Synthesis and antiviral evaluation of some 5-N-arylaminomethyl-2- glycosylsulphanyl-1,3,4-oxadiazoles and their analogs against hepatitis A and herpes simplex viruses

Article abstract of DOI:10.1080/07328300802262778

N-Arylaminomethyl-3H-1,3,4-oxadiazole-2-thiones 2a,b were prepared from the corresponding N-arylglycinoylhydrazides. A number of their thioglycoside derivatives 4-7a-c and S-functionalized analogs 8-11a,b were synthesized by the reaction with different acetobromosugars and acyclic hydroxyalkylating agents. The antiviral activity of a number of the synthesized compounds against herpes simplex virus type 1 (HSV-1) and hepatitis A virus (HAV) was evaluated. Compounds 5a and 5b showed promising results against HAV. Copyright Taylor & Francis Group, LLC.

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Synthesis and Antiviral Evaluation of Some
5‐N‐Arylaminomethyl‐2‐glycosylsulphanyl‐1,3,4‐o
and Their Analogs against Hepatitis A and
Herpes Simplex Viruses
Wael A. El‐Sayed a , Nahed M. Fathi a , W. A. Gad a & El Sayed H. El‐Ashry b c
a Photochemistry Department, National Research Centre, Cairo, Egypt
b Faculty of Science, Department of Chemistry, Alexandria University,
Alexandria, Egypt
c International Center for Chemical and Biological Sciences, University of
Karachi, Karachi, Pakistan
Version of record first published: 07 Aug 2008.
To cite this article: Wael A. El‐Sayed, Nahed M. Fathi, W. A. Gad & El Sayed H. El‐Ashry (2008): Synthesis and
Antiviral Evaluation of Some 5‐N‐Arylaminomethyl‐2‐glycosylsulphanyl‐1,3,4‐oxadiazoles and Their Analogs
against Hepatitis A and Herpes Simplex Viruses, Journal of Carbohydrate Chemistry, 27:6, 357-372
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Journal of Carbohydrate Chemistry, 27:357–372, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300802262778
Synthesis and Antiviral
Evaluation of Some
5-N-Arylaminomethyl-2-
glycosylsulphanyl-1,3,4-
oxadiazoles and Their
Analogs against Hepatitis A
and Herpes Simplex Viruses
Wael A. El-Sayed,1 Nahed M. Fathi,1 W. A. Gad,1
and El Sayed H. El-Ashry2,3
1Photochemistry Department, National Research Centre, Cairo, Egypt
2Faculty of Science, Department of Chemistry, Alexandria University, Alexandria,
Egypt
3International Center for Chemical and Biological Sciences, University of Karachi,
Karachi, Pakistan
N-Arylaminomethyl-3H-1,3,4-oxadiazole-2-thiones 2a,b were prepared from the corre-
sponding N-arylglycinoylhydrazides. A number of their thioglycoside derivatives
4–7a–c and S-functionalized analogs 8–11a,b were synthesized by the reaction with
different acetobromosugars and acyclic hydroxyalkylating agents. The antiviral
activity of a number of the synthesized compounds against herpes simplex virus type
1 (HSV-1) and hepatitis A virus (HAV) was evaluated. Compounds 5a and 5b showed
promising results against HAV.
Keywords Thioglycosides, Oxadiazole, S-Functionalized-oxadiazole, Glycinoyl
hydrazine, Antiviral activity, Herpes simplex virus type 1 (HSV-1), Hepa-
titis A virus (HAV)
Received August 1, 2007; accepted June 9, 2008.
Address correspondence to El Sayed H. El-Ashry, Faculty of Science, Department of
Chemistry, Alexandria University, Alexandria, Egypt. E-mail: eelashry60@hotmail.com
357

