656 Arch. Pharm. Chem. Life Sci.

2006, 339, 656 663

Full Paper
Synthesis and Antiviral Evaluation of Some Sugar
Arylglycinoylhydrazones and Their Oxadiazoline Derivatives

Mohammed T. Abdel-Aal1, Wael A. El-Sayed2, El-Sayed H. El-Ashry3

1
Chemistry Department, Faculty of Science, Menofia University, Shebin El-Koom, Egypt
2
Photochemistry Department, National Research Centre, Cairo, Egypt
3
Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt

Sugar N-arylaminoacetylhydrazones 2 5 were prepared by the reaction of N-arylaminoacetylhy-

drazides 1 with equivalent amounts of the corresponding monosaccharides. Per-O-acetyl deriv-
atives 6-9 of sugar hydrazones 2 5 were prepared by using acetic anhydride in pyridine at room
temperature, while on boiling with acetic anhydride, cyclization had taken place to give the oxa-
diazolines 10 12. The prepared compounds were tested for antiviral activity against Herpes Sim-
plex virus type-1 (HSV-1) and hepatitis-A virus (HAV, MBB-cell culture adapted strain). Plaque
reduction infectivity assay was used to determine virus count reduction as a result of treatment
with tested compounds.

Keywords: Antiviral activity / 1,3,4-Oxadiazolines / Sugar N-arylaminoacetylhydrazones /

Received: June 21, 2006; accepted: September 13, 2006

DOI 10.1002/ardp.200600100

Introduction enhancement of biological activity resulting from the

The combinatorial approach in organic synthesis and the
synthesis of a library of compounds become major objec-
tives for various laboratories around the world in order
to search for biologically active compounds. 1,3,4-oxadia-
zoles and 1,3,4-oxadiazolines were found to be insectici-
dal [1], fungicidal, and bactericidal agents [2]; they have
analgesic, antipyretic, antiphlogestic, anticompulsive,
paralytic, hypnotic, and sedative properties [3 7], anti-
tumor activity [8] as well as antiviral activity against HIV
[9], and a tyrosinase inhibiting effect [10]. A number of
acyclic C-nucleosides bearing five-membered nitrogen
heterocycles such as tiazofurin [11], selenazofurin [12],
and showdomycin [13] have been shown to possess a wide
range of medicinal properties, including antibiotic, anti-
viral, and anti-tumor activity. Recently, synthesis of acy-
clonucleosides has attracted much attention [14 16].
Consequently, the above significance and possible
Correspondence: Mohammed T. Abdel-Aal, Chemistry Department, Fa-
culty of Science, Menofia University, Shebin El-Koom, Egypt.
E-mail: mtaha2000_2000@yahoo.com
Fax: +20 48 223-5689
attachment of carbohydrate moieties to 1,3,4-oxadiazo-
line heterocycles and our interest in the synthesis of het-
erocyclic derivatives of carbohydrates [17 22], attracted
our attention to synthesize oxadiazoline derivatives
using monosaccharide N-arylaminoacetylhydrazones
(Scheme 1).
Results and discussion
Chemistry
Reaction of p-substituted phenylglycinoylhydrazides
with equimolar amounts of a number of monosacchar-
ides was performed by heating in an aqueous ethanolic
solution and a catalytic amount of acetic acid. The hydra-
zones 2 5 were prepared from the monosaccharides D-
galactose, D-mannose, and D-ribose. The IR spectra of
sugar N-arylaminoacetylhydrazones 2 5 showed an
absorption band due to the hydroxyl groups in addition
to a band in the carbonyl frequency region correspond-
ing to NCO. The 1H-NMR spectra of the hydrazones 2 5
confirmed the presence of sugar protons in the range d
3.15 5.70 ppm and the aromatic protons in the region d
6.50 7.50 ppm. Moreover, their 13C-NMR spectra showed

