecoxibꢀ as the reference drug (Table I).
The newly synthesized compounds were then pharmacologically
screened on male albino rats for their anti-inflammatory potency
(Tables II and III). The evaluation of the anti-inflammatory activities

Some Novel S-Pyridyl Glycosides Derivatives
3051
TABLE I Acute Toxicity (LD50)of the
Synthesized Compounds
Compound no.
LD50 [mg/kg]
5a
5b
5c
5d
6a
6b
6c
6d
7a
7d
8a
8d
10a
10d
11
12a
2.673 0.010
1.066 0.011
2.212 0.014
3.601 0.012
1.796 0.010
2.214 0.010
2.560 0.010
2.483 0.012
4.176 0.013
3.700 0.010
1.910 0.011
3.115 0.013
3.070 0.012
2.710 0.011
3.611 0.013
2.812 0.014
2.813 0.010
1.635 0.014
12b
Valdicoxib
R
ꢀ
was based on a strong biological rationale, and this involved the two
criteria present in the tested molecules.
Purpose and Rationale
For the determination of the antiphlogistic potency of the synthe-
sized compounds, two standard tests were realized at 25 and 50 mg/kg
R
rat body weight namely, the protection against Carrageenanꢀ induced
edema according Winter et al.,23 and the inhibition of plasma PGE2.
R
The later is known as a good confirming indicator for the Carrageenanꢀ
induced rat paw edema.24
R
Regarding the protection against Carrageenanꢀ induced edema,
eight compounds namely 5a, 5b, 6a, 6b, 7a, 8a, 11, and 12b were
R
found more potent than Valdecoxibꢀ. Where, their protection per-
centage against carrageenan induced edema at two dose levels 25
and 50 mg/kg are 92.66/95.95, 93.60/98.56, 91.85/98.82, 94.15/96.10,
93.18/93.75, 89.26/98.31, 88.86/97.97, and 93.86/93.81, respectively
R
(Valdecoxibꢀ80.95/92.98). On the other hand, the inhibition of plasma
PGE2 for the compounds 5a, 5b, 6a, and 8a were found more po-
R
tent than Valdecoxibꢀ at two tested doses levels 25 and 50 mg/kg.
The inhibition percentage for the latter compounds were found as:
99.84/93.56, 91.98/96.75, 80.16/90.62, and 83.76/94.98, respectively.

3052
N. M. Khalifa et al.
TABLE II Anti-Inflammatory Potencies of the Synthesized
Compounds (Protection against Carrageenan-Induced Edema)
Compound no. Dose [mg/kg] Protection against carrageenan-induced edema [%]*
5a
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
92.66 0.084
95.95 0.082
93.60 0.088
98.56 0.085
−52.16 0.080
5b
5c
5d
−38.66 0.082
6a
91.85 0.075
98.82 0.076
94.15 0.080
96.10 0.076
−84.16 0.066
6b
6c
6d
−44.80 0.055
7a
93.18 0.066
93.75 0.076
47.18 0.080
63.11 0.056
89.26 0.060
98.31 0.073
55.22 0.055
66.15 0.068
53.16 0.078
65.18 0.066
55.75 0.069
75.13 0.074
88.86 0.077
97.97 0.068
54.22 0.067
73.14 0.049
93.86 0.066
93.81 0.070
80.95 0.990
92.98 0.080
7d
8a
8d
10a
10d
11
12a
12b
Valdicoxib
R
ꢀ
*The doses tested were 25, 50 mg and carryout three determinations for each dose.
Pharmacological Screening
Determination of Acute Toxicity (LD50
)
The LD50 for compounds were determined by injected different grad-
ual increased doses of the tested compounds to adult male albino rats,
then calculating the dose that caused 50% animal death, according to
Austen and Brocklehurst.25

Some Novel S-Pyridyl Glycosides Derivatives
3053
TABLE III Anti-Inflammatory Potencies of the
Synthesized Compounds (Inhibition of Plasma
PGE2)
Compound no. Dose [mg/kg] Inhibition of plasma PGE2 [%]*
5a
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
99.84 0.085
93.56 0.092
91.98 0.088
96.75 0.105
—
5b
5c
46.61 0.090
—
5d
31.13 0.085
80.16 0.088
90.62 0.100
78.62 0.096
82.66 0.087
—
6a
6b
6c
77.50 0.086
—
6d
36.18 0.088
77.41 0.088
81.56 0.086
41.16 0.077
54.17 0.091
83.76 0.109
94.98 0.110
43.18 0.088
62.13 0.078
46.31 0.090
61.38 0.110
50.99 0.100
71.00 0.098
76.55 0.078
84.87 0.081
47.62 0.065
70.55 0.087
82.16 0.076
79.15 0.077
77.00 0.084
91.00 0.087
7a
7d
8a
8d
10a
10d
11
12a
12b
Valdicoxib
R
ꢀ
*The doses tested were 25, 50 mg and carryout three
determinations for each dose.
Anti-Inflammatory Activity
Procedure. Groups of adult male albino rats (150−180 g), each of
8 animals were orally dosed with tested compounds at a dose level

3054
N. M. Khalifa et al.
R
of 25−50 mg/kg 1 h before Carrageenanꢀchallenge. Foot paw edema
was induced by subplantar injection of 0.05 ml of 1% suspension of
R
Carrageenanꢀin saline into the planter tissue of one hind paw. An
equal volume of saline was injected to the other hind paw and served
as control. Four h after drug administration, the animals were decapi-
tated, blood was collected and the paws were rapidly excised.
