Synthesis and antiviral evaluation of novel 5-(N-arylaminomethyl-1,3,4- oxadiazol-2-yl)hydrazines and their sugars, 1,2,4-triazoles, tetrazoles and pyrazolyl derivatives

Article abstract of DOI:10.1002/ardp.200700154

A number of new N-arylaminomethyl-1,3,4-oxadiazole derivatives 2, 3a,b, and 9-12a,b were prepared. Sugar (5-N-arylaminomethyl-1,3,4-oxadiazol-2-yl) hydrazones 4-6a,b were synthesized by the reaction of the hydrazino derivatives 3a,b with the corresponding monosaccharides. The novel acyclo-C-nucleosides 7, 8a,b were prepared by heterocyclization of the sugar hydrazones 4, 5a,b with acetic anhydride. A number of the synthesized compounds were tested for their antiviral activity against herpes simplex virus type-1 (HSV-1) and hepatitis-A virus (HAV, MBBcell culture-adapted strain). The results revealed that the sugar hydrazones 6a,b showed higher antiviral activity compared to the other hydrazones and their acetylated derivatives.

Full text of DOI:10.1002/ardp.200700154

Arch. Pharm. Chem. Life Sci. 2008, 341, 307–313
M. T. Abdel-Aal et al.
307
Full Paper
Synthesis and Antiviral Evaluation of Novel 5-(N-Aryl-
aminomethyl-1,3,4-oxadiazol-2-yl)hydrazines and Their
Sugars, 1,2,4-Triazoles, Tetrazoles and Pyrazolyl Derivatives
Mohammed T. Abdel-Aal1, Waled A. El-Sayed2, Salah M. El-Kosy1, 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
A number of new N-arylaminomethyl-1,3,4-oxadiazole derivatives 2, 3a,b, and 9–12a,b were pre-
pared. Sugar (5-N-arylaminomethyl-1,3,4-oxadiazol-2-yl) hydrazones 4–6a,b were synthesized by
the reaction of the hydrazino derivatives 3a,b with the corresponding monosaccharides. The
novel acyclo-C-nucleosides 7, 8a,b were prepared by heterocyclization of the sugar hydrazones 4,
5a,b with acetic anhydride. A number of the synthesized compounds were tested for their anti-
viral activity against herpes simplex virus type-1 (HSV-1) and hepatitis-A virus (HAV, MBBcell cul-
ture-adapted strain). The results revealed that the sugar hydrazones 6a,b showed higher antiviral
activity compared to the other hydrazones and their acetylated derivatives.
Keywords: Acyclo-nucleosides / Antiviral activity / 1,3,4-Oxadiazoles / Sugar hydrazones / Triazolo-oxadiazoles /
Received: July 23 2007; accepted: January 18, 2008
DOI 10.1002/ardp.200700154
bility in biological systems. Thus, synthesis of novel 1,3,4-
oxadiazol-2-yl-hydrazines and their sugar derivatives has
been achieved. Moreover, the cyclization of sugar hydra-
zones to novel acyclonucleoside analogues, fused oxadia-
zolo-triazoles, and tetrazoles as well as oxadioazolyl-tria-
zoles has been carried out. The antiviral activity of
selected members has been evaluated.
Introduction
1,3,4-Oxadiazoles represent an important class of hetero-
cyclic compounds. Their derivatives possess a broad spec-
trum of biological activity in both agrochemicals and
pharmaceuticals such as antibacterial [1], antimicrobial
[2], insecticidal [3], herbicidal, fungicidal [4], anti-inflam-
matory [5], hypoglycemic [6], hypotension characteristics
[7], antiviral [8], and antitumor activities [9]. The nucleo-
sides as well as their acyclic and C-nucleoside analogues
possess a wide range of medicinal properties, including
antibiotic, antiviral, and antitumor activities [10–19].
We have been interested in the attachment of carbohy-
drate moieties to heterocycles, in the synthesis of acyclo-
nucleoside analogues as well as heterocycles from carbo-
hydrate precursors [20–25]. The aim of the present work
was to attach carbohydrate residues to oxadiazoles in
order to find new biologically active leads with good solu-
Results and discussion
Chemistry
Alkylation of the oxadiazole thiones 1a,b with ethyl
iodide in alkaline medium afforded 5-N-arylamino-
methyl-2-ethylmercapto-1,3,4-oxadiazoles 2a,b. Hydrazi-
nolysis of which gave the required hydrazine derivatives
5-N-arylaminomethyl-2-hydrazino-1,3,4-oxadiazoles 3a,b
in good yields. The1H-NMR spectra of 2a,b showed the sig-
nals of the ethyl group as triplet and quartet which disap-
peared in the spectra of 3a,b, whereas the NH2 signal
appeared at d 5.60 and 5.65 ppm for 3a and 3b, respec-
tively in addition to the aromatic protons in the range d
6.15–6.95 ppm. The 13C-NMR spectrum of 3b showed the
Correspondence: El Sayed H. El-Ashry, Department of Chemistry, Fac-
ulty of Science, Alexandria University, Alexandria, Egypt.