i 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2006, 339, 656 663
Scheme 1. Synthesis route of new compounds.
signals corresponding to sugar carbons (Table 1). The
assignments of the sugar carbons were based on the che-
mical shift equivalences to the assigned structure of
other sugar hydrazones [23 25]. The C-1 of the sugar resi-
due appeared in the range d 148.30 150.41 ppm and the
carbonyl-amide group at d 169.28 173.08 ppm (Table 1).
For structural data of compounds 2 12 see Table 2.
Acetylation of sugar N-arylaminoacetylhydrazones 2
5 gave products whose structures were based on the con-
dition of acetylation [26, 27]. Thus, acetylation of com-
pounds 2 5 with acetic anhydride in pyridine at room
temperature, afforded the per-O-acetyl derivatives 6 9.
Their IR spectra revealed the absence of the hydroxyl
groups and showed two absorption bands in the carbonyl
frequency region due to carbonyl ester and the carbonyl
amide groups (Table 1). The 1H-NMR spectra of the acetyl
derivatives 6 9 showed the O-acetyl-methyl groups at d
1.80 2.18 ppm. The C-6 methylene protons appeared in
the range d 4.05 4.17 ppm, and the rest of the alkyl
chain protons appeared in the range d 4.50 5.50 ppm
due to H-3, H-4, H-5, and H-2 protons followed by the aro-
matic protons and the C-1 methine proton as douplet at d
i 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Sugar Arylglycinoylhydrazones and Oxadiazoline Derivatives 657
6.50 7.80 ppm (Table 1). When the sugar hydrazones 2
5 were heated in acetic anhydride, the corresponding
oxadiazoline derivatives 10 12 were obtained. The spec-
tral data of these compounds are in agreement with the
assigned structures (Table 1). Their IR spectra showed
two absorption bands in the carbonyl frequency region
corresponding to NCO and OCO. The 1H-NMR spectra of
compounds 10 12 showed the acetyl-methyl groups at d
1.82 2.18 ppm and their 13C-NMR signals at d 20.50
21.05 ppm and the signals at d 170.05 171.45 ppm corre-
spond to OCO groups. Elemental analyses of these com-
pounds are in agreement with assigned structures indi-
cating that in addition to acetylation of the sugar hydro-
xyl groups, N-acetylation had also taken place.
Antiviral screening
Plaque infectivity assay was carried out to test the pre-
pared compounds for antiviral activity. The test was per-
formed to include three possibilities for antiviral activity,
virucidal effect, virus adsorption, and effect on virus
replication for both HAV-27 and HSV-1.
For the antiviral activity against HAV-27 it was noticed
that, at both concentrations 10 and 20 lg/105 cells, com-
pounds 4c and 10a revealed the highest antiviral activity
in this series of compounds and compound 12 revealed
high activity at 10 dg/105 cells using amantadine (C*) as a
control. Compound 3c showed moderate activity at the
two concentrations 10 and 20 dg/105 cells. Compound
11b showed the same activity at both concentrations,
while at concentration of 20 lg/105 cells, compounds 4b
and 10c revealed little antiviral activity (Fig. 1).
Figure 1. Effect of some novel compounds on HAV (MBB cell
culture strain) in comparison with amantadine (C*) as a control.
For antiviral activity against Herpes Simplex virus-1 the
results revealed that compounds 8 and 10a showed the
highest effect on HSV-1 at concentration 10 lg/105 cells.
Compounds 10c, 2a, 3c, 4b, 4c, 12, and 7a showed moder-
ate activity while compound 11b show little activity at
concentration 20 lg/105 cells and did not show any activ-
ity at concentration 10 lg/105 cells (Fig. 2).
www.archpharm.com
658 M. T. Abdel-Aal et al. Arch. Pharm. Chem. Life Sci. 2006, 339, 656 663

Table 1. IR and 1H- and 13C-NMR spectra of newly synthesized compounds.

Compd. No IR (m, cm 1) H1- and 13C-NMR (d, ppm)