W. A. El-Sayed et al.
358
INTRODUCTION
The high-throughput synthesis and screening of compound libraries have
emerged as a key objective within the pharmaceutical industry to get new
leads of potent biological activity. The 1,3,4-oxadiazole ring has been found in
the skeleton of fungicidal and bactericidal, analgetic, antipyretic, antiphlogis-
tic, anticompulsive, and paralytic hypnotic and sedative agents,[1–4] in
addition to having antiviral activity[5] and a tyrosinase inhibiting effect.[6]
On the other hand, the glycosylthio heterocycles[7–10] and the acyclicnucleo-
side[10–13] analogs including modifications of both the glycon and aglycon
parts have stimulated extensive research as biological inhibitors.[14–18]
Recently, we became interested in the synthesis of thioglycosides, compounds
of potential biological activity, in addition to their use as glycosyl donors
and/or acceptors.[10,18–20] Consequently, we have considered the attachment
of 1,3,4-oxadiazoles, functionalized with arylmethylamino groups, to sugar
moieties or open chain analogs to produce their respective thioglycosides and
their acyclic analogs and evaluating their antiviral activity.
RESULTS AND DISCUSSION
Heterocyclization of the hydrazides 1a,b with carbon disulfide in alkali gave
5-N-arylaminomethyl-3H-1,3,4-oxadiazole-2-thiones 2a,b. Reaction of 2a,b
with acetobromo sugars in the presence of potassium hydroxide gave 5-N-aryla-
minomethyl-2-(20,30,40,60-tetra-O-acetyl-b-D-galactopyranosyl)sulphan-yl-1,3,4-
oxadiazole, 5-N-arylaminomethyl-2-(20,30,40,60-tetra-O-acetyl-b-D-glucopyrano-
syl)sulphanyl-1,3,4-oxadiazole, or 5-N-arylamino-methyl-2-(20,30,40-tri-O-acetyl-
b-D-xylopyranosyl)sulphanyl-1,3,4-oxadiazole 4a–c and 5a–c. The respective
1H NMR spectra showed the anomeric proton of the sugar moiety in the range
d 5.40 to 5.78 ppm as doublet, with a coupling constant equal to 6.5 to 9.5 Hz indi-
cating the b-orientation of the thioglycosidic bond. The anomeric proton of b-N-
glucosides having an adjacent C55S was reported[21–26] to appear at higher
chemical shift (d 6.9–7.2 ppm) due to the anisotropic deshielding effect of the
C55S.[22–26] The 13C NMR spectrum of 5b showed a signal at d 78.11 correspond-
ing to the anomeric C-10, which also confirmed the b-configuration. The absence
of a peak corresponding to the C55S group indicates that the attachment of the
sugar has taken place at the sulfur atom and not on the nitrogen atom. This also
agreed with the mode of their preparation.
When compounds 4a–c and 5a–c were treated with methanolic ammonia
at 08C, the deacetylated thioglycoside derivatives 5-N-arylaminomethyl-2-(b-
D-glycopyranosyl)sulphanyl-1,3,4-oxadiazoles 6a–c and 7a–c were obtained
in moderate yields (Sch. 1).
Compounds 2a,b have been reacted with different acyclic oxygenated alkyl
halides to give a series of open chain analogs of 1,3,4-oxadiazole. Reaction of the

Synthesis and Antiviral Evaluation
359
Scheme 1
oxadiazole thiones 2a,b with chloroethyl methyl ether and 3-chloropropan-
1,2-diol in the presence of sodium hydride in anhydrous acetonitrile gave
5-N-arylaminomethyl-2-(2-methoxyethyl)sulphanyl-1,3,4-oxadiazole 8a,b and
5-N-arylaminomethyl-2-(1,2-dihydroxypropyl)-sulphanyl-1,3,4-oxadiazoles 9a,b.
When the oxadiazole thiones 2a,b were reacted with 2-(2-chloroethoxy)ethanol
in absolute ethanol and in the presence of potassium hydroxide, the corre-
sponding 5-N-arylaminomethyl-2-(2-hydroxyethoxyethyl)sulphanyl-1,3,4-oxa-
diazoles 10a,b were obtained in 78% yield.
Reaction of the oxadiazole thiones 2a,b with epichlorohydrine in anhy-
drous acetonitrile gave the corresponding 5-N-arylaminomethyl-2-[(oxiran-2-
yl)methylsulphanyl]-1,3,4-oxadiazoles 11a,b (Sch. 2).
Plaque infectivity assay was carried out to test a number of selected com-
pounds for their antiviral activity. The test was performed to include three pos-
sibilities for antiviral activity: virucidal effect, virus adsorption, and effect on
virus replication for both hepatitis A virus (HAV) and herpes simplex virus

W. A. El-Sayed et al.
360
Scheme 2
type 1 (HSV-1). The antiviral activity against HAVrevealed that compounds 5a
and 5b showed the highest activity at concentration 20 mg/105, whereas com-
pounds 4b showed little activity (Fig. 1). The activity of 5a and 5b has been
found to be even higher than that of the standard amantadine. These data
may indicate that there is not much difference between the gluco- and
galacto- analogs, but both are characterized by the presence of a constituent
Figure 1: Effect of some novel compounds on hepatitis A virus (HAV) reduction in
comparison with amantadine (Cꢀ) as a control.

Synthesis and Antiviral Evaluation
361
Figure 2: Effect of some novel compounds on herpes simplex virus-1 (HSV-1) reduction in
comparison with acyclovir (Cꢀ) as a control.
on the aromatic ring. On the other hand, the activity against HSV-1 indicated
that compound 5b showed the highest activity, while compounds 4c and 4b
showed little activity at concentrations of 10 and 20 mg/105 (Fig. 2), but all
have less activity than the standard acyclovir.
In conclusion, a series of glycosylsulphanyl-oxadiazoles has been prepared.
The biological activity studies indicated that compounds 5a and 5b are prom-
ising candidates against HAV.
EXPERIMENTAL
Melting points were determined with a Kofler block apparatus and are uncor-
rected. The IR spectra were recorded on a Perkin-Elmer model 1720 FTIR spec-
trometer for KBr disc. NMR spectra were recorded on a Varian Gemini 200
NMR Spectrometer at 300 MHz for 1H and at 75 MHz for 13C or on a
1
Brucker Ac-250 FT spectrometer at 250 MHz for H and at 62.9 MHz for 13C.
Chemical shifts were reported in d scale (ppm) relative to TMS as a standard
and the coupling constants J values are given in Hz. The progress of the reac-
tions was monitored by TLC using aluminum silica gel plates 60 F245. The
starting N-arylglycinoylhdrazides were prepared according to a literature
method.[27] Elemental analyses were performed at the Microanalytical Data
Centre at Faculty of Science, Cairo University, Egypt. Viral screening
against HAV and HSV was conducted at the Environmental Virology Lab,
Department of Water Pollution Research, National Research Centre, Cairo,
Egypt.
5-N-Arylaminomethyl-3H-1,3,4-oxadiazole-2-thione (2a,b)
General Procedure
To a solution of N-arylglycinoylhydrazide 1a,b (0.02 mol) in ethanol
(50 mL) was added a solution of potassium hydroxide (0.02 mol) in water
(2 mL) and carbon disulphide (5 mL). The solution was heated under reflux