The average weight of edema was examined for the treated as well
as the control group and the percentage inhibition of weight of edema
R
was also evaluated. Valdicoxibꢀ(5 mg/kg) was employed as standard
reference, against which the tested compounds were compared.
Calculation and Evaluation. Thirty min after the rats are challenged
by subcutaneous injection of 0.05 ml of 1% solution of carrageenan into
the planter side of the lift hind paw. The paw is marked with ink at
the level of the lateral malleolus, the paw volume was measured by
a sensitive method developed by Webb and Griswold26 that calculated
by interfacing a Mettler DeltaRange top-loading balance with a micro
computer.
%Protection = (A−B) × 100/A
A = the paw volume of non-treated group
B = the paw volume of treated group
(1)
Estimation of Plasma Prostaglandin E2 (PGE2)
Procedure. Heparinized blood samples were collected from rats ob-
tained from the previous anti-inflammatory examined groups (n = 8),
plasma was separated by centrifugation at 12,000 g for 2 min at 40◦C
and immediately stored frozen −2◦C until use.
The design correlate EIA prostaglandin E2 (PGE2) kit (Merck,
Darmstadt, Germany) is a competitive immuno assay for the quan-
titative determination of PGE2 in biological fluids. The kit uses a mon-
oclonal antibody to PGE2 to bind, in a competitive manner, the PGE2
in the sample after a simultaneous incubation at room temperature.
The excess reagents were washed away and the substrate was added,
after a short incubation time the enzyme reaction was stopped and the
yellow color generated was read on a micro plate reader (DYNATCh,
MR 5000) at 405 nm. The intensity of the bound yellow color is in-
versely proportional to the concentration of PGE2 in either standard
or samples.
Calculation and Evaluation. The PGE2 was calculated for the
treated and control groups, then the PGE2 percentage inhibition is

Some Novel S-Pyridyl Glycosides Derivatives
3055
determined by the following equation:
%Inhibition = (A−B) × 100/A
A = PGE2 in the control group
B = PGE2 in the treated group
(2)
CONCLUSION
All the tested compounds showed potent anti-inflammatory activities
at two-dose level except compounds 5c, 5d, 6c, and 6d only showed
activities at 50 mg/kg dose level. Compounds 5b, 5a, 8a, 11, 6b, 5a,
R
and 12b are more potent than the reference drug Valdecoxibꢀat in the
same time more safe than it except compound 5b. The order of activity
(in descending manner) is: 5b, 5a, 8a, 11, 6b, 5a, 12b, 7a, 6c, 10d, 12a,
8d, 10a, 7d, 5c, 6d, and 5d.
EXPERIMENTAL
Synthesis
Melting points are uncorrected and were taken on an open glass capil-
laries Melting point apparatus. Analytical data were obtained from the
microanalytical unit, Cairo University, Egypt. IR spectra (KBr discs)
1
were recorded on a Perkin Elmer 1430 spectrophotometer. H NMR
and 13CNMR spectra were determined on Joel 270 MHz in DMSO-d6
and the chemical shifts were recorded in ppm relative to TMS. The
mass spectra were run 70ev with a Finnegan SSQ GC/ MS spectrom-
eter using EI and Fast Atom Bombardment (FAB) mass spectra on a
Kratos MS 50 rf. All reactions were followed by TLC (silica gel, alu-
minum sheets 60 F254, Merck) and Merck Silica gel (0.040−0.063 mm)
was used for column chromatography.
4-(Substituted phenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-
2-thioxo-1,2-di-hydro-pyridine-3-carbonitrile 1a–c
A suspension of 6-acetyl-5,6,7,8-tetrahydronaphthalene (10 mmol),
arylidenecyanothioacetamide (10 mmol) and anhydrous ammonium ac-
etate (15 mmol) in 30 ml ethanol was heated under reflux for 6 h. The
resulting product was filtered off and crystallized from the proper sol-
vent to give 1a–c, respectively.
4-(2,4-Dichlorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-
thioxo-1,2-dihyro-pyridine-3-carbonitrile (1a). Yield (77%), m.p.

3056
N. M. Khalifa et al.
266−268◦C (dioxane); IR (KBr, cm−1) 3290 (NH), 2230 (CN), 1590
(C=N), 1209 (C S); 1H-NMR (DMSO-d6): δ 1.68−1.70 (m, 4H, 2 CH2),
2.74−2,78 (m, 4H, 2 CH2), 6.80 (s, 1H, H-5 pyridine), 7.05−7.53 (m,
6H, Ar-H), 10.19 (s, 1H, NH) ppm; MS (EI): m/z 410 (45%) [M+]. Anal.
C22H16Cl2N2S, Calcd CHN: 64.24; 3.92; 6.81. found: 66.12; 3.71; 6.57.
4-(2-Chloro-6-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-
2-thioxo-1,2-dihyro-pyridine-3-carbonitrile (1b). Yield (66%), m.p.
