Conversion of 3-arylazo-5-phenyl-2(3H)-furanones into other heterocycles of anticipated biological activity

Article abstract of DOI:10.1002/ardp.200700043

3-Arylazo-5-phenyl-2(3H)-furanones 3 were prepared and converted into a variety of heterocyclic systems of synthetic and biological importance. Hydrazine hydrate reacted with furanones as nucleophiles and gave the corresponding acid hydrazides 4. The latt

Full text of DOI:10.1002/ardp.200700043

Arch. Pharm. Chem. Life Sci. 2007, 340, 315–319
H. H. Sayed et al.
315
Full Paper
Conversion of 3-Arylazo-5-phenyl-2(3H)-furanones into Other
Heterocycles of Anticipated Biological Activity
Hayam H. Sayed1, Ahmed I. Hashem2, Nabil M. Yousif1, and Waled A. El-Sayed1
1 Photochemistry Department, National Research Centre, Dokki, Giza, Egypt
2 Chemistry Department, Faculty of Science, Ain Shams University, Abbassia, Cairo, Egypt
3-Arylazo-5-phenyl-2(3H)-furanones 3 were prepared and converted into a variety of heterocyclic
systems of synthetic and biological importance. Hydrazine hydrate reacted with furanones as
nucleophiles and gave the corresponding acid hydrazides 4. The latter products were used as
starting materials for the synthesis of 1,3,4-oxadiazoles 6, 9, and the 1,2,4-triazoles 8. Evaluation
of the antiviral activity of selected compounds obtained was performed using two viruses: HAV
and HSV-1. Some of the tested compounds showed promising activities.
Keywords: Furanones / HAV / HSV-1 / Oxadiazoles / Triazoles /
Received: March 19, 2007; accepted: April 17, 2007
DOI 10.1002/ardp.200700043
Introduction
Different examples of the conversion of 2(3H)-furanones
into other heterocyclic systems of biological importance
were already described by our research group [1–7]. Pyra-
zole derivatives show a wide spectrum of biological activ-
ities. Some substituted pyrazoles have antipyretic [8],
hyperglycemic [9], anti-inflammatory [10], and antide-
pressant [11] activities. Important applications of pyra-
Scheme 1. Synthesis route of compounds 1–3.
zole derivatives as antibiotics have also been reported
otherwise [12, 13].
These diverse pharmacological activities, coupled with
our interest in the chemistry of furanones, prompted us
to try the conversion of the furanones 3 into other hetero-
cycles bearing a pyrazolyl moiety. The study aims also to
evaluate the antiviral activity of some selected examples
of the compounds obtained.
The starting materials, 3-arylazo-5-phenyl-2(3H)-fura-
nones 3 were prepared using a previously described pro-
cedure [14] which involves coupling of diazotized ani-
lines with 5-phenyl-2(3H)-furanone 2, via ring closure of
4-oxo-4-phenylbutanoic acid 1 using acetic anhydride
(Scheme 1).
Results and discussion
Chemistry
Pyridazinones, 1,3,4-oxadiazoles and 1,2,4-triazoles are
heterocyclic systems of diverse biological activities.
Therefore, it was of interest to convert the 3-arylazo-5-
phenyl-2(3H)-furanones 3 into the above ring systems
bearing a pyrazolyl moiety. Acid hydrazides represent
key compounds for this study and for the further synthe-
sis of other used heterocyclic compounds Thus, the con-
version of the furanones 3 into the previously mentioned
heterocyclic systems should involve in the first step, ring
opening of the furanones into the corresponding acid
hydrazides. This should lead to the formation of 4-(oxo-4-
phenyl-2-aryl-hydrazono)butyric acid hydrazides 4 by
treating the furanones 3 with hydrazine hydrate in etha-
Correspondence: Hayam H. Sayed, Photochemistry Department, Na-
tional Research Centre, Dokki, Cairo 12622, Egypt
E-mail: hayamsayed@yahoo.com
Fax: +20 2 337-0931
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316
H. H. Sayed et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 315–319
Reagents and conditions: (i) NH2NH2/EtOH, r.t; (ii) PhCOCl/benzene; (iii) POCl3; (iv) PhNCS/benzene 700C; (v) 2N NaOH; (vi) CS2/alc. NaOH.
Scheme 2. Synthesis route of compounds 4–6.
nol. The latter hydrazides 4 were utilized as the key start- activities. This initiated our interest to evaluate the anti-
ing materials for the synthesis of the 1,3,4-oxadiazole viral activity of some of these compounds. Ten products
and 1,2,4-triazole derivatives all bearing a pyrazolyl moi- were selected, representing the different classes for eval-
ety as illustrated in Scheme 2.
uating their activities.