W. A. El-Sayed et al.
362
for 15 h. The solvent was evaporated and the residue was dissolved in water,
filtered, and acidified with dilute hydrochloric acid. The precipitate was
filtered off, washed with water, and crystallized from ethanol.
5-N-Phenylaminomethyl-3H-1,3,4-oxadiazole-2-thione (2a)
Yield 78%; m.p. 157–1598C; IR (KBr): 3315 (NH), 1615 cm21 (C55N).
1H NMR (DMSO-d6, 300 MHz): d 4.38 (d, 2H, J ¼ 5.4 Hz, CH2), 5.65 (t, 1H,
J ¼ 5.4 Hz, NH), 6.61 (m, 3H, Ar-3H), 7.07 (m, 2H, Ar-2H), 11.22 (s, 1H,
NH). Analysis calcd. for C9H9N3OS: C, 52.16; H, 4.38; N, 20.27. Found: C,
51.82; H, 4.77; N, 19.98%.
5-N-(4-Tolyl)aminomethyl-3H-1,3,4-oxadiazole-2-thione (2b)
Yield 81%; m.p. 155–1568C; IR (KBr): 3344 (NH), 1610 cm21 (C55N).
1H NMR (DMSO-d6, 300 MHz): d 2.14 (s, 3H, CH3), 4.24 (d, 2H, J ¼ 5.4 Hz,
CH2), 5.60 (t, 1H, J ¼ 5.4 Hz, NH), 6.55 (d, 2H, J ¼ 8.5 Hz, Ar-2H), 6.95
(d, 2H, J ¼ 8.5 Hz, Ar-2H), 14.24 (s, 1H, NH). 13C NMR (DMSO-d6): 19.96
(CH3), 38.04 (CH2), 112.44 (C-3,5), 125.40 (ArC-4), 129.32 (ArC-2,6), 144.87
(ArC-1), 162.43 (C55N), 177.76 (C55S). Analysis calcd. for C10H11N3OS: C,
54.28; H, 5.01, N, 18.99. Found: C, 54.66; H, 5.16; N, 18.70%.
5-N-Arylaminomethyl-2-(per-O-acetyl-b-D-
glycopyranosyl)sulphanyl-1,3,4-oxadiazoles (4–5a,b)
General Procedure
To a solution of the appropriate thiol 2a,b (0.01 mol) in aqueous potassium
hydroxide [0.01 mol in distilled water (16 mL)] was added a solution of 2,3,4,6-
tetra-O-acetyl-a-D-galacto (3a) or gluco- (3b) pyranosyl bromide and/or 2,3,4-
tri-O-acetyl-a-D-xylopyranosyl bromide (3c) (0.01 mol) in acetone (30 mL). The
reaction mixture was stirred at rt until reaction was judged complete by TLC
using chloroform/methanol 99.5:0.5. The solvent was evaporated under
reduced pressure at 408C and the residue was washed with distilled water to
remove potassium bromide formed. The product was dried and crystallized
from ethanol.
5-N-Phenylaminomethyl-2-(20,30,40,60-tetra-O-acetyl-b-D-
galactopyranos-yl)sulfanyl-1,3,4-oxadiazole (4a)
1
Yield 76%; m.p. 136–1378C; IR (KBr): 3296 (NH), 1753 cm21 (C55O). H
NMR (CDCl3, 300 MHz): d 1.98, 2.03, 2.15, 2.23 (4s, 12H, 4 CH3), 4.11 (dd,
1H, J ¼ 10.2 Hz, J ¼ 3.5 Hz, H-50), 4.14 (d, 2H, J ¼ 5.4 Hz, CH2), 4.15 (dd,

