Preparation of new polycyclic compounds derived from benzofurans and furochromones. An approach to novel 1,2,3-thia-, and selena-diazolofurochromones of anticipated antitumor activities

Article abstract of DOI:10.1016/j.ejmech.2010.07.065

Base catalyzed condensation of enaminoketones (3a,b) with malononitrile yields the respective 7-imino-5[2(substituted)prop-1-enyl]furochromene-6- carbonitriles (4a-d) according to the nature of base used. Compounds (3a, b) condense also with indan-1,3-diketone (5) to give α, β-unsaturated carbonyl compounds (6a) and (6b), respectively. Pyrrolidine-catalyzed condensation of visnaginone (2a) and khellinone (2b) with active methylenes yields the corresponding 1-[7,7-(substituted) furobenzodihydropyrone derivatives (7a-e) which condense with semicarbazide to give the respective semicarbazones (8a-e). Compounds (8b,e) react with thionyl chloride to give the respective 1,2,3-thiadiazoles (9a,b) meanwhile compounds (8a-e) react also with selenium dioxide to give 1,2,3-selenadiazoles (9c-g), respectively. Chalcones (11a,b) were obtained upon condensing (2a,b) with ferrocene-2-carboxaldehyde (10). Compatible elementary and spectroscopic measurements were in good accord with the structures postulated for the new compounds. The antitumor activities of certain selected new compounds were screened, in vitro, against a panel of four (breast: MCF-7, cervix: HELA, colon: HCT116 and liver: HEPG2) human solid tumor cell lines and the structure activity relationship (SAR) was discussed.

Full text of DOI:10.1016/j.ejmech.2010.07.065

European Journal of Medicinal Chemistry 45 (2010) 4920e4927
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Preparation of new polycyclic compounds derived from benzofurans and
furochromones. An approach to novel 1,2,3-thia-, and selena-
diazolofurochromones of anticipated antitumor activities
,
a
a
b
Sanaa M.Sh. Atta a , Dalia S. Farrag , Ayman M.K. Sweed , A.H. Abdel-Rahman
*
a Department of the Chemistry of Natural and Microbial Products, National Research Centre, El-Behoos Street, Dokki, 12622 Cairo, Egypt
b Chemistry Department, Faculty of Science, Mansoura University, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Base catalyzed condensation of enaminoketones (3a,b) with malononitrile yields the respective 7-imino-
5[2(substituted)prop-1-enyl]furochromene-6-carbonitriles (4aed) according to the nature of base used.
Received 9 June 2010
Received in revised form
27 July 2010
Compounds (3a, b) condense also with indan-1,3-diketone (5) to give
a, b-unsaturated carbonyl
compounds (6a) and (6b), respectively. Pyrrolidine-catalyzed condensation of visnaginone (2a) and
khellinone (2b) with active methylenes yields the corresponding 1-[7,7-(substituted) furobenzodihy-
dropyrone derivatives (7aee) which condense with semicarbazide to give the respective semicarbazones
(8aee). Compounds (8b,e) react with thionyl chloride to give the respective 1,2,3-thiadiazoles (9a,b)
meanwhile compounds (8aee) react also with selenium dioxide to give 1,2,3-selenadiazoles (9ceg),
respectively. Chalcones (11a,b) were obtained upon condensing (2a,b) with ferrocene-2-carboxaldehyde
(10). Compatible elementary and spectroscopic measurements were in good accord with the structures
postulated for the new compounds. The antitumor activities of certain selected new compounds were
screened, in vitro, against a panel of four (breast: MCF-7, cervix: HELA, colon: HCT116 and liver: HEPG2)
human solid tumor cell lines and the structure activity relationship (SAR) was discussed.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Accepted 29 July 2010
Available online 6 August 2010
Keywords:
Benzofurans
Furochromenes
1,2,3-Thiadiazoles
1,2,3-Selenadiazoles
Antitumor activity
1. Introduction
2. Results and discussion
Benzofurans and furochromones are very interesting
O-heterocycles which are ubiquitous in nature and show a wide
range of biological activities [1e5]. Aromatase inhibitory effect [6],
anti-HIV activity [7] and anticancer potency [8,9] are mere exam-
ples. Therefore, the present work has been endeavored aiming at
designing and synthesizing novel polycyclic compounds containing
the benzofuran and/or furochromone scaffold in their molecules to
be pharmacologically screened for their anticancer activities. As
starting materials, 4-methoxy-5-acetyl-6-hydroxybenzofuran (vis-
naginone, 2a) and 4,7-dimethoxy-5-acetyl-6-hydroxybenzofuran
(khellinone, 2b) were used. Compounds (2a) and (2b) are essen-
tially prepared [10] via alkali hydrolysis of the naturally occurring
Visnagin (1a) and Khellin (1b), respectively (Scheme 1).
2.1. Chemistry
The reaction of enaminoketones (3a,b) with malononitrile was
conducted in boiling ethanol in presence of few drops of triethyl-
amine (TEA) to give the respective 7-imino-5-[2(pyrrolidin-1-yl)
prop-1-enyl]furochromene-6-carbonitriles (4a,b) (Scheme 3).
On the other hand, when the reaction of (3b) with malononitrile
wasconducted in boilingethanolinpresenceof piperidine, a mixture
of 7-imino-4,9-dimethoxy-5-[(Z)-2-(pyrrolidin-1-yl)prop-1-enyl]-
7H-furo[3,2-g]chromene-6-carbonitrile (4b) and 7-imino-4,9-
dimethoxy-5-[(Z)-2-(piperidin-1-yl)prop-1-enyl]-7H-furo[3,2-g]
chromene-6-carbonitrile (4d) was obtained. Similarly the reaction
of (3a) with malononitrile under the same conditions yielded
a mixture of imino furochromene-6-carbonitriles (4a and 4c).
Structuralreasonings for (4b)were:correctelementaryanalyses and
molecular weight determination (MS) corresponded to C21H21N3O4
(MS: m/z 379, Mþ, 5.47%). Its IR spectrum (KBr, cmꢀ1) showed strong
absorption bands at 3444 (NH), 2925, 2852 (CH, aliphatic, alicyclic),
2204 (C^N),1623,1558 (C]N, C]C) and at 1122 (CeO, stretching);
The ɣ-pyrone ring in (1a) and (1b) is also cleaved upon treat-
ment with pyrrolidine in boiling ethanol to give the respective
enaminoketones (3a) and (3b) [11] which are also used as inter-
mediate synthones in the present study (Scheme 2).
