A total synthesis of a new class of biazine thioglycosides

Article abstract of DOI:10.1081/CAR-200045262

A new method for the synthesis of bipyridinyl S -glycosides 11 and 12 has provided the title compounds in a higher yield. Application of a one-pot glycosylation methodology resulted in an efficient, high-yield synthesis of biazine S -glycosides 17-20 An X-ray diffraction analysis of 11 disclosed the conformation of this glycoside as the S -glycoside and not the corresponding N -form. Copyright

Full text of DOI:10.1081/CAR-200045262

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A Total Synthesis of a New Class of
Biazine Thioglycosides
Galal H. Elgemeie a , Mona M. Hussein b & Sheakha A. Al‐Khursani c
a Chemistry Department, Faculty of Science , Helwan University ,
Ain‐Helwan, Cairo, Egypt
b Chemistry Department, Faculty of Science , Cairo University ,
Giza, Egypt
c Chemistry Department , Girls College of Science , Dammam,
Kingdom of Saudi Arabia
Published online: 09 Aug 2006.
To cite this article: Galal H. Elgemeie , Mona M. Hussein & Sheakha A. Al‐Khursani (2004) A Total
Synthesis of a New Class of Biazine Thioglycosides, Journal of Carbohydrate Chemistry, 23:8-9,
465-481, DOI: 10.1081/CAR-200045262
To link to this article: http://dx.doi.org/10.1081/CAR-200045262
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 23, No. 8–9, pp. 465–481, 2004
A Total Synthesis of a New Class of
Biazine Thioglycosides
2
3
Galal H. Elgemeie,1, Mona M. Hussein, and Sheakha A. Al-Khursani
*
1Chemistry Department, Faculty of Science, Helwan University,
Ain-Helwan, Cairo, Egypt
2Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
3Chemistry Department, Girls College of Science, Dammam,
Kingdom of Saudi Arabia
CONTENTS
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
II. RESULTS AND DISCUSSIONS . . . . . . . . . . . . . . . . . . . . . . 466
III. ANTIVIRAL ACTIVITY . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
IV. BIOLOGICAL PROCEDURE . . . . . . . . . . . . . . . . . . . . . . . . 477
V. EXPERIMENTAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
*
Correspondence: Galal H. Elgemeie, Chemistry Department, Faculty of Science, Helwan University,
Ain-Helwan, Cairo, Egypt.
465
DOI: 10.1081/CAR-200045262
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

466
Elgemeie, Hussein, and Al-Khursani
ABSTRACT
A new method for the synthesis of bipyridinyl S-glycosides 11 and 12 has provided the
title compounds in a higher yield. Application of a one-pot glycosylation methodology
resulted in an efficient, high-yield synthesis of biazine S-glycosides 17–20 An
X-ray diffraction analysis of 11 disclosed the conformation of this glycoside as the
S-glycoside and not the corresponding N-form.
Key Words: Bipyridinyl thioglycosides; Biazine thioglycosides; Antimetabolites.
INTRODUCTION
In recent years nucleoside analogues have occupied a significant position in the search
for effective antiviral agents, owing to the fact that a large number of unnatural nucleoside
derivatives have been shown to inhibit infections caused by viruses.[1] The deazapyrimi-
dine nucleosides constitute a class of analogues with potential biological activity.[2] As a
part of our program directed toward the development of new, simple, and efficient pro-
cedures for the synthesis of antimetabolites,[3–5] we have recently shown that pyridi-
nethione glycosides exerted inhibitory effects on both DNA- and RNA-containing
viruses.[6] On the basis of these findings, it was of interest to prepare modified analogues
to search for more effective agents. This part describes the synthesis of nonclassical bihe-
terocyclic glycosides. The latter compounds will be considered as precursors of modified
nucleosides.
RESULTS AND DISCUSSIONS
Thus, it has been found that pyridinylcyanothioacetamides 3 reacted with cyclo-
alkanones in boiling ethanol containing catalytic amounts of ammonium acetate to
give the corresponding mercaptobipyridinyl derivatives 5 (Sch 1). Compounds 5 could
also be prepared by the reaction of cyanothiocaetamide with 2-pyridinylmethylene-1-
cycloalkanones. The structures of the series of compounds 5 were established on the
basis of their elemental analysis and spectroscopic data. Thus, structure 5a is supported
by its mass spectrum, which showed a molecular formula C9H7N3S (Mþ ¼ 189).
1H NMR spectroscopy was used to confirm this structure for the product.
The set of compounds 5 reacted with 2,3,4,6-tetra-O-acetyl-a-D-gluco- and -galacto-
pyranosyl bromides in the presence of aqueous potassium hydroxide to give the corre-
sponding S-glucoside 11a–h or S-galactoside 11i–p, respectively (Sch 2). It was
suggested that the cis(a) sugar reacts by a simple SN2 reaction to give the b-glycoside
product. Although the coupling of 5 with the glycosyl bromides could also give the
corresponding N-glycosides, the formation of 11 was proved chemically. Reaction of 5
with hexamethyldisilazane (HMDS) in the presence of ammonium sulfate gave the corre-
sponding 2-trimethylsilylthiopyridine 6, which was subsequently treated with peracety-
lated sugars in the presence of redistilled SnCl4 to afford the corresponding S-glycosyl
compounds 11. A suggested mechanism for the formation of the S-glycosides 11 by
condensation of silylated base 6 with peracylated sugar in the presence Lewis acid catalyst

New Class of Biazine Thioglycosides
467
Scheme 1.