Synthesis and Antiviral Evaluation
363
1H, J ¼ 3.8, 10.2 Hz, H-600), 4.48 (dd, 1H, J ¼ 11.3, 3.8 Hz, H-60), 5.10 (t, 1H,
J ¼ 3.2 Hz, H-40), 5.18 (dd, 1H, J ¼ 6.6, 3.2 Hz, H-30), 5.29 (t, 1H, J ¼ 6.6 Hz,
H-20), 5.51 (d, 1H, J ¼ 8.5 Hz, H-10), 5.66 (t, 1H, J ¼ 5.4 Hz, NH), 6.60
(m, 3H, Ar-3H), 7.05 (m, 2H, Ar-2H). Analysis calcd. for C23H27N3O10S: C,
51.39; H, 5.06; N, 7.82. Found: C, 51.20; H, 4.95; N, 7.71%.
5-N-Phenylaminomethyl-2-(20,30,40,60-tetra-O-acetyl-b-D-
glucopyranos-yl)sulphanyl-1,3,4-oxadiazole (4b)
1
Yield 76%; m.p. 135–1378C; IR (KBr): 3320 (NH), 1749 cm21 (C55O). H
NMR (CDCl3, 300 MHz): d 1.99, 2.01, 2.05, 2.06 (4s, 12H, 4 CH3), 3.95
(m, 1H, H-50), 4.12 (dd, 1H, J ¼ 10.4, 3.3 Hz, H-600), 4.23 (dd, 1H, J ¼ 10.8,
3.2 Hz, H-60), 4.26 (d, 2H, J ¼ 5.4 Hz, CH2), 5.08 (dd, 1H, J ¼ 6.5 Hz,
J ¼ 2.8 Hz, H-40), 5.26 (dd, 1H, J ¼ 2.8, 5.8 Hz, H-30), 5.31 (t, 1H, J ¼ 5.8 Hz,
H-20), 5.65 (t, 1H, J ¼ 5.4 Hz, NH), 5.79 (d, 1H, J ¼ 8.8 Hz, H-10), 6.62
(m, 3H, Ar-3H), 7.16 (m, 2H, Ar-2H). Analysis calcd. for C23H27N3O10 S: C,
51.39; H, 5.06; N, 7.82. Found: C, 51.09; H, 4.81; N, 8.20%.
5-N-Phenylaminomethyl-2-(20,30,40-tri-O-acetyl-b-D-
xylopyranosyl) sulphanyl-1,3,4-oxadiazole (4c)
1
Yield 76%; m.p. 142–1448C; IR (KBr): 3482 (NH), 1751 cm21 (C55O). H
NMR (CDCl3, 300 MHz): d 2.09, 2.11, 2.16 (3s, 9H, 3 CH3), 4.17 (dd, 1H,
J ¼ 9.8, 3.2 Hz, H-50), 4.22 (dd, 1H, J ¼ 10.4, 3.4 Hz, H-500), 4.36 (m, 1H,
H-40), 4.37 (d, 2H, J ¼ 5.4 Hz, CH2), 4.88 (dd, 1H, J ¼ 6.5, 3.8 Hz, H-30), 5.22
(t, 1H, J ¼ 3.8 Hz, H-20), 5.60 (t, 1H, J ¼ 5.4 Hz, NH), 5.76 (d, 1H,
J ¼ 8.4 Hz, H-10), 6.66 (m, 3H, Ar-3H), 7.27 (m, 2H, Ar-2H). Analysis
calcd. for C20H23N3O8S: C, 51.60; H, 4.98; N, 9.03. Found: C, 51.66; H, 4.64;
N, 8.78%.
5-N-(4-Tolyl)aminomethyl-2-(20,30,40,60-tetra-O-acetyl-b-D-
galactopyran-osyl)sulphanyl-1,3,4-oxadiazole (5a)
1
Yield 79%; m.p. 135–1378C; IR (KBr): 3391 (NH), 1747 cm21 (C55O). H
NMR (CDCl3, 300 MHz): d 1.97, 2.01, 2.05, 2.09, 2.24 (5s, 15H, 5 CH3), 3.90
(dd, 2H, J ¼ 11.2, 3.4 Hz, H-60), 4.03 (dd, 1H, J ¼ 4.6 Hz, J ¼ 11.2 Hz, H-600),
4.25 (m, 1H, H-50), 4.55 (d, 2H, J ¼ 5.4 Hz, CH2), 5.08 (dd, 1H, J ¼ 6.8,
2.6 Hz, H-40), 5.26 (dd, 1H, J ¼ 2.6, 5.8 Hz, H-30), 5.29 (t, 2H, J ¼ 5.8 Hz,
H-20), 5.40 (d, 1H, J ¼ 9.5 Hz, H-10), 5.68 (t, 1H, J ¼ 5.4 Hz, NH), 6.60
(d, 2H, J ¼ 8.5 Hz, Ar-2H), 7.05 (d, 2H, J ¼ 8.5 Hz, Ar-2H). Analysis calcd.
for C24 H29N3O10S: C, 52.26; H, 5.30; N, 7.62. Found: C, 52.61; H, 5.39; N,
7.69%.