E-mail: Eelashry60@hotmail.com
Fax: +20 342 71360
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

308
M. T. Abdel-Aal et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 307–313
Scheme 1. Synthesis route of presented compounds 1–8.
signals of C=N group at 152.77 ppm and the aromatic car-
bons at d 112.44–144.87 ppm.
Scheme 2. Synthesis route of presented compounds 9–12.
When compounds 3a,b were allowed to react with a
number of monosaccharides, the corresponding alde- tion to the O-acetyl groups. The 1H-NMR spectra of 7–8a, b
hydo sugar hydrazones were obtained (Scheme 1). Thus, showed the signals of the O-acetyl-methyl protons as sin-
reaction of the hydrazine derivatives 3a,b with D-galac- glets in the range d 1.83–2.20 ppm and the N-acetyl-
tose, D-mannose and D-arabinose in an aqueous ethanolic methyl protons in the range d 2.24–2.30 ppm. The rest of
solution and catalytic amount of acetic acid gave the cor- the alditolyl chain protons appeared in the range d 3.77–
responding sugar (5-N-arylaminomethyl-1,3,4-oxadiazol- 5.75 ppm in addition to the aromatic protons as multip-
2-yl)hydrazones 4–6a,b. The structures of these com- lets in the region d 6.59–7.05 ppm. The13C-NMR spectrum
pounds were confirmed by the analytical and spectral of 7a showed the resonances of the acetyl-methyl carbons
data. The IR spectra of 4–6a,b showed the presence of at d 20.35–29.76 ppm. The value of the chemical shift of
characteristic absorption bands corresponding to the the C-1of the sugarproton appeared atd92.08 ppm whose
hydroxyl groups in the region 3200–3500 cm– 1. The 1H- value indicated its N,N-acetal nature rather than being a
NMR spectra showed the signals of the sugar chain pro- C=N; the later should appear at a lower field. The signals at
tons at d 3.30–5.78 ppm, the C-1 methine proton as dou- d 168.95–178.24 ppm corresponded to the carbonyl
blet in the range d 6.38–7.65 ppm in addition to the aro- groups. The elemental analyses were in agreement with
matic protons in the region d 6.50–7.80 ppm.
the assigned structures (Scheme 1). Consequently, the
The reaction of sugar arylhydrazones with boiling ace- reactions of 4, 5a,b with boiling acetic anhydride caused a
tic anhydride is well known to give the respective per-O,N- novel cyclization accompanying the acetylation to give
acetyl derivatives [26–29]. However, treatment of the 2-acetyl-3-(19,29,39,49,59-penta-O-acetylsugar)-6-N-arylamino-
sugar hydrazones 4–5a,b with boiling acetic anhydride methyl-2,3-dihydro[1,2,4]triazole[3,4-b]-[1,3,4-oxadiazo-
did not afford the expected per-O,N-acetyl or their per-O- les] 7–8a,b.
acetyl derivatives, but gave compounds 7–8a,b. The later
The literature indicated the broad utility of heterocy-
structures were deduced from their IR, H-NMR, and 13C- clic hydrazines for the synthesis of several condensed sys-
NMR spectra. The IR spectra of 7–8a,b showed characteris- tems containing triazole and tetrazole ring systems
tic absorption bands in the carbonyl frequency region at [30, 31]. Thus, 5-N-arylaminomethyl-2-hydrazino-1,3,4-
1653–1678 cm– 1 and 1746–1775 cm– 1 corresponding to oxadiazoles 3a,b were utilized in preparing a series of
the carbonyl amide and the carbonyl ester groups, respec- condensed heterocyclic compounds (Scheme 2). The reac-
tively, indicating the presence of N-acetyl group in addi- tion of compounds 3a,b with carbon disulphide in the
1
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2008, 341, 307–313
Novel 5-(N-Aryl-aminomethyl-1,3,4-oxadiazol-2-yl)hydrazines
309
presence of alcoholic potassium hydroxide and subse-
quent acidification gave 6-N-arylamino-methyl[1,2,4]tria-
zolo[3,4-b][1,3,4]oxadiazole-(2H)-3-thiones 9a,b in 77–79%
yield. The IR spectra of 9a,b showed the presence of char-
acteristic absorption bands corresponding to the C=N
and C=S groups. The1H-NMR spectra showed the presence
of a singlet at d 13.75 or 14.05 ppm corresponding to the
NH group of 9a and 9b, respectively, in addition to the
aromatic protons at d 7.22–7.65 ppm.
When compounds 3a,b were reacted with sodium
nitrite and hydrochloric acid (Scheme 2), the correspond-
ing 5-N-arylamino-methyl-1,3,4-oxadiazolo[1,5-d][1,2,3,4]-
tetrazoles 10a,b were obtained. Their IR spectra showed
the absence of the NH2 absorption band and the presence
of characteristic absorption band corresponding to the
C=N group. Their 1H-NMR spectra showed the CH2 group
as a doublet at d 3.39 and 4.25 ppm for 10a and 10b,
respectively and the aromatic protons as multiplets at d
6.63–7.66 ppm.
