Synthesis and anti-inflammatory activity of some benzofuran and benzopyran-4-one derivatives

Article abstract of DOI:10.1248/cpb.60.110

New series of furosalicylic acids 3a - c, furosalicylanilides 6a - n, furobenzoxazines 8a - f, 1-benzofuran- 3-arylprop-2-en-1-ones 12a,b, 6-(aryl-3-oxoprop-1-enyl)-4H-chromen-4-ones 16a - c and 6-[6-aryl-2-thioxo- 2,5-dihydropyrimidin-4-yl]-4H-chromen-4-ones 17a - c were synthesized. Anti-inflammatory activity evaluation was performed using carrageenan-induced paw edema model in rats and prostaglandin E₂ (PGE₂) synthesis inhibition activity. Some of the tested compounds revealed comparable activity with less ulcerogenic effect than Diclofenac at a dose 100 mg/kg. All the synthesized compounds were docked on the active site of cyclooxygenase-2 (COX-2) enzyme and most of them showed good interactions with the amino acids of the active site comparable to the interactions exhibited by Diclofenac.

Full text of DOI:10.1248/cpb.60.110

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110
Regular Article
Chem. Pharm. Bull. 60(1) 110 120 (2012)
Vol. 60, No. 1
Synthesis and Anti-inflammatory Activity of Some Benzofuran and
Benzopyran-4-one Derivatives
Fatma Abd El-Fattah Ragab, Nahed Mahmoud Eid, Ghaneya Sayed Hassan,* and
Yassin Mohammed Nissan
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University; El-Kasr El-Eini Street, Cairo 11562,
Egypt. Received September 11, 2011; accepted October 7, 2011
—
—
—
New series of furosalicylic acids 3a c, furosalicylanilides 6a n, furobenzoxazines 8a f, 1-benzofuran-
—
3-arylprop-2-en-1-ones 12a,b, 6-(aryl-3-oxoprop-1-enyl)-4H-chromen-4-ones 16a c and 6-[6-aryl-2-thi-
—
oxo-2,5-dihydropyrimidin-4-yl]-4H-chromen-4-ones 17a c were synthesized. Anti-inflammatory activity
evaluation was performed using carrageenan-induced paw edema model in rats and prostaglandin E2 (PGE2)
synthesis inhibition activity. Some of the tested compounds revealed comparable activity with less ulcero-
genic effect than Diclofenac at a dose 100mg/kg. All the synthesized compounds were docked on the active
site of cyclooxygenase-2 (COX-2) enzyme and most of them showed good interactions with the amino acids of
the active site comparable to the interactions exhibited by Diclofenac.
Key words anti-inflammatory activity; prostaglandin E2; benzofuran; benzopyran-4-one
In spite of the high effectiveness of the steroidal anti- rivatives (chromones and flavones) are potentially useful anti-
inflammatory drugs, their serious side effects limit their use inflammatory agents due to their ability to inhibit the protein
in common inflammation.1–3) Although non steroidal anti- kinase dependant signal transduction pathway. Furthermore,
inflammatory drugs possess great safety over steroidal drugs, some natural benzopyran derivatives showed inhibitory activ-
they still have some side effects as development of peptic and ity of prostaglandin E2 (PGE2) production.17)
duodenal ulcers, kidney and liver malfunctions.4–6) The rise of
Thus, the present investigation deals also with the synthesis
selective cyclooxygenase-2 (COX-2) inhibitors reduced the risk of certain substituted aminobenzofuranyl hydroxychalcones,
of some of these side effects.7,8) Therefore, seeking new drugs benzopyan chalcones and thioxopyrimidine-benzopyrans to be
with anti-inflammatory activity and a fewer side effects are tested for their anti-inflammatory activity. Compounds which
still a goal for medicinal chemists.
showed activity as anti-inflammatory agents in carrageenan-
Benzofuran nucleus is an isostere for indole, the potent induced paw edema model, their ability to inhibit PGE2 syn-
basic pharmacodynamic nucleus which has anti-inflammatory thesis were assayed.
activity.9,10) Many benzofuran derivatives were reported to
show potent anti-inflammatory activity and were among
COX-2 inhibitors.11,12) On the other hand, salicylic acid and
salicylates exhibit a pronounced anti-inflammatory activity,
for example the salicylanilides A and B are selective inhibi-
tors of interlukin-12 (IL-12) p40 production which is a subunit
—
component of IL-12 and IL-6 23. IL-12 is involved in type 1
helper T cell (TH1) mediated inflammation in both normal im-
mune defence as well as inflammatory diseases such as rheu-
matoid activities, asthma, psoriases and Crohn's disease.13) In
addition, the antinociceptive and anti-inflammatory activities
of 4H-2,3-dihydro-1,3-benzoxazines C as cyclic acetal like
derivatives of salicylamide were accomplished in comparison
with aspirin and were of much less ulcerogenic effect.14) Thus,
the present investigation deals with the synthesis of certain
substituted furanylsalicylic acids, furanylsalicylanilides and
Results and Discussion
Chemistry The synthetic pathways adopted for the prepa-
their cyclised furanylbenzoxazines to be evaluated as anti- ration of the desired new compounds are illustrated in Charts
—
1 4. Furosalicylic acids 2a and 3c were obtained by oxida-
inflammatory agents.
Several studies indicated that chalcones potently inhibit ni- tive cleavage of the naturally occurring furochromones 1 and
tric oxide production by the inducible nitric oxide synthetase 5, respectively.18,19) Brominating of 2a in chloroform at room
(iNOs). Nitric oxide (NO) plays an important role in immune temperature led to the formation of 3,7-dibromo benzofuran
reactions.15) Also, 2-hydroxy chalcone analogues D showed 3a. Alternatively, mono bromo derivative 3b was obtained
great activity as inhibitors for COX-2 catalyzed prostaglandin by brominating of the furochromone 1 in glacial acetic acid
production as well as lipooxygenase.16) On the other hand, thi- followed by oxidative cleavage of 9-bromofurochromone 4
oxopyrimidines E were evaluated for their anti-inflammatory with hydrogen peroxide in alkaline medium (Chart 1). Furo-
—
activity and the results were comparable with Diclofenac with salicylanilides 6a n were prepared from their corresponding
minimum ulcerogenic activity.16) With respect to anti-inflam- furosalicylic acids 3a c by reaction with the appropriate aro-
—
matory activity several studies indicated that benzopyran de- matic amines in chlorobenzene using phosphorus trichloride
*To whom correspondence should be addressed. e-mail: ghanmoom@yahoo.com
© 2012 The Pharmaceutical Society of Japan