468
Elgemeie, Hussein, and Al-Khursani
Scheme 2.

New Class of Biazine Thioglycosides
469
Scheme 3.
is illustrated in Scheme 3. The structure of the reaction products 11a–p were established
1
and confirmed by their elemental analyses and spectral data (MS, IR, UV, H NMR, 13
C
NMR). Thus, the analytical data for 11d revealed a molecular formula C29H31N3O9S (Mþ
597). The 1H NMR spectrum showed the anomeric proton as a doublet at d 6.15 ppm, with
a spin-spin coupling constant of 10.50 Hz corresponding to a diaxial orientation of H-10
and H-20 protons, indicating the b-configuration. Spectroscopic methods did not identify

470
Elgemeie, Hussein, and Al-Khursani
Figure 1. The molecule of 11e in the crystal.
the product unambiguously as an N- or a S-nucleoside and therefore an X-ray structure
determination was carried out. The X-ray analysis of 11e (Fig. 1,2)[7] confirms the exclu-
sive presence of the nucleoside in the S-form 11 and not the corresponding N-nucleoside
10 in the solid state; all H atoms could be located unamiguously, and bond lengths are also
consistent with form 11.
After deprotection of compounds 11a–p with a saturated solution of ammonia in
methanol, the final nucleosides 12a–p were obtained in almost quantitative yields, the
structures of which have been established on the basis of elemental analyses and spectral
data (Fig. 2). Thus, the analytical data for 12l reveal the molecular formula C21H23N3O5S
1
(Mþ 429). The H NMR spectrum shows the anomeric proton as a doublet at d 5.68
0
0
(J1 ,2 ¼ 9.84 Hz), indicating the presence of only the b-D-configuration.
The series of 4-quinolinyl-3-cyano-2-mercaptopyridine 15 was prepared by the reac-
tion of 4-quinolylmethylidene(cyano)thioacetamide 13 with cycloalkanones 4 in boiling
ethanol containing catalytic amounts of ammonium acetate (Scheme 4). The structures
of compounds 15 were established on the basis of their elemental analysis and spectral
1
data (MS, IR, H NMR). The formation of 15 from 13 and 4 is assumed to proceed via
addition of the active methylene group of 4 to the double bond of 13 to give intermediate
Michael adducts, which then cyclize via water elimination and oxidation under the reaction
conditions to yield 15.
Compounds 15 reacted with 2,3,4,6-tetra-O-acetyl-a-D-gluco- and -galactopyranosyl
bromides in the presence of aqueous potassium hydroxide through a Walden inversion to
afford the corresponding S-glucosides 17a–d and S-galactosides 17e–h. The structures
of the reaction products 17a–h were established and confirmed on the basis of
1
their elemental analyses and spectral data (MS, IR, UV, H NMR, 13C NMR). When
compounds 17a–h were treated with methanolic ammonia at 08C, the free glycoside

New Class of Biazine Thioglycosides
471
Figure 2. Packing diagram viewed (H atoms have been omitted for clarity).
derivatives 19a–h were obtained, the structures of which were established on the basis of
elemental analysis and spectral data. Thus, the IR spectrum of 19c showed a characteristic
1
band at 3500–3350 cm21 owing to the hydroxy groups of the glucose moiety. The H
0
0
NMR spectrum showed the anomeric proton as a doublet at d 5.58 (J1 ,2 ¼ 9.52 Hz),
indicating the presence of only the b-configuration ((Sch 4).
In a simple experimental procedure the 4-indolyl-3-cyano-pyridine- 2(1H)thiones
14 were coupled with 2,3,4,6-tetra-O-acetyl-a-D-gluco- and -galactopyranosyl bromides
in the presence of aqueous potassium hydroxide to give the corresponding S-glucosides
18a–d and S-galactosides 18e–h, respectively. The latter compounds were deacylated
by methanolic ammonia to yield the corresponding desired free glycosides 20a–h. The
structure of the products were confirmed and established on the basis of their elemental
1
analysis and spectral data (MS, IR, UV, H NMR and 13C NMR) Table 1.
In summary, we have achieved the synthesis of interesting nonclassical bipyridyl and
biazine thioglycosides by the reaction of substituted pyridinethiones with a-halosugars.

472
Elgemeie, Hussein, and Al-Khursani
Scheme 4.

New Class of Biazine Thioglycosides
473
Table 1. Characterization data for compounds 5a–h, 11a–p, 12a–p, 15a–d, 16a–d, 17a–h,
18a–h, 19a–h, and 20a–h.
Analysis: calcd/found %
Compd
no.
Yield %
color
Cryst.
form.
Mþ
m/z
M.p. 8C
M. F
C
H
N
S
5a
5b
300
78
Red
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DMF
DMF
DMF
EtOH
EtOH
EtOH
DMF
EtOH
DMF
EtOH
EtOH
EtOH
EtOH
C14H11N3S
66.2
66.4
66.4
66.4
67.3
67.4
67.1
67.4
68.5
68.3
68.0
68.3
69.2
69.1
69.1
69.1
57.4
57.6
57.4
57.6
58.5
58.3
58.3
58.3
59.1
58.9
58.7
58.9
59.5
59.5
59.6
59.5
57.6
57.6
57.7
57.6
58.3
58.3
58.1
58.3
58.9
58.9
4.1
4.4
4.1
4.4
4.8
4.9
4.5
4.9
5.4
5.4
5.3
5.4
5.5
5.8
5.6
5.8
4.9
5.0
4.8
5.0
5.1
5.2
5.3
5.2
5.5
5.4
5.2
5.4
5.7
5.6
5.4
5.6
4.9
5.0
5.2
5.0
5.1
5.2
5.1
5.2
5.4
5.4
16.7 12.5
16.6 12.7
16.7 12.5
16.6 12.7
15.8 12.0
15.7 11.9
15.5 11.8
15.7 11.9
14.9 11.4
14.9 11.4
14.6 11.1
14.9 11.4
14.0 10.8
14.2 10.9
14.0 11.1
14.2 10.9
253
253
267
267
281
281
295
295
583
583
597
579
611
611
625
625
583
583
597
597
611
260
325
259
263
257
290
251
120
175
202
85
77
Red
C14H11N3S
C15H13N3
5c
95
Yellow
93
5d
C15H13N3S
Yellow
93
5e
C16H15N3S
Yellow
92
5f
C16H15N3S
Yellow
93
5g
C17H17N3S
Yellow
91
5h
C17H17N3S
Yellow
85
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
C28H29N3SO9
C28H29N3SO9
C29H31N3O9S
C29H31N3SO9
C30H33N3O9S
C30H33N3SO9
C31H35N3SO9
C31H35N3SO9
C28H29N3SO9
C28H29N3SO9
C29H31N3SO9
C29H31N3O9S
C30H33N3SO9
7.1
7.2
7.0
7.2
7.1
7.0
7.3
7.0
7.0
6.9
6.8
6.9
6.8
6.7
6.5
6.7
7.2
7.2
7.1
7.2
7.0
7.0
6.8
7.0
6.8
6.9
5.5
5.5
5.3
5.5
5.3
5.4
5.6
5.4
5.0
5.2
5.2
5.2
5.1
5.1
5.2
5.1
5.4
5.5
5.6
5.5
5.3
5.4
5.2
5.4
5.2
5.2
Brown
82
Red
89
Yellow
85
Brown
83
183
95
Yellow
92
Yellow
81
190
101
200
175
230
180
169
Yellow
94
Yellow
86
Brown
77
Brown
95
Yellow
93
Yellow
87
Yellow
(continued)