The 1H NMR spectrum of (4b) (CDCl3,
(d, 1H, furan, JH,H ¼ 2.5 Hz), 7.49 (d, 1H, furan, JH,H ¼ 2.5 Hz), 6.84 (q,
d ppm) showed signals at 7.63
* Corresponding author.
E-mail address: sanaa_atta2@yahoo.com (S.M.Sh. Atta).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.07.065

S.M.Sh. Atta et al. / European Journal of Medicinal Chemistry 45 (2010) 4920e4927
4921
OCH3
O
Upon condensing compounds (7aee) with semicarbazide in
refluxing ethanol, the respective semicarbazones (8aee) could be
obtained in pure crystalline forms and high percentage yields
(Scheme 6).
OCH3
O
O
CH3
O
O
OH
Upon heating semicarbazones (8b,e) with thionyl chloride in
absence of solvent, the respective 7,7-(substituted)-furo[3,2-g]-7,7-
dihydrochromeno[4,3-d][1,2,3]thiadiazoles (9a,b) were obtained.
Moreover, the furochromene-1,2,3-selenadiazoles (9ceg) were
successfully prepared by reacting semicarbazones (8aee) with
freshly sublimed selenium dioxide in glacial acetic acid. In this
connection, it is worthwhile to state that the successful preparation
of the 1,2,3-selenadiazoles (9ceg) is of a particular significance. It
runs in the line with the growing interest devoted to selenium-
containing heterocycles due to their vast pharmacological and
synthetic applications [12e16]. It is widely realized that insertion of
the 1,2,3-selenadiazole ring in a biologically active compound may
lead to an increase in its activity. Moreover the diazole system itself
is found in numerous anti-parasitic, fungicidal and anti-inflam-
matory drugs [17,18]. Besides, selenium supplementation could
reduce the incidence of various cancer types such as prostate, lung,
colon and liver cancers [19,20]. A lot of potent organoselnium
compounds have been designed to achieve greater chemo-
preventive efficacy and minimal side effects by structural modifi-
cation, such as Ebselen, Selenocyanate, Selenobetaine and selenium
analogues of sulfur containing compounds with known antitumor
activities [19]. Numerous selenium compounds have been also
evidenced to be superior to many naturally occurring Se-
compounds [20] (Scheme 7).
CH3
R
R
2a, R= H (Visnaginone)
b, R= OCH3 (Khellinone)
1a, R= H (Visnagin)
b, R= OCH3 (Khellin)
Scheme 1.
OCH3
O
CH3
N
O
OH
R
3a, R= H
b, R= OCH3
Scheme 2.
1H, exocyclic methine proton, JH,H ¼ 5.4 Hz), 4.12 (s, 3H, OCH3,), 3.88
(s, 3H, OCH3), 3.87(d, 3H, CH3eC]C, JH,H ¼5.4 Hz), 2.59e1.25 [m, 8H,
N(CH2)4] and at 14.48 (s, NH, exchangeable with D2O). In the same
sense, evidences for structure (4d) were: (a) Elementary analysis
and molecular weight determination corresponded to C22H23N3O4
(MS: m/z 393, Mþ, 100%). (b) The IR spectrum (KBr, cmꢀ1) of (4d)
showed strong absorption bands at 3471 (NH), 2990, 2857, (CH,
aliphatic, alicyclic), 2224 (C^N),1596,1550 (C]N, C]C) and at 1207
The reaction of visnaginone (2a) and khellinone (2b) with
aromatic-, and heteroaromatic aldehydes to give the respective chal-
cones, is well established [21,22]. The same reaction with aldehydes
derived from organometallics has as yet been not investigated. This
prompted usto undertakethe reaction of (2a)and(2b)withferrocene-
2-carboxaldehyde (10) which yielded brown red crystalline products
for which structures (11a) and (11b) were respectively assigned.
(CeO, stretching).(c) Its 1H NMR spectrum (CDCl3,
d ppm) showed
signals at 7.73 (d, 1H, furan, JH,H ¼ 2.5 Hz), 7.47 (d,1H, furan,
JH,H ¼ 2.5 Hz), 6.82 (q,1H, exocyclic methine proton, JH,H ¼ 2.7 Hz), 4.10
(s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.59 (d, 3H, CH3eC]C, JH,H ¼ 2.7 Hz),
2.53e1.57 [m, 10H, N(CH2)5] and at 14.00 (s, NH, D2O exchangeable).
13C NMR spectrum (CDCl3,
d ppm): showed signals at d 24.35, 25.88,
OCH3
O
50.44 (H2C, piperidinyl), 21.52 (H3CeC]Ce), 130.23 (H3CeC]Ce),
113.57 (H3CeC]Ce), 61.14 (OCH3), 61.01 (OCH3),143.54 (HC-2,Furan),
109.67 (HC-3, Furan), 117.14 (NC, Nitrile), 160.33 (HN ¼ Ce).
When enaminoketones (3a,b) were allowed to condense with
indan-1,3-diketone (5) in boiling ethanol in presence of few drops
of piperidine, violet crystalline products (6a,b) were obtained and
their structures were assigned. Compatible elementary analyses
and spectral measurements for these compounds were gained (see
Experimental and Scheme 4).
CHO
Fe
O
OH
Fe
R
Pyrrolidine-catalyzed condensation of visnaginone (2a) and
khellinone (2b) with active methylene compounds, namely, acetone,
ethylmethyl ketone and cyclohexanone yielded colourless crystalline
compounds for which the 1-(6,7-dihydro-7,7-(substituted)furo
[3,2-g]chromen-5-one structures (7aee) were respectively
assigned [24,25], (Scheme 5).
10
11a, R= H
b, R= OCH3
CH3
OCH3
N
(CH2)n
CN
CN
:B
4a, R= H,
b, R= OCH3, n=1
c, R= H, n=2
d, R= OCH3, n=2
n=1
3a, b
+
H2C
ethanol
CN
O
O
NH
R
Scheme 3.