279−281oC (ethanol); IR (KBr, cm−1) 3321 (NH), 2219 (CN), 1586
1
(C N), 1206 (C S); H-NMR (DMSO-d6): δ 1.70−1.74 (m, 4H, 2CH2),
2.78−2.81 (m, 4H, 2CH2), 6.89 (s, 1H, H-5 pyridine), 7.11−7.59 (m,
6H, Ar-H), 10.37 (s, 1H, NH) ppm; MS (EI): m/z 394 (15%) [M+], Anal.
C22H16ClFN2S, calcd.: CHN: 66.91; 4.08; 7.09, found: 66.74; 3.96; 6.89.
4-(3,5-Dimethoxyphenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-
2-thioxo-1,2-dihyro-pyridine-3-carbonitrile (1c). Yield (66%), m.p.
246−247oC (ethanol); IR (KBr, cm−1) 3317 (NH), 2220 (CN), 1589
1
(C N), 1207 (C S); H-NMR (DMSO-d6): δ 1.73−1.76 (m, 4H, 2 CH2),
2.83−2.86 (m, 4H, 2 CH2), 3.87 (s, 6H, 2OCH3), 6.86 (s, 1H, H-5
pyridine), 7.10−7.56 (m, 6H, Ar-H), 10.55 (s, 1H, NH) ppm; MS (EI):
m/z 402 (18%) [M+]. Anal. C24H22N2O2S, calcd. CHN: 71.62; 5.51; 6.96,
found: 71.49; 5.37; 6.77.
Synthesis of Acetylated S-Glycosides 4a–c, 5a–c, 8a–c, and
9a–c—General Procedure
A solution of bromides 2, 3, 6, or 7 (10 mmol) in acetone 50 ml
was added to a solution of 2(1H)-pyridine thiones 1a–c (10 mmol) in
water 6 ml containing potassium hydroxide (10 mmol). The reaction
mixture was stirred at room temperature for 9 h; complete conversion of
starting material to new product was indicated by TLC. The solvent was
evaporated under reduced pressure at 40oC. The residue was washed
with water to remove potassium bromide. The mixture was filtered,
and the filtrate was evaporated to dryness. The residue was crystallized
from ethanol to afford colorless crystals of the thioglycosides 4a–c, 5a–
c, 8a–c, and 9a–c
4-(2,4-Dichlorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-(2 ꢀ,
3 ꢀ,4 ꢀ,6 ꢀ-tetra-O-acetyl-β-D-glucopyranosyl thio)-pyridine-3-carboni-
trile (4a). Yield (61%), m.p. 170−171oC; IR (KBr, cm−1) 2223 (CN),
1725 (CO ester), 1582 (C N); 1H-NMR (DMSO-d6): δ 1.70−1.72 (m,
4H, 2 CH2), 1.89, 1.97, 1.99, 2.14 (4s, 12H, 4 CH3CO), 2.82−2.85 (m,
4H, 2 CH2), 4.22−4.24 (m, 2H, H-6ꢀ, 6ꢀꢀ), 4.55−4.58 (m, 1H, H-5ꢀ),
5.28−5.32 (m, 2H, H-4ꢀ and H-3ꢀ), 5.78−5.80 (m, 1H, H-2ꢀ), 5.85 (d,
ꢀ
ꢀ
ꢀ
J1 −2 9.78 Hz, 1H, H-1 ), 6.80 (s, 1H, H-5 pyridine), 7.19−7.56 (m, 6H,

Some Novel S-Pyridyl Glycosides Derivatives
3057
Ar-H) ppm; MS (FAB): m/z 740 (13%) [M+]. Anal. C36H34Cl2N2O9S,
calcd. CHN: 58.30; 4.62; 3.78, found: 58.11; 4.40; 3.59.
4-(2-Chloro-6-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-
2-(2 ꢀ,3 ꢀ,4 ꢀ,6 ꢀ-tetra-O-acetyl-β-D-glucopyranosyl thio)-pyridine-3-
carbo-nitrile (4b). Yield (69%), m.p. 183−185oC; IR (KBr, cm−1) 2220
1
(CN), 1739 (CO ester), 1586 (C N); H-NMR (DMSO-d6): δ 1.76−1.78
(m, 4H, 2CH2), 1.95, 199, 2.01, 2.10 (4s, 12H, 4 CH3CO), 2.84–2.86
(m, 4H, 2 CH2), 4.18−4.22 (m, 2H, H-6ꢀ, 6ꢀꢀ), 4.50−4.54 (m, 1H, H-5ꢀ),
5.26−5.29 (m, 2H, H-4ꢀ and H-3ꢀ), 5.74−5.77 (m, 1H, H-2ꢀ), 5.86 (d,
ꢀ
ꢀ
ꢀ
J1 −2 9.81 Hz, 1H, H-1 ), 6.89 (s, 1H, H-5 pyridine), 7.23−7.51 (m, 6H,
Ar-H) ppm; MS (FAB): m/z 724 (22%) [M+]. Anal. C36H34ClFN2O9S,
calcd. CHN: 59.62; 4.73; 3.86, found: 59.47; 4.52; 3.60.
