Synthesis of benzo[1,2-b: 5,4-b′]-difuranyl-triazoles, -oxadiazoles, -thiazolidinones, -thiadiazoles, and the use of DNA in evaluation of their biological activity

Article abstract of DOI:10.1080/10426500490464140

Benzo[1,2-b:5,4-b′]difuran-2-carbohydrazides 5a,b were reacted with aryl or alkyl isothiocyanates to give the corresponding thiosemicarbazides 6a-h. Cyclization of the substituted thiosemicarbazides with sodium hydroxide led to the formation of benzo[1,2-b:5,4-b′]difuranyl-1,3,4-triazoles 7a-f. Desulfurization of thiosemicarbazides by mercuric oxide gave benzo[1,2-b:5,4-b′]difuronyl-1,3,4-oxadiazoles 8a-f. Treatment of thiosemicarbazides with ethyl bromoacetate or α-bromopropionic acid yielded benzo[1,2-b:5,4-b′]difuranyl-carbonyl-hydrazono-4-thiazolidinones 9a-f and 10a-f, respectively. Furthermore, the reaction of the thiosemicarbazides with phosphorus oxychloride gave benzo[1,2-b:5,4-b′] difuranyl-1,3,4-thiadiazoles 11a-f. Some compounds in this study were biologically evaluated for their ability to bind to DNA.

Full text of DOI:10.1080/10426500490464140

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SYNTHESIS OF BENZO[1,2-b: 5,4-b′]- DIFURANYL-
TRIAZOLES, -OXADIAZOLES, -THIAZOLIDINONES, -
THIADIAZOLES, AND THE USE OF DNA IN EVALUATION
OF THEIR BIOLOGICAL ACTIVITY
E. M. Keshk a , A. A. Abu-Hashem a , M. M. Girges a , A. H. Abdel-Rahman a & F. A. Badria b
a Chemistry Department, Faculty of Science, Mansoura University , Mansoura, Egypt
b Faculty of Pharmacy, Mansoura University , Mansoura, Egypt
Published online: 16 Aug 2010.
To cite this article: E. M. Keshk , A. A. Abu-Hashem , M. M. Girges , A. H. Abdel-Rahman & F. A. Badria (2004) SYNTHESIS OF
BENZO[1,2-b: 5,4-b′]- DIFURANYL-TRIAZOLES, -OXADIAZOLES, -THIAZOLIDINONES, -THIADIAZOLES, AND THE USE OF DNA IN
EVALUATION OF THEIR BIOLOGICAL ACTIVITY, Phosphorus, Sulfur, and Silicon and the Related Elements, 179:8, 1577-1593, DOI:
10.1080/10426500490464140
To link to this article: http://dx.doi.org/10.1080/10426500490464140
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Phosphorus, Sulfur, and Silicon, 179:1577–1593, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490464140
SYNTHESIS OF BENZO[1,2-b: 5,4-bꢀ]-
DIFURANYL-TRIAZOLES, -OXADIAZOLES,
-THIAZOLIDINONES, -THIADIAZOLES, AND THE
USE OF DNA IN EVALUATION OF THEIR
BIOLOGICAL ACTIVITY
E. M. Keshk,a A. A. Abu-Hashem,a M. M. Girges,a
A. H. Abdel-Rahman,a and F. A. Badriab
Chemistry Department, Faculty of Science, Mansoura
University, Mansoura-Egypt;a and Faculty of Pharmacy,
Mansoura University, Mansoura, Egyptb
(Received October 15, 2003; accepted December 1, 2003)
Benzo[1,2-b:5,4-bꢁ]difuran-2-carbohydrazides 5a,b were reacted with
aryl or alkyl isothiocyanates to give the corresponding thiosemicar-
bazides 6a–h. Cyclization of the substituted thiosemicarbazides
with sodium hydroxide led to the formation of benzo[1,2-b:5,4-
bꢁ]difuranyl-1,3,4-triazoles 7a–f. Desulfurization of thiosemicar-
bazides by mercuric oxide gave benzo[1,2-b:5,4-bꢁ]difuranyl-1,3,4-
oxadiazoles 8a–f. Treatment of thiosemicarbazides with ethyl
bromoacetate or α-bromopropionic acid yielded benzo[1,2-b:5,4-
bꢁ]difuranyl-carbonyl-hydrazono-4-thiazolidinones 9a–f and 10a–f,
respectively. Furthermore, the reaction of the thiosemicarbazides
with phosphorus oxychloride gave benzo[1,2-b:5,4-bꢁ]difuranyl-1,3,4-
thiadiazoles 11a–f. Some compounds in this study were biologically
evaluated for their ability to bind to DNA.
Keywords: Benzodifuran; oxadiazole; thiazole; thiadiazole; triazole
INTRODUCTION
A wide variety of pharmacological properties has been shown to be
associated with benzofuran1−3 and benzodifuran derivatives.4−6 Vari-
ous thiosemicarbazides7,8 and their cyclized products, e.g., triazoles,9,10
oxadiazoles,11,12 thiazolidinones,13,14 and thiadiazoles15,16 are also as-
sociated with a broad spectrum of biological properties.
Address correspondence to A. H. Abdel-Rahman, Chemistry Department, Faculty of
Science, Mansoura University, Egypt. E-mail: Scimchmdept@mans.edu.eg
1577

