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Synthesis and Antiviral Evaluation of Some Sugar Arylglycinoylhydrazones and Their Oxadiazoline Derivatives.

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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
Photochemistry Department, National Research Centre, Cairo, Egypt
3
Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
2
Sugar N-arylaminoacetylhydrazones 2 – 5 were prepared by the reaction of N-arylaminoacetylhydrazides 1 with equivalent amounts of the corresponding monosaccharides. Per-O-acetyl derivatives 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 oxadiazolines 10 – 12. The prepared compounds were tested for antiviral activity against Herpes Simplex 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
The combinatorial approach in organic synthesis and the
synthesis of a library of compounds become major objectives for various laboratories around the world in order
to search for biologically active compounds. 1,3,4-oxadiazoles and 1,3,4-oxadiazolines were found to be insecticidal [1], fungicidal, and bactericidal agents [2]; they have
analgesic, antipyretic, antiphlogestic, anticompulsive,
paralytic, hypnotic, and sedative properties [3 – 7], antitumor 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, antiviral, and anti-tumor activity. Recently, synthesis of acyclonucleosides has attracted much attention [14 – 16].
Consequently, the above significance and possible
Correspondence: Mohammed T. Abdel-Aal, Chemistry Department, Faculty of Science, Menofia University, Shebin El-Koom, Egypt.
E-mail: mtaha2000_2000@yahoo.com
Fax: +20 48 223-5689
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2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
enhancement of biological activity resulting from the
attachment of carbohydrate moieties to 1,3,4-oxadiazoline heterocycles and our interest in the synthesis of heterocyclic 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 monosaccharides was performed by heating in an aqueous ethanolic
solution and a catalytic amount of acetic acid. The hydrazones 2 – 5 were prepared from the monosaccharides Dgalactose, 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 corresponding 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
Arch. Pharm. Chem. Life Sci. 2006, 339, 656 – 663
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 spectral 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 correspond to OCO groups. Elemental analyses of these compounds are in agreement with assigned structures indicating that in addition to acetylation of the sugar hydroxyl groups, N-acetylation had also taken place.
Scheme 1. Synthesis route of new compounds.
signals corresponding to sugar carbons (Table 1). The
assignments of the sugar carbons were based on the chemical shift equivalences to the assigned structure of
other sugar hydrazones [23 – 25]. The C-1 of the sugar residue 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 condition of acetylation [26, 27]. Thus, acetylation of compounds 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 aromatic protons and the C-1 methine proton as douplet at d
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2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Antiviral screening
Plaque infectivity assay was carried out to test the prepared compounds for antiviral activity. The test was performed 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, compounds 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 moderate activity while compound 11b show little activity at
concentration 20 lg/105 cells and did not show any activity at concentration 10 lg/105 cells (Fig. 2).
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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)
2a
1605 (C=N)
1674 (NCO)
3250 (NH)
3330 – 3410 (OH)
b)
2b
1604 (C=N)
1661 (NCO)
3295 (NH)
3365 – 3425 (OH)
2c
1615 (C=N)
1675 (NCO)
3270 (NH)
3310 – 3390 (OH)
3a
1618 (C=N)
1674 (NCO)
3285 (NH)
3220 – 3405 (OH)
3b
1610 (C=N)
1670 (NCO)
3270 (NH)
3310 – 3465 (OH)
3c
1609 (C=N)
1680 (C=O)
3310 (NH)
3345 – 3395 (OH)
4a
1615 (C=N)
1662 (C=O)
3295 (NH)
3335 – 3390 (OH)
4b
1610 (C=N)
1662 (C=O)
3285 (NH)
3330 – 3375 (OH)
4c
1605 (C=N)
1680 (C=O)
3300 (NH)
3345 – 3385 (OH)
1615 (C=N)
1675 (C=O)
3310 (NH)
3355 – 3390 (OH)
5a
5b
i
1620 (C=N)
1680 (C=O)
3295 (NH)
3330 – 3356 (OH)
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),
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,
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,
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)
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),
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,
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),
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)
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,
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,
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, Ar2H), 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 (C29), 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)
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
(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)
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,
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)
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
(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,
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),
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 (ArC3,5), 124.36 (ArC-4) 129.21 (ArC-2,6), 145.90 (ArC-1), 149.48 (C-19), 171.12 (C=O)
b)
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),
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),
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 =
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)
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
(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,
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
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)
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 ),
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,
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, Ar2H), 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)
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),
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 =
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,
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)
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
(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,
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
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)
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),
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 =
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,
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).