b)
2a 1605 (C=N) 3.15 3.25 (m, 2H, H-69, H-699), 3.35 (m, 2H, H-59, H-49), 3.40 (dd, 1H, J = 5.8 Hz, J = 2.2 Hz, H-39),
1674 (NCO) 3.70 (d, 2H, J = 5.4 Hz, CH2), 3.90 (dd, 1H, J = 5.6 Hz, J = 2.2 Hz, H-29), 4.95 (m, 2H, 2OH), 5.15 (d,
3250 (NH) 1H, J = 6.3 Hz, OH), 5.20 (d, 1H, J = 5.5 Hz, OH), 5.70 (d, 1H, J = 4.5 Hz, OH), 5.95 (t, 1H, J = 5.4 Hz,
3330 3410 (OH) NH), 6.60 (m, 3H, Ar-3H), 7.47 (d, 1H, J = 5.6 Hz, H-19), 7.65 (m, 2H, Ar-2H), 9.50 (s, 1H, NH)/45.49
(CH2), 62.85 (C-699), 68.97 (C-49), 70.06 (C-59), 72.09 (C-29), 72.24 (C-39), 112.27 (ArC-3,5), 116.45
(ArC-4), 128.81 (ArC-2,6), 148.24 (ArC-1), 149.88 (C-19), 171.08 (C=O).
b)
2b 1604 (C=N) 3.55 (m, 2H, H-69, H-699), 3.70 (m, 1H, H-59), 3.80 (d, 2H, J = 5.4 Hz, CH2), 4.05 (m, 2H, H-39, H-49),
1661 (NCO) 4.20 (dd, 1H, J = 5.6 Hz, J = 2.4 Hz, H-29), 4.35 (m, 2H, 2OH), 4.40 (d, 1H, J = 6.3 Hz, OH), 5.20 (d,
3295 (NH) 1H, J = 5.5 Hz, OH), 5.65 (d, 1H, J = 4.5 Hz, OH), 5.90 (t, 1H, J = 5.4 Hz, NH), 6.65 (m, 3H, Ar-3H),
3365 3425 (OH) 7.15 (m, 2H, Ar-2H), 7.40 (d, 1H, J = 5.6 Hz, H-19), 11.20 (s, 1H, NH)/43.75 (CH2), 63.75 (C-69), 69.30
(C-49), 70.55 (C-59), 71.09 (C-29), 71.20 (C-39), 112.25 (ArC-3,5), 116.35 (ArC-4), 128.79 (ArC-2,6),
148.26 (ArC-1), 149.55 (C-19), 171.03 (C=O).
b)
2c 1615 (C=N) 3.74 (d, 2H, J = 5.4 Hz, CH2), 3.80 (m, 2H, H-59, H-599), 3.89 4.15 (m, 2H, H-39, H-49), 4.53 (dd, 1H,
1675 (NCO) J = 5.6 Hz, J = 2.4 Hz, H-29), 4.89 (d, 1H, J = 5.4 Hz, OH), 4.95 (d, 1H, J = 6.2 Hz, OH), 5.45 (m, 1H,
3270 (NH) OH), 5.70 (d, 1H, J = 4.6 Hz, OH), 5.80 (t, 1 H, J = 4.2 Hz, NH), 6.60 (m, 3H, Ar-3H), 7.65 (m, 2H, Ar-
3310 3390 (OH) 2H), 7.70 (d, 1H, J = 5.6 Hz, H-19), 9.50 (s, 1H, NH)/45.08 (CH2), 65.77 (C-59), 67.49 (C-49), 68.34 (C-
29), 72.26 (C-39), 112.28 (ArC-3, 5), 116.26 (ArC-4), 128.80 (ArC-2,6), 148.23 (ArC-1), 148.36 (C-19),
169.28 (C=O).
b)
3a 1618 (C=N) 2.14 (s, 3H, CH3), 3.40 (m, 2H, H-69, H-699), 3.50 (m, 1H, H-59), 3.80 (d, 2H, J = 5.4 Hz, CH2), 4.05
1674 (NCO) (m, 1H, H-49), 4.25 (dd, 1H, J = 2.8 Hz, J = 6.5 Hz, H-39), 4.28 (dd, 1H, J = 2.8 Hz, J = 5.6 Hz, H-29)
3285 (NH) 4.40 (d, 1H, J = 5.4 Hz, OH), 4.50 (m, 2H, 2OH), 4.90 (d, 1H, J = 6.3 Hz, OH), 5.40 (d, 1H, J = 5.5 Hz,
3220 3405 (OH) OH), 5.75 (t, 1H, J = 4.2 Hz, NH), 6.50 (m, 2H, Ar-2H), 6.90 (m, 2H, Ar-2H), 7.40 (d, 1H, J = 5.6 Hz,
H-19), 11.10 (s, 1H, NH)/20.05 (CH3), 44.04 (CH2), 63.03 (C-69), 68.97 (C-49), 69.03 (C-59), 70.10 (C-29),
72.25 (C-39), 112.40 (ArC-3,5), 124.40 (ArC-4), 129.25 (ArC-2,6), 14.90 (ArC-1), 149.85 (C-19),
171.19 (C=O).
b)
3b 1610 (C=N) 2.15 (s, 3H, CH3), 3.50 (m, 2H, H-69, H-699), 3.70 (d, 2H, J = 5.4 Hz, CH2), 4.04 (m, 1H, H-59), 4.25
1670 (NCO) (m, 2H, H-39, H-49), 4.35 (dd, 1H, J = 5.6 Hz, J = 2.2 Hz, H-29), 4.45 (d, 1H, J = 6.5 Hz, OH), 4.50 (d,
3270 (NH) 1H, J = 5.4 Hz, OH), 5.20 (m, 2H, 2OH), 5.40 (d, 1H, J = 4.5 Hz, OH), 5.75 (t, 1H, J = 5.4 Hz, NH),
3310 3465 (OH) 6.50 (m. 2H, ArH-3,5), 7.05 (m, 2H, ArH-2,6), 7.40 (d, 1H, J = 5.6 Hz, H-19), 10.50 (s, 1H, NH)/20.02
(CH3), 44.05 (CH2), 63.07 (C-69), 69.28 (C-49), 70.20 (C-59), 71.15 (C-29), 72.27 (C-39), 112.38 (ArC-