4922
S.M.Sh. Atta et al. / European Journal of Medicinal Chemistry 45 (2010) 4920e4927
O
OCH3
O
H
O
O
3a, b +
ethanol / piperidine
N
O
OH
H3C
5
R
6a, R= H
b, R= OCH3
Scheme 4.
tumor cell lines. The standard curves for the tested compounds are
also given. From Table 1, it is evident that most of the tested
compounds show antitumor activities with IC50 values ranging
OCH3
O
O
from 5.56 to 20.8
mg/ml and reaching one third that of DXR (IC50
:
2.97 g/ml) in the case of compound (4b) (IC50: 8.61
m
mg/ml). This
R`
may be attributable to presence of the pyrrolidinyl moiety in its
molecular structure. On the other hand, substitution of the pyrro-
lidinyl moiety for the piperidinyl moiety in one and the same
structure (cf. 4d, IC50: ꢀve) totally abolished the activity. The
antitumor activities of the semicarbazone derivatives (8) increase
O
R``
R
a, R= H, R`= R``= CH
b, R= H, R`+ R``= (CH2)5
c, R= OCH3, R`= R``= CH3
d, R= OCH3, R`= CH3, R``= C2H5
e, R= OCH3, R`+R``= (CH2)5
7
3
in the order: 8c < 8b < 8d < 8a < 8e. Both of compounds (8c) (IC50
:
20.80 g/ml) and (8a) (IC50: 10.90 g/ml) possess two methyl
m
m
groups at position-7 in their molecular structures. Therefore, the
marked difference in their activities can be correlated with absence
of the C-9 methoxyl group which induces the two fold activity
shown by compound (8a). The reverse behaviour is noticed in the
Scheme 5.
case of the spiro-derivatives (8b) (IC50: 14.00
10.60 g/ml) wherein the increase of activity can be correlated with
presence of the methoxyl group at C-9.
mg/ml) and (8e) (IC50:
m
2.2. Biological evaluation
The cytotoxic activities of compounds (9) increase in the order:
9d < 9a < 9e < 9g < 9b < 9f < 9c. The marked difference in the
Chemotherapy is a major approach for both localized and
metastasized cancers [23]. Therefore, eighteen of the newly
synthesized compounds were screened for their in vitro cytotoxic
and growth inhibitory activities against human breast carcinoma
cell line (MCF-7), in comparison with the activity of the known
anticancer Doxorubicin (DXR) as a reference drug. The cytotoxic
antitumor activities of 1,2,3-selenadiazole compounds (9e) (IC50
15.8 g/ml) and (9c) (IC50: 5.56 g/ml) can be correlated with
absence of the C-9 methoxyl group in 9c which is the nearest in
activity to that of the reference drug (Doxorubicin DXR, IC50
2.97 g/ml). In general, conversion of semicarbazones (8) into their
:
m
m
:
m
activities of the tested compounds were expressed as IC50 mg/ml
respective selenadiazoles (9) enhances the cytotoxicity of the
which is the dose that reduces survival to 50%. The screening results
are compiled in Table 1. The relation between the surviving fraction
and drug concentration is plotted to get the survival curves of the
tested compounds and it is reported that synthetic selenadiazole
N
OCH3
N
X
OCH3 NNHCONH2
R`
R`
O
O
R``
O
O
R
R``
R
a , X= S, R= H, R`+ R``= (CH )
b, X= S, R= OCH3; R`+ R``= (CH2)5
c, X= Se, R= H ; R`= R``= CH3
9
2 5
a, R= H, R`= R``= CH
b, R= H, R`+ R``= (CH2)5
8
3
d, X= Se, R= H ; R`+ R``= (CH2)5
e,X= Se, R= OCH3, R`=R``= CH3
f, X= Se, R= OCH3, R`= CH3, R``= C2H5
g, X= Se, R= OCH3, R`+R``= (CH2)5
c, R= OCH3, R`= R``= CH3
d, R= OCH3, R`= CH3, R``= C2H5
e, R= OCH3, R`+R``= (CH2)5
Scheme 6.
Scheme 7.

S.M.Sh. Atta et al. / European Journal of Medicinal Chemistry 45 (2010) 4920e4927
4923
Table 1
Effect of the tested compounds on MCF-7 tumor cell lines.
MCF7DOX
MCF79c
1.0
a
Compound
IC50
(
m
g/ml)
Compound
IC50 (mg/ml)
Doxorubicin
9c
11a
4b
8e
8a
11b
9f
6b
8d
2.97
5.56
6.93
8b
9b
9g
6a
9e
9a
9d
8c
4d
14.00
14.90
15.00
15.50
15.80
15.90
16.50
20.80
ꢀve
0.5
8.61
10.60
10.90
11.50
12.70
13.20
13.9
0.0
1.0
MCF7DOX
MCF76b
MCF78a
MCF74b
MCF711a
MCF79c
b
0.5
0.0
derivatives are known to induce caspase- and P53-dependent
apoptosis in breast carcinoma cells [19]. Meanwhile, the C-9
0
10
20
30
40
50
methoxyl group in the spiro-selenadiazoles (9d) (IC50: 16.5
and (9g) (IC50: 15.00 g/ml) do not seem to display an important
role on the observed activities.
The appreciable cytotoxic activity of chalcones (11a) (IC50
6.93 g/ml) and (11b) (IC50: 11.50 g/ml) may be attributable to the
mg/ml)
Conc: g / ml
m
Fig. 1. (a) The surviving fraction as a function of drug concentrations for the reference
compared particularly with compound (9c). (b) The same reference is compared with
the other compounds.
:
m
m
presence of the ferrocenyl moiety in their molecular structures. The
pronounced activity of (11a) however, may be correlated with
absence of the C-9 methoxyl group in its molecular structure.
In summation, presence of a pyrrolidinyl moiety, ferrocenyl
moiety and/or a selenium atom in the molecular structure of the
tested compounds may enhance their cytotoxic activities. Besides,
presence or absence of the C-9 methoxyl group has only a limited
role on the cytotoxic activity in one and the same group of the
tested compounds.
Moreover, nine compounds (4b, 4d, 8e, 9c, 9d, 9e, 9f, 9g and 11a)
were screened for their in vitro cytotoxic and growth inhibitory
activities against human cervix (HELA), colon (HCT116) and liver
(HEPG2) carcinoma cell lines. The screening results are compiled in
Table 2. It is evident from this table that the test compounds
carcinoma cell lines. The same compound also showed appreciable
activities against human cervix (HELA) and colon (HCT116) carci-
noma cell lines.