Figure 1. Effect of some novel compounds on Herpes simplex
virus-1 reduction in comparison with acyclovir (C*) as a control.
Condensation of 3a,b with 1,3-dicarbonyl compounds
gave the respective pyrazole and pyrazolidinone deriv-
atives. Thus, reaction of 3a,b with acetylacetone in diox-
ane gave 2-(3,5-dimethylpyrazol-1-yl)-5-N-arylamino-
methyl-1,3,4-oxadiazoles 11a,b, via a known mechanism
[32] that involved initial reaction of the NH2 group of 3a,b
with one carbonyl group of the diketone, followed by cyc-
lization of the remaining carbonyl to form the pyrazole
ring (Scheme 2).
Cyclocondensation of 3a,b with diethylmalonate
(Scheme 2) gave the 2-[3,5-dioxo-(2H)-pyrazol-1-yl]-5-N-5-
arylaminomethyl-1,3,4-oxadiazoles 12a,b. The IR spectra
of compounds 12a,b showed the presence of the expected
characteristic absorption band in the carbonyl frequency
region. The 1H-NMR spectrum of compounds 11a showed
the signals at d 2.20 and 2.23 ppm as singlets correspond-
ing to the methyl groups and the aromatic protons
appeared in the range d 6.80–7.10 ppm.
Figure 2. Effect of some novel compounds on Hepatitis A virus
reduction in comparison with amantadine (C*) as a control.
conclusion, the sugar hydrazones 6a,b showed higher
antiviral activity compared to the other hydrazones and
their acetylated derivatives.
Physical properties and spectral data of the newly syn-
thesized compounds are listed in Tables 1 and 2.
The authors have declared no conflict of interest.
Experimental
Antiviral activity
General
A plaque infectivity assay was carried out testing a num-
ber of selected compounds for their 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 and HSV-1. The
antiviral activity against herpes simplex virus (HSV)
revealed that compounds 6a and 6b showed the highest
activity at concentration 20 lg/105 and 10 lg/105, respec-
tively (Fig. 1). Compounds 5b and 7a showed little activity
at both concentrations.
Melting points were determined with a Kofler block apparatus
(C. Reichert, Vienna, Austria) and are uncorrected. The IR spectra
were recorded on a Perkin-Elmer model 1720 FTIR spectrometer
for KBr disc (Perkin-Elmer, Norwalk, CT, USA). NMR spectra were
recorded on a Varian Gemini 200 NMR Spectrometer at 300 MHz
for 1H (Varian Inc., Palo Alto, CA, USA) and 75 MHz for13C or on a
Bruker Ac-250 FT spectrometer at 250 MHz for 1H and at
62.9 MHz for 13C with TMS as a standard (Bruker Bioscience, Bill-
erica, MA, USA). The progress of the reactions was monitored by
TLC using aluminum silica gel plates 60 F 245. Elemental analy-
ses 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 Labora-
tory, Department of Water Pollution Research, National
Research Centre, Cairo, Egypt.
For the activity against hepatitis-A virus (HAV), the
results showed that compound 6a showed the highest
activity at both concentration 10 and 20 lg/105 (Fig. 2). In
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

310
M. T. Abdel-Aal et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 307–313
Table 1. Physicochemical properties of the newly synthesized compounds.
Compound
Mp. (8C)
from ethanol
Mol. Formula
Yield
(%)
Analysis % (Calcd./Found)
IR Spectra
(cm– 1
)
C
H
N
2a
2b
3a
158–159
162–163
239–231
C11H13N3OS
(235.31)
C12H15N3OS
(349.33)
C9H11N5O
(205.22)
77
79
78
56.15
55.77
57.81
57.44
52.67
52.71
5.57
5.52
6.06
5.72
5.40
5.39
17.86
17.50
16.85
16.48
34.13
34.05
1610 (C=N)
3415 (NH)