474
Elgemeie, Hussein, and Al-Khursani
Table 1. Continued.
Analysis: calcd/found %
Compd
no.
Yield %
color
Cryst.
form.
Mþ
m/z
M.p. 8C
M. F
C
H
N
S
11n
11o
11p
12a
12b
12c
12d
12e
12f
185
78
Yellow
88
EtOH
C30H33N3SO9
58.7
58.9
59.5
5.6
5.2
5.4
5.5
5.6
5.4
5.6
5.0
5.1
5.3
5.4
5.3
5.4
5.5
5.4
5.6
5.6
5.5
5.6
5.7
5.9
5.7
5.9
5.0
5.1
5.0
5.1
5.3
5.4
5.2
5.4
5.6
5.6
5.7
5.6
5.9
5.9
5.7
5.9
4.1
4.3
4.9
4.7
6.8
6.9
6.5
6.7
6.6
6.7
10.0
10.1
9.7
9.8
9.7
9.8
9.9
9.8
9.4
9.5
9.4
9.5
9.2
9.2
9.2
9.2
10.2
10.1
10.0
10.1
9.7
9.8
9.6
9.8
9.4
9.5
9.4
9.5
9.1
9.2
9.0
9.2
5.0
5.2
5.0
5.1
4.9
5.1
7.5
7.7
7.4
7.5
7.4
7.5
7.4
7.5
7.1
7.2
7.1
7.2
6.9
7.0
6.9
7.0
7.7
7.7
7.5
7.7
7.4
7.5
4.7
7.5
7.2
7.2
7.3
7.2
7.1
7.0
6.9
7.0
611
93
248
182
78
DMF
EtOH
EtOH
EtOH
MeOH
EtOH
H2O
C31H35N3SO9
C31H35N3SO9
C20H21N3SO5
C21H23N3SO5
C21H23N3SO5
C21H23N3SO5
C22H25N3SO5
C22H25N3SO5
C23H27N3SO5
C23H27N3SO5
C20H21N3SO5
C20H21N3O5S
C21H23N3SO5
C21H23N3O5S
C22H25N3SO5
C22H25N3SO5
C23H27N3SO5
C23H27N3SO5
C18H13N3S
625
625
415
429
429
429
443
443
457
457
415
415
429
429
443
443
457
457
303
317
Buff
94
59.3
59.3
57.8
57.8
58.7
58.7
58.7
58.7
58.5
58.7
59.5
59.6
59.4
59.6
60.3
60.4
60.3
60.4
57.9
57.8
57.6
57.8
58.7
58.7
58.6
58.7
59.5
59.6
59.8
59.6
60.5
60.4
60.5
60.4
71.1
71.3
71.7
71.9
Yellow
79
Red
89
Brown
89
230
155
191
150
188
135
210
182
189
160
185
195
145
140
250
130
Yellow
83
Yellow
92
Yellow
85
EtOH
EtOH
EtOH
EtOH
EtOH
DMF
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Yellow
93
12g
12h
12i
Yellow
84
Yellow
89
Brown
86
12j
Yellow
91
12k
12l
Yellow
90
Yellow
88
12m
12n
12o
12p
15a
15b
Yellow
78
Yellow
85
Brown
84
Yellow
80
13.8 10.4
13.9 10.6
Yellow
95
Yellow
C19H15N3S
13.0 9.9
13.2 10.1
(continued)