W. A. El-Sayed et al.
364
5-N-(4-Tolyl)aminomethyl-2-(20,30,40,60-tetra-O-acetyl-b-D-
glucopyranos-yl)sulphanyl-1,3,4-oxadiazole (5b)
1
Yield 78%; m.p. 130–1418C; IR (KBr): 3398 (NH), 1753 cm21 (C55O). H
NMR (CDCl3, 300 MHz): d 1.84, 1.99, 2.06, 2.09, 2.25 (5s, 15H, 5 CH3), 3.90
(m, 1H, H-50), 4.13 (dd, 1H, J ¼ 10.5, 3.4 Hz, H-600), 4.28 (dd, 1H, J ¼ 10.5,
3.4 Hz, H-60), 4.45 (d, 2H, J ¼ 5.4 Hz, CH2), 4.95 (m, 1H, H-40), 5.36 (dd, 1H,
J ¼ 6.5, 3.2 Hz, H-30), 5.58 (t, 1H, J ¼ 6.5 Hz, H-20), 5.65 (t, 1H, J ¼ 5.4 Hz,
NH), 5.78 (d, 1H, J ¼ 9.2 Hz, H-10), 6.58 (d, 2H, J ¼ 8.5 Hz, Ar-2H), 7.05
(d, 2H, J ¼ 8.5 Hz, Ar-2H). 13C NMR (CDCl3): d 15.19, 15.25, 15.35, 15.38,
15.49 (5CH3), 34.2 (CH2), 62.85 (C-60), 64.57 (C-50), 68.39 (C-40), 71.27 (C-30),
71.44 (C-20), 78.11 (C-10), 108.25 (ArC-2,6), 116.36 (ArC-4), 124.76 (ArC-3,5),
138.71 (ArC-l), 156.17 (C55N), 161.63 (C55N), 164.12, 164.21, 164.73, 165.35
(4CO). Analysis calcd. for C24H29N3O10S: C, 52.26; H, 5.30; N, 7.62. Found:
C, 52.12; H, 5.14: N, 7.39%.
5-N-(4-Tolyl)aminomethyl-2-(20,30,40-tri-O-acetyl-b-D-
xylopyranosyl)sulphanyl-1,3,4-oxadiazole (5c)
Yield 78%; m.p. 137–1398C; IR (KBr): 3420 (NH), 1750 cm21 (C55O).
1H NMR (CDCl3, 300 MHz): d 2.06, 2.08, 2.24, 2.23 (4s, 12H, 4 CH3), 4.23
(dd, 1H, J ¼ 9.8, 2.6 Hz, H-50), 4.27 (dd, 1H, J ¼ 10.2, 2.8 Hz, H-500), 4.55
(d, 2H, J ¼ 5.4 Hz, CH2), 4.91 (m, 1H, H-40), 5.08 (t, 1H, J ¼ 4.2 Hz, H-30),
5.19 (dd, 1H, J ¼ 6.5, 4.2 Hz, H-20), 5.62 (d, 1H, J ¼ 8.5 Hz, H-10), 5.70 (t, 1H,
J ¼ 5.4 Hz, NH), 6.60 (d, 2H, J ¼ 8.5 Hz, Ar-2H), 7.05 (d, 2H, J ¼ 8.5 Hz, Ar-
2H). Analysis calcd. for C21H25N3O8 S: C, 52.60; H, 5.26; N, 8.76. Found: C,
52.31; H, 5.53; N, 8.53%.
5-N-Arylaminomethyl-2-[(b-D-glycopyranosyl)]sulphanyl-
1,3,4-oxadiazoles (6–7a–c)
General Procedure
Dry gaseous ammonia was passed through a solution of a protected nucleo-
side 4–5a–c (0.5 g) in dry methanol (20 mL) at 08C for 0.5 h, and then the
mixture was stirred at 08C for about 5 h. The solvent was evaporated under
reduced pressure at 408C to give a solid residue, which was crystallized from
ethanol.
5-N-Phenylaminomethyl-2-(b-D-galactopyranosyl)sulphanyl-
1,3,4-oxadiazole (6a)
Yield 69%; m.p. 182–1838C; IR (KBr): 3490–3446 (OH), 3288 cm21 (NH).
1H NMR (DMSO-d6, 300 MHz): d 3.38 (m, 1H, H-60), 4.41 (dd, 1H, J ¼ 10.2,