1578
E. M. Keshk et al.
In continuation of our research on the synthesis of new heterocyclic
compounds derived from the naturally occurring furochromones (vis-
nagin and khellin) of pharmacological interest,17,18 this work deals
with the synthesis and characterization of new compounds containing a
benzodifuran nucleus combined with thiosemicarbazide, 1,3,4-triazole,
1,3,4-oxadiazole, thiazolidinone, and 1,3,4-thiadiazole moieties, which
are expected to possess high biological activity.
RESULTS AND DISCUSSION
The naturally occurring furochromones (visnagin and khellin) yielded
visnaginone 1a and khellinone 1b upon hydrolysis with aqueous potas-
sium hydroxide.19,20 In the present work, both visnaginone 1a and
khellinone 1b were treated with ethyl bromoacetate in the presence
of potassium carbonate to give (4-methoxy- (2a) and 4,7-dimethoxy-5-
1
acetylbenzofuran-6-yloxy)acetic acid ethyl ester (2b).21 The H NMR
spectrum of compound 2a showed ethyl signals at δ = 1.28 (CH3), 4.20
(CH2), and a singlet at δ = 4.65, characteristic for (OCH2).
Refluxing 2a or 2b in dimethylformamide containing anhy-
drous potassium carbonate afforded 4-methoxy- and 4,8-dimethoxy-
3-methylbenzo[1,2-b:5,4-bꢁ]difuran-2-carboxylic acid 3a,b, respectively.
Compound 3b was previously prepared by treatment of khellinone with
chloroacetanilide followed by cyclization with 10% NaOH.21
The IR spectrum of 3a revealed an absorption band at 1675 cm−1
(C O). The mass spectrum of 3a showed a molecular ion peak at m/z =
246.
Treatment of 3a,b with absolute ethanol containing 2–3 drops
of concentrated H2SO4 gave benzo[1,2-b:5,4-bꢁ]difuran-2-carboxylic
acid ethyl esters 4a,b, respectively. The 1H NMR spectra of com-
pounds 4a,b showed ethyl signals at their expected locations. How-
ever, refluxing 4a,b with hydrazine hydrate led to the formation
of 4-methoxy- and 4,8-dimethoxy-3-methylbenzo[1,2-b:5,4-bꢁ]difuran-2-
carbohydrazides 5a,b, respectively. Their infrared (IR) spectra revealed
the absence of an ester group and showed absorption band at 1667–1664
cm−1 due to the (CONH) group.
Compounds 5a,b were reacted with isothiocyanate derivatives,
namely phenyl-, benzyl-, ethyl-, and cyclohexylisothiocyanate, to afford
1-(4-methoxy- and 4,8-dimethoxy-3-methylbenzo[1,2-b:5,4-bꢁ]difuran-
2-yl-carbonyl)-4-substituted thiosemicarbazides 6a–h in excellent
yields.
The structures of 6a–h were assigned on the basis of their elemen-
tal analyses and spectral data. IR spectra showed absorption bands

Synthesis of Azoles
1579
at 3320–3112 cm−1 (NH), 1680–1668 cm−1 (C O), and the vibration
coupling due to N C S functions at 1352–1342 cm−1
.
Cyclization of 4-substituted thiosemicarbazides 6a–e,h by heat-
ing with aqueous sodium hydroxide leads to the formation of 2-(4-
methoxy- and 4,8-dimethoxy-3-methylbenzo[1,2-b:5,4-bꢁ]difuran-2-yl)-
1-substituted-5-mercapto-1H-1,3,4-triazoles 7a–f.
The elemental analyses and spectral data of compounds 7a–f were
compatible with the suggested structures. IR spectra showed absorp-
tion bands at 3175–3123 cm−1 (NH) and a stretching band in the region
of 1620–1613 cm−1 , characteristic for the C N of triazole ring. Mean-
while, the stretching frequency of the band C O disappeared. In the
solid states, compounds 7a–f exist predominantly in the thioxo form,
as is shown by the C S band at 1350–1345 cm−1 in the IR spectra
1
of these compounds.9 The H NMR spectra of 7a–f clearly revealed
the absence of two singlet signals corresponding to the two protons
of (2 NH) and exhibited one singlet due to SH (exchangeable with
D2O).
Desulfurization of thiosemicarbazides 6a–e,h by yellow mercuric
oxide in boiling ethanol yielded 2-(4-methoxy- and 4,8-dimethoxy-
3-methylbenzo [1,2-b:5,4-bꢁ]difuran-2-yl)-5-substituted amino-1,3,4-
oxadiazoles 8a–f in a good yields. Assignment of structures 8a–f were
established on the basis of elemental analyses, IR, 1H NMR, and mass
spectra. The IR spectra lacked the C O absorption band and showed
the NH and C N vibrational bands at 3247–3221 cm−1, and 1621–
1613 cm−1, respectively. The mass spectrum of 8a showed a molecular
ion peak at m/z = 361.
Treatment of 6a–e,h with ethyl bromoacetate furnished 2-{[(4-
methoxy- and 4,8-dimethoxy-3-methylbenzo[1,2-b:5,4-bꢁ]difuran-2-yl)-
carbonyl]hydrazono}-3-substituted-4-thiazolidinones 9a–f. The struc-
tures of compounds 9a–f were confirmed by elemental analyses and
spectral data. The IR spectra showed the C O bands at 1660–1650
cm−1 (CONH N) and strong bands at 1725–1713 cm−1 characteristic
for C O of thiazolidinone ring, which provided firm support for ring clo-
1
sure. The H NMR spectra of 9a–f revealed clearly the absence of two
singlet signals corresponding to the two protons of (2 NH) and displayed
an additional singlet signal at δ = 3.95–4.10 ppm due to S CH2.
However, treatment of compounds 6a–e,h with α-bromopropionic
acid yielded 2-{[(4-methoxy- and 4,8-dimethoxy-3-methylbenzo[1,
2-b:5,4-bꢁ]difuran-2-yl)carbonyl]hydrazono}-3-substituted-5-methyl-4-
thiazolidinones 10a–f, respectively. The structures of 10a–f were
assigned on the basis of their elemental analyses and spectral data.
The 1H NMR spectra of 10a–f clearly revealed a signal at δ = 4.00–4.10
as a quartet characteristic for the methine proton of thiazolidinone

1580
E. M. Keshk et al.
SCHEME 1

Synthesis of Azoles
1581
SCHEME 2

1582
E. M. Keshk et al.
ring (H-3), with the disappearance of two singlet signals corresponding
to the two protons of 2 NH, which proved thiazolidinone ring closure.
Furthermore, several procedures were reported for the dehydrative
cyclization of substituted thiosemicarbazides to their 1,3,4-thiadiazole
analogs utilizing a variety of dehydrating agents, e.g., sulphuric
acid, phosphorus oxychloride, or polyphosphoric acid. Accordingly, the
treatment of compounds 6a–e,h with phosphorus oxychloride yielded
2-(4-methoxy- and 4,8-dimethoxy-3-methylbenzo[1,2-b:5,4-bꢁ]difuran-
2-yl)-5-substituted amino-1,3,4-thiadiazoles 11a–f. All analytical and
spectral data supported the suggested structures.
EXPERIMENTAL
Melting points are uncorrected. Elemental analyses were carried out
in the Microanalytical Unit of the Faculty of Science, Cairo Univer-
sity, Egypt. IR spectra were recorded on a Mattson 5000 fourier trans-
1
form infrared (FTIR) spectrometer. H NMR spectra were taken on a
Varian-Ex-300 MHz NMR spectrometer using TMS as an internal stan-
dard with (δ = 0 ppm). Mass spectra were determined on a GC-MS. QP-
1000 (Shimadzu, Japan). The purity of the synthesized compounds was
tested by thin layer chromatography (TLC): Merck Plates. The physical
and spectral data of the newly compounds are listed in Tables I and II.
(5-Acetyl-4-methoxy-benzofuran-6-yloxy)acetic Acid
Ethyl Ester (2a)
A mixture of visnaginone 1a (0.01 mol), ethyl bromoacetate (0.01 mol),
and anhydrous potassium carbonate (0.015 mol) in dry acetone (25 ml)
was refluxed for 5 h. The reaction mixture was allowed to cool to room
temperature. Water (25 ml) was added, and then the solid that sep-
arated was filtered off, dried, and crystallized from pet ether to give
2a.
4-Methoxy- and 4,8-Dimethoxy-3-methylbenzo-
[1,2-b:5,4-bꢀ]difuran-2-carboxylic Acid (3a,b)
A mixture of 2a or 2b (0.01 mol) and anhydrous potassium carbonate
(0.015 mol) in dimethylformamide (25 ml) was refluxed for 4 h. The
reaction mixture was allowed to cool to room temperature. Water (25 ml)
was added, and then the solid that separated was filtered off, dried, and
crystallized from ethanol to give 3a,b, respectively.