3,5), 124.36 (ArC-4) 129.21 (ArC-2,6), 145.90 (ArC-1), 149.48 (C-19), 171.12 (C=O)
b)
3c 1609 (C=N) 2.14 (s, 3H, CH3), 3.44-3.52 (m, 2H, H-59, H-599), 3.70 (d, 2H, J = 5.4 Hz, CH2), 4.01 (m, 1H, H-49),
1680 (C=O) 4.13 (t, 1H, J = 2.8 Hz, H-39), 4.33 (dd, 1H, J = 5.6 Hz, J = 2.8 Hz, H-29), 4.39 (d, 1H, J = 5.4 Hz, OH),
3310 (NH) 4.85 (d, 1H, J = 6.2 Hz, OH), 5.25 (t, 1H, J = 5.6 Hz, OH), 5.30 (d, 1H, J = 4.6 Hz, OH), 5.65 (t, 1H, J =
3345 3395 (OH) 5.4 Hz, NH), 6.48 (m, 2H, ArH-3,5), 6.91 (m, 2H, ArH-2,6), 7.45 (d, 1 H, J = 5.6 Hz, H-19), 11.01 (s,
1H, NH).
b)
4a 1615 (C=N) 3.30 (m, 2H, H-69, H-699), 3.63 (s, 3H, OCH3), 3.69 (m, 1H, H-59), 3.99 (d, 2H, J = 5.4 Hz, CH2), 4.10
1662 (C=O) (m, 1H, H-49 ), 4.12 (t, 1H, J = 2.6 Hz, H-39), 4.25 (dd, 1H, J = 5.6 Hz, J = 2.6 Hz, H-29), 4.32 (m, 2H,
3295 (NH) 2OH), 4.45 (d, 1H, J = 5.4 Hz, OH), 5.15 (t, 1H, J = 5.6 Hz, OH), 5.25 (m, 1H, OH), 5.65 (t, 1H, J = 5.4
3335 3390 (OH) Hz, NH), 6.53 (m, 2H, ArH-2,6), 6.74 (m, 2H, ArH-3,5), 7.15 (d, 1H, J = 5.6 Hz, H-19), 10.40 (s, 1H,
NH).
b)
4b 1610 (C=N) 3.55 (m, 2H, H-69, H-699), 3.60 (s, 3H, OCH3), 3.70 (d, 2H, J = 5.4 Hz, CH2), 3.85 (m, 2H, H-49, H-59 ),
1662 (C=O) 4.1 (dd, 1H, J = 5.8 Hz, J = 2.2 Hz, H-39), 4.25 (dd, 1H, J = 5.6 Hz, J = 2.2 Hz, H-29), 4.30 (m, 2H,
3285 (NH) 2OH), 4.40 (d, 1H, J = 5.5 Hz, OH), 5.25 (m, 2H, 2OH), 5.50 (t, 1H, J = 5.4 Hz, NH), 6.50 (m, 2H, Ar-
3330 3375 (OH) 2H), 6.75 (m, 2H, Ar-2H), 7.35 (d, 1H, J = 5.6 Hz, H-19), 10.60 (s, 1H, NH)/45.50 (CH2), 56.19
(OCH3), 64.67 (C-69), 70.22 (C-49), 70.66 (C-59), 71.82 (C-29), 72.01 (C-39), 114.05 (ArC-2,6), 115.43
(ArC-3,5), 143.30 (ArC-1), 150.41 (C-19), 152.05 (ArC-4), 172.21 (C=O).
b)
4c 1605 (C=N) 3.50 (m, 2H, H 69, H-699), 3.75 (s, 3H, OCH3), 4.15 (d, 2H, J = 5.4 Hz, CH2), 4.20 (m, 2H, H-49, H-59),
1680 (C=O) 4.25 (dd, 1H, J = 5.8 Hz, J = 2.4 Hz, H-39), 4.30 (dd, 1H, J = 5.6 Hz, J = 2.4 Hz, H-29), 4.75 (d, 1H, J =
3300 (NH) 5.4 Hz, OH), 5.14 (m, 2H, OH), 5.60 (d, 1H, J = 4.6 Hz, OH), 5.90 (t, 1H, J = 5.4 Hz, NH), 6.60 (m,
3345 3385 (OH) 2H, Ar-2H), 7.10 (m, 2H, Ar-2H), 7.40 (d, 1H, J = 5.6 Hz, H-19), 10.50 (s, 1H, NH).
b)
5a 1615 (C=N) 3.55 (m, 2H, H-69, H-699), 3.70 (d, 2H, J = 5.4 Hz, CH2), 4.05 (m, 1H, H-59), 4.1 (m, 1H, H-49), 4.20
1675 (C=O) (dd, 1H, J = 6.2 Hz, J = 2.4 Hz, H-39), 4.45 (dd, 1H, J = 5.6 Hz, J = 2.4 Hz, H-29), 4.50 (d, 1H, J = 5.6 Hz,
3310 (NH) OH), 4.75 (d, 1H, J = 5.4 Hz, OH), 4.80 (m, 1H, OH), 5.2 (d, 1H, J = 6.3 Hz, OH), 5.60 (d, 1H, J = 5.5
3355 3390 (OH) Hz, OH), 5.90 (t, 1H, J = 5.4 Hz, NH), 6.66 (m, 2H, Ar-2H), 7.20 (m, 2H, Ar-2H), 7.45 (d, 1H, J = 5.6
Hz, H-19), 10.60 (s, 1H, NH).
b)
5b 1620 (C=N) 3.35 3.40 (m, 2H, H-69, H-699), 3.65 (m, 1H, H-59), 3.80 (m, 1H, H-49), 3.90 (d, 2H, J = 5.4 Hz, CH2),
1680 (C=O) 3.95 (dd, 1H, J = 6.2 Hz, J = 2.4 Hz, H-39), 4.25 (dd, 1H, J = 5.6 Hz, J = 2.4 Hz, H-29), 4.75 (d, 1H, J =
3295 (NH) 6.5 Hz, OH), 4.80 (m, 2H, 2OH), 4.90 (d, 1H, J = 5.5 Hz, OH), 5.05 (d, 1H, J = 4.5 Hz, OH), 5.70 (t,
3330 3356 (OH) 1H, J = 5.4 Hz, NH), 6. 90 (d, 2H, J = 8.5 Hz, Ar-2H), 7.30 (d, 1H, J = 5.6 Hz, H-19), 8.10 (d, 1H, J = 8.5
Hz, Ar-2H), 10.75 (s, 1H, NH).