1605 (C=N)
3423 (NH)
1615 (C=N)
3291 (NH)
3393 (NH2)
1614 (C=N)
3310 (NH)
3351 (NH2)
1605 (C=N)
3130 (NH)
3391–4440 (OH)
1610 (C=N)
3310 (NH)
3350–3490 (OH)
1605 (C=N)
3120 (NH)
3398–3450 (OH)
1590 (C=N)
3285 (NH)
3373–3420 (OH)
1615 (C=N)
3150 (NH)
3320–3400 (OH)
1605 (C=N)
3160 (NH)
3477–3500 (OH)
1658 (OCN)
1751 (OAc)
3472 (NH)
3b
4a
4b
5a
5b
6a
6b
7a
7b
8a
8b
225–227
188–190
187–189
187–189
184–185
188–189
184–185
145–147
151–152
149–150
151–152
C10H13N5O
(219.24.36)
79
54.78
55.14
5.98
5.62
31.94
31.59
C15H21N5O6
(367.38)
83
49.04
48.82
5.76
5.51
19.06
18.82
C16H23N5O6
(381.38)
82.5
82
50.39
50.66
6.08
5.91
18.36
18.12
C15H21N5O6
(367.38)
49.04
48.69
5.76
5.48
19.06
18.84
C16H23N5O6
(381.38)
78.5
79
50.39
50.69
6.08
5.89
18.36
18.15
C14H19N5O5
(337.33)
49.85
50.05
5.68
5.78
20.76
20.51
C15H21N5O5
(351.39)
81.5
68.5
73.5
71.5
72
51.28
51.41
6.02
6.19
19.93
19.71
C27H33N5O12
(619.58)
52.34
52.12
5.37
5.24
11.30
11.41
C28H35N5O12
(633.60)
53.08
53.42
5.57
5.53
11.05
11.02
1653 (OCN)
1751 (OAc)
3481 (NH)
1657 (OCN)
1746 (OAc)
3466 (NH)
1678 (OCN)
1775 (OAc)
3371(NH)
C27H33N5O12
(619.58)
52.34
52.22
5.37
5.18
11.32
11.71
C28H35N5O12
(633.60)
53.08
52.82
5.57
5.83
11.05
10.82
9a
9b
205–207
208–207
225–226
223–225
217–218
219-221
C10H9N5OS
(247.29)
C11H11N5OS
(261.30)
C9H8N6O
(216.20)
C10H10N6O
(230.27)
C14H15N5O
(269.30)
C15H17N5O
(238.33)
C12H11N5O3
(273.25)
77
79
77
79
85
87
75
48.57
48.45
50.56
50.38
50.00
49.82
52.17
51.95
62.44
62.62
63.59
63.25
52.75
52.37
3.67
3.55
4.24
4.11
3.73
3.52
4.38
4.58
5.61
5.62
6.05
5.83
4.06
3.84
28.32
28.15
26.80
26.65
38.87
38.77
36.50
36.28
26.01
25.82
24.72
24.43
25.63
25.21
1605 (C=N)
3368 (NH)
1615 (C=N)
3334 (NH)
1610 (C=N)
3105 (NH)
1620 (C=N)
3350 (NH)
1615 (C=N)
3180 (NH)
1615 (C=N)
3250 (NH)
1604 (C=N)
1677 (C=O)
3371 (NH)
10a
10b
11a
11b
12a
209–210
12b
210–212
C13H13N5O3
(287.27)
76
54.35
54.12
4.56
4.31
24.38
24.13
1610 (C=N)
1662 (C=O)
3434 (NH)
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2008, 341, 307–313
Novel 5-(N-Aryl-aminomethyl-1,3,4-oxadiazol-2-yl)hydrazines
311
1
Table 2. H- and 13C-NMR spectra of the newly synthesized compounds.
H1 –NMR/13C-NMR (d, ppm)
Compound
1.19 (t, 3H, J = 6.2 Hz, CH3), 3.84 (d, 2H, J = 5.4 Hz, CH2), 4.09 (q, 2H, J = 6.2 Hz, CH2), 5.70 (t, 1H, J = 5.4 Hz, NH), 6.47
(m, 2H, J = 8.5 Hz, Ar-2H), 6.89 (m, 3H, J = 8.5 Hz, Ar-3H).
1.19 (t, 3H, J = 6.2 Hz, CH3), 2.14 (s, 3H, CH3), 3.84 (d, 2H, J = 5.4 Hz, CH2), 4.09 (q, 2H, J = 6.2 Hz, CH2), 5.70 (t, 1H,
J = 5.4 Hz, NH), 6.47 (d, 2H, J = 8.5 Hz, Ar-2H), 6.89 (d, 2H, J = 8.5 Hz, Ar-2H).
4.30 (d, 2H, J = 5.4 Hz, CH2), 5.60 (s, 2H, NH2), 6.05 (s, 1H, NH), 6.65 (m, 3H, Ar-3H), 7.15 (m, 2H, Ar-2H), 13.15
(s, 1H, NH).
2.12 (s, 3H, CH3), 4.12 (d, 2H, J = 5.4 Hz, CH2), 5.65 (s, 2H, NH2), 5.80 (s, 1H, NH), 6.15 (d, 2H, J = 8.5 Hz, Ar-2H), 6.95
(d, 2H, J = 8.5 Hz, Ar-2H), 13.16 (s, 1H, NH)/19.98 (CH3), 37.20 (CH2), 112.62 (ArC-3,5), 124.69 (ArC-4), 129.09 (ArC-2,6),
145.79 (ArC-1), 152.77 (C=N), 162.81 (C=N).
2a
2b
3a
3b
3.30-3.42 (m, 2H, H-6‘, H-6''), 3.61 (m, 1H, H-5'), 3.66 (m, 1H, H-4'), 3.71 (dd, 1H, J = 2.8 Hz, J = 5.8 Hz, H-3'), 4.29 (t, 1H,
J = 5.8 Hz, H-2'), 4.33 (d, 2H, J = 5.4 Hz, CH2), 4.53 (m, 1H, OH), 4.94 (d, 1H, J = 6.3 Hz, OH), 5.25 (m, 1H, OH), 5.75 (t, 1H,
J = 4.5 Hz, OH), 5.85 (t, 1H, J = 4.5 Hz, OH), 5.96 (t, 1 H, J = 5.4 Hz, NH), 6.6 (m, 3H, Ar-3H), 7.4 (d, 1H, J = 5.8 Hz, H-1'),
7.6 (m, 2 H, Ar-2H), 11.2 (s, 1H, NH).