Synthesis of Azoles
1583
TABLE I The Physical and Aanalytical Data of the Newly Compounds
Analysis calcd. found %
Compd.
no.
m.p.◦C
(Yield %)
Color solvent
of cryst.
Formula
(m. wt)
C
H
N
S
2a
3a
4a
4b
5a
5b
6a
6b
6c
6d
6e
6f
72–74
(95)
229–231
(85)
135–137
(85)
80–82
(82)
169–171
(85)
150–152
(80)
202–204
(92)
184–186
(90)
194–196
(88)
212–214
(85)
198–200
(90)
209–211
(85)
217–219
(86)
206–208
(82)
239–241
(75)
182–184
(72)
>250
(70)
180–182
(68)
138–140
(70)
141–143
(66)
218–220
(70)
139–141
(67)
122–124
(65)
White
Pet. ether
Yellow
Ethanol
Yellow
Ethanol
Yellow
Acetone
White
Acetone
White
Ethanol
White
Ethanol
White
Ethanol
White
Ethanol
White
Acetone
White
Ethanol
White
Acetone
White
Ethanol
White
Ethanol
Yellow
Ethanol
White
Ethanol
White
C15H16O6
(292.29)
C13H10O5
(246.22)
C15H14O5
(274.27)
C16H1606
(304.30)
C13H12N2O4
(260.25)
C14H14N2O5
(290.27)
C20H17N3O4S
(395.43)
21H19N3O4S
(409.46)
16H17N3O4S
(347.39)
20H23N3O4S
(401.48)
C21H19N3O5S
(425.46)
22H21N3O5S
(439.48)
C17H19N3O5S
(377.41)
21H25N3O5S
(431.50)
20H15N3O3S
(377.42)
21H17N3O3S
(391.44)
61.64
61.46
63.42
63.25
65.69
65.88
63.15
63.00
60.00
59.85
57.93
57.75
60.75
60.57
61.60
61.49
55.32
55.12
59.83
59.61
59.28
59.11
60.12
60.29
54.10
54.25
58.45
58.28
63.65
63.47
64.44
64.27
58.35
58.26
62.64
62.46
61.90
61.80
61.00
61.12
66.48
66.31
67.20
67.34
61.34
61.16
5.52
5.34
4.10
4.21
5.14
5.00
5.30
5.13
4.65
4.47
4.86
4.67
4.33
4.15
4.68
4.49
4.93
4.74
5.77
5.58
4.50
4.31
4.82
4.98
5.07
5.22
5.84
5.66
4.01
4.13
4.38
4.21
4.59
4.41
5.52
5.34
4.20
4.35
5.61
5.48
4.18
4.35
4.56
4.68
4.82
4.64
10.76
10.84
9.65
9.52
10.63
10.55
10.26
10.38
12.10
12.20
10.47
10.40
9.88
9.97
9.56
9.50
11.13
11.25
9.74
8.11
8.00
7.83
7.94
9.23
9.12
7.98
7.90
7.54
7.45
7.30
7.22
8.50
8.42
7.43
7.35
8.49
8.40
8.19
8.30
9.73
9.63
8.36
8.23
7.87
7.80
7.75
7.82
C
C
C
C
6g
6h
7a
7b
7c
7d
7e
7f
C
C
C
C
9.65
11.13
11.20
10.73
10.65
12.76
12.65
10.96
10.84
10.31
10.40
10.16
10.08
11.63
11.70
11.19
11.30
13.41
13.30
16H15N3O3S
(329.37)
C20H21N3O3S
(383.46)
21H17N3O4S
(407.44)
21H23N3O4S
(413.49)
Ethanol
White
Ethanol
White
Ethanol
White
Ethanol
Yellow
Ethanol
Yellow
Ethanol
Yellow
C
C
8a
8b
8c
C
20H15N3O4
(361.35)
C21H17N3O4
(375.38)
C16H15N3O4
(313.31)
Ethanol
(Continued on next page)

