Synthesis and antiviral evaluation of sugar uracil-1-ylmethylhydrazones and their oxadiazoline derivatives

Article abstract of DOI:10.1055/s-2007-983878

1-Carbethoxymethyluracils have been synthesized and derivatized to the corresponding hydrazides, which were reacted with monosaccharides to afford the corresponding sugar hydrazones. Acetylation of the latter with acetic anhydride in pyridine, afforded the per-O-acetyl derivatives, while heating in acetic anhydride gave the corresponding oxadiazolines. The prepared compounds were tested for antiviral activity against hepatitis B virus and showed moderate activities. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983878

PAPER
2823
Synthesis and Antiviral Evaluation of Sugar Uracil-1-ylmethylhydrazones and
Their Oxadiazoline Derivatives
S
O
ynthesis and Anti
m
viral Evaluation of
a
Sugar
U
rac
r
il-1-ylmethylh
My drazone Derivatives . Ali,* Hamada H. Amer, Adel A.-H. Abdel-Rahman*
Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt
Fax +20(48)2235689; E-mail: adelnassar63@hotmail.com; E-mail: omasaf@hotmail.com
Received 12 March 2007; revised 18 June 2007
responding hydrazides 3a and 3b, respectively, in 90–
3% yields. Reaction of the latter hydrazides with
equimolar amounts of a range of monosaccharides was
Abstract: 1-Carbethoxymethyluracils have been synthesized and
derivatized to the corresponding hydrazides, which were reacted
with monosaccharides to afford the corresponding sugar hydra-
9
zones. Acetylation of the latter with acetic anhydride in pyridine, af- performed by heating an aqueous ethanolic solution in the
forded the per-O-acetyl derivatives, while heating in acetic presence of a catalytic amount of acetic acid. Hydrazones
anhydride gave the corresponding oxadiazolines. The prepared
compounds were tested for antiviral activity against hepatitis B vi-
rus and showed moderate activities.
4
and 5 were prepared from the monosaccharides L-arabi-
1
nose, D-xylose, D-glucose and D-mannose. The H NMR
spectra of the hydrazones 4 and 5 confirmed the presence
of sugar protons, which gave signals in the range d =
3
7
Key words: antiviral agents, carbohydrates, hydrazones, nucleo-
bases, nucleosides
.25–4.10 ppm and anomeric protons in the region d =
.44–7.55 ppm (Table 1). Assignment of the sugar pro-
tons was based on the chemical shift equivalencies to the
1
,3,4-Oxadiazoles and 1,3,4-oxadiazolines have been the assigned structure of other related sugar hydrazones.9
,10
subject of chemical and biological studies on account of
their interesting pharmacological properties; they possess
antimicrobial, anti-inflammatory, analgesic and anti-tu-
O
N
O
N
HN
R
HN
R
1
mor activities. In addition, several 1,3,4-oxadiazole and
O
ii
O
O
O
1
,3,4-oxadiazoline derivatives have been reported to pos-
OEt
NHNH2
2
3
a R = H
b R = Me
sess diverse biological activities as well as antiviral activ-
2 a R = H
b R = Me
ity against HIV3 and tyrosinase inhibiting effects.4
iii
i
Although there are numerous antibiotics that are commer-
cially used in medicine, the synthesis of new compounds
is of vital importance due to increasing drug resistance.
Moreover, it is important to obtain therapeutical com-
pounds with less toxic effects. A number of syntheses for
substituted derivatives of these heterocyclic systems have
been developed, in particular, C-nucleosides bearing five-
O
O
N
HN
R
HN
O
NH
O
O
R1
N
N
H
1 a R = H
b R = Me
R
4 R = H
R = Me
5
v
O
iv
O
N
Ac
N
5
HN
HN
N
membered nitrogen heterocycles such as tiazofurin,
O
O
N
R2
O
6
7
N
selenazofurin and showdomycin have been shown to
possess a wide range of medicinal properties, including
antibiotic, antiviral and anti-tumor activity. Recently, the
synthesis of acyclonucleosides has attracted much atten-
R2
N
H
O
R
R
8 R = H
9 R = Me
6
7
R = H
R = Me
8
1
O
O
tion. As a consequence of the above significance and pos-
R CHO =
O
O
OH
sible enhancement of biological activity resulting from
the attachment of carbohydrate moieties to 1,3,4-oxadiaz-
oline heterocycles, together with our interest in the syn-
OH HO
HO
HO
HO
HO
OH HO
OH
OH
OH
OH
OH
9
thesis of heterocyclic derivatives of carbohydrates, our
OH
OH
OH
attention was drawn to the synthesis of oxadiazoline de-
rivatives using monosaccharide 1-acetylhydrazinouracils.
OH
R2
=
Uracil derivatives 1a and 1b were allowed to react with
ethyl chloroacetate in acetone and anhydrous potassium
carbonate, to afford 1-carbethoxymethyluracils 2a and
OAc AcO
AcO
AcO
AcO
OAc AcO
OAc AcO
OAc
OAc
OAc
2
b, respectively. Hydrazinolysis of the ethyl ester group
OAc
OAc
OAc
OAc
OAc
was carried out in ethanol under reflux, to afford the cor-
OAc
Scheme 1 Reagents and conditions: i) ClCH CO Et, K CO , ace-
2
2
2
3
SYNTHESIS 2007, No. 18, pp 2823–2828
x
x.
x
x
.
2
0
0
7
tone, reflux, 3 h, 85–89%; ii) N H ·H O, EtOH, reflux, 4 h, 90–93%;
2
4
2
Advanced online publication: 29.08.2007
DOI: 10.1055/s-2007-983878; Art ID: T05007SS
Georg Thieme Verlag Stuttgart · New York
1
iii) R CHO, EtOH, AcOH, reflux, 5 h, 88–95%; iv) Ac O, Py, r.t.,
2
overnight, 95–99%; v) Ac O, reflux, 1 h, 68–71%.