2.14 (s, 3H, CH3), 3.39 (m, 2H, H-6‘, H-6''), 3.54 (m, 1H, H-5'), 3.66 (m, 1H, H-4'), 4.02 (dd, 1H, J = 5.6 Hz, J = 2.6 Hz, H-3'),
4.11 (dd, 1H, J = 2.6 Hz, J = 5.8 Hz, H-2'), 4.31 (d, 2H, J = 5.4 Hz, CH2), 4.45 (d, 1H, J = 2.8 Hz, OH), 4.85 (d, 1H, J = 3.5 Hz,
OH), 5.19 (m, 1 H, OH), 5.30 (t, 1H, J = 5.8 Hz, OH), 5.55 (d, 1H, J = 3.5 Hz, OH), 5.75 (t, 1H, J = 5.4 Hz, NH), 6.51 (d, 2H,
J = 8.5 Hz, Ar-2H), 6.91 (d, 2H, J = 8.5 Hz, Ar-2H), 7.45 (d, 1H, J = 5.8 Hz, H-1'), 11.01 (s, 1H, NH).
3.36 (m, 1H, H-6`), 3.39 (dd, 1H, J = 10.5 Hz, 3.6 Hz, H-6''), 3.53 (dd, 1H, J = 3.6 Hz, 6.2 Hz, H-5'), 3.61 (m, 1H, H-4'),
3.79 (dd, 1H, 2.8 Hz, 6.2 Hz, H-3'), 4.17 (d, 2H, J = 5.4 Hz, CH2), 4.18 (dd, 1H, J = 2.8 Hz, J = 5.8 Hz, H-2'), 4.34 (m, 1H,
J = 6.2 Hz, OH), 4.9 (d, 1H, J = 2.8 Hz, OH), 4.99 (d, 1H, J = 3.6 Hz, OH), 5.03 (t, 1H, J = 4.5 Hz, OH), 5.18 (m, 1H, OH),
6.02 (t, 1H, J = 5.4 Hz, NH), 6.65 (m, 3H, Ar-3H), 7.09 (m, 2H, Ar-2H), 7.32 (m, 2H, Ar-2H), 6.38 (d, 1H, J = 5.8 Hz, H-1'),
11.21 (s, 1H, NH).
4a
4b
5a
3.04 (m, 1H, H-5'), 3.22 (dd, 1H, J = 9.8 Hz, J = 2.8 Hz, H-5''), 3.49 (m, 1H, H-4'), 3.75 (t, 1H, J = 2.2 Hz, H-3'), 3.90 (dd, 1H,
J = 5.8 Hz, J = 2.2 Hz, H-2'), 4.22 (d, 2H, J = 5.4 Hz, CH2), 4.45 (m, 1H, OH), 5.17 (d, 1H, J = 2.8 Hz, J = 6.3 Hz, OH), 5.57
(t, 1H, J = 2.2 Hz, OH), 5.79 (d, 1H, J = 4.5 Hz, OH), 5.90 (t, 1H, J = 5.4 Hz, NH), 7.54 (m, 2H, Ar-2H), 7.80 (m, 3H, Ar-3H),
7.65 (d, 1H, J = 5.8 Hz, H-1'), 11.48 (s, 1H, NH).
2.14 (s, 3H, CH3), 3.42 (m, 2H, H-5‘, H-5''), 3.68 (m, 1H, H-4'), 3.72 (t, 1H, J = 2.8 Hz, H-3'), 4.16 (d, 2H, J = 5.4 Hz, CH2),
4.28 (dd, 1H, 2.8 Hz, J = 5.8 Hz, H-2'), 4.43 (d, 1H, J = 2.8 Hz, OH), 5.15 (d, 1H, J = 4.5 Hz, OH), 5.25 (m, 1H, OH), 5.60
(t, 1H, J = 6.2 Hz, OH), 5.78 (t, 1H, J = 5.4 Hz, NH), 6.5 (m, 2H, Ar-2H), 6.9 (d, 2H, J = 8.5 Hz, Ar-2H), 7.40 (d, 1H, J = 5.8 Hz,
H-1'), 11.11 (s, 1H, NH).