2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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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)
5c
1602 (C=N)
1670 (C=O)
3215 (NH)
3354 – 3420 (OH)
1675 (OCN)
1750 (OAc)
3450 (NH)
b)
6
7a
1670 (OCN)
1750 (OAc)
3390 (NH)
7b
1661 (OCN)
1745 (OAc)
3440 (NH)
8
1675 (OCN)
1740 (OAC)
3490 (NH)
9
1670 (OCN)
1735 (OAC)
3395 (NH)
10a
1685 (OCN)
1740 (OAc)
3305 (NH)
10b
1680 (OCN)
1745 (OAc)
3310 (NH)
10c
1675 (OCN)
1740 (OAc)
3350 (NH)
11a
1680 (OCN)
1735 (OAc)
3300 (NH)
11b
1680 (OCN)
1750 (OAc)
3200 (NH)
i
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
= 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,
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
(d, 1H, J = 5.6 Hz, H-19), 7.90 (d, 1H, J = 8.5 Hz, Ar-2H), 10.50 (s, 1H, NH).
b)
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,
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
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)
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,
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
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)
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,
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
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)
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,
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,
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)
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
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
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)
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
(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
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)
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 =
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, H29), 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)
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
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),
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)
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
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,
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)
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),
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,
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).
2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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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)
12
1675 (OCN)
1745 (OAc)
3255 (NH)
a)
a)
b)
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, H599), 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
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).
In DMSO-d6.
In CDCl3.
Table 2. Structural data of compounds 2 – 12.
Compound No.
R
R1CHO
R2
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6
7a
7b
8
9
10a
10b
10c
11a
11b
12
H
H
H
CH3
CH3
CH3
OCH3
OCH3
OCH3
NO2
NO2
NO2
H
CH3
CH3
OCH3
NO2
H
H
H
CH3
CH3
OCH3
D-galactose
D-mannose
D-ribose
D-galactose
D-mannose
D-ribose
D-galactose
D-mannose
D-ribose
D-galactose
D-mannose
D-ribose
–
–
–
–
–
–
–
–
–
–
–
–
penta-O-acetyl-D-mannopentitolyl
penta-O-acetyl-D-galactopentitolyl
penta-O-acetyl-D-mannopentitolyl
penta-O-acetyl-D-mannopentitolyl
tetra-O-acetyl-D-ribotetritolyl
penta-O-acetyl-D-galactopentitolyl
penta-O-acetyl-D-mannopentitolyl
tetra-O-acetyl-D-ribotetritolyl
penta-O-acetyl-D-galactopentitolyl
penta-O-acetyl-D-mannopentitolyl
penta-O-acetyl-D-mannopentitolyl
–
–
–
–
–
–
–
–
–
–
–
Conclusion
Some sugar N-arylaminoacetylhydrazones, O-acetylated
derivatives of sugar N-arylaminoacetylhydrazones and 4acetyl-5-(O-acetylalditolyl)-2-N-arylaminomethyl-1,3,4-oxadiazoline 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
and 10a showed higher activity against HSV-1 than the
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 antiviral activity, followed by compounds 10a and 12 in
which 1,3,4-oxadiazoline ring is attached to the O-acetylated sugar moiety.
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2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 2. Effect of some novel compounds on Herpes Simplex
virus-1 reduction in comparison with acyclovir (C*) as a control.