New Class of Biazine Thioglycosides
Table 1. Continued.
475
Analysis: calcd/found %
Compd
no.
Yield %
color
Cryst.
form.
Mþ
m/z
M.p. 8C
M. F
C
H
N
S
15c
15d
16a
16b
16c
16d
17a
17b
17c
17d
17e
17f
160
82
Yellow
93
EtOH
C20H17N3S
72.5
72.5
73.1
73.0
69.9
70.1
70.7
70.8
71.4
71.5
71.8
72.1
60.6
60.7
61.2
61.2
61.9
61.7
62.1
62.2
60.5
60.7
61.0
61.2
61.5
61.7
62.1
62.2
59.8
59.9
60.3
60.5
60.8
61.0
61.3
61.5
59.9
59.9
60.3
60.5
61.2
61.0
5.3
5.1
5.3
5.5
4.6
4.5
4.7
4.9
5.3
5.3
5.6
5.7
4.8
4.9
5.0
5.1
5.2
5.3
5.3
5.5
4.7
4.9
5.0
5.1
5.1
5.3
5.3
5.5
4.9
5.0
5.0
5.0
5.3
5.4
5.4
5.6
4.9
5.0
5.1
5.2
5.3
5.4
12.5
12.7
12.1
12.2
9.9
9.7
9.5
9.3
331
345
291
305
319
333
633
647
661
675
633
647
661
675
621
635
649
663
621
635
649
205
100
144
196
160
117
98
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
.EtOH
.EtOH
.EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
C21H19N3S
C17H13N3S
Yellow
79
Red
14.6 11.1
14.4 10.9
13.9 10.7
13.8 10.5
13.0 10.1
13.2 10.0
85
Red
C18H15N3S
81
Yellow
80
C19H17N3S
C20H19N3S
12.6
12.6
6.4
6.6
6.4
6.5
6.2
6.4
6.3
6.2
6.6
6.6
6.5
6.5
6.4
6.4
6.0
6.2
6.9
6.8
6.4
6.6
6.4
6.5
6.2
6.3
6.7
6.8
6.4
6.6
6.7
6.5
9.7
9.6
5.0
5.1
4.9
4.9
4.8
4.8
4.5
4.7
5.1
5.1
4.7
4.9
4.9
4.8
4.7
4.7
5.1
5.2
5.2
5.0
4.8
4.9
4.9
4.8
5.0
5.2
4.8
5.0
5.1
4.9
Yellow
98
Red
C32H31N3SO9
C33H33N3SO9
C34H35N3SO9
C35H37N3SO9
C32H31N3SO9
C33H33N3SO9
C34H35N3SO9
C35H37N3SO9
C31H31N3SO9
C32H33N3SO9
C33H35N3SO9
C34H37N3SO9
C31H31N3SO9
C32H33N3SO9
C33H35N3SO9
89
Yellow
92
110
113
154
123
111
242
160
110
132
196
180
124
156
White
85
Yellow
80
Red
70
Orange
88
17g
17h
18a
18b
18c
18d
18e
18f
Yellow
82
Yellow
89
Red
84
Yellow
90
Yellow
77
Yellow
83
Red
85
Orange
91
Yellow
18g
(continued)

476
Elgemeie, Hussein, and Al-Khursani
Table 1. Continued.
Analysis: calcd/found %
Compd
no.
Yield %
color
Cryst.
form.
Mþ
m/z
M.p. 8C
M. F
C
H
N
S
18h
19a
19b
19c
19d
19e
19f
150
91
Yellow
80
EtOH
C34H37N3SO9
61.3
61.5
61.7
61.9
62.4
62.6
63.0
63.3
63.9
63.9
61.8
61.9
62.5
62.6
63.5
63.3
63.9
63.9
60.7
60.9
61.5
61.7
62.3
62.4
62.8
63.0
61.0
60.9
61.6
61.7
62.2
62.4
62.9
63.0
5.5
5.6
4.7
4.9
5.3
5.2
5.4
5.5
5.5
5.7
4.8
4.9
5.1
5.2
5.4
5.5
5.7
5.7
5.0
5.1
5.2
5.4
5.4
5.6
5.7
5.9
5.0
5.1
5.3
5.4
5.4
5.6
5.7
5.9
6.5
6.3
9.1
9.0
8.7
8.8
8.5
8.5
8.2
8.3
9.0
9.0
8.9
8.8
8.4
8.5
8.2
8.3
9.3
9.3
8.9
9.0
8.8
8.7
8.3
8.5
9.2
9.3
9.1
9.0
8.8
8.7
8.3
8.5
4.9
4.8
6.8
6.9
6.6
6.7
6.3
6.5
6.1
6.3
6.7
6.9
6.5
6.7
6.3
6.5
6.1
6.3
6.9
7.1
7.0
6.9
6.5
6.7
6.7
6.5
7.0
7.1
7.0
6.9
6.6
6.7
6.7
6.5
663
170
155
152
179
143
117
160
154
140
150
162
160
180
155
160
158
EtOH
EtOH
EtOH
DMF
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
C24H23N3SO5
C25H25N3O5S
C26H27O5S
465
479
493
507
465
479
493
507
453
467
481
495
453
467
481
495
Yellow
80
Yellow
78
Yellow
81
C27H29N3SO5
C24H23N3SO5
C25H25N3O5S
C26H27N3SO5
C27H29N3SO5
C23H23N3SO5
C24H25N3SO5
C25H27N3SO5
C26H29N3SO5
C23H23N3SO5
C24H25N3SO5
C25H27N3SO5
C26H29N3SO5
Yellow
70
Yellow
70
Yellow
84
19g
19h
20a
20b
20c
20d
20e
20f
Yellow
75
Yellow
90
Red
86
Yellow
79
Yellow
86
Yellow
78
Red
85
Orange
87
20g
20h
Yellow
90
Yellow
These nucleosides can be utilized as an excellent starting material for the synthesis of other
carbohydrate derivatives and for further biological evaluation studies.
ANTIVIRAL ACTIVITY
The anti-HIV activity and cytotoxicity of the condensed pyridine-2-(1H)-thione
nucleoside derivative are shown in Table 2. Among the acetylated derivatives, compound