1584
E. M. Keshk et al.
TABLE I The Physical and Aanalytical Data of the Newly Compounds
(Continued)
Analysis calcd. found %
Compd.
no.
m.p.◦C
(Yield %)
Color solvent
of cryst.
Formula
(m. wt)
C
H
N
S
8d
8e
175–177
(65)
228–230
(69)
190–192
(63)
208–210
(93)
>250
(90)
218–220
(88)
222–224
(85)
178–180
(86)
181–183
(82)
197–199
(88)
175–177
(86)
152–154
(85)
248–250
(82)
185–187
(85)
240–242
(80)
Yellow
Ethanol
Yellow
Methanol
Brown
Acetone
White
Ethanol
White
Dioxane
White
Ethanol
White
Methanol
White
Ethanol
White
Acetone
White
Ethanol
White
Ethanol
White
Ethanol
White
Methanol
White
Ethanol
White
Ethanol
Yellow
Dioxane
Yellow
Acetone
Yellow
Ethanol
Yellow
Acetone
Yellow
Ethanol
Yellow
Ethanol
C20H21N3O4
(367.40)
65.38
65.21
64.45
64.29
63.46
63.32
60.68
60.51
61.46
61.28
55.80
55.95
59.85
59.68
59.35
59.47
58.59
58.41
61.46
61.29
62.19
62.33
56.85
56.66
60.64
60.46
60.12
60.28
59.37
59.20
63.65
63.47
64.43
64.25
58.35
58.48
62.64
62.46
61.90
61.77
61.00
61.17
5.76
5.62
4.38
4.24
5.83
5.69
3.93
3.78
4.26
4.39
4.42
4.55
5.25
5.38
4.11
4.25
5.34
5.20
4.26
4.40
4.57
4.43
4.77
4.59
5.53
5.38
4.41
4.57
5.60
5.42
4.01
4.15
4.38
4.26
4.59
4.45
5.52
5.38
4.21
4.32
5.61
5.47
11.44
11.55
10.74
10.66
10.57
10.49
9.65
9.73
9.35
9.42
10.85
10.74
9.52
9.60
9.03
9.10
8.91
9.00
9.35
9.42
9.07
9.15
10.47
10.54
9.22
9.15
8.76
C21H17N3O5
(391.38)
8f
C21H23N3O5
(397.43)
9a
C22H17N3O5S
(435.45)
7.36
7.45
7.13
7.20
8.27
8.16
7.26
7.32
6.89
6.76
6.80
6.72
7.13
7.20
6.92
6.85
7.99
7.87
7.04
7.10
6.69
6.80
6.60
6.50
8.50
8.40
8.19
8.25
9.73
9.63
8.36
8.45
7.87
7.80
7.75
7.63
9b
C
C
C
C
23H19N3O5S
(449.48)
18H17N3O5S
(387.41)
22H23N3O5S
(441.50)
23H19N3O6S
(465.48)
9c
9d
9e
9f
C23H25N3O6S
(471.53)
10a
10b
10c
10d
10e
10f
11a
11b
11c
11d
11e
11f
C
C
C
C
C
C
C
23H19N3O5S
(449.48)
24H21N3O5S
(463.51)
19H19N3O5S
(401.44)
23H25N3O5S
(455.53)
24H21N3O6S
(479.51)
24H27N3O6S
(485.55)
20H15N3O3S
(377.42)
8.69
8.65
8.53
>250
(68)
145–147
(66)
205–207
(65)
130–132
(62)
164–166
(67)
126–128
(60)
11.13
11.20
10.73
10.80
12.76
12.66
10.96
10.90
10.31
10.20
10.16
10.23
C21H17N3O3S
(391.44)
C
16H15N3O3S
(329.37)
C
20H21N3O3S
(383.46)
C21H17N3O4S
(407.44)
C
21H23N3O4S
(413.49)

Synthesis of Azoles
1585
TABLE II The Spectral Data of the Newly Compounds
Comp.
no.
MS
(m/z)
IR (ν, cm−1) KBr
1H-NMR (CDCl3, δ, ppm)
2a
2928, 2850 (CH-aliph), 1.28 (t, 3H, CH2CH3), 2.57 (s, 3H, COCH3),
1745 (COOEt), 1690
(C O)
4.07 (s, 3H, OCH3), 4.20 (q, H, CH2CH3),
4.65 (s, 2H, OCH2), 6.67 (s, 1H, H-7), 6.87
(d, 1H, J = 2.30 Hz, Furan H-3), 7.50 (d,
1H, J = 2.30 Hz, Furan H-2)
3a
4a
2955, 2859 (CH-aliph), 2.39 (s, 3H, CH3), 4.15 (s, 3H, OCH3), 6.95
246
1675 (C O)
(d, 1H, J = 2.30 Hz, Furan H-3), 7.30
(s, 1H, H-8), 7.53 (d, 1H, J = 2.30 Hz,
Furan H-2)
2947, 2852 (CH-aliph), 1.44 (t, 3H, CH2CH3), 2.77 (s, 3H, CH3),
1708 (COOEt)
4.22 (s, 3H, OCH3), 4.42 (q, 2H,
CH2CH3), 6.99 (d, 1H, J = 2.30 Hz Furan
H-3), 7.30 (s, 1H, H-8),7.55 (d, 1H, J =
2.30 Furan H-2)
4b
5a
5b
6a
6b
6c
2945, 2858 (CH-aliph), 1.42 (t, 3H, CH2CH3), 2.74 (s, 3H, CH3),
1707 (COOEt)
4.07 (s, 3H, OCH3), 4.24 (s, 3H, OCH3),
4.40 (q, 2H, CH2CH3) 6.90 (d,1H, J =
2.30 Hz, Furan H-3), 7.52 (d, 1H, J =
2.30 Hz, Furan H-2)
3324, 3238, 3195 (NH,
NH2), 2949, 2848
(CH-aliph), 1667
(C O)
2.78 (s, 3H, CH3), 4.00 (s, 3H, OCH3), 6.90
(d, 1H, J = 2.30 Hz, Furan H-3), 7.28
(s, 1H, 8-H), 7.55 (d, 1H, J = 2.30 Hz,
Furan H-2), 7.80 (br.s, 2H, NH2). 9.20
(br.s, 1H, NH)
260
395
347
3314, 3225, 3127 (NH,
NH2), 2945, 2849
(CH-aliph), 1664
(C O)
2.81 (s, 3H, CH3), 4.06 (s, 3H, OCH3), 4.26
(s, 3H, OCH3), 6.92 (d, 1H, J = 2.30 Hz,
Furan H-3), 7.56 (d, 1H, J = 2.30 Hz,
Furan H-2), 7.82 (br.s, 2H, NH2), 9.25
(br. s, 1H, NH)
3320, 3233, 3149
(NH), 2971, 2851
(CH-aliph), 1679
(C O), 1352 (C S)
2.73 (s, 3H, CH3), 4.10 (s, 3H, OCH3), 6.90
(d, 1H, J = 2.30 Hz, Furan H-3),
7.15–7.40 (m, 6H, 5Ar-H, H-8), 7.55
(d, 1H, J = 2.30 Hz Furan H-2), 9.70,
9.86, 10.50 (3br.s, 3H, 3NH)
3308, 3252, 3141
(NH), 2978, 2848
(CH-aliph), 1674
(C O), 1342 (C S)
2.68 (s, 3H, CH3), 4.05 (s, 3H, OCH3), 4.85
(d, 2H, CH2-Ph), 6.91 (d, 1H, J = 2.30 Hz,
Furan H-3), 7.20–7.35 (m, 6H, 5 Ar-H,
H-8), 7.54 (d,1H, J = 2.30 Hz, Furan
H-2), 8.70 , 9.15, 10.35 (3br.s, 3H, 3NH)
1.17 (t, 3H, CH2CH3), 2.70 (s, 3H, CH3),
3.55 (q, 2H, CH2CH3), 4.10 (s, 3H,
OCH3), 6.96 (d, 1H, J = 2.30 Hz,
Furan H-3), 7.27 (s, 1H, H-8), 7.50 (d, 1H,
J = 2.30 Hz, Furan H-2), 7.70, 9.50, 10.25
(3br.s, 3H, 3NH)
3283, 3264, 3148
(NH), 2937, 2865
(CH-aliph), 1673
(C O), 1343 (C S)
(Continued on next page)