4-(3,5-Dimethoxyphenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-2–
(2ꢀ,3 ꢀ,4 ꢀ,6 ꢀ-tetra-O-acetyl-β-D-glucopyranosyl thio)-pyridine-3-carbo-
nitrile (4c). Yield (57%), m.p. 206−207oC; IR (KBr, cm−1) 2216 (CN),
1751 (CO ester), 1580 (C N); 1H-NMR (DMSO-d6): δ 1.70−1.73 (m,
4H, 2 CH2), 1.96, 1.98, 2.02, 2.11 (4s, 12H, 4 CH3CO), 2.86−2.88 (m,
4H, 2 CH2), 4.24−2.27 (m, 2H, H-6ꢀ, 6ꢀꢀ), 4.55−4.57 (m, 1H, H-5ꢀ),
5.32−5.35 (m, 2H, H-4ꢀ and H-3ꢀ), 5.80−5.84 (m, 1H, H-2ꢀ), 5.82 (d,
ꢀ
ꢀ
ꢀ
J1 −2 9.92 Hz, 1H, H-1 ), 6.86 (s, 1H, H-5 pyridine), 7.27−7.55 (m, 6H,
Ar-H) ppm; MS (FAB): m/z 732 (43%) [M+]. Anal. C38H40N2O11S, calcd.
CHN: 62.28; 5.50; 3.82, found: 62.06; 5.43; 3.65.
4-(2,4-Dichlorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-(2 ꢀ,
3ꢀ, 4ꢀ,6ꢀ-tetra-O-acetyl-β-D-galactopyranosyl thio)-pyridine-3-carb-
onitrile (5a). Yield (73%), m.p. 115−116oC; IR (KBr, cm−1) 2218 (CN),
1755 (CO ester), 1580 (C N); 1H-NMR (DMSO-d6): δ 1.73−1.76 (m,
4H, 2 CH2), 1.94, 1.98, 2.03, 2.12 (4s, 12H, 4 CH3CO), 2.85−2.87 (m,
4H, 2 CH2), 4.21−4.25 (m, 2H, H-6ꢀ, 6ꢀꢀ and 1H, H-5ꢀ), 4.63 (t, 1H, H-4ꢀ),
ꢀ
5.52−5.6 (m, 2H, H-3ꢀ and H-2ꢀ), 5.78 (d, J1 −2 9.98 Hz, 1H, H-1 ), 6.84
(s, 1H, H-5 pyridine), 7.23−7.57 (m, 6H, Ar-H) ppm; MS (FAB): m/z
740 (23%) [M+]. Anal. C36H34Cl2N2O9S, calcd. CHN: 58.30; 4.62; 3.78,
found: 58.09; 4.49; 3.50.
ꢀ
ꢀ
4-(2-Chloro-6-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-
2- (2 ꢀ,3 ꢀ,4 ꢀ,6 ꢀ-tetra-O-acetyl-β-D-galactopyranosyl thio)-pyridine-3-ca-
rbonitrile (5b). Yield (76%), m.p. 168−170oC; IR (KBr, cm−1) 2222
1
(CN), 1760 (CO ester), 1585 (C N); H-NMR (DMSO-d6): δ 1.76 (m,
4H, 2 CH2), 1.96, 1.98, 2.00, 2.18 (4s, 12H, 4 CH3CO), 2.86−2.90 (m,
4H, 2 CH2), 4.14−4.18 (m, 2H, H-6ꢀ, 6ꢀꢀ and 1H, H-5ꢀ), 4.65−4.68 (m,
1H, H-4ꢀ), 5.52−5.55 (m, 2H, H-3ꢀ and H-2ꢀ), 5.68 (d, J1 −2 9.91Hz, 1H,
H-1ꢀ), 6.80 (s, 1H, H-5 pyridine), 7.22−7.54 (m, 6H, Ar-H) ppm; MS
ꢀ
ꢀ

3058
N. M. Khalifa et al.
(FAB): m/z 724 (12%) [M+]. Anal. C36H34ClFN2O9S, calcd. CHN: 59.62;
4.73; 3.86, found: 59.52; 4.58; 3.67.
4-(3,5-Dimethoxyphenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-2–
(2 ꢀ,3 ꢀ,4 ꢀ,6 ꢀ-tetra-O-acetyl-β-D-galactopyranosyl thio)-pyridine-3-carb-
onitrile (5c). Yield (83%), m.p. 218−219oC; IR (KBr, cm−1) 2218 (CN),
1756 (CO ester), 1581 (C N); 1H-NMR (DMSO-d6): δ 1.70−1.74 (m,
4H, 2 CH2), 1.89, 1.96, 1.99, 2.17 (4s, 12H, 4 CH3CO), 2.84−2.86 (m,
4H, 2 CH2), 4.12−4.16 (m, 2H, H-6ꢀ, 6ꢀꢀ), 4.62−4.66 (m, 1H, H-5ꢀ),
5.33−5.37 (m, 2H, H-4ꢀ and H-3ꢀ), 5.63−5.68 (m, 1H, H-2ꢀ), 5.83 (d,
J1‘−2‘9.97 Hz, 1H, H-1ꢀ), 6.85 (s, 1H, H-5 pyridine), 7.27−7.58 (m, 6H,
Ar-H) ppm; 13C-NMR (DMSO-d6): δ 20.1−20.7 (4 CH3CO), 22.9−31.2
(4 CH2), 56.7 (OCH3), 61.3 (C-6ꢀ), 67.5 (C-4), 67.9 (C-2‘), 69.7 (C-3), 71.1
(C-5‘), 93.1 (C-1‘), 118.1 (CN), 118.3 (C-5- pyridine ring), 123.9-164.1
(Ar-C), 169.1−169.9 (4 COCH3) ppm; MS (FAB): m/z 732 (14%) [M+].