1.83, 1.98, 2.04, 2.11, 2.20, 2.30 (6s, 18H, 6CH3), 4.15 (dd, 1H, J = 11.2 Hz, J = 2.4 Hz, H-5''), 4.20 (dd, 1H, J = 10.6 Hz,
J = 2.4 Hz, H-5''), 4.53 (d, 2H, J = 5.4 Hz, CH2), 5.15 (dd, 1H, J = 2.8 Hz, J = 6.5 Hz, H-4'), 5.25 (dd, 1H, J = 3.2 Hz, J = 6.5 Hz,
H-3'), 5.50 (dd, 1H, J = 3.2 Hz, J = 6.2 Hz, H-2'), 5.70 (t, 1H, J = 6.2 Hz, H-1'), 5.73 (t, 1H, J = 5.4 Hz, NH), 5.78 (d, 1H,
J = 6.2 Hz, triazole-H), 6.61 (m, 3H, Ar-2H), 7.01 (m, 3H, Ar-2H)/20.35, 20.50, 20.58, 20.67, 20.76, 29.67 (6CH3), 39.57
(CH2), 62.82 (C-5'), 65.38 (C-4'), 68.36 (C-3'), 69.7 (C-2'), 71.04 (C-1'), 92.08 (C-N), 113.05 (ArC-2,6), 128.57 (ArC-4), 129.96
(ArC-3,5), 143.32 (C-1), 158.45 (C=N), 160.35 (C=N), 168.95 (C=O), 169.64 (C=O), 169.75 (C=O), 169.93 (C=O), 170.05
(C=O), 178.24 (C=O).
6a
6b
7a
1.98, 2.01, 2.05, 2.09, 2.13, 2.24, 2.36 (7s, 21H, 7CH3), 3.77 (dd, 1H, J = 2.6 Hz, J = 11.8 Hz, H-5'), 4.03 (dd, 1H, J = 3.5 Hz,
J = 11.8 Hz, H-5''), 4.26 (dd, 1H, J = 3.5 Hz, J = 5.8 Hz, H-4'), 4.55 (d, 2H, J = 5.4 Hz, CH2), 5.13-5.16 (m, 2H, H-2‘, H-3'), 5.37
(dd, 1H, J = 3.2 Hz, J = 6.2 Hz, H-1'), 5.45 (d, 1H, J = 6.2 Hz, triazole-H), 5.72 (t, 1H, J = 5.4 Hz, NH), 6.62 (d, 2H, J = 8.5 Hz,
Ar-2H), 7.03 (m, 2H, Ar-2H).
2.03, 2.06, 2.08, 2.11, 2.17, 2.24 (6s, 18H, 6CH3), 3.95 (dd, 1H, J = 18.8 Hz, J = 2.5 Hz, H-5''), 4.15 (dd, 1H, J = 11.3 Hz,
J = 2.5 Hz, H-5''), 4.38 (m, 1H, H-4'), 4.55 (d, 2H, J = 5.4 Hz, CH2), 5.15 (dd. 1H, J = 4.8 Hz, J = 2.2 Hz, H-3'), 5.20 (t, 1H,
J = 3.2 Hz, H-2'), 5.45 (dd, 1H, J = 3.2 Hz, J = 6.2 Hz, H-1'), 5.71 (d, 1H, J = 6.2 Hz, triazole-H), 5.81 (t, 1H, J = 5.4 Hz, NH),
6.59 (m, 2H, Ar-3H), 7.03 (m, 3H, Ar-2H).
7b
8a
5.05 (d, 2H, J = 5.4 Hz, CH2), 5.70 (t, 1H, J = 5.4 Hz, NH), 7.40 (m, 3H, Ar-3H), 7.55 (m, 2H, Ar-2H), 14.05 (s, 1H, NH).
2.20 (s, 3H, CH3), 5.05 (d, 2H, J = 5.4 Hz, CH2), 5.75 (t, 1H, J = 5.4 Hz, NH), 7.22 (d, 2H, J = 8.5 Hz, Ar-2H), 7.65 (d, 2H,
J = 8.5 Hz, Ar-2H), 13.75 (s, 1H, NH).
9a
9b
3.39 (d, 2H, J = 5.4 Hz, CH2), 6.22 (t, 1H, J = 5.4 Hz, NH), 6.63 (m, 3H, Ar-3H), 7.15 (m, 2H, Ar-2H).
2.25 (s, 3H, CH3), 4.25 (d, 2H, J = 5.4 Hz, CH2), 5.78 (t, 1H, J = 5.4 Hz, NH), 7.15 (d, 2H, J = 8.5 Hz, Ar-2H), 7.66 (d, 2H,
J = 8.5 Hz, Ar-2H).
10a
10b
2.20 (s, 3H, CH3), 2.23 (s, 3H, CH3), 4.40 (d, 2H, J = 5.4 Hz, CH2), 6.03 (t, 1H, J = 5.4 Hz, NH), 6.15 (s, 1H, CH), 6.59
(m, 1H, Ar-1H), 6.75 (m, 2H, Ar-2H), 7.01 (m, 2H, Ar-2H).
3.67 (s, 2H, CH2), 4.23 (d, 2H, J = 5.4 Hz, CH2), 5.78 (t, 1H, J = 5.4 Hz, NH), 6.56 (m, 3H, Ar-3H), 7.07 (m, 2H, Ar-2H),
9.04 (s, 1H, NH).
2.15 (s, 3H, CH3), 3.61 (s, 2H, CH2), 4.42 (d, 2H, J = 5.4 Hz, CH2), 5.65 (t, 1H, J = 5.4 Hz, NH), 6.45 (d, 2H, J = 8.5 Hz,
Ar-2H), 6.88 (d, 2H, J = 8.5 Hz, Ar-2H), 9.05 (s, 1H, NH).