The structures of all the products obtained were
Two viruses were utilized: hepatitis A virus (HAV) and
inferred from their analytical, as well as, spectral data herpes simplex virus type 1 (HSV-1). The plague infectiv-
(Table 1).
ity reduction assay rapid screening method was applied
[13]. The two known drugs commonly utilized for thera-
peutic treatments of HAV and HSV-1 are amantadine and
Antiviral activity
The different heterocyclic ring systems obtained in this acyclovir, respectively. So, these two drugs were consid-
investigation are expected to exhibit diverse biological ered as control. The results obtained from the antiviral
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Arch. Pharm. Chem. Life Sci. 2007, 340, 315–319
Table 1. Spectral data of compounds 4–9.
3-Arylazo-5-phenyl-2(3H)-furanones
317
No.
IR (mmax) KBr(cm– 1
)
1H–NMR (DMSO–d6)
mNH
mC=O
mC=S
4a
4b
3353–3280
1685
1648
2.8–3.2 (s, 2H, –CH2), 3.9 (s, 2H, NH2 exchangeable), 6.7–7.4 (m, 11H, 2
Ar-H + NHCO– exchangeable), 9.6 (s, 1H, NH-Ar exchangeable)
3340–3275
3255–3280
1689
1655
2.75–3.2 (s, 2H, –CH2), 3.85(s, 2H, NH2 exchangeable), 6.75 (s, 1H,
NHCO– exchangeable), 7.1–7.45 (m, 9H, Ar-H), 9.75 (s, 1H, NH-Ar ex-
changeable)
4c
1676
1651
2.9–3.2 (s, 2H, –CH2), 3.8 (s, 3H, –OCH3), 4.4 (br, 2H, NH2 exchangeable),
6.85 (d, 2H, Ar-H), 7.11 (d, 2H, Ar-H), 7.23 (s, 1H, NHCO– exchangeable),
7.31–7.41(m, 5H, Ar-H), 9.43 (s, 1H, NH-Ar exchangeable)
5a
5b
5c
3209–3213
3206–3220
3338–3340
1685
1676
1693
7.15 (s,1H, Pyrazole H),7.2–7.6 (m, 13H, 3 Ar–H), 7.9 (m, 2H, Ar-H), 10.3
(s,1H, NH exchangeable), 10.45 (s, 1H, NH exchangeable)
7.15 (s, 1H, Pyrazole H), 7.25–7.6 (m, 12H, Ar-H), 7.9 (m, 2H, Ar-H), 10.4
(s, 1H, NH exchangeable), 10.6 (s, 1H, NH exchangeable)
3.75 (s,3H, –OCH3), 6.9 (d, 2H, Ar-H) 7.05 (s, 1H, pyrazole H), 7.25 (m, 7H,
Ar-H), 7.5 (m, 3H, Ar-H), 7.7 (m, 2H, Ar-H), 10.2 (s, 1H, NH exchangeable),
10.45 (s, 1H, NH exchangeable)
6a
6b
7.3–7.5 (m, 8H, pyrazole H + 7Ar-H), 7.6 (m, 3H, Ar-H), 8.2 (m, 2H, Ar-H).
7.1 (d, 2H, Ar-H), 7.3–7.5 (m, 8H, pyrazole H + Ar-H), 7.7 (m, 3H, Ar-H), 8.2
(m, 2H, Ar-H)
6c
7a
7b
7c
8a
8b
8c
9a
9b
9c
3.75 (s, 3H, –OCH3), 7.0 (d, 2H, Ar-H) 7.2–7.4 (m, 8H, pyrazole H + Ar-H),
7.6 (m, 3H, Ar-H), 8.1 (m, 2H, Ar-H)
3292–3199
3292–3199
3322–3223
3076–3100
3084–3105
3085–3104
3077–3110
3095–3115
3076–3114
1655
1649
1648
1250
1255
1252
1250
1250
1254
1250
1251
1250
7.11 (s, 1H, Pyrazole H), 7.2–7.5(m, 15H, Ar-H), 9.75 (br, 2H, NH ex-
changeable), 10.37 (s, 1H, NH exchangeable)
7.2 (s, 1H, Pyrazole H), 7.3–7.9 (m, 14H, Ar-H), 9.8 (br, 2H, NH exchange-
able), 10.4 (s ,1H, NH exchangeable)
3.77 (s, 3H, –OCH3), 7.1 (s, 1H, Pyrazole H),7.35–7.8 (m, 14H, Ar-H), 9.9
(br, 2H, NH exchangeable), 10.4 (s, 1H, NH exchangeable)
6.60 (s, 1H, Pyrazole H) ,6.9–7.56 (m, 15H, Ar-H), 14.16 (br, 1H, NH ex-
changeable)
6.75 (s, H, Pyrazole H), 7.0–7.7 (m, 14H, Ar-H), 13.75 (br, 1H, NH ex-
changeable)
3.8 (s, 3H, –OCH3), 6.8 (s, 1H, Pyrazole H) ,7.15–7.75 (m, 15H, Ar-H),
14.16 (br, 1H, NH exchangeable)
7.19 (s, 1H, Pyrazole H), 7.2–7.4 (m, 10H, Ar-H), 14.7 (br, 1H, NH ex-
changeable)
7.15 (s, 1H, Pyrazole H), 7.15–7.50 (m, 9H, Ar-H), 14.4 (br, 1H, NH ex-
changeable)
3.8 (s, 3H, –OCH3), 7.13 (s, 1H, Pyrazole H), 7.2–7.6 (m, 9H, Ar-H), 14.5
(br, 1H, NH exchangeable)
evaluation of the tested compounds are listed in (Table 2) Their activities are comparable to that of amantadine,
and are illustrated by (Figs. 1 and 2). The physical data of especially at a concentration of 20 lg/mL, while oxadia-
compounds 3–14 are listed in Table 3.