Anal. C38H40N2O11S, calcd. CHN: 62.28; 5.50; 3.82, found: 62.13; 5.29;
3.56.
4-(2,4-Dichlorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-(2 ꢀ,
3 ꢀ,4 ꢀ-tri-O-acetyl-α-D-xylopyranosyl thio)-pyridine-3-carbonitrile (8a).
Yield (51%), m.p. 188−189oC; IR (KBr, cm−1) 2220 (CN), 1758 (CO
1
ester), 1586 (C N); H-NMR (DMSO-d6): δ 1.74−1.78 (m, 4H, 2 CH2),
1.87, 1.98, 2.03 (3s, 9H, 3 CH3CO), 2.86−2.90 (m, 4H, 2 CH2), 4.01
(q, 2H, H-5ꢀ, 5ꢀꢀ), 4.78−4.82 (m, 1H, H-4ꢀ), 4.96 (t, 1H, H-2ꢀ), 5.16 (t,
ꢀ
1H, H-3ꢀ), 6.19 (d, J1 −2 7.33 Hz, 1H, H-1 ), 6.80 (s, 1H, H-5 pyridine),
7.27−7.50 (m, 6H, Ar-H) ppm; MS (FAB): m/z 668 (18%) [M+]. Anal.
C33H30Cl2N2O7S, calcd. CHN: 59.20; 4.52; 4.18, found: 58.99; 4.37;
3.98.
ꢀ
ꢀ
4-(2-Chloro-6-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-
2-(2 ꢀ,3 ꢀ,4 ꢀ-tri-O-acetyl-α-D-xylopyranosyl thio)-pyridine-3-carbonitrile
(8b). Yield (60%), m.p. 197−198oC; IR (KBr, cm−1) 2224 (CN), 1761
1
(CO ester), 1580 (C N); H-NMR (DMSO-d6): δ 1.74−1.79 (m, 4H, 2
CH2), 1.90, 2.02, 2.03 (3s, 9H, 3 CH3CO), 2.85−2.88 (m, 4H, 2 CH2),
4.07 (q, 2H, H-5ꢀ, 5ꢀꢀ), 4.84-4.88 (m, 1H, H-4ꢀ), 4.98 (t, 1H, H-2ꢀ), 5.25 (t,
ꢀ
1H, H-3ꢀ), 6.17(d, J1 −2 7.51 Hz, 1H, H-1 ), 6.85 (s, 1H, H-5 pyridine),
7.23−7.58 (m, 6H, Ar-H) ppm; MS (FAB): m/z 652 (32%) [M+]. Anal.
C33H30ClFN2O7S, calcd. CHN: 60.69; 4.63; 4.29, found: 60.57; 4.45;
4.12.
ꢀ
ꢀ
4-(3,5-Dimethoxyphenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-2–
(2 ꢀ,3 ꢀ,4 ꢀ-tri-O-acetyl-α-D-xylopyranosyl thio)-pyridine-3-carbonitrile
(8c). Yield (55%), m.p. 164−166oC; IR (KBr, cm−1) 2226 (CN), 1759
1
(CO ester), 1583 (C N); H-NMR (DMSO-d6): δ 1.71−1.76 (m, 4H, 2

Some Novel S-Pyridyl Glycosides Derivatives
3059
CH2), 1.89, 1.99, 2.10 (3s, 9H, 3 CH3CO), 2.85−2.89 (m, 4H, 2 CH2),
4.23 (q, 2H, H-5ꢀ, 5ꢀꢀ), 4.84−4.87 (m, 1H, H-4ꢀ), 4.99 (t, 1H, H-2ꢀ), 5.26
ꢀ
(t, 1H, H-3ꢀ), 6.19 (d, J1 −2 7.60 Hz, 1H, H-1 ), 6.86 (s, 1H, H-5 pyridine),
7.20−7.52 (m, 6H, Ar-H) ppm; MS (FAB): m/z 660 (44%) [M+]. Anal.
C35H36N2O9S, calcd. CHN: 63.62; 5.49; 4.24, found: 63.46; 5.27; 4.04.
ꢀ
ꢀ
4-(2,4-Dichlorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-
(2 ꢀ,3 ꢀ,4-tri-O-acetyl-α-L-arabinopyranosyl thio)-pyridine-3-carbonitrile
(9a). Yield (35%), m.p. 183−184oC; IR (KBr, cm−1) 2223 (CN), 1762
(CO ester), 1589 (C N); 1H-NMR (DMSO-d6): δ 1.70−1.75 (m, 4H,
2 CH2), 1.87, 2.09, 2.15 (3s, 9H, 3 CH3CO), 2.83−2.86 (m, 4H, 2
CH2), 3.87 (q, 1H, H-5ꢀꢀ), 4.01 (q, 1H, H-5ꢀ), 5.15−5.18 (m, 1H, H-4ꢀ),
5.22−5.26 (m, 1H, H-3ꢀ), 5.39 (d, 1H, H-2ꢀ), 6.17 (d, J1 −2 9.61 Hz, 1H,
H-1ꢀ), 6.85 (s, 1H, H-5 pyridine), 7.25−7.55 (m, 6H, Ar-H) ppm; MS
(FAB): m/z 668 (16%) [M+]. Anal. C33H30Cl2N2O7S, calcd. CNH: 59.20;
4.52; 4.18, found: 59.06; 4.39; 4.03.