11a
12a
12b
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

312
M. T. Abdel-Aal et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 307–313
Chemistry
2-(3,5-Dimethylpyrazol-1-yl)-5-N-arylaminomethyl-1,3,4-
oxadiazoles 11a,b and 2-[3,5-Dioxo-(2H)-pyrazolidin-1-
yl]-5-N-arylaminomethyl-1,3,4-oxadiazoles 12a,b
5-N-Arylaminomethyl-2-ethylmercapto-1,3,4-oxadiazoles
2a,b
To a solution of N-arylaminomethyl-1,3,4-oxadiazole-2-thione
1a,b (0.01 mol) and potassium hydroxide (0.01 mol) in water
(25 mL), was added ethyl iodide (0.01 mol). The solution was
stirred at room temperature for 2 h. The resulting precipitate
was filtered off and crystallized from ethanol.
General procedure: Acetylacetone or diethylmalonate (0.01 mol)
was added to a solution of 5-N-arylaminomethyle-2-hydrazino-
1,3,4-oxadiazole 3a,b (0.01 mol) in dioxane (20 mL) as well as a
few drops of triethylamine. The mixture was refluxed for 4 h.
The reaction mixture was then concentrated, cooled to room
temperature, and the formed precipitate was filtered off, and
crystallized from ethanol to give compounds 11a,b or 12a,b.
5-N-Arylaminomethyl-2-hydrazino-1,3,4-oxadiazoles
3a,b
Antiviral screening
A solution of N-arylaminomethyl-2-ethylmercapto-1,3,4-oxadia-
zole 2a,b (0.01 mol) and hydrazine hydrate (0.03 mol) in ethanol
was heated under reflux for 6 h. The solution was cooled and the
resulting precipitate was filtered and crystallized from ethanol.
Preparation of the compounds for bioassay
The test compounds (100 mg) were dissolved each in 1 mL of
10% DMSO (in water). The final concentration was 100 lg/lL
(stock solution). The stock solutions were decontaminated by
addition of 50 lg/mL antibiotic antimycotic mixture (10000 U
penicillin G sodium, 10000 lg streptomycin sulfate, and 250 lg
amphotericin B; PAA Laboratories GmbH, Austria).
Sugar (5-N-arylaminomethyl-1,3,4-oxadiazol-2-yl-
hydrazones 4–6a–c
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 5-N-arylaminomethyl-2-
hydrazino-1,3,4-oxadiazole 3a,b (0.01 mol) in ethanol (10 mL).
The mixture was heated under reflux for 3 h, the resulting solu-
tion was concentrated and left to cool. The precipitate formed
was filtered off, washed with water and ethanol, then dried and
crystallized from ethanol.
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 sol-
ution. The mixture was sterilized by filtration through 0.2 lm-
pore size nitrocellulose membrane.
2-Acetyl-3-(19,29,39,49,5'-penta-O-acetyl-alditol-1-yl)-6-N-
arylamino-methyl-2,3-dihydro[1,2,4 ]triazolo[3,4-b]
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.
[1,3,4]-oxadiazoles 7–8a,b
General procedure: A solution of sugar (5-N-arylaminomethyl-
1,3,4-oxadiazol-2-yl)-hydrazones 4–5a,b (1 mmol) in acetic anhy-
dride (5 mL) was boiled under reflux for 1 h. The resulting solu-
tion was poured onto crushed ice, and the product that sepa-
rated out was filtered off, washed with sodium hydrogen carbo-
nate and water, and was then dried.
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 both by cell morphology and cell viabil-
ity by staining with trypan blue dye.
6-N-Arylaminomethyl[1,2,4]triazolo[3,4-b][1,3,4]-
oxadiazole-(2H)-3-thiones 9a,b
To a solution of N-arylaminomethyl-2-hydrazino-1,3,4-oxadia-
zole 3a, b (0.02 mol) in ethanol (50 mL) was added a solution of
potassium hydroxide (0.02 mol) dissolved in water (2 mL) and
carbon disulphide (5 mL). The solution was heated under reflux
for 15 h. The solvent was evaporated and the residue was dis-
solved in water, filtered off, and acidified with dilute hydro-
chloric acid. The formed precipitate was filtered off, washed
with water, and crystallized from ethanol.
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 as final concentration 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 the virus-compound mixture was inocu-
lated (100 lL/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
the chemical compounds. Virus plaques were counted and the
percentage of reduction was calculated [33].
5-N-Arylaminomethyl-1,3,4-oxadiazolo[1,5-d][1,2,3,4]-
tetrazoles 10a,b
A solution of sodium nitrite (0.01 mol) in water (3 mL) was added
to a cooled and stirred solution of 5-N-arylaminomethyl-2-hydra-
zino-1,3,4-oxadiazole 3a,b (0.01 mol) in 50% aqueous HCl (10 mL)
over the time span of 1 h. The resulting precipitate was filtered
off and recrystallized from ethanol.
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2008, 341, 307–313
Novel 5-(N-Aryl-aminomethyl-1,3,4-oxadiazol-2-yl)hydrazines
313
[18] P. Franchetti, L. Cappellacci, G. AbuSheikha, H. N.