2
©

2
824
O. M. Ali et al.
PAPER
Table 1 Mass, H and 13C NMR Spectra of Newly Synthesized Compounds
1
+
1
13C NMR (DMSO-d6)
Compd m/z [M ] H NMR (DMSO-d )
6
2
2
3
a
b
a
198
212
184
1.20 (t, J = 8.1 Hz, 3 H, CH CH ), 4.19 (q, J = 8.1 Hz, 2 H, CH CH ), 14.0 (CH CH O), 46.1 (CH ), 61.4 (CH CH O),
3
2
3
2
3
2
2
3
2
4
1
.61 (s, 2 H, CH ), 6.50 (d, J = 5.5 Hz, 1 H, H-5), 8.28 (d, J = 5.5 Hz, 101.1 (C-5), 142.5 (C-6), 150.9 (C-2), 163.9 (C-4),
2
H, H-6), 10.81 (br s, 1 H, NH).
166.9 (C=O).
1.19 (t, J = 8.1 Hz, 3 H, CH CH ), 2.11 (s, 3 H, CH ), 4.17 (q, J = 8.1 11.9 (CH ), 14.1 (CH CH O), 46.3 (CH ), 61.6
3
2
3
3
3
2
2
Hz, 2 H, CH CH ), 4.61 (s, 2 H, CH ), 8.10 (s, 1 H, H-6), 11.09 (br s, (CH CH O), 111.1 (C-5), 137.5 (C-6), 151.4 (C-2),
3
2
2
3
2
1
H, NH).
164.4 (C-4), 166.7 (C=O).
4.20 (br s, 2 H, NH ), 4.63 (s, 2 H, CH ), 6.80 (d, J = 5.5 Hz, 1 H, H- 51.3 (CH ), 101.7 (C-5), 143.7 (C-6), 151.7 (C-2),
2
2
2
5
), 8.05 (d, J = 5.5 Hz, 1 H, H-6), 9.55 (br s, 1 H, NH), 11.22 (br s, 1 H, 164.2 (C-4), 168.4 (C=O).
NH).
3
4
b
a
198
317
2.01 (s, 3 H, CH ), 4.22 (br s, 2 H, NH ), 4.63 (s, 2 H, CH ), 8.19 (s, 12.1 (CH ), 51.9 (CH ), 110.8 (C-5), 137.9 (C-6),
3
2
2
3
2
1
H, H-6), 9.60 (br s, 1 H, NH), 10.81 (br s, 1 H, NH).
150.6 (C-2), 163.9 (C-4), 168.7 (C=O).
3.35–3.58 (m, 4 H, H-3¢, H-4¢, H-5¢), 3.65 (m, 1 H, H-2¢), 4.39 (br s, 53.4 (CH ), 63.0 (C-5¢), 69.2 (C-4¢), 75.7 (C-2¢),
2
1
5
1
H, OH), 4.60 (br s, 1 H, OH), 4.63 (s, 2 H, CH ), 4.78 (br s, 1 H, OH), 76.6 (C-3¢), 102.6 (C-5), 141.7 (C-6), 149.4 (C-1¢),
.11 (br s, 1 H, OH), 6.78 (d, J = 5.5 Hz, 1 H, H-5), 7.55 (d, J = 2.5 Hz, 150.2 (C-2), 163.8 (C-4), 167.5 (C=O).
H, H-1¢), 8.40 (d, J = 5.5 Hz, 1 H, H-6), 11.20 (br s, 1 H, NH), 12.18
2
(
br s, 1 H, NH).
4
4
b
c
317
346
3.25–3.57 (m, 5 H, H-2¢, H-3¢, H-4¢, H-5¢), 4.30 (br s, 1 H, OH), 4.50 53.2 (CH ), 62.9 (C-5¢), 69.3 (C-4¢), 75.4 (C-2¢),
2
(
br s, 2 H, 2 × OH), 4.63 (s, 2 H, CH ), 5.20 (br s, 1 H, OH), 6.78 (d, 76.9 (C-3¢), 101.9 (C-5), 141.1 (C-6), 148.1 (C-1¢),
2
J = 5.5 Hz, 1 H, H-5), 7.50 (d, J = 2.5 Hz, 1 H, H-1¢), 8.28 (d, J = 5.5 149.4 (C-2), 163.2 (C-4), 166.2 (C=O).
Hz, 1 H, H-6), 11.20 (br s, 1 H, NH), 12.00 (br s, 1 H, NH).
3.28–3.92 (m, 5 H, H-3¢, H-4¢, H-5¢, H-6¢), 4.10 (m, 1 H, H-2¢), 4.40 53.3 (CH ), 62.9 (C-6¢), 69.0 (C-4¢), 70.0 (C-5¢),
2
(
br s, 1 H, OH), 4.60 (br s, 2 H, 2 × OH), 4.63 (s, 2 H, CH ), 5.02 (br 73.0 (C-2¢), 73.4 (C-3¢), 101.6 (C-5), 141.0 (C-6),
2
s, 1 H, OH), 5.40 (br s, 1 H, OH), 6.90 (d, J = 5.5 Hz, 1 H, H-5), 7.48 149.9 (C-1¢), 150.3 (C-2), 163.0 (C-4), 169.9
d, J = 2.5 Hz, 1 H, H-1¢), 8.30 (d, J = 5.5 Hz, 1 H, H-6), 11.00 (br s, (C=O).
H, NH), 11.60 (br s, 1 H, NH).
(
1
4
5
5
5
d
a
b
c
346
330
330
360
3.27–4.05 (m, 6 H, H-2¢, H-3¢, H-4¢, H-5¢, H-6¢), 4.63 (s, 2 H, CH2),
53.5 (CH ), 62.4 (C-6¢), 68.3 (C-4¢), 69.7 (C-5¢),
2
4
1
.78 (br s, 1 H, OH), 6.60 (d, J = 5.5 Hz, 1 H, H-5), 7.46 (d, J = 2.5 Hz, 71.6 (C-2¢), 72.5 (C-3¢), 101.7 (C-5), 140.4 (C-6),
H, H-1¢), 8.20 (d, J = 5.5 Hz, 1 H, H-6), 10.40 (br s, 1 H, NH), 11.08 147.3 (C-1¢), 150.1 (C-2), 163.3 (C-4), 170.0
(C=O).