Synthesis and Antiviral Evaluation
365
2.2 Hz, H-600), 3.62 (m, 1H, H-50), 3.64 (m, 1H, H-40), 4.04 (t, 1H, J ¼ 4.8 Hz, H-30),
4.13 (dd, 1H, J ¼ 8.2, 4.8 Hz, H-20), 4.35 (m, 1H, OH), 4.36 (d, 2H, J ¼ 5.4 Hz,
CH2), 4.92 (d, 1H, J ¼ 4.5 Hz, OH), 5.13 (d, 1H, J ¼ 4.5 Hz, OH), 5.57 (t, 1H,
J ¼ 4.2 Hz, OH), 5.75 (t, 1H, J ¼ 5.4 Hz, NH), 5.81 (d, 1H, J ¼ 8.2 Hz, H-10),
6.56 (m, 3H, Ar-3H), 7.06 (m, 2H, Ar-2H). Analysis calcd. for C15H19N3O6S: C,
48.76; H, 5.19; N, 11.38. Found: C, 48.51; H, 5.03; N, 11.25%.
5-N-Phenylaminomethyl-2-(b-D-glucopyranosyl)sulfanyl-
1,3,4-oxadiazole (6b)
Yield 70%; m.p. 177–1788C; IR (KBr): 3350–3400 (OH), 3220 cm21 (NH).
1H NMR (DMSO-d6, 300 MHz): d 3.42 (m, 1H, H-60), 3.54 (dd, 1H, J ¼ 10.4,
2.8 Hz, H-600), 3.65 (m, 1H, H-50), 3.94 (m, 1H, H-40), 4.16 (t, 1H, J ¼ 3.8 Hz,
H-30), 4.24 (d, 2H, J ¼ 5.4 Hz, CH2), 4.53 (t, 1H, J ¼ 8.4 Hz, H-20), 4.77
(d, 1H, J ¼ 4.5 Hz, OH), 4.88 (dd, 1H, J ¼ 5.2, 2.4 Hz, OH), 5.07 (t, 1H,
J ¼ 5.2 Hz, OH), 5.44 (d, 1H, J ¼ 2.4 Hz, OH), 5.68 (t, 1H, J ¼ 5.4 Hz, NH),
5.73 (d, 1H, J ¼ 8.4 Hz, H-10), 6.01 (t, 1H, J ¼ 5.4 Hz, NH), 6.58 (m, 3H, Ar-
3H), 6.92 (m, 2H, Ar-2H). Analysis calcd. for C15H19N3O6S: C, 48.76; H, 5.19;
N, 11.38%. Found: C, 48.69; H, 5.21; N, 11.31%.
5-N-Phenylaminomethyl-2-(b-D-xylopyranosyl)sulfanyl-
1,3,4-oxadiazole (6c)
Yield 68%; m.p. 183–1858C; IR (KBr): 3335–3420 (OH), 3195 cm21 (NH). 1H
NMR (DMSO-d6, 300 MHz): d 3.62 (m, 2H, H-50, H-500), 3.69 (dd, 1H, J ¼ 6.4,
2.4 Hz, H-40), 4.80 (m, 1H, H-30), 4.04 (d, 2H, J ¼ 5.4 Hz, CH2), 5.26 (dd, 1H,
J ¼ 6.5, 2.4 Hz, H-20), 4.95 (m, 1H, OH), 5.38 (m, 2H, 2OH), 5.65 (t, 1H,
J ¼ 5.4 Hz, NH), 5.70 (d, 1H, J ¼ 6.5 Hz, H-10), 6.21 (t, 1H, J ¼ 5.4 Hz, NH),
6.62 (m, 3H, Ar-3H), 7.35 (m, 2H, Ar-2H). Analysis calcd. for C14H17N3O5S: C,
49.54; H, 5.05; N, 12.38. Found: C, 49.65; H, 5.16; N, 12.42%.
5-N-(4-Tolyl)aminomethyl-2-(b-D-galactopyranosyl)sulfanyl-
1,3,4-oxadiazole (7a)
Yield 72%; m.p. 179–1818C; IR (KBr): 3315–3390 (OH), 3220 cm21 (NH).
Analysis calcd. for C16H21N3O6S: C, 50.11; H, 5.52; N, 10.96. Found: C, 50.09;
H, 5.48; N, 10.59%.
5-N-(4-Tolyl)aminomethyl-2-(b-D-glucopyranosyl)sulfanyl-
1,3,4-oxadiazole (7b)
Yield 71%; m.p. 187–1898C; IR (KBr): 3380–3410 (OH), 3255 cm21 (NH).
Analysis calcd. for C16H21N3O6S: C, 50.11; H, 5.52; N, 10.96. Found: C, 49.88;
H, 5.38; N, 10.78%.

W. A. El-Sayed et al.
366
5-N-(4-Tolyl)aminomethyl-2-(b-D-xylopyranosyl)sulfanyl-
1,3,4-oxadiazole (7c)
Yield 70%; m.p. 182–1848C; IR (KBr): 3390–3450 (OH), 3305 cm21 (NH).
1H NMR (DMSO-d6, 300 MHz): d 2.14 (s, 3H, CH3), 3.54 (m, 1H, H-50), 3.57
(dd, 1H, J ¼ 9.5, 3.2 Hz, H-500), 3.65 (dd, 1H, J ¼ 3.2, 6.8 Hz, H-40), 3.81 (dd,
1H, J ¼ 6.8, 2.4 Hz, H-30), 4.03 (t, 1H, J ¼ 6.8 Hz, H-20), 4.35 (d, 2H,
J ¼ 5.4 Hz, CH2), 4.89 (m, 1H, OH), 5.46 (m, 2H, 2OH), 5.88 (d, 1H,
J ¼ 6.8 Hz, H-10), 6.11 (t, 1H, J ¼ 5.4 Hz, NH), 6.54 (d, 2H, J ¼ 8.5 Hz, Ar-
2H), 6.93 (d, 2H, J ¼ 8.5 Hz, Ar-2H). Analysis calcd. for C15H19N3O5S: C,
50.97; H, 5.42; N, 11.89. Found: C, 50.65; H, 5.12; N, 11.81%.
5-N-Arylaminomethyl-2-(2-methoxyethyl)sulfanyl-1,3,4-
oxadiazole (8a,b)
A
mixture of 5-N-arylaminomethyl-1,3,4-oxadiazole-2-thiones 2a,b
(0.01 mol) and sodium hydride (0.01 mol) in anhydrous acetonitrile was
stirred for 2 h. The reaction mixture was cooled to 08C and chloroethylmethyl
ether (0.01 mol) was added. The mixture was stirred for 8 h, the solid precipi-
tate was filtered, and the filtrate was removed under reduced pressure. The
residue was purified on silica gel column chromatography using chloroform/
methanol (95:5) to give 8a,b.
5-N-Phenylaminomethyl-2-(2-methoxyethyl)thio-1,3,4-
oxadiazole (8a)
Yield 72%; IR (KBr): 3329 (NH), 1612 cm21 (C55N). 1H NMR (CDCl3,
300 MHz): d 3.35 (s, 3H, OCH3), 3.36 (t, 2H, J ¼ 4.5 Hz, CH2), 3.70 (t, 2H,
J ¼ 4.5 Hz, CH2), 4.55 (d, 2H, J ¼ 5.4 Hz, CH2), 5.70 (t, 1H, J ¼ 5.4 Hz, NH),
6.75 (m, 3H, Ar-3H), 7.35 (m, 2H, Ar-2H). Analysis calcd. for C12H15N3O2S:
C, 54.32; H, 5.70, N, 15.84. Found: C, 54.12; H, 5.36; N, 15.71%.
5-N-(4-Tolyl)aminomethyl-2-(2-methoxyethyl)sulfanyl-
1,3,4-oxadiazole (8b)
Yield 77%; IR (KBr): 3281 (NH), 1615 cm21 (C55N). 1H NMR (CDCl3,
300 MHz): d 2.25 (s, 3H, CH3), 3.35 (s, 3H, OCH3), 3.40 (t, 2H, J ¼ 4.5 Hz,
CH2), 3.70 (t, 2 H, J ¼ 4.5 Hz, CH2), 4.55 (d, 2H, J ¼ 5.4 Hz, CH2), 5.45
(t, 1H, J ¼ 5.4 Hz, NH), 6.55 (d, 2H, J ¼ 8.5 Hz, Ar-2H), 7.05 (d, 2H,
J ¼ 8.5 Hz, Ar-2H). Analysis calcd. for C13H17N3O2S: C, 55.89; H, 6.13, N,
15.04. Found: C, 55.52; H, 5.95; N, 14.70%.