3. Conclusion
The present study reports on simple and efficient approaches for
the synthesis of new sulfur-, selenium-, iron-, and nitrogen-con-
taining benzofuran and furochromone derivatives. The naturally
occurring Visnagin (1a) and Khellin (1b) were successfully used as
suitable starting materials for implementing these goals. Many of
the new compounds revealed pronounced in vitro antitumor
activities when tested against human MCF-7, HELA, HCT116 and
HEPG2 carcinoma cell lines. The most promising result against
breast carcinoma (MCF-7) was recorded by the selenium-contain-
showed moderate (IC50: 8.46
activities towards liver carcinoma (HEPG2) cell lines. On the other
hand, the same compounds exhibited excellent (IC50: 4.19 g/ml) to
moderate (IC50: 7.24 g/ml) potencies towards cervix carcinoma
(HELA) cell lines wherein compound (8e) has recorded the same
activity (IC50: 4.19 g/ml) of the reference drug (Doxorubicin, DXR).
In the same sense, the cytotoxic and growth inhibitory activity of
compound (9d) (IC50: 3.89 g/ml) was very close to that of the
reference drug (IC50: 3.73 g/ml) against human colon (HCT116)
mg/ml) to weak (IC50: 15.90 mg/ml)
m
ing compound (9c). It showed IC50 value of (5.56
the closest in value to that recorded by the reference drug Doxo-
rubicin (DXR, IC50: 2.97 g/ml). Similarly, the cytotoxic and growth
inhibitory activity of the selenium-containing compound (9d)
mg/ml) which is
m
m
m
(IC50: 3.89
(IC50: 3.73
m
m
g/ml) was very close to that of the same reference drug
g/ml) against human colon (HCT116) carcinoma cell
m
m
lines These results supplement to the well known ability of Se-
containing compounds in reducing the incidence of various cancer
types such as prostate, lung, colon and liver cancers [19,20].
carcinoma cell lines. It is also of interest to report that while
compound (4d) was inactive towards breast (MCF-7) carcinoma cell
lines (cf. Table 1) (Fig. 1), its activity was on the top (IC50
:
8.46 g/ml) of those of the tested compounds against liver (HEPG2)
m
4. Experimental
All melting points are uncorrected and were recorded on an open
glass capillaries using an Electrothermal 1A 9000 digital melting
point apparatus. Analytical data were obtained from the Microana-
lytical unit, Cairo University, Egypt. IR spectra (KBr discs, cmꢀ1) were
recorded on a Perkin Elmer 1430 infracord.1H NMR spectra were
measured with Joel 270 MHz or Joel ECA 500 MHz spectrometer and
the 13C NMR spectrum was recorded on JOEL 500 AS (at 500 MHz)
using TMS as an internal standard and chemical shift values are
Table 2
Effect of some selected new compounds on HELA, HCT116 and HEPG2 tumor cell
lines.a
Compound IC50
HELA
(mg/ml)
HCT116
HEPG2
Doxorubicin
4.19
4.19
4.35
4.80
5.11
5.57
5.72
6.02
6.02
7.24
Doxorubicin
3.73
3.89
4.04
4.19
4.34
4.50
4.65
4.80
4.80
8.92
Doxorubicin
3.73
8.46
8.61
9.53
9.53
10.10
10.90
11.50
14.60
15.90
8e
9e
4d
4b
9g
11a
9c
9d
8e
9g
4d
11a
9e
4b
9c
4d
8e
9f
9g
11a
4b
9c
recorded in d ppm scale. The mass spectra were run on Finnigan Mat
SSQ-7000 or on GCMS-QP 1000 EX Shimadzo GC/MS Specrometer,
Japan at E.I. 70eV. Follow-up of the reactions and checking the purity
of the products were made by TLC on Silica gel pre-coated aluminum
sheets (type 60 F254, Merck, Darmstadt, Germany) and the spots
were detected by exposure to UV lamp at l254 nm. Visnagin (1a) and
Khellin (1b) were purchased from Memphis Company, Cairo, Egypt.
9f
9d
9d
9e
9f
a
Arranged according to their descending orders of activities.

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S.M.Sh. Atta et al. / European Journal of Medicinal Chemistry 45 (2010) 4920e4927
4.1. Synthesis of 5-[2-(pyrrolidin-1-yl)prop-1-enyl]furochromene-
6-carbonitriles (4a,b)
Successive elution with petroleum ether (40e60 ꢁC)/ethyl
acetate (90:10 v/v) yielded compound 4b (m.p. mixed m.p. and
comparative IR spectra). Yield: 45%.
General procedure: A mixture of 3a (or 3b) (5 mmol) and
malononitrile (7 mmol) in ethanol (30 ml) in the presence of a few
drops of TEA was refluxed for 3 h. After removing the solvent, in
vacuo, the residual material was recrystallized from ethanol to give
(4a,b).
4.3. Synthesis of 2-(benzofuran-5-yl)-3-(pyrrolidin-1-yl)but-2-
enylidine)-2H-indene-1,3-diones (6a,b)
General procedure: A mixture of 3a (or 3b) (5 mmol) and indan-
1, 3-dione (5 mmol) in ethanol (25 ml) containing few drops of
piperidine was refluxed for 2 h. After removing the solvent, in
vacuo, the residual material was subjected to column chromatog-
raphy to give (6a,b).
4.1.1. 7-Imino-4-methoxy-5-[(Z)-2-(pyrrolidin-1-yl) prop-1-enyl]-
7H-furo[3,2-g]chromene-6-carbonitrile (4a)
Yellow crystals. m.p. 164e166 ꢁC. Yield: (80%). IR (KBr, cmꢀ1
)
showed strong absorption bands at 3427 (NH), 3124 (CH, aromatic),
2954, 2857 (CH, aliphatic, alicyclic), 2200 (C^N) 1616 (C]N), 1559
(C]C, aromatic), 1260 (CeO, stretching); 1H NMR (CDCl3,
d
ppm):
4.3.1. (E)-2-(1-(6-Hydroxy-4-methoxybenzofuran-5-yl)-3-
7.56(d,1H, furan, JH,H ¼ 2.5 Hz), 7.43 (d, 1H, furan, JH,H ¼ 2.5 Hz), 6.83
(m, 2H, exocyclic methine proton þ Aromatic proton), 3.97 (s, 3H,
OCH3), 3.82 (d, 3H, CH3eC]C, JH,H ¼ 3.2 Hz), 2.51e2.03 [m, 8H, N
(CH2)4] and at 14.20 (s, NH, exchangeable with D2O). MS: m/z 349
(Mþ, 49.19%). Anal. Calcd. for C20H19N3O3: (349.39) C, 68.75; H,
5.48; N, 12.02. Found: C, 68.65; H, 5.38; N, 12.30.