(
br s, 1 H, NH).
2.08 (s, 3 H, CH ), 3.38–3.55 (m, 4 H, H-3¢, H-4¢, H-5¢), 3.67 (m, 1 H, 12.6 (CH ), 52.7 (CH ), 62.4 (C-5¢), 67.2 (C-4¢),
3
3
2
H-2¢), 4.40 (br s, 1 H, OH), 4.61 (br s, 1 H, OH), 4.63 (s, 2 H, CH2), 70.5 (C-2¢), 71.9 (C-3¢), 111.2 (C-5), 138.0 (C-6),
4
1
.75 (br s, 1 H, OH), 5.16 (br s, 1 H, OH), 7.50 (d, J = 2.5 Hz, 1 H, H- 146.2 (C-1¢), 150.0 (C-2), 164.0 (C-4), 166.7
¢), 8.21 (s, 1 H, H-6), 11.19 (br s, 1 H, NH), 12.18 (br s, 1 H, NH). (C=O).
2.02 (s, 3 H, CH ), 3.30–3.60 (m, 5 H, H-2¢, H-3¢, H-4¢, H-5¢), 4.30 (br 11.9 (CH ), 52.9 (CH ), 62.3 (C-5¢), 68.6 (C-4¢),
3
3
2
s, 1 H, OH), 4.58 (br s, 2 H, 2 × OH), 4.63 (s, 2 H, CH ), 5.20 (br s,
73.0 (C-2¢), 74.3 (C-3¢), 111.0 (C-5), 137.7 (C-6),
2
1
H, OH), 7.45 (d, J = 2.5 Hz, 1 H, H-1¢), 8.18 (s, 1 H, H-6), 11.20 (br 147.3 (C-1¢), 150.1 (C-2), 163.0 (C-4), 167.7
s, 1 H, NH), 12.09 (br s, 1 H, NH).
(C=O).
2.06 (s, 3 H, CH ), 3.25–3.45 (m, 5 H, H-3¢, H-4¢, H-5¢, H-6¢), 3.70 (m, 12.2 (CH ), 53.5 (CH ), 62.5 (C-6¢), 68.1 (C-4¢),
3
3
2
1
1
1
H, H-2¢), 4.00 (br s, 1 H, OH), 4.18 (br s, 2 H, 2 × OH), 4.60 (br s, 72.0 (C-5¢), 72.9 (C-2¢), 73.7 (C-3¢), 111.2 (C-5),
H, OH), 4.63 (s, 2 H, CH ), 4.92 (br s, 1 H, OH), 7.48 (d, J = 2.5 Hz, 137.7 (C-6), 148.3 (C-1¢), 150.4 (C-2), 162.5 (C-
2
H, H-1¢), 8.20 (s, 1 H, H-6), 10.50 (br s, 1 H, NH), 11.18 (br s, 1 H, 4), 167.4 (C=O).
NH).
5
6
d
a
360
2.02 (s, 3 H, CH ), 3.25–3.45 (m, 5 H, H-3¢, H-4¢, H-5¢, H-6¢), 3.70 (m, 12.1 (CH ), 53.5 (CH ), 62.4 (C-6¢), 68.3 (C-4¢),
3
3
2
1
1
1
H, H-2¢), 3.80 (br s, 3 H, 3 × OH), 3.90 (br s, 1 H, OH), 4.45 (br s, 69.7 (C-5¢), 71.6 (C-2¢), 72.5 (C-3¢), 101.7 (C-5),
H, OH), 4.63 (s, 2 H, CH ), 7.44 (d, J = 2.5 Hz, 1 H, H-1¢), 8.22 (s, 140.4 (C-6), 147.3 (C-1¢), 150.1 (C-2), 163.3 (C-
2
H, H-6), 10.11 (br s, 1 H, NH), 10.80 (br s, 1 H, NH).
4), 170.0 (C=O).
485a
1.95, 2.04, 2.10, 2.13, (4 × s, 12 H, 4 × CH CO), 4.17 (m, 2 H, H-5¢), 20.4, 20.6, 21.0, 21.3 (4 × CH CO), 53.0 (CH ),
3
3
2
4
1
1
1
.25 (m, 1 H, H-4¢), 4.50 (s, 2 H, CH ), 5.60 (m, 1 H, H-3¢), 5.75 (m, 58.0 (C-5¢), 67.2 (C-4¢), 71.7 (C-2¢), 73.3 (C-3¢),
2
H, H-2¢), 6.61 (d, J = 5.5 Hz, 1 H, H-5), 7.26 (d, J = 2.5 Hz, 1 H, H- 103.2 (C-5), 140.4 (C-1¢), 146.7 (C-6), 149.6 (C-
¢), 8.25 (d, J = 5.5 Hz, 1 H, H-6), 10.10 (br s, 1 H, NH), 11.04 (br s, 2), 164.3 (C-4), 167.4, 167.9, 168.6, 169.5, 169.9
H, NH).
(5 × C=O).
6
b
485a
1.96, 2.04, 2.09, 2.12, (4 × s, 12 H, 4 × CH CO), 4.15 (m, 2 H, H-5¢), 20.7, 20.9, 21.1, 21.3 (4 × CH CO), 52.7 (CH ),
3
3
2
4
1
1
1
.23 (m, 1 H, H-4¢), 4.48 (s, 2 H, CH ), 5.61 (m, 1 H, H-3¢), 5.70 (m, 58.2 (C-5¢), 66.3 (C-4¢), 71.6 (C-2¢), 73.6 (C-3¢),
2
H, H-2¢), 6.62 (d, J = 5.5 Hz, 1 H, H-5), 7.27 (d, J = 2.5 Hz, 1 H, H- 102.3 (C-5), 140.8 (C-1¢), 141.4 (C-6), 149.3 (C-
¢), 8.22 (d, J = 5.5 Hz, 1 H, H-6), 10.08 (br s, 1 H, NH), 11.05 (br s, 2), 162.6 (C-4), 166.5, 166.9, 168.0, 169.2, 169.7
H, NH).