Synthesis and Antiviral Evaluation
367
5-N-Arylaminomethyl-2-[(1,2-dihydroxypropyl)sulfanyl]-
1,3,4-oxadiazole (9a,b)
A
mixture of 5-N-arylaminomethyl-1,3,4-oxadiazole-2-thiones 2a,b
(0.01 mol) and sodium hydride (0.01 mol) in dry acetonitrile was stirred for
2 h. The reaction mixture was cooled to 08C and 3-chloropropan-1,2-diol
(0.01 mol) was added. The mixture was stirred for 6 h, and the solid precipitate
was filtered off. The filtrate was evaporated under reduced pressure. The
residue was purified on silica gel column chromatography using chloroform/
methanol (95:5) as mobile phase to give 9a,b.
5-N-Phenylaminomethyl-2-(1,2-dihydroxypropyl)sulfanyl]-
1,3,4-oxadiazole (9a)
Yield 78%; IR (KBr): 3328 (OH), 3250 cm21 (NH). 1H NMR (DMSO-d6,
300 MHz): d 3.48 (m, 2H, CH2), 3.64 (d, 2H, J ¼ 4.5 Hz, CH2), 3.78 (d, 2H,
J ¼ 5.4 Hz, CH2), 3.60 (m, 1H, CH), 4.19 (t, 1H, J ¼ 4.2 Hz, OH), 4.49
(d, 1 H, J ¼ 3.8 Hz, OH), 5.55 (t, 1H, J ¼ 5.4 Hz, NH), 6.62 (m, 3H, Ar-3H),
7.11 (m 2H, Ar-2H). Analysis calcd. for C12H15N3O3S: C, 51.23; H, 5.73, N,
14.94. Found: C, 51.66; H, 5.40; N, 15.16%.
5-N-(4-Tolyl)aminomethyl-2-[(1,2-dihydroxypropyl)sulfanyl]-
1,3,4-oxadiazole (9b)
Yield 80%; IR (KBr): 3393 (OH), 3319 cm21 (NH). 1H NMR (DMSO-d6,
300 MHz): d 2.20 (s, 3H, CH3), 3.54 (m, 2H, CH2), 3.56 (d, 2H, J ¼ 4.5 Hz,
CH2), 3.60 (m, 1H, CH), 3.89 (d, 2H, J ¼ 5.4 Hz, CH2) 3.91 (t, 1H, J ¼ 4.2 Hz,
OH), 4.48 (d, 1H, J ¼ 3.8 Hz, OH), 5.60 (t, 1H, J ¼ 5.4 Hz, NH), 6.58 (d, 2H,
J ¼ 8.5 Hz, Ar-2H), 6.97 (d, 2H, J ¼ 8.5 Hz, Ar-2H). Analysis calcd. for
C13H17N3O3S: C, 52.86; H, 5.80, N, 14.23. Found: C, 52.66; H, 6.16; N, 13.86%.
5-N-Arylaminomethyl-2-[(2-hydroxyethoxyethyl)sulfanyl]-
1,3,4-oxadiazoles (10a,b)
A
solution of 5-N-arylaminomethyl-1,3,4-oxadiazole-2-thiones 2a,b
(0.01 mol) and potassium hydroxide (0.01 mol) in ethanol (25 mL) was
warmed until all potassium hydroxide was dissolved, and then 2-(2-chloro-
ethoxy)ethanol (0.01 mol) was added. The reaction mixture was heated under
reflux for 5 h. The resulting precipitate was filtered off, the solvent was
removed under reduced pressure and the remained precipitate was washed
and crystallized.