i 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2006, 339, 656 663 Sugar Arylglycinoylhydrazones and Oxadiazoline Derivatives 659

Table 1. Continued ...

Compd. No IR (m, cm 1) H1- and 13C-NMR (d, ppm)

b)
5c 1602 (C=N) 3.35 (m, 2H, H-59, H-599), 3.40 (m, 1H, H-49), 3.80 (dd, 1H, J = 6.2 Hz, J = 2.4 Hz, H-39), 3.90 (d, 2H, J
1670 (C=O) = 5.4 Hz, CH2), 4.25 (dd, 1H, J = 5.6 Hz, J = 2.4 Hz, H-29), 4.45 (d, 1H, J = 5.4 Hz, OH), 4.77 (m, 2H,
3215 (NH) OH), 5.40 (d, 1H, J = 4.6 Hz, OH), 5.65 (t, 1H, J = 5.4 Hz, NH), 7.05 (d, 2H, J = 8.5 Hz, Ar-2H), 7.40
3354 3420 (OH) (d, 1H, J = 5.6 Hz, H-19), 7.90 (d, 1H, J = 8.5 Hz, Ar-2H), 10.50 (s, 1H, NH).
b)
6 1675 (OCN) 1.95, 2.05, 2.10, 2.14, 2.17 (5s, 15H, 5CH3), 4.05 (dd, 1H, J = 8.2 Hz, J = 2.6 Hz, H-69), 4.11 (m,
1750 (OAc) 1H, H-699), 4.25 (d, 2H, J = 5.4 Hz, CH2), 4.50 (m, 1H, H-59), 4.60 (m, 1H, H-49), 5.15 (dd, 1H, J = 6.8
3450 (NH) Hz, J = 2.4 Hz, H-39), 5.50 (dd, 1H, J = 2.4 Hz, J = 5.6 Hz, H-29), 5.75 (t, 1H, J = 5.4 Hz, NH), 7.05 (d,
1H, J = 5.6 Hz, H-19), 7.20 (m, 3H, Ar-3H), 7.45 (m, 2H, Ar-2H), 9.80 (s, 1H, NH)/20.40, 20.49,
20.58, 20.61, 20.89 (5CH3), 51.08 (CH2), 61.68 (C-69), 67.82 (C-59), 68.34 (C-49), 69.74 (C-29), 73.54
(C-39), 127.83 (ArC-3,5), 130.56 (ArC-2,6), 138.03 (ArC-4), 141.09 (ArC-1), 143.2 (C-19), 169.04,
169.08, 170.14, 170.16, 170.69, 171.14 (6CO).
b)
7a 1670 (OCN) 1.95, 2.04, 2.10, 2.13, 2.15, 2.18 (6s, 18H, 6CH3), 4.10 (dd, 1H, J = 8.1 Hz, 2.6 Hz, H-69), 4.11 (m,
1750 (OAc) 1H, H-699), 4.15 (d, 2H, J = 5.4 Hz, CH2), 4.25 (m, 1H, H-59), 5.10 (m, 1H, H-49), 5.25 (t, 1H, J = 5.6
3390 (NH) Hz, H-39), 5.40 (t, 1H, J = 5.6 Hz, H-29), 5.70 (t, 1H, J = 5.4 Hz, NH), 7.05 (d, 2H, J = 8.5 Hz, Ar-2H),
7.25 (d, 1 H, J = 5.6 Hz, H-19), 7.44 (d, 2H, J = 8.5 Hz, Ar-2H), 11.50 (s, 1H, NH)/20.45, 20.55, 21.62,
21.08, 21.88, 22.88 (6CH3), 55.28 (CH2), 61.80 (C-69), 66.75 (C-59), 67.31 (C-49), 67.88 (C-39), 70.55
(C-29), 127.59 (ArC-3,5), 130.17 (ArC-2,6), 138.06 (ArC-4), 140.73 (ArC-1), 141.85 (C-19), 169.50,
170.45, 170.90, 171.25, 171.75, 172.15 (6CO).
b)
7b 1661 (OCN) 1.80, 1.89, 1.92, 1.98, 2.05, 2.15 (6s, 18H, 6CH3), 4.07 (dd, 1H, J = 7.9 Hz, 2.6 Hz, H-69), 4.11 (m,
1745 (OAc) 1H, H-699), 4.15 (m, 1H, H-59), 4.20 (d, 2H, J = 5.4 Hz, CH2), 5.10 (m, 1H, H-49), 5.15 (t, 1H, J = 4.5
3440 (NH) Hz, H-39), 5.33 (t, 1H, J = 5.6, H-29), 5.80 (t, 1H, J = 5.4 Hz, NH), 7.15 (d, 1H, J = 5.6 Hz, H-19), 7.20 (d,
2H, J = 8.5 Hz, Ar-2H), 7.45 (d, 2H, J = 8.5 Hz, Ar-2H), 11.40 (s, 1H, NH)/ 20.05, 20.09, 20.15,
20.27, 20.90, 21.95 (6CH3), 45.15 (CH2), 61.88 (C-69), 65.75 (C-59), 66.51 (C-49), 67.48 (C-39), 69.50
(C-29), 125.25 (ArC-3,5), 127.80 (ArC-2,6), 135.50 (C-4), 137.45 (ArC-1), 138.6 (C-19), 169.15,
170.25, 170.50, 179.90, 171.15, 171.35 (6CO).
b)
8 1675 (OCN) 1.85, 1.95, 2.05, 2.14, 2.18 (5s, 15H, 5CH3), 3.85 (s, 3H, OCH3), 3.95 (dd, 1H, J = 8.4 Hz, 2.4 Hz,
1740 (OAC) H-69), 4.05 (m,1H, H-699), 4.20 (d, 2H, J = 5.4 Hz, CH2), 4.15 (m, 1H, H-59), 5.05 (m, 1H, H-49), 5.24 (t,
3490 (NH) 1H, J = 5.6 Hz, H-39), 5.45 (t, 1H, J = 5.6 Hz, H-29), 5.85 (t, 1H, J = 5.4 Hz, NH), 6.80 (d, 2H, J = 8.5 Hz,