January 2012
111
as a condensing agent20–22) (Chart 2). Furobenzoxazines 8a
f
in prescence of alkali (Claisn–Schmidt condensation) to give
—
were obtained from the corresponding anilides by reaction 1-(benzofuran-5-yl)-3-arylprop-2-en-1-ones 10a,b. Subsequent
with ethyl chloroformate and subsequent cyclization of the introduction of amino group was carried out through coupling
—
resultant esters 7a f with sodium ethoxide in ethanol (Chart with benzenediazonium chloride followed by reductive cleav-
2). 1-(7-Amino-6-hydroxy-4-methoxy-1-benzofuran-5-yl)-3-ar- age of the azo derivatives 11a and 11b with sodium dithio-
ylprop-2-en-1-ones 12a,b have been synthesized by alkaline nite to give 12a,b (Chart 3). A similar sequence was used to
cleavage of the furochromone 1 to 5-acetyl-6-hydroxy-4-meth- prepare (E)-8-amino-6-(aryl-3-oxoprop-1-enyl)-4H-chromen-
oxy benzofuran 9,23) which reacted with aromatic aldehydes 4-ones 16a c from the furchromone 1 which is subjected
—
to oxidative cleavage by potassium dichromate and sulphuric
acid to produce 4-oxo-4H-chromen-6-carbaldehyde 13, fol-
Reagents and solvents: a) 30% H2O2, 5% NaOH; b) Br2, CHCl3; c) Br2, glacial
acetic acid.
Reagents and solvents: a) 10% KOH; b) aromatic aldehydes, 30% NaOH, etha-
nol; c) aniline, NaNO2, HCl; d) sodium dithionite, ethanol.
Chart 1
Chart 3
Reagents and solvents: a) aromatic amines, phosphorus trichloride, chlorobenzene; b) ethylchloroformate, pyridine; c) sodium ethoxide, absolute ethanol.
Chart 2