ꢀ
ꢀ
4-(2-Chloro-6-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-
yl)- 2-(2 ꢀ,3 ꢀ,4 ꢀ-tri-O-acetyl-α-L-arabinopyranosyl thio)-pyridine-3-
carbonitr- ile (9b). Yield (20%), m.p. 189−190oC; IR (KBr, cm−1) 2220
1
(CN), 1758 (CO ester), 1586 (C N); H-NMR (DMSO-d6): δ 1.7−1.76
(m, 4H, 2 CH2), 1.90, 2.05, 2.11 (3s, 9H, 3 CH3CO), 2.83−2.87 (m, 4H,
2 CH2), 3.83 (q, 1H, H-5ꢀꢀ), 4.02 (q, 1H, H-5ꢀ), 5.18−5.20 (m, 1H, H-4ꢀ),
5.26−5.29 (m, 1H, H-3ꢀ), 5.36 (d, 1H, H-2ꢀ), 6.21 (d, J1 −2 9.47 Hz, 1H,
H-1ꢀ), 6.80 (s, 1H, H-5 pyridine), 7.24−7.59 (m, 6H, Ar-H) ppm; MS
(FAB): m/z 652 (12%) [M+]. Anal. C33H30ClFN2O7S, calcd. CHN: 60.69;
4.63; 4.29, found: 60.61; 4.39; 4.09.
ꢀ
ꢀ
4-(3,5-Dimethoxyphenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-
yl)-2–(2 ꢀ,3 ꢀ,4 ꢀ-tri-O-acetyl-α-L-arabinopyranosyl
thio)-pyridine-3-
carbonitrile (9c). Yield (16%), m.p. 210−212oC; IR (KBr, cm−1) 2220
1
(CN), 1755 (CO ester), 1585 (C N); H-NMR (DMSO-d6): δ 1.70−1.75
(m, 4H, 2 CH2), 1.88, 1.98, 2.09 (3s, 9H, 3 CH3CO), 2.85−2.88 (m, 4H,
2 CH2), 3.79 (q, 1H, H-5ꢀꢀ), 4.01 (q, 1H, H-5ꢀ), 5.16−5.19 (m, 1H, H-4ꢀ),
5.22−5.26 (m, 1H, H-3ꢀ), 5.39 (d, 1H, H-2ꢀ), 6.23 (d, J1 −2 9.67 Hz, 1H,
H-1ꢀ), 6.80 (s, 1H, H-5 pyridine), 7.26−7.59 (m, 6H, Ar-H) ppm; MS
(FAB): m/z 660 (21%) [M+]. Anal. C35H36N2O9S, calcd. CHN: 63.62;
5.49; 4.24, found: 63.40; 5.33; 4.12.
ꢀ
ꢀ
Oxidation of thioglycosides 5a–c—General Procedure
A solution of the S-glycosides 5a–c (1mmol) in 10 ml of glacial acetic
acid containing 1ml of 30% hydrogen peroxide was stirred for 20 h at
room temperature, then poured into ice-water (200 ml). The separated

3060
N. M. Khalifa et al.
solid was collected on filtration. The corresponding sulfones 10a–c was
obtained in good yield and high purity.
4-(2,4-Dichlorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-(2 ꢀ,
3 ꢀ,4 ꢀ,6 ꢀ-tetra-O-acetyl-β-D-galactopyranosyl
sulfonyl)-pyridine-3-
carb- onitrile (10a). Yield (53%), m.p. 107−109oC; IR (KBr, cm−1) 2224
1
(CN), 1750 (CO ester), 1581 (C N); H-NMR (DMSO-d6): δ 1.69−1.75
(m, 4H, 2 CH2), 2.02, 2.05, 2.10, 2.14 (4s, 12H, 4 CH3CO), 2.80−2.85
(m, 4H, 2 CH2), 4.05−4.15 (m, 2H, H-6ꢀ, 6ꢀꢀ54−4.58 ( m, 1H, H-5ꢀ), 5.29
(t, 1H, H-4ꢀ), 5.54−5.58 (m, 2H, H-3ꢀ and H-2ꢀ), 5.79 (d, J1 −2 9.97 Hz,
1H, H-1ꢀ), 6.80 (s, 1H, H-5 pyridine), 7.25−7.61 (m, 6H, Ar-H) ppm;
MS (FAB): m/z 772 (42%) [M+]. Anal. C36H34Cl2N2O11S, calcd. CHN:
55.89; 4.43; 3.62, found: 55.58; 4.26; 3.56.