Ar-2H), 7.15 (d, 1H, J = 5.6 Hz, H-19), 7.40 (m, 2H, Ar-2H), 10.66 (s, 1H, NH)/20.05, 20.09, 20.15,
20.75, 20.90 (5CH3), 51.15 (CH2), 55.30 (OCH3), 61.95 (C-69), 67.04 (C-59), 68.50 (C-49), 69.52 (C-39),
70.55 (C-29), 114.75 (ArC-2,6), 129.90 (ArC-3,5), 136.45 (ArC-l), 140.60 (C-19), 143.50 (ArC-4),
168.75, 170.70, 171.05, 171.25, 171.68, 171.94 (6CO).
b)
9 1670 (OCN) 1.95, 2.01, 2.08, 2.15 (4s, 12H, 4CH3), 4.17 (dd, 1H, J = 8.2 Hz, 2.6 Hz, H-59), 4.20 (dd, 1H, J = 8.2
1735 (OAC) Hz, J = 3.5 Hz H-599), 4.30 (d, 2H, J = 5.4 Hz, CH2), 5.25 (m, 1H, H-49), 5.70 (dd, 1H, J = 2.8 Hz, J = 5.6
3395 (NH) Hz, H-39), 5.77 (dd, 1H, J = 5.6, J = 2.8 Hz, H-39), 5.79 (dd, 1H, J = 2.6 Hz, J = 5.6 Hz, H-29), 5.85 (t,
1H, J = 5.4 Hz, NH),7.05 (d, 1H, J = 5.6 Hz, H-19), 7.45, (d, 2H, J = 8.5 Hz, Ar-2H), 7.58 (d, 2H, J = 8.5
Hz, Ar-2H), 9.77 (s, 1H, NH)
a)
10a 1685 (OCN) 1.82, 1.99, 2.02, 2.03, 2.13, 2.33 (6s, 18H, 6CH3), 3.85 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz, H-59), 4.18
1740 (OAc) (dd, 1H, J = 2.8 Hz, J = 6.8 Hz, H-599), 4.36 (dd, 2H, J = 2.8 Hz, J = 6.5 Hz, H-49), 4.54 (d, 2H, J = 5.4
3305 (NH) Hz, CH2), 5.14 (m, 1H, H-39), 5.36 (dd, 1H, J = 5.8 Hz, J = 3.5 Hz, H-29), 5.55 (t, 1H, J = 5.8 Hz, H-19),
5.78 (d, 1H, J = 5.8 Hz, oxadiazoline-H), 5.85 (t, 1H, J = 5.4 Hz, NH), 6.51 (m, 3H, Ar-3H), 7.01 (m,
2H, Ar-2H).
a)
10b 1680 (OCN) 1.94, 2.01, 2.05, 2.09, 2.15, 2.44 (6s, 18H, 6CH3), 4.01 (m, 1H, H-59), 4.25 (dd, 1H, J = 2.4 Hz, J =
1745 (OAc) 6.5 Hz, H-599), 4.38 (d, 2H, J = 5.4 Hz, CH2), 4.75 (m, 1H, H-49), 5.14 (m, 1H, H-39), 5.36 (m, 1H, H-
3310 (NH) 29), 5.56 (dd, 1H, J = 5.8 Hz, J = 2.2 Hz, H-19), 5.78 (d, 1H, J = 5.8 Hz, oxadiazoline-H), 5.95 (t, 1H,
J = 5.4 Hz, NH), 7.27 (m, 3H, Ar-3H), 7.40 (m, 2H, Ar-2H).
a)
10c 1675 (OCN) 1.96, 2.05, 2.08, 2.17, 2.40 (5s, 15H, 5CH3), 4.05 (m, 1H, H-49), 4.30 (dd, 1H, J = 2.4 Hz, J = 6.5
1740 (OAc) Hz, H-499), 4.45 (m, 1H, H-39), 4.50 (d, 2H, J = 5.4 Hz, CH2), 5.05 (m, 1H, H-39), 5.14 (m, 1H, H-29),
3350 (NH) 5.36 (dd, 1H, J = 5.8 Hz, J = 2.2 Hz, H-19), 5.78 (d, 1H, J = 5.8 Hz, oxadiazoline-H), 5.82 (t, 1H, J =
5.4 Hz, NH), 7.25 (m, 3H, Ar-3H), 7.45 (m, 2H, Ar-2H).
a)
11a 1680 (OCN) 1.92, 1.98, 2.07, 2.11, 2.13, 2.18, 2.45 (7s, 21H, 7CH3), 4.07 (m, 1H, H-59), 4.25 (dd, 1H, J = 2.4
1735 (OAc) Hz, J = 6.5 Hz, H-599), 4.35 (d, 2H, J = 5.4 Hz, CH2), 4.35 (m, 1H, H-49), 5.07 (m, 1H, H-39), 5.14 (m,
3300 (NH) 1H, H-29), 5.40 (dd, 1H, J = 5.8 Hz, J = 2.2 Hz, H-19), 5.80 (t, 1H, J = 5.4 Hz, NH), 5.78 (d, 1H, J = 5.8
Hz, oxadiazoline-H), 7.20 (m, 2H, Ar-2H), 7.40 (m, 2H, Ar-2H).
a)
11b 1680 (OCN) 1.84, 1.98, 2.08, 2.09, 2.11, 2.17, 2.24 (7s, 21H, 6CH3), 4.15 (dd, 1H, J = 2.4 Hz, J = 6.5 Hz, H-59),
1750 (OAc) 4.25 (m, 1H, H-599), 4.40 (d, 2H, J = 5.4 Hz, CH2), 4.05 (m, 1H, H-49), 5.187 (m, 1H, H-39), 5.14 (t, 1H,
3200 (NH) J = 2.5 Hz, H-29), 5.47 (dd, 1H, J = 5.8 Hz, J = 2.5 Hz, H-19), 5.80 (t, 1H, J = 5.4 Hz, NH), 5.77 (d, 1H, J
= 5.8 Hz, oxadiazoline-H), 6.59 (d, 2H, J = 8.5 Hz, Ar-2H), 7.03 (d, 2H, J = 8.5 Hz, Ar-2H).