(5 × C=O).
Synthesis 2007, No. 18, 2823–2828 © Thieme Stuttgart · New York

PAPER
Synthesis and Antiviral Evaluation of Sugar Uracil-1-ylmethylhydrazone Derivatives
2825
Table 1 Mass, H and 13C NMR Spectra of Newly Synthesized Compounds (continued)
1
+
1
13C NMR (DMSO-d6)
Compd m/z [M ] H NMR (DMSO-d )
6
6
c
557a
1.95, 2.04, 2.10, 2.13, 2.15 (5 × s, 15 H, 5× CH CO), 4.00–4.11 (m,
20.5, 20.6, 20.8, 20.9, 21.3 (5 × CH CO), 53.5
3
3
2
5
5
H, H-6¢), 4.50 (m, 1 H, H-5¢), 4.60 (s, 2 H, CH ), 4.70 (m, 1 H, H-4¢), (CH ), 61.9 (C-6¢), 65.5 (C-5¢), 67.5 (C-4¢), 72.0
2
2
.15 (m, 1 H, H-3¢), 5.45 (m, 1 H, H-2¢), 6.61 (d, J = 5.5 Hz, 1 H, H- (C-2¢), 73.1 (C-3¢), 102.9 (C-5), 140.7 (C-6), 141.5
), 7.27 (d, J = 2.5 Hz, 1 H, H-1¢), 8.23 (d, J = 5.5 Hz, 1 H, H-6), 10.06 (C-1¢), 150.0 (C-2), 162.7 (C-4), 167.4, 168.0,
(
br s, 1 H, NH), 11.03 (br s, 1 H, NH).
168.2, 168.5, 169.5, 169.9 (6 × C=O).
6
7
7
7
7
8
d
a
b
c
557a
499a
499a
571a
571a
599a
1.95, 2.04, 2.10, 2.13, 2.15 (5 × s, 15 H, 5 × CH CO), 4.06 (m, 2 H, H- 20.2, 20.4, 20.6, 21.0, 21.2 (5 × CH CO), 52.1
3
3
6
¢), 4.40 (m, 1 H, H-5¢), 4.60 (s, 2 H, CH ), 4.68 (m, 1 H, H-4¢), 5.15 (CH ), 62.0 (C-6¢), 65.5 (C-5¢), 67.2 (C-4¢), 71.4
2 2
(
(
1
m, 1 H, H-3¢), 5.50 (m, 1 H, H-2¢), 6.62 (d, J = 5.5 Hz, 1 H, H-5), 7.28 (C-2¢), 72.9 (C-3¢), 101.9 (C-5), 140.0 (C-6), 141.4
d, J = 2.5 Hz, 1 H, H-1¢), 8.20 (d, J = 5.5 Hz, 1 H, H-6), 10.10 (br s, (C-1¢), 150.4 (C-2), 163.0 (C-4), 167.9, 168.0,
H, NH), 11.08 (br s, 1 H, NH).
168.5, 169.0, 169.6, 170.0 (6 × C=O).
1.95, 2.04, 2.08, 2.10, 2.13 (5 × s, 15 H, 4 × CH CO, CH ), 4.17 (m, 12.2 (CH ), 20.2, 20.4, 21.1, 21.3 (4 × CH CO),
3
3
3
3
2
5
1
H, H-5¢), 4.26 (m, 1 H, H-4¢), 4.49 (s, 2 H, CH ), 5.64 (m, 1 H, H-3¢), 53.9 (CH ), 57.9 (C-5¢), 67.3 (C-4¢), 71.5 (C-2¢),
2 2
.71 (m, 1 H, H-2¢), 7.27 (d, J = 2.5 Hz, 1 H, H-1¢), 8.21 (s, 1 H, H-6), 73.6 (C-3¢), 111.8 (C-5), 138.3 (C-6), 141.3 (C-1¢),
0.05 (br s, 1 H, NH), 11.05 (br s, 1 H, NH). 148.9 (C-2), 164.2 (C-4), 167.3, 167.7, 168.1,
68.5, 169.5 (5 × C=O).
1
1.95, 2.04, 2.08, 2.10, 2.13 (5 × s, 15 H, 4 × CH CO, CH ), 4.20 (m, 12.1 (CH ), 20.2, 20.5, 21.0, 21.4 (4 × CH CO),
3
3
3
3
2
5
1
H, H-5¢), 4.29 (m, 1 H, H-4¢), 4.51 (s, 2 H, CH ), 5.67 (m, 1 H, H-3¢), 53.4 (CH ), 58.0 (C-5¢), 67.6 (C-4¢), 71.8 (C-2¢),
2
2
.76 (m, 1 H, H-2¢), 7.29 (d, J = 2.5 Hz, 1 H, H-1¢), 8.18 (s, 1 H, H-6), 73.7 (C-3¢), 111.9 (C-5), 137.9 (C-6), 141.5 (C-1¢),
0.06 (br s, 1 H, NH), 11.01 (br s, 1 H, NH). 150.0 (C-2), 163.9 (C-4), 167.7, 167.9, 168.1,
68.9, 170.1 (5 × C=O).
1
1.95, 2.04, 2.08, 2.10, 2.13, 2.15 (6 × s, 18 H, 5 × CH CO, CH ), 4.03– 12.1 (CH ), 20.4, 20.6, 21.0, 21.1, 21.3 (5 ×
3
3
3
4
1
.12 (m, 2 H, H-6¢), 4.48 (m, 1 H, H-5¢), 4.68 (s, 2 H, CH ), 4.72 (m, CH CO), 53.2 (CH ), 61.7 (C-6¢), 65.6 (C-5¢), 67.4
2
3
2
H, H-4¢), 5.21 (m, 1 H, H-3¢), 5.50 (m, 1 H, H-2¢), 7.31 (d, J = 2.5
(C-4¢), 71.9 (C-2¢), 72.9 (C-3¢), 111.3 (C-5), 137.9
Hz, 1 H, H-1¢), 8.21 (s, 1 H, H-6), 10.09 (br s, 1 H, NH), 11.03 (br s, (C-6), 141.8 (C-1¢), 150.0 (C-2), 162.8 (C-4),
1
H, NH).