ꢀ
ꢀ
4-(2-Chloro-6-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-
2-(2 ꢀ,3 ꢀ,4 ꢀ,6 ꢀ-tetra-O-acetyl-β-D-galactopyranosyl sulfonyl)-pyridine-
3-carbonitrile (10b). Yield (50%), m.p. 139−140oC; IR (KBr, cm−1
)
2221 (CN), 1753 (CO ester), 1587 (C N); 1H-NMR (DMSO-d6): δ
1.72−1.77 (m, 4H, 2 CH2), 2.04, 2.07, 2.11, 2.16 (4s, 12H, 4 CH3CO),
2.83−2.87 (m, 4H, 2 CH2), 4.01−4.10 (m, 2H, H-6ꢀ, 6ꢀꢀ), 4.48−4.52 (m,
1H, H-5ꢀ), 5.37 (t, 1H, H-4ꢀ), 5.59−5.62 (m, 2H, H-3ꢀ and H-2ꢀ), 5.86 (d,
ꢀ
ꢀ
ꢀ
J1 −2 9.95 Hz, 1H, H-1 ), 6.80 (s, 1H, H-5 pyridine), 7.18−7.54 (m, 6H,
Ar-H) ppm; MS (FAB): m/z 756 (26%) [M+]. Anal. C36H34ClFN2O11S,
calcd. CHN: 57.10; 4.53; 3.70, found: 56.90; 4.46; 3.53.
4-(3,5-Dimethoxyphenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-
(2 ꢀ,3 ꢀ,4 ꢀ,6 ꢀ-tetra-O-acetyl-β-D-galactopyranosyl sulfonyl)-pyridine-3-
carbonitrile (10c). Yield (53%), m.p. 146−147oC; IR (KBr, cm−1) 2223
1
(CN), 1755 (CO ester), 1585 (C N); H-NMR (DMSO-d6): δ 1.72−1.76
(m, 4H, 2 CH2), 2.00, 2.03, 2.09, 2.12 (4s, 12H, 4 CH3CO), 2.84−2.89
(m, 4H, 2 CH2), 4.00−4.15 (m, 2H, H-6ꢀ, 6ꢀꢀ), 4.60−4.66 (m, 1H, H-5ꢀ),
5.41 (t, 1H, H-4ꢀ), 5.62−5.67 (m, 2H, H-3ꢀ and H-2ꢀ), 5.86 (d, J1 −2 9.96
Hz, 1H, H-1ꢀ), 6.80 (s, 1H, H-5 pyridine), 7.23−7.53 (m, 6H, Ar-H) ppm;
MS, MS (FAB): m/z 764 (8%) [M+]. Anal. C38H40N2O13S, calcd. CHN:
59.68; 5.27; 3.66, found: 59.47; 5.12; 3.37.
ꢀ
ꢀ
2-(Substituted)-6-(5,6,7,8-tetrahydronaphthalen-6-yl)-4-(3,5-
dimethoxyphenyl) pyridine-3-carbonitrile (12a–c)—General
Procedure
To a stirred suspension of 4-(3,5-Dimethoxyphenyl)-6-(5,6,7,8-
tetrahydro-naphthalen-2-yl)-2-thioxo-1,2-dihyropyridine-3-carbonitri-
le 1c (10 mmol) in dry acetonitrile (50 ml) was added a solution of
sodium borohydride (10 mmol) . The mixture was stirred until a clear
solution was obtained (30 min). The reaction mixture was cooled to

Some Novel S-Pyridyl Glycosides Derivatives
3061
0◦C and then acyclic sugar halides, namely chloromethylethyl ether,
chloromethyl methyl sulfide, and 3-bromo-1-propanol 11a–c (10 mmol)
was added dropwise into dry acetonitrile (10 ml). The mixture was
stirred for 8 h; the solid precipitate was filtered; and the filtrate
was removed under reduced pressure. The products were purified by
silica gel column chromatography [25−30% EtOAc in petroleum ether
(60−80◦C)].
2-(Ethoxymethylthio)-6-(5,6,7,8-tetrahydronaphthalen-6-yl)-4-(3,5-
di-methoxyphenyl) pyridine-3-carbonitrile (12a). Yield (53%), m.p.
141−143◦C; IR (KBr, cm−1) 2223 (CN), 1586 (C N); 1H-NMR (DMSO-
d6): δ 1.14 (t, 3H, CH3), 1.73−1.77 (m, 4H, 2 CH2), 2.83−2.87 (m, 4H,
2 CH2), 3.49 (q, 2H, OCH2), 3.87 (s, 6H, 2OCH3), 5.11 (s, 2H, OCH2S),
6.81 (s, 1H, H-5 pyridine), 7.15−7.60 (m, 6H, Ar-H) ppm; 13C-NMR
(DMSO-d6): δ 15.01 (CH3), 23.11, 23.17, 32.37, 32.50 (4 CH2), 57.39
(2 OCH3), 67.26 (OCH2), 76.95 (OCH2S), 119.08 (CN), 121.00 (CH of
pyridine), 120.29−168.26 (Ar-C) ppm; MS (EI): m/z 460 (11%) [M+].
Anal. C27H28N2O3S, calcd. CHN: 70.41; 6.13; 6.08, found: 70.28; 5.97;
5.93.
2-[(Methylthio)methylthio]-6-(5,6,7,8-tetrahydronaphthalen-6-yl)-
4-(3,5-dimethoxy phenyl) pyridine-3-carbonitrile (12b). Yield (50%),
m.p. 166−168◦C; IR (KBr, cm−1) 2220 (CN), 1588 (C N); 1H-NMR
(DMSO-d6): δ 1.75−1.79 (m, 4H, 2 CH2), 2.17 (s, 3H, CH3), 2.82−2.87
(m, 4H, 2 CH2), 3.87 (s, 6H, 2OCH3), 4.15 (s, 2H, SCH2), 6.79 (s, 1H,
H-5 pyridine), 7.12−7.66 (m, 6H, Ar-H) ppm; 13C-NMR (DMSO-d6):
δ 16.4 (CH3), 23.15, 23.19, 32.29, 32.40 (4 CH2), 40.1 (SCH2), 56.7
(OCH3), 118.1 (CN), 118.3 (C5-pyridine ring), 123.2−164.3 (Ar-C) ppm;
MS (EI): m/z 462 (52%) [M+]. Anal. C26H26N2O2S2, calcd. CHN: 66.18;
5.32; 6.43, found: 66.06; 5.17; 6.31.