112
Vol. 60, No. 1
lowed by reaction with substituted acetophenones (Claisen– animals.26) The most active anti-inflammatory compounds
—
—
Schmidt reaction) to yield 6-(3-oxo-3-aryllprop-1-en-1-yl)- 3a c, 6d, 6i, 6k, 6n, 12a, 12b, and 16a c were assayed
—
7-hydroxy-5-methoxy-2-methyl-4H-chromen-4-ones 14a c. using Diclofenac as a reference drug. The percentage inhibi-
The amino group was introduced in position 8 as mentioned tion of PGE2 was calculated and the data were expressed as
—
±
above through the diazo compounds 15a c, followed by the mean S.E.M. All the tested compounds showed inhibi-
—
—
reductive cleavage to give 16a c (Chart 4). 6-(6-Aryl-2- tory effect on PGE2 synthesis. Compounds 3a c showed ac-
—
thioxo-2,5-dihydropyrimidin-4-yl)-4H-chromen-4-ones 17a
tivity comparable to Diclofenac (Table 2).
—
c were obtained by reaction of 6-(3-aryl-3-oxoprop-1-en-1-yl)-
Compounds 3a c and 12a,b which showed the highest
4H-chromen-4-ones 14a c with thiourea and sulphuric acid percentage inhibition in carrageenan induced rat paw edema
(Chart 4). model, showed the highest PGE2 synthesis inhibition. It has
—
Pharmacological Screening Pharmacological evaluation been noticed that the PGE2 inhibitory properties of the tested
was carried in Department of Pharmacology, Faculty of Phar- compounds coincide greatly with our described anti-inflam-
macy, Cairo University, Egypt.
matory properties.
The experimental tests on animals have been performed
Ulcerogenic Effect The active compounds as anti-
—
in accordance with the Institutional Ethical Committee Ap- inflammatory agents 3a c, 6d, 6i, 6k, 6n, 12a, 12b, and
—
16a c were evaluated for their ulcerogenic potential in rats.
proval, Faculty of Pharmacy, Cairo University.
Anti-inflammatory Activity The newly synthesized Diclofenac was used as reference standard27) and the results
—
—
—
—
—
compounds 3a c, 6a n, 8a f, 12a, 12b, 14a, 15a, 16a c, were calculated as ulcer index. Compounds 3a c showed
—
and 17a c were evaluated for their anti-inflammatory activ- more ulcerative effect than Diclofenac. On the other hand,
ity using carrageenan induced rat paw edema model. The furosalicylanilides 6d, 6i, 6k and 6n were of much less ulcer-
injection of carrageenan to the hind paw of rats causes edema ogenic effect. The best results were for 1-(7-amino-6-hydroxy-
and an increase in paw volume associated with hyperalgesia 4-methoxy-1-benzofuran-5-yl)-3-arylprop-2-en-1-ones 12a,b
as reported by Winter et al.24) The development of the paw and 6-(aryl-3-oxoprop-1-enyl)-4H-chromen-4-ones 16a,b
edema has been described as a biphasic event, where the which showed lesser ulcerogenic insults (Table 2).
initial inflammatory phase has been attributed to the release
Molecular Docking Previous literatures showed that
of histamine, serotonin and a kinin-like substance and the series of anti-inflammatory drugs inhibit PGE2 synthesis by
second accelerating phase of swelling attributed to the release interacting with Tyr385 and Ser530 in the active site of COX-2
of a prostaglandin-like substance.25) The percentage inhibition enzyme and compounds that could interact with such amino
of edema was calculated and the data were expressed as the acids can exhibit anti-inflammatory activity.28–30) Interactions
±
mean S.E.M. Diclofenac was used as a reference (Table 1).
with Arg120 may play also a role in the inhibitory activity of
PGE2 Synthesis Inhibition Activity PGE2 concentrations COX-2.30,31)
were estimated using rat specific immunoassay kit in serum
Consequently, all the synthesized compounds were docked
samples prepared by centrifugation of blood of the injected on the active site of cyclooxygenase-2 enzyme (COX-2) based
Reagents and solvents: a) potassium dichromate, 10% sulphuric acid; b) acetophenones, 5% NaOH, ethanol; c) aniline, NaNO2, HCl; d) sodium dithionite, ethanol; e)
thiourea, sulphuric acid.
Chart 4