1586
E. M. Keshk et al.
TABLE II The Spectral Data of the Newly Compounds (Continued)
Comp.
no.
MS
(m/z)
IR (ν, cm−1) KBr
1H-NMR (CDCl3, δ, ppm)
6d
3301, 3244, 3142
(NH), 2933, 2854
(CH-aliph), 1675
(C O), 1348 (C S)
1.24–1.75 (m, 10H, cyclohexyl), 2.74 (s, 3H,
CH3), 4.12 (m, 1H, cyclohexyl), 4.26 (s, 3H,
OCH3), 6.75 (br.s, 1H, NH), 6.89 (d, 1H,
J = 2.30 Hz, Furan H-3), 7.35 (s, 1H, 8-H),
7.54 (d, 1H, J = 2.30 Hz, Furan H-2),
9.00, 10.52 (2br.s, 2H, 2NH).
401
6e
6f
3290, 3211, 3112
(NH), 3938, 2862
(CH-aliph), 1680
(C O), 1345 (C S)
2.74 (s, 3H, CH3), 4.12 (s, 3H, OCH3), 4.23
(s, 3H, OCH3), 6.92 (d, 1H, J = 2.30 Hz,
Furan H-3), 7.20–7.40 (m, 5H, Ar-H), 7.57
(d, 1H, J = 2.30 Hz, Furan H-2), 9.73, 9.90,
10.51 (3br.s, 3H, 3NH).
2.69 (s, 3H, CH3), 4.06 (s, 3H, OCH3), 4.22
(s, 3H, OCH3), 4.86 (d, 2H, CH2-Ph), 6.90
(d, 1H, J = 2.30 Hz, Furan H-3), 7.22–7.35
(m, 5H, Ar-H), 7.50 (d, 1H, J = 2.30 Hz,
Furan H-2), 8.72, 9.17, 10.40 (3br.s, 3H,
3NH).
3300, 3253, 3163
(NH), 2931, 2850
(CH-aliph), 1668
(C O), 1344 (C S)
439
6g
6h
3297, 3257, 3133
(NH), 2945, 2862
(CH-aliph), 1672
(C O), 1345 (C S)
1.20 (t, 3H, CH2CH3), 2.72 (s, 3H, CH3), 3.56
(q, 2H, CH2CH3), 4.08 (s, 3H, OCH3) ,
4.17(s, 3H, OCH3), 6.98 (d, 1H, J = 2.30
Hz, Furan H-3), 7.56 (d, 1H, J = 2.30 Hz,
Furan H-2), 7.78, 9.52, 10.28 (3br.s, 3H,
3NH).
1.25–1.80 (m, 10H, cyclohexyl), 2.75 (s, 3H,
CH3), 4.15 (m, 1H, cyclohexyl), 4.25 (s, 3H,
OCH3), 4.42 (s, 3H, OCH3), 6.70 (br.s, 1H,
NH), 6.85 (d, 1H, J = 2.30 Hz, Furan H-3),
7.52 (d, 1H, J = 2.30 Hz, Furan H-2), 9.16,
10.78 (2br.s, 2H, 2NH)
3300, 3242, 3140
(NH), 2934, 2853
(CH-aliph), 1678
(C O), 1349 (C S)
7a
7b
3169 (NH), 2942, 2853 2.52 (s, 3H, CH3), 4.13 (s, 3H, OCH3), 6.88
377
(CH-aliph), 1620
(C N), 1347 (C S)
(d, 1H, J = 2.30 Hz, Furan H-3), 7.16–7.30
(m, 6H, 5Ar-H, H-8), 7.51 (d, 1H, J = 2.30
Hz, Furan H-2), 14.20 (s, 1H, SH).
3123 (NH), 2930, 2852 2.55 (s, 3H, CH3), 4.11 (s, 3H, OCH3), 6.10
(CH-aliph), 1618
(C N), 1350 (C S)
(s, 2H, CH2-Ph), 6.90 (d, 1H, J = 2.30 Hz,
Furan H-3), 7.15–7.35 (m, 6H, 5Ar-H, H-8),
7.55 (d, 1H, J = 2.30 Hz, Furan H-2), 14.00
(br.s, 1H, SH)
7c
7d
3159 (NH), 2921, 2851 0.9 (t, 3H, CH2CH3), 2.53 (s, 3H, CH3), 4.00
329
(CH-aliph),1614
(C N), 1345 (C S).
(s, 3H, OCH3), 4.20 (q, 2H, CH2CH3), 6.98
(d, 1H, J = 2.30 Hz, Furan H-3), 7.22
(s, 1H, H-8), 7.58 (d, 1H, J = 2.30 Hz,
Furan H-2), 14.05 (br.s, 1H, SH)
3164 (NH), 2931, 2855 1.20–1.90 (m, 10H, cyclohexyl), 2.56 (s, 3H,
(CH-aliph),1615
(C N), 1349 (C S)
CH3), 4.16 (s, 3H, OCH3), 5.28 (m, 1H,
cyclohexyl), 6.95 (d, 1H, J = 2.30 Hz, Furan
H-3), 7.28 (s, 1H, H-8), 7.55 (d, 1H, J = 2.30
Hz, Furan H-2), 14.00 (br.s, 1H, SH)