(pyrrolidin-1-yl) but-2-enylidene)-1H-indene-1,3(2H)-dione (6a)
Violet crystals purified by silica gel for column using chloroform/
ethyl acetate mixture as 70:30 v/v. m.p. > 200 ꢁC. Yield: (75%). IR (KBr,
cmꢀ1) showed strong absorption bands at 3429 (OH), 2926, 2861 (CH,
aliphatic, alicyclic),1633 (C]O, aryl ketone; hydrogen-bonded),1588
(C]C) and 1201 (CeO, stretching); 1H NMR (CDCl3,
d ppm): showed
signals at 7.76e7.16 (m, 8H, furans þ aromatics þ exocyclic methine
proton), 4.05 (s, 3H, OCH3), 3.78 (d, 3H, CH3eC]C, JH,H ¼ 3.1 Hz),
2.09e1.57 [8H, N(CH2)4, m] and at 9.26 (s, OH, exchangeable with
D2O). MS: m/z 383 [Mþ ꢀ (C]O þ H2O)]. Anal. Calcd. for C26H23NO5
(429.478): C, 72.71; H, 5.39; N, 3.26. Found: C, 72.56; H, 5.67; N, 3.32.
4.1.2. 7-Imino-4,9-dimethoxy-5-[(Z)-2-(pyrrolidin-1-yl)prop-1-
enyl]-7H-furo[3,2-g]chromene-6-carbonitrile (4b)
Yellow crystals. m.p. 150e152 ꢁC. Yield: (85%). MS: m/z 379 (Mþ,
5.47%). Anal. Calcd. for C21H21N3O4 (379.42): C, 66.47; H, 5.57; N,
11.07. Found: C, 66.56; H, 5.31; N, 11.10.
4.3.2. (E)-2-(1-(6-Hydroxy-4,7-dimethoxybenzofuran-5-yl)-3-
(pyrrolidin-1-yl) but-2-enylidene)-1H-indene-1,3(2H)-dione (6b)
Violet crystals purified by silica gel for column using chloro-
form/ethyl acetate mixture (70:30 v/v). m.p. 82e84 ꢁC. Yield: (77%).
IR (KBr, cmꢀ1) showed strong absorption bands at 3429 (OH), 2930
(CH, aliphatic, alicyclic), 1628 (C]O, aryl ketone), 1383 (C]C) and
4.2. Synthesis of 5-[2-(piperidin-1-yl)prop-1-enyl]furochromene-6-
carbonitriles (4c,d)
General procedure: A mixture of 3a (or 3b) (10 mmol) and
malononitrile (12 mmol) in ethanol (30 ml) in the presence of
excess of piperidine (1 ml) was refluxed for 3 h. After removing the
solvent, in vacuo, the residual material was a mixture of two major
components which were subjected to silica gel column chroma-
tography to give (4a, 4c) and (4b, 4d).
1202 (CeO, stretching); 1H NMR (CDCl3,
d ppm): showed signals at
7.63e7.02 (m, 6H,furans þ aromatics), 6.06 (q, 1H, exocyclic
methine proton, JH,H ¼ 3.1 Hz), 4.20 (s, 3H, OCH3), 4.06 (s, 3H,
OCH3), 3.82 (d, 3H, CH3eC]C, JH,H ¼ 3.3 Hz), 2.40e1.26 [m, 8H, N
(CH2)4] and at 9.30 (s, OH, exchangeable with D2O). Anal. calcd. for
C27H25NO6 (459.505): C, 70.57; H, 5.48; N, 3.04. Found: C, 70.49; H,
5.35; N, 3.15.
4.2.1. 7-Imino-4-methoxy-5-[((Z)-2-(piperidin-1-yl) prop-1-enyl]-
7H-furo[3,2-g]chromene-6-carbonitrile (4c)
Yellow crystals purified by silica gel for column using light
petroleum (40e60 ꢁC)/ethyl acetate mixture (95:5 v/v). m.p.
95e97 ꢁC. Yield: (50%). IR (KBr, cmꢀ1) showed strong absorption
bands at 3430 (NH), 3131 (CH, aromatic), 2938, 2844 (CH, aliphatic,
alicyclic), 2204 (C^N), 1620, 1571 (C]N, C]C) 1120 (CeO,
4.4. Synthesis of 7-ethyl-4, 9-dimethoxy-7-methyl-6,7-dihydro-5H-
furo[3,2-g]chromen-5-one (7d)
To a solution of 4,7-dimethoxy-5-acetyl-6-hydroxybenzofuran
(2b) (15 mmol) and 2-butanone (20e25 mmol) in ethanol (30 ml)
was added pyrrolidine (18 mmol) in one portion. The mixture was
heated to reflux for 5 h. After reaction completion monitored by
TLC, the solvent was removed in vacuo. The resultant was diluted by
EtOAc and washed with aqueous NH4Cl solution (two times) and
brine. The organic layer was dried over anhydrous MgSO4 and
filtered. Then, the filtrate was concentrated in vacuo, and the
resulting mixture was purified with silica gel flash column chro-
matography (petroleum ether 60e80ꢁC/ethylacetate 90:10 v/v) to
give (7d) as white solid crystals. m.p. 38e40 IR (KBr, cmꢀ1) showed
strong absorption bands at 3139 (CH, aromatic), 2970, 2934 (CH,
aliphatic), 1684 (C]O, ɣ-pyrone); 1H NMR spectrum showed
signals at 7.48 (d, 1H, furan, JH,H ¼ 2.00 Hz), 6,90 (d, 1H, furan,
JH,H ¼ 2.00 Hz), 4.04 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 2.79, 2.65 (2d,
2H, each with JH,H ¼ 16.00 Hz, ɣ-pyrone ring protons), 1.79 (m, 2H,
CH3eCH2), 1.41 (s, 3H, CH3), 1.00 (t, 3H, CH2eCH3, JH,H ¼ 7.6 Hz).