167.2, 168.0, 168.3, 168.9, 169.3, 170.1 (6 × C=O).
d
c
1.95, 2.04, 2.08, 2.10, 2.13, 2.15 (6 × s, 18 H, 5 × CH CO, CH ), 4.09 12.2 (CH ), 20.4, 20.6, 21.0, 21.2, 21.3 (5 ×
3
3
3
(
m, 2 H, H-6¢), 4.46 (m, 1 H, H-5¢), 4.69 (s, 2 H, CH ), 4.70 (m, 1 H, CH CO), 53.6 (CH ), 62.0 (C-6¢), 66.3 (C-5¢), 67.6
2 3 2
H-4¢), 5.18 (m, 1 H, H-3¢), 5.51 (m, 1 H, H-2¢), 7.30 (d, J = 2.5 Hz,
1
NH).
(C-4¢), 71.9 (C-2¢), 72.9 (C-3¢), 101.9 (C-5), 140.0
H, H-1¢), 8.22 (s, 1 H, H-6), 10.10 (br s, 1 H, NH), 11.00 (br s, 1 H, (C-6), 141.9 (C-1¢), 150.0 (C-2), 163.1 (C-4),
167.6, 167.9, 168.1, 168.8, 169.4, 170.1 (6 × C=O).
1.80, 1.99, 2.02, 2.06, 2.15, 2.35 (6 × s, 18 H, 6 × CH CO), 3.87 (dd, 20.4, 20.6, 20.8, 21.0, 21.1, 21.9 (6 × CH CO),
3
3
J = 2.5, 8.5 Hz, 1 H, H-5¢), 4.20 (dd, J = 2.5, 6.5 Hz, 1 H, H-5¢¢), 4.39 46.5 (CH ), 62.1 (C-5¢), 64.1 (C-3¢), 65.6 (C-4¢),
2
(
dd, J = 2.5, 6.5 Hz, 2 H, H-4¢), 4.50 (s, 2 H, CH ), 5.19 (m, 1 H, H-3¢), 66.1 (C-2¢), 67.9 (C-1¢), 87.0 (C-2¢¢, oxadiazoline),
2
5
5
5
.40 (dd, J = 3.5, 5.8 Hz, 1 H, H-2¢), 5.58 (t, J = 5.8 Hz, 1 H, H-1¢),
.81 (d, J = 5.8 Hz, 1 H, oxadiazoline-H), 6.67 (d, J = 5.5 Hz, 1 H, H- oxadiazoline), 165.4 (C-4), 168.4, 168.9, 169.1,
), 8.25 (d, J = 5.5 Hz, 1 H, H-6), 11.00 (br s, 1 H, NH). 169.4, 169.9, 171.2 (6 × CH CO).
101.6 (C-5), 143.1 (C-6), 149.6 (C-2), 159.7 (C-5¢¢,
3
8
9
d
599a
1.90, 2.01, 2.07, 2.10, 2.15, 2.46 (6 × s, 18 H, 6 × CH CO), 4.09 (m, 20.2, 20.6, 20.9, 21.1, 21.5, 21.9 (6 × CH CO),
3
3
1
4
H, H-5¢), 4.30 (dd, J = 2.4, 6.5 Hz, 1 H, H-5¢¢), 4.53 (s, 2 H, CH ), 46.7 (CH ), 62.4 (C-5¢), 64.7 (C-3¢), 65.9 (C-4¢),
2
2
.77 (m, 1 H, H-4¢), 5.19 (m, 1 H, H-3¢), 5.39 (m, 1 H, H-2¢), 5.50 (dd, 66.2 (C-2¢), 68.1 (C-1¢), 87.4 (C-2¢¢, oxadiazoline),
J = 2.5, 5.8 Hz, 1 H, H-1¢), 5.80 (d, J = 5.8 Hz, 1 H, oxadiazoline-H), 102.3 (C-5), 143.0 (C-6), 149.1 (C-2), 160.2 (C-5¢¢,
.65 (d, J = 5.5 Hz, 1 H, H-5), 8.25 (d, J = 5.5 Hz, 1 H, H-6), 11.02 (br oxadiazoline), 163.2 (C-4), 168.3, 168.5, 169.3,
s, 1 H, NH). 169.5, 169.9, 171.1 (6 × CH CO).
6
3
c
613a
613a
1.84, 1.99, 2.08, 2.13, 2.15, 2.38, 2.43 (7 × s, 21 H, 6 × CH CO, CH ), 12.2 (CH ), 20.1, 20.5, 20.7, 21.1, 21.4, 21.8 (6 ×
3
3
3
3
5
1
1
6
.95(dd, J = 2.5, 8.5 Hz, 1 H, H-5¢), 4.10 (dd, J = 2.5, 6.5 Hz, 1 H, H- CH CO), 47.3 (CH ), 62.2 (C-5¢), 64.3 (C-3¢), 65.9
3 2
¢¢), 4.40 (dd, J = 2.8, 6.5 Hz, 2 H, H-4¢), 4.51 (s, 2 H, CH ), 5.22 (m, (C-4¢), 66.3 (C-2¢), 68.4 (C-1¢), 86.7 (C-2¢¢, oxadi-
2
H, H-3¢), 5.43 (dd, J = 3.5, 5.8, Hz, 1 H, H-2¢), 5.60 (t, J = 5.8 Hz, azoline), 111.2 (C-5), 138.5 (C-6), 150.2 (C-2),
H, H-1¢), 5.85 (d, J = 5.8 Hz, 1 H, oxadiazoline-H), 8.26 (s, 1 H, H- 159.9 (C-5¢¢, oxadiazoline), 164.3 (C-4), 168.2,
), 11.02 (br s, 1 H, NH).
168.6, 169.3, 169.5, 169.9, 171.3 (6 × CH CO).