zolethione 9b showed the highest activity towards HSV-1
The results presented in Table 2 and Figs. 1 and 2 compared to that of the other compounds tested, which
reveal that oxadiazole 6b, thiosemicarbazide 7b, and oxa- show moderate activities especially at the aforemen-
diazolethione 9a show the highest activities towards the tioned concentration.
HAV virus compared with the other tested compounds.
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Arch. Pharm. Chem. Life Sci. 2007, 340, 315–319
Table 2. Antiviral activity of the compounds (5–9).
Compound
No
HSV-1
HAV
Percentage of reduction Percentage of reduction
(%) (%)
10 lg/mL
20 lg/mL
10 lg/mL
20 lg/mL
5c
6b
7b
7c
7c
8a
8b
9a
9b
9c
0
33
20
26
22
13
0
11
25
60
13
10
T
42.8
36
20
16
38
68
93
37
33
67
20
0
44
53
94
30
4.9
44
8.1
34
34
34
0
4.9
24
24
24
Figure 1. Effect of some compounds on HAV in comparison to
amantadine (amen.) as control at two different concentrations
(10 and 20 lg/mL).
Table 3. Physical data of compounds 3–14.
No. M.p. (8C)
Yield
(%)
Solvent
of cryst.
Mol. Formula
(MW)
(Color)
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
8c
9a
9b
9c
175-7 (colorless)
71
63
52
66
63
55
71
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
C16H16 N4O2 (296.3)
C16H15N4O2Cl (330.7)
161-2 (colorless)
125-6 (colorless)
100-3 (colorless)
225-6 (colorless)
217-9 (colorless)
178-9 (colorless)
C
C
17H18N4O3 (326.3)
23H18N4O4 (382.4)
C23H17CIN4O2 (416.8)
C24H20N4O3 (412.4)
C
23H16N4O (364.3)
C23H18CIN4O (456.5)
24H18N4O2 (394.4)
149-151 (colorless) 75
175-7 (colorless)
203-4 (colorless)
211-13 (colorless)
67
81
75
C
EtOH-Benzene C23H19N5OS (413.4)
EtOH- Benzene C23H18CIN5OS (447.9)
EtOH- Benzene C24H21N5O2S (443.5)
209-210 (colorless) 79
228-9 (colorless)
283-4 (colorless)
260-1 (colorless)
70-2 (yellow)
74-5 (yellow)
82-3 (yellow)
68
73
59
61
79
69
EtOH- Water
C23H17N5S (395.4)
EtOH- Water C23H16CIN5S (429.9)
EtOH- Water C24H19N5OS (425.5)
Benzene-Petro C17H12N4OS (320.3)
Benzene-Petro C17H11CIN4OS (354.8)
Benzene-Petro C18H14N4O2S (350.3)
Figure 2. Effect of some compounds on HSV-1 in comparison to
acyclovir (acycl.) as control at two different concentrations (10
and 20 lg/mL).
reaction mixture was left at room temperature with occasional
shaking. The product obtained was filtered off, washed with
ethanol, and was shown to be 4-(oxo-4-phenyl-2-aryl-hydrazono)-
butyric acid hydrazides 4 (Table 3).