Synthesis of Azoles
1587
TABLE II The Spectral Data of the Newly Compounds (Continued)
Comp.
no.
MS
(m/z)
IR (ν, cm−1) KBr
1H-NMR (CDCl3, δ, ppm)
7e
3175 (NH), 2938, 2847 2.52 (s, 3H, CH3), 4.11 (s, 3H, OCH3), 4.23 (s,
407
(CH-aliph),1619
(C N), 1348 (C S)
3H, OCH3), 6.89 (d, 1H, J = 2.30 Hz,
Furan H-3), 7.15–7.35 (m, 5H, Ar-H), 7.53
(d,1H, J = 2.30 Hz, Furan H-2), 14.15 (br.s,
1H, SH)
7f
3166 (NH), 2931, 2854 1.24–1.96 (m, 10H, cyclohexyl), 2.50 (s, 3H,
(CH-aliph), 1613
(C N), 1347(C S)
CH3), 4.08 (s, 3H, OCH3), 4.20 (s, 3H,
OCH3), 5.25 (m, 1H, cyclohexyl), 6.93 (d,
1H, J = 2.30 Hz, Furan H-3), 7.32 (s, 1H,
H-8), 7.57 (d, 1H, J = 2.30 Hz, Furan H-2),
14.08 (br.s, 1H, SH)
8a
8b
3247 (NH), 2969, 2850 2.70 (s, 3H, CH3), 3.98 (s, 3H, OCH3), 6.91 (d,
361
(CH-aliph), 1621
(C N)
1H, J = 2.30 Hz, Furan H-3), 7.10–7.40 (m,
6H, 5Ar-H, H-8), 7.56 (d, 1H, J = 2.30 Hz,
Furan H-2), 10.50 (br.s, 1H, NH)
3236 (NH), 2931, 2842 2.72 (s, 3H, CH3), 4.06 (s, 3H, OCH3), 4.50 (d,
(CH-aliph), 1617
(C N)
2H, CH2-Ph), 6.89 (d, 1H, J = 2.30 Hz,
Furan H-3), 7.12–7.38 (m, 6H, 5Ar-H, H-8),
7.55 (d, 1H, J = 2.30 Hz, Furan H-2), 8.50
(br.s, 1H, NH)
8c
8d
8e
8f
3224 (NH), 2937, 2841 1.30 (t, 3H, CH2CH3), 2.69 (s, 3H, CH3), 3.55
313
(CH-aliph), 1614
(C N)
(q, 2H, CH2CH3), 4.00 (s, 3H, OCH3), 5.85
(br.s, 1H, NH), 6.90 (d, 1H, J = 2.30 Hz,
Furan H-3), 7.27 (s, 1H, H-8), 7.57 (d, 1H,
J = 2.30 Hz, Furan H-2)
3221 (NH), 2934, 2850 1.17–1.70 (m, 10H, cyclohexyl), 2.68 (s, 3H,
(CH-aliph), 1612
(C N)
CH3), 3.79 (m, 1H, cyclohexyl), 4.12 (s, 3H,
OCH3), 4.92 (br.s, 1H, NH), 6.89 (d, 1H,
J = 2.30 Hz, Furan 3-H), 7.29 (s, 1H, H-8),
7.52 (d, 1H, J = 2.30 Hz, Furan H-2)
3241 (NH), 2970, 2852 2.71 (s, 3H, CH3), 4.00 (s, 3H, OCH3), 4.24
391
(CH-aliph), 1615
(C N)
(s, 3H, OCH3), 6.90 (d, 1H, J = 2.30 Hz,
Furan H-3), 7.12–7.38 (m, 5H, Ar-H), 7.58
(d, 1H, J = 2.30 Hz, Furan H-2),
10.60 (br.s, 1H, NH)
3230 (NH), 2929, 2854 1.20–1.80 (m, 10H, cyclohexyl), 2.66 (s, 3H,
(CH-aliph),1613
(C N)
CH3), 3.77 (m, 1H, cyclohexyl), 4.10 (s, 3H,
OCH3), 4.25 (s, 3H, OCH3), 4.95 (br.s, 1H,
NH), 6.91 (d, 1H, J = 2.30 Hz, Furan H-3),
7.56 (d, 1H, J = 2.30 Hz, Furan H-2)
9a
3297 (NH), 2947, 2887 2.73 (s, 3H, CH3), 4.09 (s, 2H, CH2
435
(CH-aliph), 1722,
1660 (2C O), 1618
(C N)
thiazolidinone ring), 4.13 (s, 3H, OCH3),
6.93 (d, 1H, J = 2.30 Hz, Furan H-3),
7.15–7.40 (m, 6H, 5Ar-H, H-8), 7.6 (d, 1H,
J = 2.30 Hz, Furan H-2), 10.95 (br.s, 1H,
NH)
(Continued on next page)

1588
E. M. Keshk et al.
TABLE II The Spectral Data of the Newly Compounds (Continued)
Comp.
no.
MS
(m/z)
IR (ν, cm−1) KBr
1H-NMR (CDCl3, δ, ppm)
9b
3282 (NH), 2945, 2880 2.70 (s, 3H, CH3), 4.02 (s, 2H, CH2
(CH-aliph), 1717,
1657 (2C O), 1619
(C N)
thiazolidinone ring), 4.11 (s, 3H, OCH3), 5.00
(s, 2H, CH2-Ph), 6.90 (d, 1H, J = 2.30 Hz,
Furan H-3), 7.12–7.40 (m, 6H, 5Ar-H, H-8),
7.62 (d, 1H, J = 2.30 Hz, Furan H-2), 10.35
(br.s, 1H, NH)
9c
3273 (NH), 2978, 2873 1.25 (t, 3H, CH2CH3), 2.71 (s, 3H, CH3), 3.90 (q, 387
(CH-aliph), 1713,
1650 (2C O), 1615
(C N)
2H, CH2CH3), 4.00 (s, 2H, CH2 thiazolidinone
ring), 4.17 (s, 3H, OCH3), 6.96 (d, 1H,
J = 2.30 Hz, Furan H-3), 7.30 (s, 1H, H-8),
7.65 (d, 1H, J = 2.30 Hz, Furan H-2), 10.37
(br.s, 1H, NH)
9d
9e
3282 (NH), 2930,
2854(CH-aliph),
1724, 1658 (2C O),
1613 (C N)
1.20–1.80 (m, 10H, cyclohexyl), 2.69 (s, 3H,
CH3), 3.95 (s, 2H, CH2 thiazolidinone ring),
4.15 (s, 3H, OCH3), 4.25 (m, 1H, cyclohexyl),
7.00 (d, 1H, J = 2.30 Hz, Furan H-3), 7.32
(s, 1H, H-8), 7.67 (d, 1H, J = 2.30 Hz, Furan
H-2), 10.32 (br.s, 1H, NH)
3295 (NH), 2945,
2883(CH-aliph),
725, 1660 (2C O),
1616 (C N)
2.70 (s, 3H, CH3), 4.10 (s, 2H, CH2
465
thiazolidinone ring), 4.16 (s, 3H, OCH3), 4.27
(s, 3H, OCH3), 6.98 (d, 1H, J = 2.30 Hz,
Furan H-3), 7.10–7.35 (m, 5H, Ar-H), 7.62 (d,
1H, J = 2.30 Hz, Furan H-2), 11.00 (br.s, 1H,
NH)
9f
3288 (NH), 2928,
2852(CH-aliph),
1720, 1652 (2C O),
1610 (C N)
1.22–1.86 (m, 10H, cyclohexyl), 2.72 (s, 3H,
CH3), 4.00 (s, 2H, CH2 thiazolodinone ring),
4.13 (s, 3H, OCH3), 4.27 (m, 1H, cyclohexyl),
4.30 (s, 3H, OCH3), 7.00 (d, 1H, J = 2.30 Hz,
Furan H-3), 7.65 (d, 1H, J = 2.30 Hz, Furan
H-2), 10.42 (br.s, 1H, NH)
10a
10b
10c
3290 (NH), 2974, 2850 1.67 (d, 3H, CH3), 2.72 (s, 3H, CH3), 4.07 (q, 1H, 449
(CH-aliph), 1720,
1659 (2C O), 1620
(C N)
methine proton of thiazolidinone ring), 4.11
(s, 3H, OCH3), 6.93 (d,1H, J = 2.30 Hz, Furan
H-3), 7.15–7.40 (m, 6H, 5Ar-H, H-8), 7.60 (d,
1H, J = 2.30 Hz, Furan H-2), 10.90 (br.s, 1H,
NH)
3281 (NH), 2985, 2855 1.65 (d, 3H, CH3), 2.70 (s, 3H, CH3), 4.05 (q, 1H, 463
(CH-aliph), 1716,
1657 (2C O), 1619
(C N)
methine proton of thiazolidinone ring), 4.10
(s, 3H, OCH3), 5.00 (s, 2H, CH2-Ph), 6.90 (d,
1H, J = 2.30 Hz, Furan H-3), 7.20–7.50 (m,
6H, 5Ar-H, H-8), 7.56 (d, 1H, J = 2.30 Hz,
Furan H-2), 10.27 (br.s, 1H, NH)
3277 (NH), 2979, 2875 1.30 (t, 3H, CH2CH3), 1.63 (d, 3H, CH3), 2.70 (s, 401
(CH-aliph), 1711,
1650 (2C O), 1614
(C N)
3H, CH3), 3.95 (q, 2H, CH2CH3), 4.02 (q, 1H,
methine proton of thiazolidinone ring), 4.15
(s, 3H, OCH3), 6.96 (d, 1H, J = 2.30 Hz,
Furan H-3), 7.30 (s, 1H, H-8), 7.62 (d, 1H,
J = 2.30 Hz, Furan H-2), 10.32 (br.s, 1H, NH)