3
9
d
1.93, 2.07, 2.11, 2.14, 2.17, 2.46, 2.50 (7 × s, 21 H, 6 × CH CO, CH ), 12.3 (CH ), 20.1, 20.4, 20.8, 21.3, 21.5, 21.8 (6 ×
3
3
3
4
.17 (m, 1 H, H-5¢), 4.38 (dd, J = 2.5, 6.5 Hz, 1 H, H-5¢¢), 4.51 (s, 2 H, CH CO), 47.5 (CH ), 62.3 (C-5¢), 64.5 (C-3¢), 66.1
2
.54 (dd, J = 2.5, 5.8 Hz, 1 H, H-1¢), 5.81 (d, J = 5.8 Hz, 1 H, oxadia- azoline), 111.3 (C-5), 138.7 (C-6), 150.0 (C-2),
3
2
CH ), 4.75 (m, 1 H, H-4¢), 5.23 (m, 1 H, H-3¢), 5.44 (m, 1 H, H-2¢),
5
zoline-H), 8.23 (s, 1 H, H-6), 11.06 (br s, 1 H, NH).
(C-4¢), 66.9 (C-2¢), 68.7 (C-1¢), 86.9 (C-2¢¢, oxadi-
160.0 (C-5¢¢, oxadiazoline), 164.0 (C-4), 168.2,
68.5, 169.4, 169.7, 169.9, 171.4 (6 × CH CO).
1
3
a
+
MS-FAB [M + 1].
Synthesis 2007, No. 18, 2823–2828 © Thieme Stuttgart · New York

2
826
O. M. Ali et al.
PAPER
Table 2 Structural Data of Compounds 4–9
toxicity. The drug Lamivudine, which is a potent selective
inhibitor of HBV replication, was used as a standard for
the comparative studies.
1
3
1
R2
Compd R
R CHO
L-arabinose
D-xylose
D-glucose
D-mannose
L-arabinose
D-xylose
D-glucose
D-mannose
–
4
4
4
4
5
5
5
5
6
6
6
a
b
c
H
–
In conclusion, a number of sugar uracil-1-ylmethylhydra-
zones, O-acetylated derivatives of sugar uracil-1-ylmeth-
H
–
ylhydrazones
and
4-acetyl-5-(O-acetylalditolyl)-2-
H
–
(
uracil-1-ylmethyl)-1,3,4-oxadiazolines were prepared.
Some of these were tested for antiviral activity against
Hepatitis-B virus (HBV, Hep G2 2.2.15 cell method).
Structure activity correlation of the obtained results re-
vealed that O-acetylated derivatives 6a, 6d and 7a–d, fol-
lowed by compounds 8c, 8d, 9c and 9d, in which the
d
a
b
c
H
–
Me
Me
Me
Me
H
–
–
–
1
,3,4-oxadiazoline ring is attached to the O-acetylated
sugar moiety, showed higher activity against HBV than
did the deprotected sugar hydrazones.
d
a
b
c
–
tetra-O-acetyl-L-arabinotetritolyl
tetra-O-acetyl-D-xylotetritolyl
penta-O-acetyl-D-glucopentitolyl
H
–
Melting points were determined using a Kofler block instrument
1
and are uncorrected. H NMR spectra were recorded with a Bruker
H
–
AC 250 FT NMR spectrometer at 250 MHz. Chemical shifts are re-
ported in ppm (d) relative to TMS as an internal standard. EIMS and
FABMS spectra were recorded with a Finnigen MAT 312/AMD.
Elemental analyses were performed at the microanalytical unit,
Cairo University, Egypt. TLC analyses were conducted on silica gel
Merck 60F254 coated on aluminum sheets. The detection was
achieved by treatment with a solution of 15% H SO in MeOH and
6
7
7
7
7
8
8
9
9
d
a
b
c
H
–
–
–
–
–
–
–
–
–
penta-O-acetyl-D-mannopentitolyl
tetra-O-acetyl-L-arabinotetritolyl
tetra-O-acetyl-D-xylotetritolyl
Me
Me
Me
Me
H
2
4
heating at 150 °C. All reactions requiring anhydrous conditions
were conducted in dried apparatus. All commercially available re-
agents were used without further purification. Pyridine was distilled
penta-O-acetyl-D-glucopentitolyl
penta-O-acetyl-D-mannopentitolyl
penta-O-acetyl-D-glucopentitolyl
penta-O-acetyl-D-mannopentitolyl
penta-O-acetyl-D-glucopentitolyl
penta-O-acetyl-D-mannopentitolyl
d
c
from CaH and stored over molecular sieves. Concentrations were
2
carried out on a rotary evaporator at a temperature below 40 °C. Vi-
ral screening against HBV was conducted at the National Liver In-
stitute, Menoufia University, Shebin El-Koam, Egypt.
d
c
H
Me
Me
1
-Carbethoxymethyluracils 2a,b; General Procedure
A mixture of uracil derivatives 1a,b (0.1 mole), anhydrous acetone
300 mL), anhydrous K CO (85.0 g, 0.6 mole) and ethyl chloro-
d
(
2
3
acetate (16.0 g, 0.13 mole) was heated under reflux for 3 h (moni-
For structural data of compounds 2–9, see Table 2. Acety- tored by TLC). The reaction mixture was filtered and the filtrate was
evaporated under reduced pressure. The residue was crystallized
from EtOH to afford 2a,b as colorless needles in 85–89% yields.
lation of sugar uracil-1-ylmethylhydrazones 4 and 5 gave
differing products depending on the conditions of acetyla-
1
1
tion. Thus, acetylation of compounds 4 and 5 with acetic
1
-Acetylhydrazinouracils 3a,b; General Procedure
anhydride in pyridine at room temperature, afforded the
A mixture of 2a,b (0.1 mole), hydrazine hydrate (10 mL) and
1
per-O-acetyl derivatives 6 and 7. The H NMR spectra of
MeOH (20 mL) was heated under reflux for 4 h. The product was
the latter showed the O-acetyl methyl groups at d = 1.95– filtered off and recrystallized from MeOH to give 3a,b as colorless
2
7
.15 ppm and the methine proton as a doublet at d = 7.26– needles in 90–93% yields.