Experimental
General
Melting points were determined with a Kofler block apparatus
(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
No
M.P (8C)
from ethanol
Mol. Formula
Yield
(%)
C
2a
179–181
2b
195–197
2c
178–180
3a
183–184
3b
210–211
3c
182–184
4a
190–192
4b
195–196
4c
184–185
5a
185–186
5b
189–190
5c
180–182
6
110–112
7a
112–114
7b
118–119
8
118–120
9
108–109
10a
125–127
10b
124–125
10c
122–123
11a
125–126
11b
127–128
12
124–125
C14H21N3O6
(327.33)
C14H21N3O6
(327.33)
C13H19N3O5
(297.31)
C15H23N3O6
(341.36)
C15H23N3O6
(341.36)
C14H21N3O5
(311.33)
C15H23N3O7
(357.36)
C15H23N3O7
(357.36)
C14H21N3O6
(327.33)
C14H20N4O8
(372.33)
C14H20N4O8
(372.33)
C13H18N4O7
(342.31)
C24H31N3O11
(537.52)
C25H33N3O11
(551.54)
C25H33N3O11
(551.54)
C25H33N3O12
(567.54)
C21H26N4O11
(510.45)
C26H33N3O12
(579.55)
C26H33N3O12
(579.55)
C23H29N3O10
(507.49)
C27H35N3O12
(593.58)
C27H35N3O12
(593.58)
C27H35N3O13
(609.58)
81
83
79
78.5
82.5
77
79
78
77
76
78.5
75
72
77
80
78
72
66.5
66
68
69
70
67
were recorded with a Perkin-Elmer model 1720 FTIR spectrometer for KBr discs (Perkin-Elmer). NMR spectra were recorded
on a Varian Gemini 200 NMR Spectrometer at 300 MHz for 1Hand 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 screening against HAV and HSV was conducted at the Environmental
Virology Lab., Department of Water Pollution Research,
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2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
51.37
51.42
51.37
51.05
52.52
52.20
52.78
52.51
52.78
52.43
54.01
53.96
50.42
50.20
50.42
50.50
51.37
51.20
45.16
45.50
45.16
45.43
45.61
45.55
53.63
53.30
54.44
54.80
54.44
54.70
52.91
52.90
49,41
49.70
53.88
53.94
53.88
53.55
54.43
54.24
54.63
54,37
54.63
54.35
53.20
52.91
Analysis%
(Calcd./Found)
H
N
6.46
6.18
6.64
6.32
6.43
6.35
6.78
6.45
6.78
6.39
6.79
6.48
6.48
6.21
6.48
6.17
6.47
6.35
5.41
5.22
5.41
5.09
5.30
5.28
5.81
5.60
6.03
5.80
6.03
5.95
5.86
5.59
5.13
4.90
5.74
6.05
5.74
5.73
5.76
5.42
5.94
6.27
5.94
5.67
5.79
5.60
12.84
12.50
12.84
13.20
14.13
14.45
12.31
12.55
12.31
12.25
13.49
13.30
11.76
11.40
11.76
11.37
12.84
12.90
15.05
15.01
15.05
15.40
16.37
16.50
7.82
7.52
7.62
7.67
7.62
7.60
7.40
7.15
10.98
11.10
7.25
6.97
7.25
7.57
8.28
7.88
7.08
6.94
7.08
6.84
6.89
6.65
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 ethanol, dried, and crystallized from ethanol.
O-Acetylated derivatives of sugar N-arylaminoacetylhydrazones 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 anhydride (5 mL). The reaction mixture was left overnight with stirring, then poured onto crushed ice and the separated product
was filtered off, washed repeatedly with water, dried, and crystallized from ethanol-water mixture.
4-Acetyl-5-(O-acetylalditolyl)-2-N-arylaminomethyl1,3,4-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 decontaminated 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
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 incubated 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 aspirated 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 percentage of reduction was calculated [28].
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2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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