Similarly compounds (7a) [25], (7b) [24], (7c) [25], (7e) [24] were
obtained and characterized (m.p. and mixed m.p.) by reacting 2a
(or 2b) with the appropriate active methylene derivative.
stretching); 1H NMR (CDCl3,
d ppm): showed signals at 7.67 (d,1H,
furan, JH,H ¼ 2.7 Hz), 7.43 (d, 1H, furan, JH,H ¼ 2.7 Hz), 6.83 (2H,
exocyclic methine proton þ Aromatic proton, two overlapped
signals), 3.97 (s, 3H, OCH3), 3.59 (d, 3H, CH3eC]C, JH,H ¼ 5.4 Hz),
2.52e1.23 [m, 10H, N(CH2)5] and at 13.90 (s, NH, exchangeable with
D2O). MS: m/z 363(Mþ, 56.57%).Anal. Calcd. for C21H21N3O3
(363.42): C, 69.40; H, 5.82; N, 11.65. Found: C, 69.38; H, 5.71; N,
11.55.
Successive elution with petroleum ether (40e60 ꢁC)/ethyl
acetate (9:10 v/v) yielded compound 4a (M.p. mixed M.p. and
comparative IR spectra). Yield: 45%.
4.2.2. 7-Imino-4,9-dimethoxy-5-[(Z)-2-(piperidin-1-yl)prop-1-
enyl]-7H-furo[3,2-g]chromene-6-carbonitrile (4d)
Bright yellow crystals purified by silica gel for column using
light petroleum (40e60 ꢁC)/ethyl acetateþmixture as 97:3 v/v. m.p.
88e90 ꢁC. Yield: (43%). MS: m/z 393(M , 100%). Anal. Calcd. for
C22H23N3O4 (393.45): C, 67.16; H, 5.89; N, 10.68. Found: C, 66.85; H,
5.67; N, 10.69.

S.M.Sh. Atta et al. / European Journal of Medicinal Chemistry 45 (2010) 4920e4927
4925
4.5. Synthesis of furo[3,2-g]chromen-5-ylidene)semicarbazones
(8aee)
4.5.5. 2-(40,90-Dimethoxy-spiro[cyclohexane-1,70-furo[3,2-g]
chromene]-50(60H)-ylidene)hydrazinecarboxamide (8e)
Yellowish white crystals. m.p. 177e179 ꢁC. Yield: (83%). IR (KBr,
cmꢀ1) showed strong absorption bands at 3455 (NH), 3274 (NH),
3204 (CH, furan), 2933, 2853 (CH, aliphatic, alicyclic), 1687 (C]O,
General procedure: Semicarbazide hydrochloride (12 mmol) and
sodium acetate (15 mmol) were dissolved in 35 ml of distilled
water. 7,7-(Substituted) furochromones (7aee) (10 mmol) in
ethanol was added dropwise and the content was warmed on
a water bath for 6e8 h. A white product separated on cooling the
content, which was filtered off, dried, and crystallized from ethanol
to give the corresponding semicarbazones (8aee).
amide) and 1127 (CeO, stretching); 1H NMR (CDCl3,
d ppm):
showed signals at 7.50 (d,1H, furan, JH,H ¼ 2.7 Hz), 7.26 (d, 1H,
furan, JH,H ¼ 2.7 Hz), 4.08 (s, 3H, OCH3), 3.92 (s, 3H, OCH3). The
methylene protons appeared at
d 2.67 (s, 2H), 1.89e1.37 [m, 10H, C
(CH2)5]. The D2O exchangeable signals present at
d 8.85, 6.84 are
assignable to the NH, NH2 group protons. Anal. calcd. for
C19H23N3O5 (373.41): C, 61.11; H, 6.20; N, 11.25. Found: C, 61.35; H,
6.22; N, 11.18.
4.5.1. 2-(4-Methoxy-7,7-dimethyl-6,7-dihydro-5H-furo[3,2-g]
chromen-5-ylidene)hydrazinecarboxamide (8a)
White crystals. m.p. 138e140 ꢁC. Yield: (90%). IR (KBr, cmꢀ1
)
showed strong absorption bands at 3433 (NH), 3275 (NH), 3200
(CH, furan), 2975, 2935 (CH, aliphatic, alicyclic), 1687 (C]O, amide)
4.6. Synthesis of 7,7-(substituted)furochromone-1,2,3-thiadiazoles
(9a,b)
and 1123 (CeO, stretching); 1H NMR (CDCl3,
d
ppm): showed
signals at 7.44 (1H, furan, d, JH,H ¼ 2.7 Hz), 7.24 (d, 1H, furan,
JH,H ¼ 2.7 Hz), 6.82 (s, 1H, aromatic), 4.0 (s, 3H, OCH3), 1.41 [s, 6H, C
(CH3)2]. The methylene protons on the chromenylidene ring
General procedure: The semicarbazone derivative (8b,e)
(5 mmol) was added portion wise to an excess of freshly distilled
thionyl chloride (3 ml) at 0 ꢁC. The reaction mixture was then
allowed to attain room temperature. After 1 h, methylene chloride
(15 ml) was added and the resulting mixture was decomposed with
saturated aqueous sodium carbonate solution. The methylene
chloride layer was separated and washed thoroughly with water
then dried over anhydrous Na2SO4. After evaporation of solvent, in
vacuo, the residual material was recrystallized from ethanol to give
(9a,b).
appeared at
d 2.67 (s, 2H). D2O exchangeable signals were present
at 8.83, 8.39 (bs, 3H, NHs). Anal. calcd. for C15H17N3O4 (303.325):
d
C, 59.39; H, 5.64; N, 13.85. Found: C, 59.26; H, 5.52; N, 13.70.
4.5.2. 2-(40-methoxy-spiro[cyclohexane-1,70-furo[3,2-g]
chromene]-50(60H)-ylidene)hydrazinecarboxamide (8b)
Yellowish white crystals. m.p. 183e185 ꢁC. Yield: (69%). IR (KBr,
cmꢀ1) showed strong absorption bands at 3455 (NH), 3200 (NH),
2928, 2855 (CH, aliphatic, alicyclic), 1678 (C]O, amide) and 1136
(CeO, stretching); 1H NMR (CDCl3,
d
ppm): showed signals at 7.44
4.6.1. 100-Methoxy-spiro[cyclohexane-1,40-furo[20,30:7,6]chromeno
(d, 1H, furan, JH,H ¼ 2.7 Hz), 7.24 (d, 1H, furan, JH,H ¼ 2.7 Hz), 6.83 (s,
[4, 3-d] [1,2,3]thiadiazole] (9a)
1H, aromatic), 3.99 (s, 3H, OCH3). The methylene protons appeared
Yellow crystals. m.p. 113e115 ꢁC. Yield: (31%). IR (KBr, cmꢀ1
)
as a singlet at
d
2.56 (s, 2H) and the cyclohexyl protons appeared at
3134 (CH, furan), 2932, 2848 (CH, aliphatic), 1587 (N]N) and 1138
d
1.89e1.39 [m, 10H, C(CH2)5]. The D2O exchangeable singlet
(CeO, stretching); 1H NMR (CDCl3,
d
ppm): showed signals at 7.61
present at
d
7.99 is assignable to the NH group proton. Anal. calcd.