.31 ppm (Table 1). When the sugar hydrazones 4 and 5
were heated in acetic anhydride, the corresponding oxadi-
azoline derivatives 8 and 9 were obtained. The spectral
Sugar Uracil-1-ylmethyl Hydrazones 4–5; General Procedure
To a well stirred solution of the respective monosaccharide (2.80
mmol) and glacial AcOH (0.6 mL) in H O (15 mL), was added the
appropriate 1-acetylhydrazinouracils 3a,b (2.80 mmol) in EtOH (80
2
data of these compounds were in agreement with the as-
1
signed structures, with the H NMR spectra showing the mL). The mixture was heated under reflux for 5 h (monitored by
acetyl methyl groups at d = 1.80–2.46 ppm. Elemental TLC) and the resulting solution was concentrated under reduced
pressure and left to cool. The formed precipitate was filtered off,
analyses of these compounds (Table 3) were in agreement
washed with H O (5 mL) and EtOH (5 mL), dried and recrystallized
with the assigned structures, confirming that, in addition
to acetylation of the sugar hydroxyl groups, N-acetylation
had also taken place (Scheme 1).
2
from EtOH to give 4 and 5 in 88–95% yields.
O-Acetylated Derivatives of Sugar Uracilylmethylhydrazones
Preliminary viral screening against HBV (Hep G2 2.2.15 6–7; General Procedure
1
2
A cold solution of sugar uraciloylhydrazones 4 and/or 5 (1 mmol)
cell method), indicated that compounds 5c, 5d, 6c, 6d,
a–d, 8c, 8d, 9c and 9d were found to be active against
HBV replication with IC = ~79–94 mM and CC = ~85–
in anhydrous pyridine (3 mL) was treated with Ac O (3 mL). The
2
7
reaction mixture was stirred overnight then poured onto crushed ice
5
0
50
(
10 g). The separated product was filtered off, washed with H O (5
2
9
5 mM, while compounds 4a–d, 5a, 5b, 6a and 6b showed
moderate viral replication inhibition and moderate cyto- 6 and 7 in 95–99% yields.
mL), dried and crystallized from EtOH–H O (20 mL, 1:1), to afford
2
Synthesis 2007, No. 18, 2823–2828 © Thieme Stuttgart · New York

PAPER
Synthesis and Antiviral Evaluation of Sugar Uracil-1-ylmethylhydrazone Derivatives
2827
Table 3 Physicochemical Data of New Compounds
Compd
Mp (°C)a
[a]D20(c 1, DMSO) Mol formula (mol wt) Yield (%)
Analysis (%, Calcd/Found)
C
H
N
2
2
3
3
4
a
b
a
b
a
111–113
135–137
202–204
193–195
145–147
–
C H N O
85
89
90
93
93
48.22/
48.20
5.09/
4.97
14.14/
14.07
8
10
2
4
4
(
198.17)
–
C H N O
50.94/
50.88
5.70/
5.61
13.20/
13.09
9
12
2
(
212.20)
C H N O
3
–
39.13/
38.97
4.38/
4.27
30.42/
30.33
6
8
4
(
184.15)
–
C H N O
42.42/
42.22
5.09/
4.98
28.27/
28.13
7
10
4
3
(
198.18)
–4.1
C H N O
41.77/
41.56
5.10/
5.04
17.72/
17.67
1
1
16
4
7
(
317.26)
4
4
4
5
5
5
5
6
6
6
6
7
7
7
7
8
8
9
9
b
c
150–152
188–190
177–179
160–161
173–175
150–152
180–181
130–132
125–126
160–162
144–146
140–142
155–157
foam
+30.1
+5.2
C H N O
92
90
88
92
93
95
90
95
96
97
95
95
96
99
96
69
68
71
68
41.77/
41.61
5.10/
5.02
17.72/
17.69
1
1
16
4
7
(
317.26)
C H N O
41.62/
41.50
5.24/
5.17
16.18/
16.07
1
2
18
4
8
(
346.29)
d
a
b
c
+22.7
–12.5
+6.4
C H N O
41.62/
41.43
5.24/
5.13
16.18/
16.02
1
2
18
4
8
(
346.29)
C H N O
43.64/
43.51
5.49/
5.37
16.96/
16.77
1
2
18
4
7
(
330.29)
C H N O
43.64/
43.57
5.49/
5.33
16.96/
16.79
1
2
18
4
7
(
330.29)
+33.2
+12.3
–11.5
+63.6
+22.1
+19.2
–34.5
+12.3
+22.9
+28.2
+5.7
C H N O
43.33/
43.21
5.59/
5.43
15.55/
15.44
1
3
20
4
8
(
360.32)
d
a
b
c
C H N O
43.33/
43.19
5.59/
5.40
15.55/
15.34
1
3
20
4
8
(
360.32)
C H N O
47.11/
47.00
4.99/
4.88
11.57/
11.52
1
9
24
4
11
11
13
13
11
11
13
13
14
14
14
14
(
484.41)
C H N O
47.11/
47.02
4.99/
4.77
11.57/
11.37
1
9
24
4
(
484.41)
C H N O
47.48/
47.42
5.07/
5.00
10.07/
10.01
2
2
28
4
(
556.47)
d
a
b
c
C H N O
47.48/
47.37
5.07/
4.98
10.07/
10.00
2
2
28
4
(
556.47)
C H N O
48.19/
48.10
5.26/
5.21
11.24/
11.13
2
0
24
4
(
498.44)
C H N O
48.19/
48.11
5.26/
5.17
11.24/
11.10
2
0
24
4
(
498.44)
C H N O
48.42/
48.33
5.30/
5.23
9.82/
9.76
2
3
30
4
(
570.50)
d
c
foam
C H N O
48.42/
48.34
5.30/
5.19
9.82/
9.66
2
3
30
4
(
570.50)
114–115
124–126
129–130
134–136
C H N O
48.16/
48.00
5.05/
4.91
9.36/
9.19
2
4
30
4
(
598.51)
d
c
+7.6
C H N O
48.16/
48.01
5.05/
4.90
9.36/
9.16
2
4
30
4
(
598.51)
+12.1
+19.3
C H N O
49.02/
48.88
5.27/
5.07
9.15/
9.02
2
5
32
4
(
612.54)
d
C H N O
49.02/
48.82
5.27/
5.20
9.15/
9.10
2
5
32
4
(
612.54)
a
Recrystallized from EtOH.