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660 M. T. Abdel-Aal et al. Arch. Pharm. Chem. Life Sci. 2006, 339, 656 663

Table 1. Continued ...

Compd. No IR (m, cm 1) H1- and 13C-NMR (d, ppm)

a)
12 1675 (OCN) 1.87, 1.93, 2.03, 2.09, 2.16, 2.46 (6s, 18H, 6CH3), 3.81 (s, 3H, OCH3), 4.05-4.20 (m, 2H, H-59, H-
1745 (OAc) 599), 4.32 (d, 2H, J = 5.4 Hz, CH2), 4.49 (m, 1H, H-49, H-39), 5.35 (m, 1H, H-29), 5.65 (dd, 1H, J = 5.8
3255 (NH) Hz, J = 2.4 Hz, H-19), 5.72 (d, 1H, J = 6.5 Hz, oxadiazoline-H), 5.75 (s, 1H, NH), 6.92 (d, 2H, J = 8.5
Hz, Ar-2H), 7.52 (d, 2H, J = 8.5 Hz, Ar-2H)/20.05, 20.15, 21.25, 21.40, 21.05, 21.45 (6CH3), 50.25
(CH2), 53.50 (OCH3), 62.55 (C-59), 69.50 (C-49), 70.65 (C-39), 75.20 (C-29), 77.75 (C-19), 88.10 (C-N),
116.05 (ArC-2,6), 129.15 (ArC-3,5), 138.20 (ArC-4), 145.05 (C-19), 160.20 (C=N), 170.05 (CO),
170.14 (CO), 170.25 (CO), 170.75 (CO), 171.20 (CO), 171.45 (CO).
a)
In DMSO-d6.
b)
In CDCl3.

Table 2. Structural data of compounds 2 12.

Compound No. R R1CHO R2

2a H D-galactose
2b H D-mannose
2c H D-ribose
3a CH3 D-galactose
3b CH3 D-mannose
3c CH3 D-ribose
4a OCH3 D-galactose
4b OCH3 D-mannose
4c OCH3 D-ribose
5a NO2 D-galactose
5b NO2 D-mannose
5c NO2 D-ribose
6 H penta-O-acetyl-D-mannopentitolyl
7a CH3 penta-O-acetyl-D-galactopentitolyl
7b CH3 penta-O-acetyl-D-mannopentitolyl
8 OCH3 penta-O-acetyl-D-mannopentitolyl
9 NO2 tetra-O-acetyl-D-ribotetritolyl
10a H penta-O-acetyl-D-galactopentitolyl
10b H penta-O-acetyl-D-mannopentitolyl
10c H tetra-O-acetyl-D-ribotetritolyl
11a CH3 penta-O-acetyl-D-galactopentitolyl
11b CH3 penta-O-acetyl-D-mannopentitolyl
12 OCH3 penta-O-acetyl-D-mannopentitolyl

Conclusion
Some sugar N-arylaminoacetylhydrazones, O-acetylated
derivatives of sugar N-arylaminoacetylhydrazones and 4-
acetyl-5-(O-acetylalditolyl)-2-N-arylaminomethyl-1,3,4-oxa-
diazoline were prepared. Some of the prepared products
were tested for antiviral activity against Hepatitis-A virus
(HAV, MBB-cell culture adapted strain) and Herpes Simplex
virus type-1 (HSV-1). Structure activity correlation of the
obtained results revealed that O-acetylated derivatives 8c
Figure 2. Effect of some novel compounds on Herpes Simplex
and 10a showed higher activity against HSV-1 than the virus-1 reduction in comparison with acyclovir (C*) as a control.
deprotected sugar hydrazones. For the antiviral activity
against HAV-27 the free sugar hydrazone 4c (R = OCH3
and the sugar moiety is D-ribose) showed the highest anti-
Experimental
viral activity, followed by compounds 10a and 12 in General
which 1,3,4-oxadiazoline ring is attached to the O-acety- Melting points were determined with a Kofler block apparatus
lated sugar moiety. (C. Reichert, Vienna, Austria) and are uncorrected. The IR spectra

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Arch. Pharm. Chem. Life Sci. 2006, 339, 656 663 Sugar Arylglycinoylhydrazones and Oxadiazoline Derivatives 661

Table 3. Physicochemical data of new compounds.

Compound M.P (8C) Mol. Formula Yield Analysis%

No from ethanol (%) (Calcd./Found)
C H N

2a 179181 C14H21N3O6 81 51.37 6.46 12.84

(327.33) 51.42 6.18 12.50
2b 195197 C14H21N3O6 83 51.37 6.64 12.84
(327.33) 51.05 6.32 13.20
2c 178180 C13H19N3O5 79 52.52 6.43 14.13
(297.31) 52.20 6.35 14.45
3a 183184 C15H23N3O6 78.5 52.78 6.78 12.31
(341.36) 52.51 6.45 12.55
3b 210211 C15H23N3O6 82.5 52.78 6.78 12.31
(341.36) 52.43 6.39 12.25
3c 182184 C14H21N3O5 77 54.01 6.79 13.49
(311.33) 53.96 6.48 13.30
4a 190192 C15H23N3O7 79 50.42 6.48 11.76
(357.36) 50.20 6.21 11.40
4b 195196 C15H23N3O7 78 50.42 6.48 11.76
(357.36) 50.50 6.17 11.37
4c 184185 C14H21N3O6 77 51.37 6.47 12.84
(327.33) 51.20 6.35 12.90
5a 185186 C14H20N4O8 76 45.16 5.41 15.05
(372.33) 45.50 5.22 15.01
5b 189190 C14H20N4O8 78.5 45.16 5.41 15.05
(372.33) 45.43 5.09 15.40
5c 180182 C13H18N4O7 75 45.61 5.30 16.37
(342.31) 45.55 5.28 16.50
6 110112 C24H31N3O11 72 53.63 5.81 7.82
(537.52) 53.30 5.60 7.52
7a 112114 C25H33N3O11 77 54.44 6.03 7.62
(551.54) 54.80 5.80 7.67
7b 118119 C25H33N3O11 80 54.44 6.03 7.62
(551.54) 54.70 5.95 7.60
8 118120 C25H33N3O12 78 52.91 5.86 7.40
(567.54) 52.90 5.59 7.15
9 108109 C21H26N4O11 72 49,41 5.13 10.98
(510.45) 49.70 4.90 11.10
10a 125127 C26H33N3O12 66.5 53.88 5.74 7.25
(579.55) 53.94 6.05 6.97
10b 124125 C26H33N3O12 66 53.88 5.74 7.25
(579.55) 53.55 5.73 7.57
10c 122123 C23H29N3O10 68 54.43 5.76 8.28
(507.49) 54.24 5.42 7.88
11a 125126 C27H35N3O12 69 54.63 5.94 7.08
(593.58) 54,37 6.27 6.94
11b 127128 C27H35N3O12 70 54.63 5.94 7.08
(593.58) 54.35 5.67 6.84
12 124125 C27H35N3O13 67 53.20 5.79 6.89
(609.58) 52.91 5.60 6.65