New Class of Biazine Thioglycosides
477
Table 2. Comparative potency and selectivity of 3-cyano-2-(2,3,4,6-tetra-O-acetyl-b-D-gluco- and
-galactopyranosylthio)pyridines 11k, 18e, and 19c as inhibitors of HIV replicain MT-4 cells.
a
b
EC50
mM
IC50
mM
TIc
(ratio IC50/EC50)
Compd
11k
18e
19c
1.86
0.19
2.43
11.96
3.91
9.13
6.43
20.58
3.75
aApproximate values for 50% effective concentration of MT-4 cells against the cytopathic effect of
HIV (EC50).
bInhibitory concentration for 50% (IC50).
cTherapeutic index (IC50/EC50).
11k turned out to be the most selective anti-HIV agent, followed by 18e. The other com-
pounds were virtually devoid of any anti-HIV activity. Among the free glycoside deri-
vatives, the free nucleoside 19c proved clearly more active and selective than the
corresponding protected derivative. None of the other free sugars showed any selectivity
and/or antiviral activity. Because compounds 11, 12, and 17–20 belong to a new class of
active nucleosides and also were active against HIV, further investigations are needed to
determine the mechanism of their action against herpes virus.
BIOLOGICAL PROCEDURE
The series of compounds 11, 12, and 17–20 was dissolved in dimethyl sulfoxide and
then diluted 1 : 100 in cell culture medium preparing serial half-Log10 dilutions. T4
Lymphocytes were added, and after a brief interval HIV-1 was added, resulting in 1 : 20
final dilution of the compound. Uninfected cells with the compound served as a toxicity
control, and infected and uninfected cells without the compound served as basic controls.
Cultures were incubated at 378C in a % carbon dioxide atmosphere for 6 days. The tetra-
zolium salt, XTT, was added to all wells, and cultures were incubated to allow formazan
color development by viable cells. Individual wells were analyzed spectrophotometrically
to quantitate formazan production, and in addition were viewed microscopically for
detection of viable cells and confirmation of protective activity. Drug-treated virus-
infected cells were compared with drug-treated noninfected cells and with other appropri-
ate controls on the same plate. Data were reviewed in comparison with other tests done at
the same time and a determination about activity was made.
EXPERIMENTAL
All evaporations were carried out under reduced pressure at 408C. IR spectra were
1
obtained (KBr disc) with a Pye Unicam Spectra-1000. H NMR and 13C NMR spectra
were measured with a Wilmad 270-MHz or a Varian 400-MHz spectrometer for solution
in (CD3)2SO by using SiMe4 as the internal standard. Mass spectra were recorded with a
Varian MAT 112 spectrometer. Analytical data were obtained from the microanalytical
data center at Cairo University.

478
Elgemeie, Hussein, and Al-Khursani
Cycloalkane ring fused 4-pyridinyl-, 4-quinolinyl-, and 4-indolinyl-3-cyano-
pyridine-2(1H)-thiones 5a–h, 15a–d, and 16a-d. To a mixture of 4 and 3 or 13 or 14
(0.01 mol) in ethanol (50 mL), ammonium acetate (3.8 g) was added. The mixture was
heated under reflux for 3 hr, and then set aside overnight. The resultant precipitate was
filtered off and washed with distilled water several times to dissolve the excess of