Synthesis 2007, No. 18, 2823–2828 © Thieme Stuttgart · New York

2
828
O. M. Ali et al.
PAPER
(2) (a) Mishrah, L.; Said, M. K.; Itokawa, H.; Takeya, K.
4
-Acetyl-5-(O-acetylalditolyl)-2-(uracil-1-ylmethyl)-1,3,4-oxa-
diazolines 8–9; General Procedure
A solution of sugar uraciloylhydrazones 4 and/or 5 (1 mmol) in
Bioorg. Med. Chem. 1995, 3, 1241. (b) Ateş, O.;
Kocabalkanli, A.; Cesur, N.; Otuk, G. Farmaco 1998, 53,
541. (c) Kocabalkanli, A.; Ateş, O.; Otuk, G. Farmaco 2001,
56, 975. (d) Sahin, G.; Palaska, E.; Ekizoglu, M.; Özalp, M.
Farmaco 2002, 57, 530. (e) Küçükgüzel, Ş. G.; Oruç, E. E.;
Rollas, S.; Şahin, F.; Özbek, A. Eur. J. Med. Chem. 2002, 37,
187. (f) Demirbas, N. Turk. J. Chem. 2005, 29, 125.
3) El-Emam, A. A.; Al-Deep, A. O.; Al-Omar, M.; Lehmann, J.
Bioorg. Med. Chem. 2004, 12, 5107.
Ac O (5 mL) was refluxed for 1 h. The resulting solution was
2
poured onto crushed ice (10 g) and the product that separated out
was filtered off, washed with a sat. HaHCO (3 × 10 mL) followed
3
by H O (3 × 10 mL) and then dried well. The products were recrys-
2
tallized from EtOH to afford 8 and 9 in 68–71% yields.
(
Preparation and Culture of Hep G2 2.2.15 Cells
The required cell line was made by transfection of Hep G2-cells
(4) Hassan Khan, M. T.; Choudhary, M. I.; Mohammed Khan,
K.; Rani, M.; Rahman, A. Bioorg. Med. Chem. 2005, 13,
3385.
(5) (a) Srivastava, P. C.; Pickering, M. V.; Allen, L. B.; Streeter,
D. G. J. Med. Chem. 1977, 20, 256. (b) Markar, G. M.;
Keseru, G. M. J. Med. Chem. 1997, 40, 4154.
(6) (a) Srivastava, P. C.; Robins, R. K. J. Med. Chem. 1983, 26,
445. (b) Franchetti, P.; Cappellacci, L.; AbuSheikha, G.;
Jayaram, H. N. J. Med. Chem. 1997, 40, 1731.
(7) (a) Petrie, C. R.; Revankar, G. R.; Dalley, N. K.; George, R.
D. J. Med. Chem. 1986, 29, 268. (b) Hammerschmidt, F.;
Peric, B.; Ohler, E. Monatsh. Chem. 1997, 128, 183.
(8) (a) El Ashry, E. S. H.; El Kilany, Y. Acyclonucleosides: Part
1, In Advances in Heterocyclic Chemistry, Vol. 67;
Katritzky, A. R., Ed.; Academic Press: New York, 1996,
391. (b) El Ashry, E. S. H.; El Kilany, Y. Acyclonucleosides:
Part 2, In Advances in Heterocyclic Chemistry, Vol. 68;
Katritzky, A. R., Ed.; Academic Press: New York, 1997, 1.
with a plasmid containing multiple tandem copies of the HBV ge-
1
2a
nome (subtype ayw). The 2.2.15 cell line was maintained in
RPMI-1640 (Glutamax) culture media containing 100 IU/mL nys-
tatin and 380 mg/mL G418 (geneticin). The transferred HEP G2-
2
3
.2.15 cell line was kept in tissue culture flasks with 5% CO at
7 °C. Subcultures were set up after a week by aspiration of the me-
2
dia from culture flask and washing the cells twice with PBS. A 10%
solution of versene/trypsin was added and the cells were incubated
for 1 min at 37 °C.
Cytotoxicity Assay
A colorimetric assay for living cells utilized the colorless substrate
3
-(3,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide
(
MTT) that is modified to produce the colored product by any living
cells, but not by dead cells or tissue culture medium. The cytotoxic
effect of the compounds was accessed by culturing the Hep G2-
1
2b,c
2
.2.15 cells in the presence of compounds using a MTT-assay.
(c) El Ashry, E. S. H.; El Kilany, Y. Acyclonucleosides: Part
Calculation of IC50 and CC50
The 50% inhibitory concentration of antiviral drugs (IC ) was de-
termined by interpolation from the plots of amount of DNA copies
versus antiviral drug concentration. The 50% cytotoxic effect
3, In Advances in Heterocyclic Chemistry; Katritzky, A. R.,
Ed.; Academic Press: New York, 1998, Vol. 69; 129.
(9) El-Essawy, F. A.; Khattab, A. F.; Abdel-Rahman, A. A.-H.
Monatsh. Chem., in press.
5
0
(
CC ) was calculated from the average viability of the cells with
(10) (a) Rashed, N.; Shoukry, M.; El Ashry, E. S. H. Bull. Chem.
Soc. Jpn. 1994, 67, 149. (b) El Ashry, E. S. H.; Abdul-
Ghani, M. M. Nucleosides, Nucleotides 2004, 23, 567.
50
1
2c
concentration of drugs.
(
c) Mousaad, A.; Rashed, N.; Ramadan, E.; El Ashry, E. S.
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1) (a) Henichart, J. P.; Houssin, R.; Berier, J. L. J. Heterocycl.
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