January 2012
113
Table 1. Anti-inflammatory Activity of the Tested Compounds Using Acute Carrageenan Induced Paw Oedema in Rats at a Dose of 100mg/kg of
Body Weight
Compound No.
1h
2h
3h
4h
±
±
±
±
83 2.60
±
76 4.11
Diclofenac
3a
77 2.32
79 2.15
80 2.63
±
±
±
69 3.21
73 1.77
76 3.21
±
±
±
±
66 2.56
3b
61 1.34
65 2.34
66 2.42
±
±
±
±
73 2.86
3c
70 2.13
71 2.21
73 3.11
±
±
±
±
54 2.44
6a
46 2.34
49 2.77
50 3.41
±
±
±
±
50 2.59
6b
41 1.67
44 3.67
48 1.26
±
±
±
±
49 3.33
6c
39 2.22
42 2.66
45 2.19
±
±
±
±
60 2.01
6d
47 1.58
50 3.22
56 2.09
±
±
±
±
44 5.13
6e
37 2.11
39 4.33
42 3.03
±
±
±
±
49 3.26
6f
40 3.76
41 2.55
44 1.96
±
±
±
±
40 4.99
6g
32 3.21
36 1.53
38 4.21
±
±
±
±
39 5.35
6h
30 2.57
35 2.99
37 3.69
±
±
±
±
50 2.76
6i
41 2.45
44 3.13
45 2.76
±
±
±
±
39 5.88
6j
29 2.65
32 2.64
34 2.55
±
±
±
±
58 2.69
6k
50 1.89
55 2.56
57 2.41
±
±
±
±
53 4.78
6l
46 2.54
49 4.79
50 2.22
±
±
±
±
51 3.87
±
62 2.69
6m
6n
44 1.80
46 2.49
49 3.10
±
±
±
56 1.99
58 2.61
58 1.89
±
±
±
±
27 5.12
8a
24 2.77
27 4.98
27 2.76
±
±
±
±
24 4.99
8b
22 5.23
22 3.54
23 3.24
±
±
±
±
27 4.32
8c
20 4.99
23 2.63
27 3.21
±
±
±
±
24 4.10
8d
18 3.75
21 1.97
24 3.78
±
±
±
±
36 2.14
8e
32 6.21
33 3.77
35 4.67
±
±
±
±
33 3.65
8f
31 3.89
33 2.55
33 1.76
±
±
±
±
60 1.78
±
63 2.54
±
52 1.99
±
22 1.06
±
56 2.18
±
59 4.11
±
52 2.10
±
27 4.73
12a
12b
14a
15a
16a
16b
16c
17a
17b
17c
59 2.89
60 4.10
60 1.99
±
±
±
60 3.11
62 2.22
63 2.10
±
±
±
50 1.47
51 2.97
52 2.65
±
±
±
21 2.13
21 2.01
22 2.16
±
±
±
52 1.99
56 6.21
56 2.45
±
±
±
55 2.04
57 5.32
59 3.89
±
±
±
50 3.56
51 4.13
51 2.11
±
±
±
21 2.55
25 1.56
25 2.67
±
±
±
±
28 2.01
±
35 4.37
26 4.06
26 3.22
26 2.89
±
±
±
30 5.98
34 4.21
34 4.25
All results are statistically significant at p<0.05.
Table 2. PGE2 Inhibitory Activity of the Most Promising Prepared Anti-inflammatory Active Agents, Ulcerogenic Activity and LD50 of the Tested
Compounds
Compound No.
% PGE2 inhibition
Ulcer index
LD50 mg/kg
±
±
±
370 1.78
±
127 2.33
Diclofenac
3a
68 3.56
40 2.21
±
±
60 2.44
49 1.24
±
±
±
118 3.21
3b
54 3.21
47 3.21
±
±
±
170 3.87
3c
61 1.34
49 1.34
±
±
±
109 2.55
6d
29 2.06
40 2.06
±
±
±
115 2.65
6i
21 1.89
39 3.01
±
±
±
133 3.02
6k
39 1.24
41 1.92
±
±
±
124 1.11
6n
37 2.45
41 2.35
±
±
±
214 2.34
±
221 3.22
±
225 1.98
±
216 2.67
12a
12b
16a
16b
16c
49 3.97
33 1.31
±
±
49 2.67
30 2.21
±
±
40 2.10
32 1.10
±
±
47 4.10
30 2.15
±
±
±
219 3.11
46 5.21
31 0.42
All the results are statistically significant at p<0.05.