ammonium acetate. The precipitate was crystallized from the appropriate solvent.
15a. IR (KBr) 3400 (NH), 2220 (CN) cm21; 1.10 (m, 2H, CH2), 2.20–2.30 (m, 2H,
CH2), 2.60–2.85 (m, 2H, CH2), 7.00–8.60 (m, 6H, quinoline-H), 14.00 (s, br, 1H, NH).
15b. IR (KBr) 3330 (NH), 2220 (CN) cm21; 1.10 (m, 2H, CH2), 1.50–1.80 (m, 2H,
CH2). 1.70–1.85 (m, 2H, CH2), 2.30–2.60 (m, 2H, CH2), 7.00–8.20 (m, 6H, quinoline-
H), 13.90 (s, br, 1H, NH).
1
15c. IR (KBr) 3450, 3400 (NH), 2220 (CN) cm21; H NMR dH 1.20–1.59 (m, 2H,
CH2), 1.60–1.78 (m, 4H, 2CH2), 2.40–2.52 (m, 2H, CH2), 3.00–3.10 (m, 2H, CH2),
7.0–8.22 (m, 6H, quinoline-H), 14.0 (s, br, 1H, NH).
1
15d. IR (KBr) 3460, 3370, 3300 (NH), 2220 (CN) cm21; H NMR dH 1.10–1.18
(m, 2H, CH2), 1.26–1.80 (m, 2H, CH2), 1.90–1.95 (m, 2H, CH2), 2.44 (m, 2H, CH2),
2.55 (m, 2H, CH2), 2.80–2.99 (m, 2H, CH2), 7.0–7.6 (m, 6H, quinoline-H), 13.90
(s, br, 1H, NH).
1
16a. IR (KBr) 3450, 3400 (NH), 2220 (CN) cm21; H NMR dH 1.19 (m, 2H, CH2)
2.21–2.32 (m, 2H, CH2), 2.67–2.80 (m, 2H, CH2), 7.02–8.68 (m, 5H, indole-H), 12.27
(s, br, 1H, NH), 14.08 (s, br, 1H, NH).
16b. IR (KBr) 3370 (NH), 2218 (CN) cm21; 1H NMR dH 1.21 (m, 2H, CH2), 1.62–
1.93 (m, 2H, CH2), 1.86–1.96 (m, 2H, CH2), 2.45–2.62 (m, 2H, CH2), 7.02–8.37 (m, 5H,
indole-H), 11.78 (s, br, 1H, NH), 13.77 (s, br, 1H, NH); 13C NMR dC 20.59 (CH2), 21.50
(CH2), 25.45 (CH2), 27.25 (CH2), 109.08 (CN), 112.27 (C-3), 114.47–136.10 (indole-C),
151.4 (C-5), 152.48 (C-4), 169.00 (C-6), 175.40 (C-2).
16c. IR (KBr) 3520, 3400 (NH), 2210 (CN) cm21; 1H NMR dH 1.29–1.50 (m, 2H, CH2),
1.58–1.72 (m, 4H, 2CH2), 2.47–2.49 (m, 2H, CH2), 3.02–3.04 (m, 2H, CH2), 7.06–8.28
(m, 5H, indole-H), 11.60 (s, br, 1H, NH), 13.9 (s, br, 1H, NH); 13C NMR dC 24.96 (CH2),
26.57 (CH2), 28.43 (CH2), 31.03 (CH2), 32.52 (CH2), 109.74 (CN), 112.21 (C-3), 117.52–
135.96 (indole-C), 151.78 (C-5), 157.91 (C-4), 168.70 (C-6), 174.79 (C-2).
1
16d. IR (KBr) 3370, 3320, 3300 (NH), 2222 (CN) cm21; H NMR dH 1.06–1.16
(m, 2H, CH2), 1.37–1.52 (m, 2H, CH2), 1.67–1.91 (m, 2H, CH2), 2.50 (m, 2H, CH2),
2.50 (m, 2H, CH2), 2.87–2.96 (m, 2H, CH2), 7.03–8.02 (m, 5H, indole-H), 11.64
(s, br, 1H, NH), 13.92 (s, br, 1H, NH); 13C NMR dC 25.27 (CH2), 25.4 (CH2), 25.96
(CH2), 29.50 (CH2), 29.92 (CH2), 30.05 (CH2), 109.57 (CN), 112.17 (C-3), 116.19–
135.91 (indole-C), 152.43 (C-5), 155.48 (C-4), 167.90 (C-6), 175.61 (C-2).
2-(20, 30, 40, 60-Tetra-O-acetyl-b-D-gluco- and galactopyranosylthio)-4-pyridinyl-,
4-quinolinyl-, and 4-indolinyl-cycloalkeno[b]pyridine-3-carbonitriles 11a–p, 17a–h,
and 18a–h. General Coupling Procedures. Method A. To a solution of condensed
pyridine-2(1H)-thiones 5, 15, or 16 (0.01 mol) in aqueous potassium hydroxide [0.56 g,
0.01 mol, in distilled water (6 cm3)] was added a solution of 2,3,4,6-tetra-O-acetyl-a-D-
gluco- or -galactopyranosyl bromide (4.521 g, 0.011 mol) in acetone (30 cm3). The reac-
tion mixture was stirred at room temperature for ca. (30 min to 2 hr). The mixture was
evaporated under reduced pressure at 408C and the residue was washed with distilled
water to remove the potassium bromide formed. The product was dried and crystallized
from the appropriate solvent.