W. A. El-Sayed et al.
368
5-N-Phenylaminomethyl-2-[(2-hydroxyethoxyethy)sulfanyl]-
1,3,4-oxadiazole (10a)
Yield 79%; m.p. 167–1698C; yield 79%; IR (KBr): 3315 (OH), 3225 cm21
(NH). 1H NMR (CDCl3, 300 MHz): d 3.36 (m, 2H, CH2), 3.53 (t, 2H, J ¼ 5.2 Hz,
CH2) 3.67 (t, 2H, J ¼ 4.5 Hz, CH2), 3.71 (t, 2H, J ¼ 5.2 Hz, CH2), 4.35 (d, 2 H,
J ¼ 5.4 Hz, CH2), 4.51 (t, J ¼ 4.4 Hz, 1H, OH), 5.65 (t, 1H, J ¼ 5.4 Hz, NH),
6.69 (m, 3H, Ar-3H), 7.13 (m, 2H, Ar-2H). Analysis calcd. for C13H17N3O3S: C,
52.86; H, 5.80, N, 14.23. Found: C, 53.11; H, 5.75; N, 14.49%.
5-N-(4-Tolyl)aminomethyl-2-[(2-hydroxyethoxyethyl)
sulfanyl]-1,3,4-oxadiazole (10b)
Yield 78%; m.p. 164–1658C; IR (KBr): 3359 (OH), 3190 cm21 (NH).
1H NMR (CDCl3, 300 MHz): d 2.22 (s, 3H, CH3), 3.40 (m, 2H, CH2), 3.57
(t, 2H, J ¼ 5.2 Hz, CH2), 3.62 (t, 2H, J ¼ 4.4 Hz, CH2), 3.80 (t, 2H,
J ¼ 5.2 Hz, CH2), 4.48 (d, 2H, J ¼ 5.4 Hz, CH2), 4.51 (t, 1H, J ¼ 4.4 Hz, OH),
5.70 (t, 1H, J ¼ 5.4 Hz, NH), 6.61 (d, 2H, J ¼ 8.5 Hz, Ar-2H), 6.99 (d, 2H,
J ¼ 8.5 Hz, Ar-2H). Analysis calcd. for C14H19N3O3S: C, 54.35; H, 6.19; N,
13.58%. Found: C, 54.22; H, 5.85; N, 13.34%.
5-N-Arylaminomethyl-2-[(oxiran-2-yl)methylsulfanyl]-
1,3,4-oxadiazoles (11a,b)
A mixture of 5-N-arylaminomethyl-1,3,4-oxadiazole-2-thiones 2a,b
(0.01 mol) and sodium hydride (0.01 mol) in anhydrous acetonitrile was
stirred for 2 h. The reaction mixture was cooled to 08C and epichlorohydrine
(0.01 mol) was added. The mixture was stirred for 6 h. at 60 to 708C, the
solid precipitate was filtered off and the filtrate was reduced under reduced
pressure, and the formed precipitate was washed and recrystallized from
ethanol.
5-N-Phenylaminomethyl-2-[(oxiran-2-yl)methylsulfanyl]-
1,3,4-oxadiazole (11a)
Yield 72%; m.p. 169–1708C; IR (KBr): 3325 (NH), 1605 (C55N) Analysis
calcd. for C25H13N3O2S: C, 54.74; H, 4.98; N, 15.96. Found: C, 54.63; H, 4.92;
N, 15.65%.
5-N-(4-Tolyl)aminomethyl-2-[(oxiran-2-yl)methylsulfanyl]-
1,3,4-oxadiazole (11b)
Yield 74%; m.p. 166–1688C; IR (KBr): 3320 (NH), 1610 cm21 (C55N).
1H NMR (CDCl3, 300 MHz): d 2.22 (s, 3H, CH3), 3.66 (d, 2H, J ¼ 5.8 Hz,

Synthesis and Antiviral Evaluation
369
CH2), 3.82 (d, 2H, J ¼ 5.2 Hz, CH2), 4.22 (d, 2H, J ¼ 5.4 Hz, CH2), 4.55 (m, 1H,
CH), 6.54 (d, 2H, J ¼ 8.5 Hz, Ar-2H), 6.99 (d, 2H, J ¼ 8.5 Hz, Ar-2H). Analysis
calcd. for C13H17N3O2S: C, 56.30; H, 5.45; N, 15.15. Found: C, 55.95; H, 5.21; N,
15.29%.
BIOLOGICAL ACTIVITY STUDIES
Preparation of Compounds for Bioassay
Tested compounds were dissolved as 100 mg each in 1 mL of 10% DMSO in
water. The final concentration was 100 mg/mL (stock solution). The dissolved
stock solutions were decontaminated by addition of 50 mg/mL antibiotic anti-
mycotic mixture (10,000 U penicillin G sodium, 10,000 mg streptomycin
sulfate, 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 Dulbecco’s Minimal
Essential Medium (DMEM) supplemented with 10% foetal bovine serum and
1% antibiotic-antimycotic mixture. The pH was adjusted at 7.2 to 7.4 by 7.5%
sodium bicarbonate solution. The mixture was sterilized by filtration through
0.2-mm pore size nitrocellulose membrane.
Viruses
HSV-1 and HAV (MBB-cell culture adapted strain) were obtained from
Environmental 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 concen-
tration (MTC) for each compound was determined by both cell morphology
and cell viability by staining with tryban blue dye.
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 con-
centrations for each virus and mixed with the tested compound at the previous
concentration and incubated overnight at 48C. Growth medium was removed

W. A. El-Sayed et al.
370
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 on 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% formalin 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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