References
Jayaram, et al., J. Med. Chem. 1997, 40, 1731–1737.
[1] O. Ates, A. Kocabalkanli, G. O. Sanis, A. C. Ekinci, A. Vidin,
[19] F. Hammerschmidt, B. Peric, E. Ohler, Monatsh. Chem. 1997,
128, 183–190.
Drug Res. 1997, 47, 1134–1138.
[2] A. R. Farghaly, J. Chin. Chem. Soc. 2004, 51, 147–165.
[20] E. S. H. El Ashry, A. El Nemr in Synthesis of naturally occur-
ring nitrogen heterocycles from carbohydrates, Blackwell,
Oxford, UK, 2005, pp. 1–45; E. S. H. El Ashry, Y. El Kilany,
N. M. Nahas in Heterocycles from carbohydrate precursors
(Ed.: E. S. H. El Ashry) Top. Heterocycl. Chem. (Ed.: R. R.
Gupta) Springer, Germany, 2007, 7, pp. 1–30.
[3] X. Z. Z. Li, Y. Wang, W. Chen, Q. Huang, et al., J. Fluor.
Chem. 2003, 123, 163–169.
[4] X. Zou, Z. Zhang, G. J. Jin, J. Chem. Res. Synop. 2002, 5, 228–
230.
[5] E. Palaska, G. Sahin, P. Kelicen, N. T. Durlu, G. Altinok,
[21] N. Rashed, A. Abdel Hamid, E. S. Ramadan, E. S. H. El
Farmaco 2002, 57, 101–107.
Ashry, Nucleosides Nucleotides 1998, 17, 1373–1384.
[6] M. Y. Mhasalkar, M. H. Shah, P. D. Pilankar, S. T. Nikan, et
al., J. Med. Chem. 1971, 14, 1000–1003.
[22] E. S. H. El Ashry, Y. El Kilany, F. Singab, Carbohydr. Res.
1977, 56, 93–104.
[7] M. Tyagi, A. Kumar, Orient. J. Chem. 2002, 18, 125–130.
[23] E. S. H. El Ashry, M. Nassr, F. Singab, Carbohydr. Res. 1977,
56, 200–206.
[8] A. A. El-Emam, A. O. Al-Deep, M. Al-Omar, J. Lehmann, Bio-
org. Med. Chem. 2004, 12, 5107–5113.
[24] E. S. H. El Ashry, I. E. El Kholy, Y. El Kilany, Carbohydr. Res.
1978, 59, 417–426.
[9] H. Liszkiewicz, M. W. Kowalska, J. Wietrzyk, A. Opolski,
Ind. J. Chem. Sec. B–Org. Chem. Including Med. Chem. 2003,
42B, 2846–2852; K. M. Lokanatha Rai, N. Linganna, Farm-
aco 2000, 55, 389–392.
[25] A. Hamid, E. R. Abo-Amaym, E. S. H. El Ashry, Nucleosides
Nucleotides 1998, 17, 1385–1407.
[10] A. Holy, Nucleosides Nucleotides 1987, 6, 147–155.
[26] L. Somogyi, Carbohydr. Res. 1978, 64, 289–292.
[11] R. J. Remy, J. A. Secrist, Nucleosides Nucleotides 1985, 4,
[27] M. M. Abdel Rahman, E. S. H. El Ashry, A. A. Abdalla, N.
411–427.
Rashed, Carbohydr. Res. 1979, 73, 103–111.
[12] A. Larson, S. Alenius, N. G. Johnsson, B. Oberg, Antiviral
Res. 1983, 3, 77–86.
[28] E. S. H. El Ashry, R. Soliman, K. Mackawy, Carbohydr. Res.
1979, 72, 305–308.
[13] E. S. H. El Ashry, Y. El Kilany, Adv. Heterocycl. Chem. 1996,
67, 391–438.
[29] L. Somogyi, Carbohydr. Res. 1977, 54, C14–C16.
[30] A. Monge Vega, I. Aldama, M. M. Rabbani, A. E. Fernandez,
[14] E. S. H. El Ashry, Y. El Kilany, Adv. Heterocycl. Chem. 1997,
68, 1–88.
J. Heterocycl. Chem. 1980, 17, 77–81.
[31] R. C. Joshi, P. Chand, J. Heterocycl. Chem. 1980, 17, 1983–
[15] E. S. H. El Ashry, Y. El Kilany, Adv. Heterocycl. Chem. 1998,
69, 129–215.
1989.
[32] K. A. Brien, C. M. Garner, K. G. Pinney, Tetrahedron 2006,
62, 3663–3666.
[16] C. K. Chu, S. J. Cutler, J. Heterocycl. Chem. 1986, 23, 289–
319.
[17] G. M. Markar, G. M. Keseru, J. Med. Chem. 1997, 40, 4154–
[33] R. S. Farag, A. S. Shalaby, G. A. El-Baroty, N. A. Ibrahim, et
al., Phytother. Res. 2004, 18, 30–35.
4159.
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com