New Class of Biazine Thioglycosides
479
Method B. Condensed pyridine-2(1H)-thiones 5 (0.01 mol) was boiled under reflux,
with stirring, under anhydrous conditions for 48 hr with hexamethyldisilazane (25 mL)
and ammonium sulphate (0.02 g). The excess of hexamethyldisilazane was removed
under diminished pressure, providing the silylated bases 7 as a colorless oil. To a
solution of silylated base in dry acetonitrile (30 mL) was added a solution of
1,2,3,4,6-penta-O-acetyl-a-D-gluco- or galactopyranose (0.011 mol) in dry acetonitrile
(20 mL), followed by SnCl4 (1.6 mL). The reaction mixture was stirred at room temp-
erature for ca. (3 to 6 hr), then poured into saturated NaHCO3 solution and extracted
with CHCl3. The organic layers were dried over MgSO4, filtered, and concentrated to
give the crude glycosides, which were purified by recrystallization from the appropriate
solvent.
11a. IR (KBr) 2222 (CN) cm21; 1H NMR dH 1.66 (m, 2H, CH2), 1.80 (m, 2H, CH2),
1.89–2.09 (4s, 12H, 4 ꢀ AcO), 2.60 (m, 2H, CH2), 4.05 (m, 2H, 60-H2), 4.30 (t, 1H, 50-H),
5.18 (t, 1H, 40-H), 5.28 (t, 1H, 30-H), 5.45 (t-1H, 20-H), 6.00 (d, 1H, J1 ,2 ¼ 10.50, 10-H),
7.34–8.60 (m, 4H, pyridine-H), 13C NMR dC 20.0–20.20 (4 ꢀ CH3), 21.30–33.20
(3 ꢀ CH2), 61.20 (C-60), 66.20 (C-40), 67.50 (C-20), 71.5 (C-30), 74.20 (C-50), 80.91
(C-10), 107.20 (CN), 115.10 (C-3), 122.50–148.10 (pyridine-C), 151.10 (C-5), 156.10
(C-4), 158.66 (C-6), 162.50 (C-2), 170.00–170.70 (4 CO).
0
0
11c. IR (KBr) 2222 (CN) cm21; 1H NMR dH 1.70 (m, 2H, CH2), 1.85 (m, 2H, CH2),
1.90–2.12 (4s, 12H, 4 ꢀ AcO), 2.70 (m, 2H, CH2), 2.90 (m, 2H, CH2), 4.09 (m, 2H, 60-
H2), 4.32 (t, 1H, 50-H), 5.20 (t, 1H, 40-H), 5.30 (t, 1H, 30-H), 5.48 (t-1H, 20-H), 6.09
(d, 1H, J1 ,2 ¼ 10.58, 10-H), 7.41–8.68 (m, 4H, pyridine-H), 13C NMR dC 20.1–20.25
(4 ꢀ CH3), 21.32–33.22 (4 ꢀ CH2), 61.22 (C-60), 66.22 (C-40), 67.52 (C-20), 71.2 (C-
30), 74.22 (C-50), 80.91 (C-10), 107.22 (CN), 115.15 (C-3), 122.56–148.11 (pyridine-C),
151.17 (C-5), 156.17 (C-4), 162.70 (C-6), 164.22 (C-2), 170.02–171.10 (4 CO).
0
0
1
11e. IR (KBr) 2218 (CN) cm21; H NMR dH 1.18–1.52 (m, 2H, CH2), 1.58–1.60
(m, 4H, 2CH2), 1.92–2.08 (4s, 12H, 4 ꢀ AcO), 2.61–2.80 (m, 2H, CH2), 3.02–3.12
(m, 2H, CH2), 4.08 (m, 2H, 60-H2), 4.20 (m, 1H, 50-H), 5.18 (t, 1H, 40-H), 5.20 (t,
1H, 30-H), 5.60 (t, 1H, 20-H), 6.12 (d, 1H, J1 ,2 ¼ 10.20, 10-H), 7.08–8.77 (m, 4H,
00 00
pyridine-H); 13C NMR dC 20.12–20.32 (4 ꢀ Me), 21.22–36.22 (5 ꢀ CH2), 62.22
(C-60), 68.12 (C-40), 69.12 (C-20), 72.33 (C-30), 76.08 (C-50), 80.12 (C-10), 107.18 (CN),
118.15 (C-3), 123.11–142.80 (pyridine-C), 150.20 (C-5), 151.23 (C-4), 155.22 (C-6),
167.54 (C-2), 170.09–171.20 (4 CO).
11l. IR (KBr) 2225 (CN) cm21; 1H NMR dH 1.41–1.60 (m, 2H, CH2), 1.61–1.72 (m, 2H,
CH2), 1.78–1.85 (m, 2H, CH2), 1.95–2.05 (4s, 12H, 4 ꢀ AcO), 2.58–2.66 (m, 2H, CH2), 4.03
(m, 2H, 60-H2), 4.35 (m, 1H, 50-H), 5.25 (t, 1H, 40-H), 5.32 (t, 1H, 30-H), 5.55 (t, 1H, 20-H), 6.15
(d, 1H, J1 ,2 ¼ 10.50, 10-H), 7.18–8.80 (m, 4H, pyridine-H). 13C NMR dC 20.1–20.4
00 00
(4 ꢀ Me), 21.20–33.00 (4 ꢀ CH2), 61.20 (C-60), 66.09 (C-40), 67.6 (C-20), 70.05 (C-30),
74.22 (C-50), 80.62 (C-10), 105.22 (CN), 116.51 (C-3), 122.23–149.28 (pyridine-C), 150.13
(C-5), 154.32 (C-4), 165.44 (C-6), 169.21 (C-2), 172.53–172.89 (4 CO).
17b. IR (KBr) 2222 (CN) cm21; 1H NMR dH 1.97 (m, 2H, CH2), 1.98 (m, 2H, CH2),
1.00–2.03 (m, 12H, 4 ꢀ AcO), 2.49–2.50 (m, 2H, CH2), 3.07 (m, 2H, CH2), 4.18 (m, 3H,
60-H2, 50-H), 5.03 (m, 1H, 40-H), 5.14 (m, 1H, 30-H), 5.55 (t, 1H, 20-H), 6.13 (m, 1H, 10-H),
6.39–9.07 (m, 6H, quinoline-H); 13C NMR dC 20.33–33.09 (4 ꢀ CH2 and 4 ꢀ CH3),
61.84 (C-60), 68.14 (C-40), 68.90 (C-20), 73.21 (C-30), 75.02 (C-50), 80.33 (C-10), 105.03
(CN), 116.23 (C-3), 121.56–149.23 (quinoline-C), 150.56 (C-5), 154.17 (C-4), 162.78
(C-6), 163.99 (C-2), 170.13 (4 CO).