(d, 1H, furan, JH,H ¼ 2.7 Hz), 7.36 (d, 1H, furan, JH,H ¼ 2.7 Hz), 7.03
(s, 1H, aromatic), 4.27 (s, 3H, OCH3) and 2.26e0.86 [m, 10H, C
(CH2)5]. MS: m/z 328(Mþ, 46.48%). Anal. Calcd. For C17H16N2O3S
(328.331): C, 62.18; H, 4.91; N, 8.53; S, 9.74. Found: C, 62.25; H,
4.80; N, 8.35; S, 9.85.
for C18H21N3O4 (343.39): C, 62.95; H, 6.16; N, 12.23. Found: C, 62.85;
H, 6.07; N, 12.30.
4.5.3. 2-(4,9-Dimethoxy-7,7-dimethyl-6,7-dihydro-5H-furo[3,2-g]
chromen-5-ylidene) hydrazinecarboxamide (8c)
White crystals. m.p.128e130 ꢁC. Yield: (87%). IR (KBr, cmꢀ1
)
4.6.2. 60,100-Dimethoxy-spiro[cyclohexane-1,40-furo[20,30:7,6]
chromeno[4, 3-d] [1,2,3]thiadiazole] (9b)
showed strong absorption bands at 3429 (NH), 3279 (NH), 3197
(CH, furan), 2971, 2931 (CH, aliphatic, alicyclic), 1691 (C]O, amide)
Brown crystals, m.p.132e134 ꢁC. Yield: (30%). 3132 (CH, furan),
2931, 2852 (CH, aliphatic), 1552 (N]N) and 1233 (CeO, stretching);
and 1129 (CeO, stretching); 1H NMR (CDCl3,
d ppm): showed
signals at 7.51 (d, 1H, furan, JH,H ¼ 2.7 Hz), 7.28 (d, 1H, furan,
1H NMR (CDCl3
, d ppm): showed signals at 7.66 (d, 1H, furan,
JH,H ¼ 2.7 Hz), 4.04 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 1.47 (s, 6H, C
JH,H ¼ 2.7 Hz), 7.01 (d, 1H, furan, JH,H ¼ 2.7 Hz), 4.14 (s, 3H, OCH3),
4.10 (s, 3H, OCH3) and 2.34e1.22 [m, 10H, C(CH2)5]. Anal. calcd. for
C18H18N2O4S (358.35): C, 60.33; H, 5.06; N, 7.81; S, 8.92. Found: C,
60.29; H, 5.23; N, 7.75; S, 8.81.
(CH3)2). The methylene protons appeared at d 1.81 (s, 2H). The D2O
exchangeable signals present at
d 8.46 and 6.85 are assignable to
the NH, NH2 group protons. MS: m/z 333(Mþ, 100%). Anal. calcd. for
C16H19N3O5 (333.35): C, 57.64; H, 5.74; N,12.60. Found: C, 57.33; H,
6.01; N, 12.38.
4.7. Synthesis of 7,7-(substituted)furochromone-1,2,3-
4.5.4. 2-(7-Ethyl-4,9-dimethoxy-7-methyl-6,7-dihydro-5H-furo
selenadiazoles (9ceg)
[3,2-g] chromen-5-ylidene) hydrazinecarboxamide (8d)
White crystals, m.p. 156e158 ꢁC. Yield: (80%). IR (KBr, cmꢀ1
showed strong absorption bands at 3456 (NH), 3195 (NH), 3160 (CH,
)
General procedure: The semicarbazone derivative (8aee)
(5 mmol) was dissolved in glacial acetic acid (15 ml) and
warmed to 60 ꢁC under stirring. Selenium dioxide (7 mmol) was
added portionwise during a period of 30 min and stirring was
continued at 60 ꢁC for 1e2 h, till the evolution of gas ceased.
After completion of the reaction, it was filtered to remove the
deposited selenium. The filtrate was poured onto crushed ice
and the solid obtained was filtered, washed thoroughly with cold
water then with aqueous sodium carbonate solution and again
with water. The residue was recrystallized from ethanol to give
(9ceg).
furan), 2973, 2935 (CH, aliphatic, alicyclic), 1698 (C]O, amide) and
1128 (CeO, stretching); 1H NMR (CDCl3,
d ppm): showed signals at
7.49 (d,1H, furan, JH,H ¼ 2.7 Hz), 7.27 (d,1H, furan, JH,H ¼ 2.7 Hz), 4.03
(s, 3H, OCH3), 3.92 (s, 3H, OCH3),1.01 (t, 3H, CH3eCH2, JH,H ¼ 8.1 Hz),
1.72 (q, 2H, CH3eCH2, JH,H ¼ 8.1 Hz),1.36 (s, 3H, CH3). The methylene
protons appeared at d 2.70 (s, 2H). D2O exchangeable signals present
at d 8.99 and 6.84 are assignable to the NH, NH2 group protons. MS:
m/z 347(Mþ, 2.16%). Anal. calcd. for C17H21N3O5 (347.37): C, 58.77; H,
6.09; N, 12.09. Found: C, 58.64; H, 6.16; N, 12.01.

4926
S.M.Sh. Atta et al. / European Journal of Medicinal Chemistry 45 (2010) 4920e4927
4.7.1. 10-Methoxy-4,4-dimethyl-4H-furo[20,30:7,6]chromeno[4,3-d]
[1,2,3]selenadiazole (9c)
with water and recrystallized from chloroform/petroleum ether
(40e60 ꢁC) to give (11a, b).
Yellow crystals, m.p.75e77 ꢁC. Yield: (60%). IR (KBr, cmꢀ1
)
showed strong absorption bands at 3439(CH, furan), 2970, 2930,
4.8.1. (E)-Cyclopenta-2,4-dienyl(2-(3-(6-hydroxy-4-
methoxybenzofuran-5-yl)-3-oxoprop-1-enyl)cyclopenta-2,4-dienyl)
iron (11a)
2839 (CH, aliphatic), 1536 (N]N) and 1245 (CeO, stretching); 1H
NMR (CDCl3,
d ppm): showed signals at 7.52 (d, 1H, furan,
JH,H ¼ 2.7 Hz), 6.96 (d, 2H, furan þ aromatic, JH,H ¼ 2.7 Hz), 4.20 (s,
3H, OCH3) and 1.75 [s, 6H, C(CH3)2]. Anal. calcd. for C14H12N2O3Se
(335.26): C, 50.15; H, 3.60; N, 8.35. Found: C, 50.25; H, 3.50; N 8.20.