Experimental
Chemistry
N9-[1-Aryl-5-phenyl-1H-pyrazole-3-carbonyl]-hydrazides
5
Melting points were measured on an electrothermal melting
point apparatus and are uncorrected. Elemental analyses were
carried out at the Micro-Analytical Unit, Cairo University, Giza,
Egypt. IR Spectra were measured on a Unicam SP-1200 spectro-
photometer (Pye Unicam Ltd. Cambridge, UK) using KBr-wafer
technique. 1H-NMR spectra were measured in DMSO–d6 on a
Varian Plus instrument (300 MHz; Varian Inc. Palo Alto, CA,
USA).
Reaction of the hydrazides 4 with benzoyl chloride: To a solution
of the hydrazides 4 (0.01 mol) in dry benzene (20 mL), benzoyl
chloride (0.01 mol) was added. The reaction mixture was heated
under reflux for 2 h. The solvent was distilled off under reduced
pressure, and the solid residue was washed thoroughly with
water, drained, and recrystallized from the suitable solvent
(Table 3) to give benzoic acid N9-[1-aryl-5-phenyl-1H-pyrazole-3-
carbonyl]-hydrazides 5.
3-Arylazo-5-phenyl-2(3H)-furanones 3
These compounds were prepared according to the procedure
described previously [14].
2-(1-Aryl-5-phenyl-1H-pyrazol-3-yl)-5-phenyl-[1,3,4]-
oxadiazoles 6
Reaction of the 3-arylazo-5-phenyl-2(3H)-furanones 3 with
hydrazine hydrate: To a solution of the furanones 3 (1 mmol) in
ethanol (20 mL), hydrazine hydrate (1.1 mmol) was added. The
Ring closure of the diaroyl hydrazine 5 using phosphorus oxy-
chloride: Phosphorus oxychloride (10 mL) was added dropwise
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Arch. Pharm. Chem. Life Sci. 2007, 340, 315–319
3-Arylazo-5-phenyl-2(3H)-furanones
319
to 1.0 g of the diaroylhydrazine 5. The reaction mixture was
refluxed for 20 min, left to cool, and was then poured onto
crushed ice. The solid obtained was filtered off, washed with
water, and recrystallized from the suitable solvent (Table 3) to
solved as 100 mg each in 1 mL of 10% DMSO in water. Final con-
centration was 100 lg/lL (stock solution). The dissolved stock
solutions were sterilized by addition of 50 lg/mL antibiotic-anti-
mycotic mixture (10000 U) penicillin G sodium, 10000 lg strep-
tomycin sulfate, and 250 lg amphotericin B. A 6-well plate was
cultivated with Vero cell culture (105 cells/mL) and incubated for
two days at 378C. HSV-1 and HAV were diluted to give 104 PFU/mL
final concentration for each virus and mixed with the tested
compound at the previous concentration and incubated over-
night at 48C. Growth medium was removed from the multi-well
plate and the virus-compound mixture was inoculated (100 lL/
well). After 1 h contact time, the inoculum was aspirated and
3 mL of MEM with 1% agars 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 with 10%
formalin solution for 2 h and stained with crystal violet stain.
Control virus and cells were treated identically without chemi-
cal compound. Virus plaques were counted and the percentage
of reduction was calculated.
give
2-(1-aryl-5-phenyl-1H-pyrazol-3-yl)-5-phenyl-[1,3,4]-oxadia-
zoles 6.
1-Phenyl-3-(1-aryl-5-phenylpyrazol-3-yl)
thiosemicarbazides 7
Reaction of the hydrazides 4 with phenyl isothiocyanate: A solu-
tion of 2(3H)-furanones 3 (3 mmol) in ethanol (30 mL) with a phe-
nyl isothiocyanate (3.1 mmol) was refluxed for 2 h. The solid
obtained was filtered off and recrystallized from a suitable sol-
vent to give 1-phenyl-3-(1-aryl-5-phenylpyrazol-3-yl) thiosemicar-
bazides 7 (Table 3).
5-[1-(Aryl)-5-phenyl-1H-pyrazol-3-yl]-4-phenyl-2,4-
dihydro-[1,2,4]triazole-3-thione 8
Ring closure of the thiosemicarbazide derivatives 7. A solution
of 2N NaOH (40 mL) was added to thiosemicarbazide derivatives
7 (0.01 mol). The reaction mixture was refluxed for 2 h, filtered
while hot, acidified with hydrochloric acid, and diluted with
60 mL water. The solid separated out was filtered off, washed
with water, and recrystallized from the suitable solvent (Table 3)
to give 5-[1-(aryl)-5-phenyl-1H-pyrazol-3-yl]-4-phenyl-2,4-dihydro-
[1,2,4]triazole-3-thione 8.
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