were recorded with a Perkin-Elmer model 1720 FTIR spectro-
meter for KBr discs (Perkin-Elmer). NMR spectra were recorded
on a Varian Gemini 200 NMR Spectrometer at 300 MHz for 1H-
and 75 MHz for 13C- NMR (Varian Inc., Palo Alto, CA, USA) or on a
Brucker Ac-250 FT spectrometer at 250 MHz for 1H- and at
62.9 MHz for 13C-NMR (Bruker) with TMS as internal standard.
The progress of the reactions was monitored by TLC analytical
silica gel plates 60 F245. Elemental analyses were performed at
the unit of Microanalysis at Cairo University, Egypt. Viral screen-
ing against HAV and HSV was conducted at the Environmental
Virology Lab., Department of Water Pollution Research,
National Research Centre, Cairo, Egypt. Physicochemical and
spectral data for the synthesized compounds are given in
Tables 2 and 3. For further physicochemical data of synthesized
compounds see Supplemental Material.
Sugar N-arylaminoacetylhydrazones 2 5
General procedure
To a well stirred solution of the respective monosaccharide
(0.01 mol) in water (2 mL) and glacial acetic acid (0.2 mL) was
added the appropriate N-arylaminoacetyl hydrazide 1 (0.01 mol)

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662 M. T. Abdel-Aal et al.
in ethanol (10 mL). The mixture was heated under reflux for 3 h
and the resulting solution was concentrated and left to cool. The
formed precipitate was filtered off, washed with water and etha-
nol, dried, and crystallized from ethanol.
O-Acetylated derivatives of sugar N-arylaminoacetyl-
hydrazones 6 9
General Procedure
A cold solution of sugar N-arylaminoacetyl hydrazones 2 5
(2 mmol) in dry pyridine (5 mL) was treated with acetic anhy-
dride (5 mL). The reaction mixture was left overnight with stir-
ring, then poured onto crushed ice and the separated product
was filtered off, washed repeatedly with water, dried, and crys-
tallized from ethanol-water mixture.
4-Acetyl-5-(O-acetylalditolyl)-2-N-arylaminomethyl-
1,3,4-oxadiazoline 10 12
General procedure
A solution of sugar N-arylaminoacetyl hydrazone 2 5 (1 mmol)
in acetic anhydride (5 mL) was boiled under reflux for 1 h. The
resulting solution was poured onto crushed ice, and the product
that separated out was filtered off, washed with a solution of
sodium hydrogen carbonate followed by water and then dried.
The products were recrystallized from ethanol.
Antiviral screening
Preparation of synthetic compounds for bioassay.
Tested compounds were dissolved as 100 mg each in 1 mL of
10% DMSO in water. The final concentration was 100 lg/mL
(stock solution). The dissolved stock solutions were decontami-
nated by addition of 50 lg/mL antibiotic-antimycotic mixture
(10 000 U penicillin G sodium, 10 000 lg streptomycin sulfates,
and 250 mg amphotericin B, PAA Laboratories GmbH, Austria).
Cell culture
African green monkey kidney-derived cells (Vero) and human
hepatoma cell line (HepG2) were used. Cells were propagated in
Dulbeccos' Minimal Essential Medium (DMEM) supplemented
with 10% fetal bovine serum, 1% antibiotic-antimycotic mixture.
The pH was adjusted at 7.2 7.4 by 7.5% sodium bicarbonate
solution. The mixture was sterilized by filtration through
0.2 mm pore size nitrocellulose membrane.
Viruses
Herpes Simplex virus type-1 (HSV-1) and Hepatitis-A virus (HAV,
MBB-cell culture adapted strain) were obtained from Environ-
mental Virology Lab., Department of Water Pollution Research,
National Research Centre, Cairo, Egypt.
Cytotoxicity assay
Cytotoxicity was assayed for both dimethyl sulfoxide (DMSO)
and the tested compounds. Serial dilutions were prepared and
inoculated on Vero cells grown in 96-well tissue culture plates.
The maximum tolerated concentration (MTC) for each com-
pound was determined by both cell morphology and cell viabi-
lity by staining with tryban blue dye.
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Arch. Pharm. Chem. Life Sci. 2006, 339, 656 663
Plaque reduction infectivity assay
A 6-well plate was cultivated with cell culture (105 cell/mL) and
incubated for 2 days at 378C. HSV-1 and HAV were diluted to give
104 PFU/mL final concentrations for each virus and mixed with
the tested compound at the previous concentration and incu-
bated overnight at 48C. Growth medium was removed from the
multiwell plate and virus-compound mixture was inoculated
(100 mL/well). After 1 h contact time, the inoculum was aspi-
rated and 3 mL of MEM with 1% agarose was overlaid the cell
sheets. The plates were left to solidify and incubated at 378C
until the development of virus plaques. Cell sheets were fixed in
10% formaline solution for 2 h and stained with crystal violet
stain. Control virus and cells were treated identically without
chemical compound. Virus plaques were counted and the per-
centage of reduction was calculated [28].
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