Red crystals. m.p. 47e49 ꢁC yield: (80%). IR (KBr, cmꢀ1) showed
strong absorption bands at 3165, 3091 (CH, aromatic), 2990, 2926
(CH, aliphatic), 1623 (C]O) and 1146 (CeO, stretching). 1H NMR
(CDCl3,
d
ppm): showed signals at 6.96 (d, 1H, furan, JH,H ¼ 2.7 Hz),
4.7.2. 100-Methoxy-spiro[cyclohexane-1,40-furo[20,30:7,6]chromeno
6.71 (d, 1H, furan, JH,H ¼ 2.7 Hz), 6.32 (d, 1H, O]CeCH]CH,
JH,H ¼ 12.8 Hz), 6.26 (d, 1H, O]CeCH]CH, JH,H ¼ 12.8 Hz), 7.33 (s,
1H, aromatic) 3.58 (s, 3H, OCH3) and at 4.06e3.69 [m, 9H, ferrocene
ring protons]. MS: m/z 402 (Mþ, 35%). Anal. calcd. for C22H18FeO4
(402.18): C, 65.70; H, 4.51. Found: C, 65.58; H, 4.62.
[4, 3-d] [1,2,3]selenadiazole] (9d)
Yellow crystals. m.p.106e108 ꢁC. Yield: (68%). IR (KBr, cmꢀ1
)
showed strong absorption bands at 3431 (CH, furan), 2929, 2854
(CH, aliphatic), 1507 (N]N) and 1140 (CeO, stretching); 1H NMR
(CDCl3,
d
ppm): showed signals at 7.51 (d, 1H, furan, JH,H ¼ 2.7 Hz),
7.01 (d, 1H, furan, JH,H ¼ 2.7 Hz), 6.95 (s, 1H, aromatic), 4.13 (s, 3H,
OCH3) and 2.32e1.34 [m, 10H, C(CH2)5]. Anal. calcd. for
C17H16N2O3Se (375.33): C, 54.40; H, 4.29; N, 7.46. Found: C, 54.19; H,
4.19; N, 7.35.
4.8.2. (E)-Cyclopenta-2,4-dienyl(2-(3-(6-hydroxy-4,7-
dimethoxybenzofuran-5-yl)-3-oxoprop-1-enyl)cyclopenta-2,4-
dienyl)iron (11b)
Red crystals. m.p. 52e54 ꢁC. Yield: (76%). IR (KBr, cmꢀ1) showed
strong absorption bands at 3436 (CH, aromatic), 2925, 2859 (CH,
aliphatic), 1635(C]O) and1145 (CeO, stretching); 1H NMR (CDCl3,
4.7.3. 6,10-Dimethoxy-4,4-dimethyl-4H-furo[20,30:7,6]chromeno
[4,3-d] [1,2,3]selenadiazole (9e)
Yellow crystals. m.p.75e77 ꢁC yield: (73%). IR (KBr, cmꢀ1
)
d
ppm): showed signals at 7.52 (d, 1H, furan, JH,H ¼ 2.5 Hz), 7.26 (d,
1H, furan, JH,H ¼ 2.5 Hz), 7.87 (d, 1H, O]CeCH]CH, JH,H ¼ 16.2),
6.87 (d, 1H, O]CeCH]CH, JH,H ¼ 16.2), 4.09 (s, 3H, OCH3), 4.03 (s,
3H, OCH3).The OH group proton gave a D2O exchangeable singlet
at 12.90. The characteristic pattern of ferrocene ring protons
(m, 9H) appeared in the region 4.62e4.20 ppm. The large coupling
constant (16.2 Hz) indicates that the two protons on the exocyclic
ethylenic bond are oriented E (trans) to one another. Anal.
calcd. for C23H20FeO5 (432.21): C, 63.91; H, 4.66. Found: C, 63.98;
H, 4.70.
showed strong absorption bands at 3121(CH, furan), 2974, 2930,
2828 (CH, aliphatic), 1545 (N]N) and 1231 (CeO, stretching). 1H
NMR (CDCl3,
d ppm): showed signals at 7.58 (d, 1H, furan,
JH,H ¼ 2.7 Hz), 6.96 (d, 1H, furan, JH,H ¼ 2.7 Hz), 4.13 (s, 3H, OCH3),
4.10 (s, 3H, OCH3) and at 1.82 [s, 6H, C(CH3)2]. MS: m/z 364 (Mþ ꢀ 1,
27%). Anal. calcd. for C15H14N2O4Se (365.29): C, 49.32; H, 3.86; N,
7.66. Found: C, 49.36; H, 3.65; N, 7.59.
4.7.4. 4-Ethyl-6,10-dimethoxy-4-methyl-4H-furo[20,30:7,6]
chromeno[4,3-d] [1,2,3]selenadiazole (9f)
Yellow oil. Yield: (75%). IR (KBr, cmꢀ1) showed strong absorption
bands at 3435 (CH, furan), 2974, 2935 (CH, aliphatic), 1616, 1510
Acknowledgment
(N]N, C]C) and 1134 (CeO, stretching); 1H NMR (CDCl3,
d ppm):
We are grateful to the Cancer Biology Department, National
Cancer Institute, Cairo University for the pharmacological
evaluation.
showed signals at 7.58 (d, 1H, furan, JH,H ¼ 2.7 Hz), 6.95 (d,1H, furan,
JH,H ¼ 2.7 Hz), 4.13 (s, 3H, OCH3), 4.11 (s, 3H, OCH3), 1.06 (t, 3H,
CH3eCH2, JH,H ¼ 8.1 Hz), 2.06 (q, 2H, CH3eCH2, JH,H ¼ 8.1 Hz) and
1.78 (s, 3H, CH3). MS: m/z 380 (Mþ þ 1, 32%). Anal. calcd. for
C16H16N2O4Se (379. 32): C, 50.66; H, 4.25; N, 7.38. Found: C, 50.67;
H, 4.23; N, 7.48.
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d
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