480
Elgemeie, Hussein, and Al-Khursani
17c. 2212 (CN) cm21; 1H NMR dH 1.77–1.95 (m, 2H, CH2), 1.97 (m, 2H, CH2), 1.98
(m, 2H, CH2), 2.00–2.02 (4s, 12H, 4 ꢀ AcO), 2.22 (m, 2H, CH2), 3.01 (m, 2H, CH2),
4.09–4.10 (m, 3H, 60-H2, 50-H), 5.05 (t, 1H, 40-H), 5.09 (m, 1H, 30-H), 5.58 (t, 1H, 20-
H), 6.10 (m, 1H, 10-H), 7.39–9.08 (m, 6H, quinoline-H); 13C NMR dC 20.33–31.19
(4 ꢀ CH2), 61.84 (C-60), 68.93 (C-40), 69.23 (C-20), 72.91 (C-30), 75.62 (C-50), 80.12
(C-10), 107.23 (CN), 117.21 (C-3), 121.2–148.50 (quinoline-C), 150.55 (C-5), 153.20
(C-4), 162.11 (C-6), 162.97 (C-2), 171.05 (4 CO).
17d. IR (KBr) 2215 (CN) cm21; 1H NMR dH 1.05–1.48 (m, 6H, 3 CH2), 1.85–2.06
(4s, 12H, 4 ꢀ AcO), 2.02–2.22 (m, 2H, CH2), 2.62 (m, 2H, CH2), 3.12 (m, 2H, CH2),
4.02–4.17 (m, 3H, 60-H2, 50-H), 5.12 (m. 1H, 30-H), 5.62 (t, 1H, 20-H), 6.13 (m, 1H, 10-
H), 7.20–9.12 (m, 6H, quinoline-H); 13C NMR dC 20.12–33.20 (6 ꢀ CH2 and
4 ꢀ CH3), 63.25 (C-60), 68.21 (C-40), 68.56 (C-20), 75.91 (C-30), 72.22 (C-50), 80.9
(C-10), 106.25 (CN), 115.78 (C-3), 123.99–148.43 (quinoline-C), 149.78 (C-5), 150.02
(C-4), 154.11 (C-6), 166.20 (C-2), 170.00–171.23 (4 CO).
2-(b-D-Gluco- and galactopyranosylthio)-4-pyridinyl-, 4-quinolinyl- and 4-indo-
linyl-cycloalkeno[b]pyridine-3-carbonitriles 12a–p, 19a–h, and 20a–h. General
Procedures. Dry gaseous ammonia was passed through a solution of protected glyco-
sides 11, 17, or 18 (0.5 g) in dry methanol (20 cm3) at 08C for ca. 0.5 hr; then the
mixture was stirred at 08C (for ca.) (2 to 6 hr). The mixture was evaporated under
reduced pressure at 408C to give a solid residue, which was crystallized from the
appropriate solvent.
1
12c. IR (KBr) 2225 (CN) cm21; H NMR dH 1.40–1.55 (m, 2H, CH2), 1.60–1.70
(m, 2H, CH2), 1.90–2.22 (m, 2H, CH2), 2.88–2.92 (m, 2H, CH2), 3.22–3.70 (6H, m,
60-H2, 50-H, 40-H, 30-H and 20-H), 4.50 (s, 2H, 20-OH and 30-OH), 5.16 (s, 1H, 40-OH),
5.38 (s, 1H, 60-OH), 5.59 (m, 1H, 10-H), 7.15–8.45 (m, 4H, pyridine-H).
1
12g. IR (KBr) 2220 (CN) cm21; H NMR dH 1.00–1.33 (m, 2H, CH2), 1.50–1.77
(m, 6H, 3CH2), 2.20–2.39 (m, 2H, CH2), 3.00–3.16 (m, 2H, CH2), 3.34–3.60 (6H, m,
60-H2, 50-H, 40-H, 30-H, and 20-H), 4.40 (s, 2H, 20-OH, and 30-OH), 5.00 (s, 1H, 40-OH),
5.20 (s, 1H, 60-OH), 5.50–5.60 (m, 1H, 10-H), 7.11–8.23 (m, 4H, pyridine-H).
1
19b. IR (KBr) 2225 (CN) cm21; H NMR dH 1.42–1.58 (m, 2H, CH2), 1.65–1.72
(m, 2H, CH2), 1.93–2.20 (m, 2H, CH2), 2.90–2.96 (m, 2H, CH2), 3.30–3.68 (6H, m,
60-H2, 50-H, 40-H, 30-H, and 20-H), 4.53 (s, 2H, 20-OH, and 30-OH), 5.10 (s, 1H, 40-OH),
5.30 (s, 1H, 60-OH), 5.52 (m, 1H, 10-H), 7.18–9.02 (m, 6H, quinoline-H); 13C NMR dC
21.53–33.17 (4 ꢀ CH2), 60.79 (C-60), 60.90 (C-400), 69.75 (C-20), 71.79 (C-30), 78.67
(C-50), 81.74 (C-10), 83.62 (C-30), 107.22 (CN), 117.09 (C-3), 121.08–148.15 (quino-
line-C), 149.99 (C-5), 150.9 (C-4), 158.20 (C-6), 162.35 (C-2).
1
19c. IR (KBr) 2220 (CN) cm21; H NMR dH 1.08–1.40 (m, 2H, CH2), 1.58–1.80
(m, 6H, 3CH2), 2.22–2.40 (m, 2H, CH2), 3.02–3.10 (m, 2H, CH2), 3.24–3.69 (6H, m,
60-H2, 50-H, 40-H, 30-H, and 20-H), 4.42 (s, 2H, 20-OH, and 30-OH), 5.02 (s, 1H, 40-OH),
5.22 (s, 1H, 60-OH), 5.58–5.62 (m, 1H, 10-H), 7.28–9.05 (m, 6H, quinoline-H), 13C
NMR dC 25.41–31.17 (6 ꢀ CH2), 60.72 (C-60), 60.87 (C-40), 69.73 (C-20), 71.78 (C-30),
78.65 (C-50), 81.72 (C-10), 83.58 (C-10), 105.10 (CN), 116.22 (C-3), 121.01–148.18
(quinoline-C), 149.55 (C-5), 150.10 (C-4), 157.11 (C-6), 168.99 (C-2).
1
20a. IR (KBr) 2225 (CN) cm21; H NMR dH 1.40–1.50 (m, 2H, CH2), 1.65–1.72
(m, 2H, CH2), 1.93–2.20 (m, 2H, CH2), 3.30–3.60 (6H, m, 60-H2, 50-H, 40-H, 30-H, and
20-H), 4.50 (s, 2H, 20-OH, and 30-OH), 5.17 (s, 1H, 40-OH), 5.37 (s, 1H, 60-OH), 5.59
(m, 1H, 10-H), 7.10–8.75 (m, 5H, indole-H).

New Class of Biazine Thioglycosides
481
1
20b. IR (KBr) 2220 (CN) cm21; H NMR dH 1.37–1.45 (m, 2H, CH2), 1.55–1.67
(m, 2H, CH2), 1.88–2.09 (m, 2H, CH2), 2.85–2.99 (m, 2H, CH2), 3.41–3.70 (6H, m,
60-H2, 50-H, 40-H, 30-H, and 20-H), 4.77 (s, 2H, 20-OH, and 30-OH), 5.13 (s, 1H, 40-OH),
5.47 (s, 1H, 60-OH), 5.79 (m, 1H, 10-H), 7.10–8.99 (m, 5H, indole-H).
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