Synthesis of Azoles
1589
TABLE II The Spectral Data of the Newly Compounds (Continued)
Comp.
no.
MS
(m/z)
IR (ν, cm−1) KBr
1H-NMR (CDCl3, δ, ppm)
10d
3285 (NH), 2931, 2857 1.26–1.88 (m, 10H, cyclohexyl), 1.65 (d, 3H,
(CH-aliph), 1717,
1654 (2C O), 1615
(C N)
CH3), 2.68 (s, 3H, CH3), 4.00 (q, 1H,
methine proton of thiazolidinone ring),
4.15 (s, 3H, OCH3), 4.26 (m, 1H,
cyclohexyl), 7.00 (d, 1H, J = 2.30 Hz,
Furan H-3), 7.32 (s, 1H, H-8), 7.65 (d, 1H,
J = 2.30 Hz, Furan H-2), 10.30 (br.s, 1H,
NH)
10e
10f
3287 (NH), 2975, 2852 1.69 (d, 3H, CH3), 2.71 (s, 3H, CH3), 4.10 (q,
479
(CH-aliph), 1722,
1660 (2C O), 1618
(C N)
1H, methine proton of thiazolidinone
ring), 4.15 (s, 3H, OCH3), 4.28 (s, 3H,
OCH3), 6.90 (d, 1H, J = 2.30 Hz, Furan
H-3), 7.10–7.35 (m, 5H, Ar-H), 7.62 (d, 1H,
J = 2.30 Hz, Furan H-2), 10.92 (br.s, 1H,
NH)
3280 (NH), 2929, 2855 1.20–1.85 (m, 10H, cyclohexyl), 1.65 (d, 3H,
(CH-aliph), 1718,
1652 (2C O), 1612
(C N)
CH3), 2.70 (s, 3H, CH3), 4.05 (q, 1H,
methine proton of thiazolidinone ring),
4.11 (s, 3H, OCH3), 4.27 (m, 1H,
cyclohexyl), 4.30 (s, 3H, OCH3), 7.00 (d,
1H, J = 2.30 Hz, Furan H-3), 7.65 (d, 1H,
J = 2.30Hz, Furan H-2), 10.40 (br.s, 1H,
NH)
11a
11b
3189 (NH), 2972, 2852 2.68 (s, 3H, CH3), 4.00 (s, 3H, OCH3), 6.92
377
(CH-aliph), 1621
(C N)
(d, 1H, J = 2.30 Hz, Furan H-3), 7.00–7.40
(m, 6H, 5Ar-H, H-8), 7.56 (d, 1H, J = 2.30
Hz, Furan H-2), 10.60 (br.s, 1H, NH)
3182 (NH), 2930, 2850 2.70 (s, 3H, CH3), 4.07 (s, 3H, OCH3), 4.58
(CH-aliph), 1619
(C N)
(d, 2H, CH2-Ph), 6.90 (d, 1H, J = 2.30,
Furan H-3), 7.15–7.40 (m, 6H, 5Ar-H,
H-8), 7.57 (d, 1H, J = 2.30 Hz, Furan H-2),
8.60 (br.s, 1H, NH)
11c
11d
11e
3175 (NH), 2928, 2851 1.25 (t, 3H, CH2CH3), 2.69 (s, 3H, CH3),
329
(CH-aliph), 1615
(C N)
3.45(q, 2H, CH2CH3), 4.02 (s, 3H, OCH3),
6.85 (br.s, 1H, NH), 6.90 (d, 1H, J = 2.30
Hz, Furan H-3), 7.29 (s, 1H, H-8), 7.57 (d,
1H, J = 2.30 Hz, Furan H-2)
3179 (NH), 2933, 2857 1.21–1.90 (m, 10H, cyclohexyl), 2.68 (s, 3H,
(CH-aliph), 1623
(C N)
CH3), 3.44 (m, 1H, cyclohexyl), 4.10 (s, 3H,
OCH3), 5.60 (br.s, 1H, NH), 6.90 (d, 1H,
J = 2.30 Hz, Furan H-3), 7.32 (s, 1H, H-8),
7.54 (d, 1H, J = 2.30 Hz, Furan H-2)
3186 (NH), 2975, 2850 2.71 (s, 3H, CH3), 4.00 (s, 3H, OCH3), 4.24
407
(CH-aliph), 1620
(C N).
(s, 3H, OCH3), 6.90 (d, 1H, J = 2.30 Hz,
Furan H-3), 7.12–7.38 (m, 5H, Ar-H), 7.58
(d, 1H, J = 2.30 Hz, Furan H-2), 10.65
(br.s, 1H, NH)
(Continued on next page)