2-(3-Hydroxypropylthio)-6-(5,6,7,8-tetrahydronaphthalen-6-yl)-4-
(3,5-dimethoxy phenyl) pyridine-3-carbonitrile (12c). Yield (65%),
m.p. 178−180◦C; IR (KBr, cm−1) 2225 (CN), 1580 (C N); 1H-NMR
(DMSO-d6): δ 1.73−1.78 (m, 4H, 2 CH2), 1.90−1.93 (m, 2H, CH2),
2.85−2.88 (m, 4H, 2 CH2), 3.07 (t, 2H, SCH2), 3.59 (t, 2H, CH2OH),
3.89 (s, 6H, 2OCH3), 6.79 (s, 1H, H-5 pyridine), 7.10−7.61 (m, 6H,
Ar-H) ppm; MS (EI): m/z 460 (14%) [M+]. Anal. C27H28N2O3S, calcd.
CHN: 70.41; 6.13; 6.08, found: 70.19; 5.86; 5.90.
REFERENCES
[1] M. J. Robins, B. L. Currie, R. K. Robins, and A. Bloch, Proc. Am. Assoc. Cancer Res.,
10, 73 (1969).

3062
N. M. Khalifa et al.
[2] W. M. Shannon, G. Arnett, and F. M. Schabel, Antimicrob. Agents Chemother., 2,
159 (1972).
[3] R. R. Copp and V. S. Marquez, J. Med. Chem., 34, 208 (1991).
[4] M. J. Robins and A. S. K. Lee, J. Med. Chem., 18, 1070 (1975).
[5] M. Legraverend, Z. C. Nguycn, and E. B. Aurelio, Nucleosides & Nucleotides, 5, 125
(1986).
[6] K. A. Watanabe, U. Reichman, N. Greenberg, C. Lopez, and J. Fox, J. Med. Chem.,
27, 91 (1984).
[7] J. I. Degraw, P. H. Christine, R. L. Kisliuk, Y. Gaumont, F. M. Sirotnak, J. Med.
Chem., 33, 673 (1990).
[8] M. Abo-Ghalia and A. E. Amer, Amino Acids, 26, 283 (2004).
[9] M. Abo-Ghalia, A. E. Amer, and M. M. Abdulla, Z. Naturforsch., 58 (B), 903 (2003).
[10] B. Levant, D. E. Grigoriadis, and E. B. De-Souza, Eur. J. Pharmacol., 278, 243
(2003).
[11] J. R. Raymond, J. Kim, R. E. Beach, and C. C. Tisher, Am. J. Physiol., 264 (1Pt2),
F9–19 (1993).
[12] M. H. Parker, R. Chen, K. A. Conway, D. H. Lee, R. E. Boyed, S. O. Nortey, T. Ross,
M. Scott, and A. B. Reitz, Bioorg. Med. Chem., 10, 3565 (2002).
[13] S. Yous, S. Durieux, E. Belloli, H. Guelzim, C. Bochu, V. Audinot, and D. Lesieur,
Bioorg. Med. Chem., 11, 753 (2003).
[14] K. Bhandari, S. Srivastava, and G. Shankar, Bioorg. Med. Chem., 12, 4189 (2004).
[15] L. Petersen, T. H. Hansen, N. M. Khalifa, P. T. Jorgensen, E. B. Pedersen, and C.
Nielsen, Monatshefte fu¨r Chemie, 133, 1031 (2002).
[16] M. Bahgat and N. M. Khalifa, Acta Poloniae pharmaceutica-Drug Research, 63, 181
(2006).
[17] N. M. Khalifa, J. Biol. Pharm. Sci., 2, 57 (2004).
[18] N. M. Khalifa and A. O. El-nezhawy, J. Biol. Pharm. Sci., 2, 17 (2004).
[19] A. E. Amr, Ind. J. Heterocycl. Chem., 10, 49 (2000).
[20] M. F. Abdel-Megeed and M. A. Saleh, Sulfur Letters, 6, 115 (1987).
[21] P. L. Durette and D. Horton, Carbohydrate Res., 18, 57 (1971).
[22] C. V Holland, D. Horton, M. J. Miller, and N. S. Bhacca, J. Org. Chem., 32, 3077
(1967).
[23] C. A. Winter, E. A. Risly, and G. W. Nuss, Proc. Soc. Exp. Bio. Med., 111, 544 (1962).
[24] F. Herrmann, A. Lindemann, J. Gauss, and R. Mertelsmann, Eur. J. Immunol., 20,
2513 (1990).
[25] K. F. Austen, and W. E. Brocklehurst, J. Exp. Med., 113, 521 (1961).
[26] E. F. Webb and D. E. Griswold, J. Pharmacol. Meth., 12, 149 (1984).