1590
E. M. Keshk et al.
TABLE II The Spectral Data of the Newly Compounds (Continued)
Comp.
no.
MS
(m/z)
IR (ν, cm−1) KBr
1H-NMR (CDCl3, δ, ppm)
11f
3180 (NH), 2932, 2855 1.20–1.92 (m, 10H, cyclohexyl), 2.70 (s, 3H,
(CH-aliph), 1624
(C N)
CH3), 3.45 (m, 1H, cyclohexyl), 4.12 (s, 3H,
OCH3), 4.25 (s, 3H, OCH3), 5.62 (br.s, 1H,
NH), 6.90 (d, 1H, J = 2.30 Hz, Furan H-3),
7.56 (d, 1H, J = 2.30 Hz, Furan H-2)
4-Methoxy- and 4,8-Dimethoxy-3-methylbenzo-
[1,2-b: 5,4-bꢀ]difuran-2-carboxylic Acid Ethyl Ester (4a,b)
A mixture of 3a or 3b (0.01 mol) in absolute ethanol (25 ml) containing a
few drops of concentrated sulphuric acid was refluxed for 2 h. The solid
formed was filtered off, dried, and crystallized from the proper solvent
to give 4a,b, respectively.
4-Methoxy- and 4,8-Dimethoxy-3-methylbenzo-
[1,2-b: 5,4-bꢀ]difuran-2-carbohydrazides (5a,b)
A mixture of 4a or 4b (0.01 mol) and hydrazine monohydrate (0.01 mol)
in absolute ethanol (25 ml) was refluxed for 2 h and then left to cool.
The precipitate formed was filtered off, dried, and crystallized from the
proper solvent to give 5a,b, respectively.
1-(4-Methoxy- and 4,8-Dimethoxy-3-methylbenzo-
[1,2-b:5,4-bꢀ]difuran-2-yl-carbonyl)-4-substituted
Thiosemicarbazides (6a--h)
General Procedure
A mixture of 5a or 5b (0.01 mol) and the appropriate isothiocyanate
(0.01 mol) in absolute ethanol (25 ml) was refluxed for 2 h and then left
to cool. The precipitate formed was filtered off, dried, and crystallized
from the appropriate solvent to give 6a–h.
2-(4-Methoxy- and 4,8-Dimethoxy-3-methylbenzo-
[1,2-b: 5,4-bꢀ]difuran-2-yl)-1-substituted-5-mercapto-
1H-1,3,4-triazoles (7a--f)
General Procedure
A suspension of appropriate thiosemicarbazides 6a–e,h (0.01 mol)
in sodium hydroxide (50 ml, 2 N) was refluxed under stirring for 4
h. The reaction mixture was then cooled and neutralized with dilute

Synthesis of Azoles
1591
hydrochloric acid. The precipitate obtained was filtered off, washed with
water several times, dried, and crystallized from the proper solvent to
give 7a–f.
2-(4-Methoxy- and 4,8-Dimethoxy-3-methylbenzo-
[1,2-b:5,4-bꢀ]difuran-2-yl)-5-substituted
Amino-1,3,4-oxadiazoles (8a--f)
General Procedure
A mixture of the appropriate thiosemicarbazides 6a–e,h (0.01 mol)
and excess yellow mercuric oxide (0.015 mol) in ethanol (30 ml) was re-
fluxed for 4–6 h. The reaction mixture was allowed to cool to room tem-
perature (to allow the sedimentation of the black mercuric sulphide),
was filtered, and the mercuric sulphide was washed with ethanol. The
filtrate and alcoholic washing were combined, treated with water un-
til a permenant turbidity existed, and allowed to stand overnight. The
product was separated and crystallized from the proper solvent to give
8a–f.
2-{[(4-Methoxy- and 4,8-Dimethoxy-3-methylbenzo-
[1,2-b:5,4-bꢀ]difuran-2-yl)carbonyl]hydrazono}-
3-substituted-4-thiazolidinones (9a--f)
General Procedure
A mixture of the appropriate thiosemicarbazides 6a–e,h (0.01 mol),
ethyl bromoacetate (0.01 mol), and anhydrous sodium acetate
(0.015 mol) in absolute ethanol (30 ml) was refluxed for 3 h. The re-
action mixture was cooled, diluted with water, and allowed to stand
overnight. The solid obtained was filtered off, dried, and crystallized
from the proper solvent to give 9a–f.
2-{[(4-Methoxy- and 4,8-Dimethoxy-3-methylbenzo-
[1,2-b:5,4-bꢀ]difuran-2-yl)carbonyl] hydrazono}-
3-substituted-5-methyl-4-thiazolidinones (10a--f)
General Procedure
A mixture of the appropriate thiosemicarbazides 6a–e,h (0.01 mol),
α-bromopropionic acid (0.01 mol), and anhydrous sodium acetate
(0.015 mol) in absolute ethanol (30 ml) was refluxed for 3 h. The re-
action mixture was cooled, diluted with water, and allowed to stand
overnight. The solid obtained was filtered off, dried, and crystallized
from the proper solvent to give 10a–f.

1592
E. M. Keshk et al.
2-(4-Methoxy- and 4,8-Dimethoxy-3-methylbenzo-
[1,2-b:5,4-bꢀ]difuran-2-yl)-5-substituted
Amino-1,3,4-thiadiazoles (11a--f)
General Procedure
Phosphorus oxychloride (30 ml) was added to the appropriate
thiosemicarbazides 6a–e,h (0.01 mol), and the mixture was refluxed
for 2–4 h. The mixture was then evaporated in vacuo, and the residue
was washed with dilute ammonium hydroxide solution and water. The
solid obtained was filtered off, dried, and crystallized from the proper
solvent to give 11a–f.
DNA-BINDING ASSAY
The mechanism of several known antitumor agents involves interaction
with DNA. Examples include alkylating agents (e.g., chlorabucil, cy-
clophosphamide, melphalan, streptozocin), antitumor, antibiotics (e.g.,
bleomycin, doxorubicin, mithramycin), and various other substances
(e.g., cisplatin, chloroquine). Based on the interaction of small molecu-
lar weight with DNA, some short-term procedures have been devised
that are applicable for the discovery and evaluation of naturally occur-
ring and synthetic compounds that function by this mechanism.22−25
Some of the new compounds were screened towards the affinity DNA
binding using a colorimetric assay.26 Compound 7c showed the highest
TABLE III Activity of Compounds in the
Methyl Green/DNA Displacement Assay∗
DNA/methyl green
DNA-active compounds
IC50, µg/ml
7c
7a,b
5a
5b
8c
8a,b
11c
11a,b
2a,4a
2b,4b
30
49
59
62
65
68
72
74
82
88
3
1
1
1
1
2
1
1
2
2
∗Values represent the concentration (mean
SD, n = 3 to separate determinations) required
for 50% decrease in the initial absorpance of the
DNA methyl green solution.

Synthesis of Azoles
1593
affinity to DNA; compounds 5a,b, 7a,b, 8a–c, and 11a–c showed a mod-
erate activity; and the compounds 2a,b, 4a,b showed a weak activity
(Table III).
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