114
Vol. 60, No. 1
Fig. 3. Compound (3a) Interactions 2D
Fig. 1. Interactions of Diclofenac on the Active Site of Cox-2 (2D)
Fig. 4. Compound (3a) Interactions 3D
Fig. 2. Interactions of Diclofenac on the Active Site of Cox-2 (3D)
with Tyr355 and Tyr385. Only compound 12b interacted with
Arg120. The rest of tested compounds interacted with Ser530
on the protein data bank file code 1PXX. The file contains the only, Table 3.
COX-2 enzyme with Diclofenac as a co-crystallized ligand
Correlation of the Anti-inflammatory Activity with the
using MOE software using force field energy MMFX9 with Molecular Docking Study The most active compounds
−
—
S= 7.5072kcal/mol and rmsd=0.3682. Diclofenac interacted were furosalicylic acids 3a c (inhibition % 76, 66, 73 respec-
with Ser530 with 2 hydrogen bonds 2.7Å and 2.9Å and with tively). Molecular docking showed that the most active one 3a
Tyr385 with one hydrogen bond 2.7Å as illustrated in Figs. 1 interacted with both amino acids Tyr385 and Ser530 with 2
— —
hydrogen bonds Figs. 3 and 4 while 3c interacted with one
and 2.
Most of the tested compounds showed moderate to good amino acid Ser530 with 2 hydrogen bonds, and the least active
fitting in the active site pocket with interactions of the amino derivative 3b interacted with Ser530 with only one hydrogen
acids, Tyr385 and/or Ser530 except compound 8d which bond.
showed no interactions with any of the amino acids of the
Conversion of the furosalicylic acids into their correspond-
—
pocket. Three compounds 6k, 6n and 12b interacted with the ing anilides 6a n generally decreased the anti-inflammatory
same amino acids as Diclofenac with 3 hydrogen bonds. Three activity. The most active anilides were 6n, 6d, and 6k. From
compounds 6b, 6c and 12c interacted with the same amino docking study it was noticed that the 2 active anilides 6n and
acids by 2 hydrogen bonds. Only compound 6d interacted 6k interacted with both Tyr385 and Ser530 with 3 hydrogen
with Ser530 and Arg120. Compounds 12a and 13a interacted bonds while 6d interacted with Ser530, Arg120 with 2 hydro-
with the amino acid Tyr355 while compound 13b interact gen bonds. The rest of anilides which showed lower activity

January 2012
115
Table 3. Amino Acid Interactions and Hydrogen Bond Lengths
—
model. Furosalicylic acids 3a c and 1-(7-amino-6-hydroxy-
4-methoxy-1-benzofuran-5-yl)-3-arylprop-2-en-1-ones 12a,b
showed the highest percentage inhibition in carrageenan in-
duced rat paw edema model, and the highest PGE2 synthesis
inhibition.
Hydrogen bond
length (Å)
Compound No.
Amino acid
3a
3b
3c
Tyr 385, Ser 530
Ser 530
2.50, 2.40
2.30
—
Conversion of the furosalicylic acids into anilides 6a
generally decreased the anti-inflammatory activity. Also,
cyclization of the anilides 6a n to their corresponding
furobenzoxazines 8a f and 6-(aryl-3-oxoprop-1-enyl)-4H-
chromen-4-ones 16a c to 6-[6-aryl-2-thioxo-2,5-dihydro-
pyrimidin-4-yl]-4H-chromen-4-ones 17a
anti-inflammatory activity. Concerning 1-benzofuran-3-aryl-
prop-2-en-1-ones 12a,b and 6-(aryl-3-oxoprop-1-enyl)-4H-
chromen-4-ones 16a c, the benzofuran derivatives were
n
Ser 530
2.60, 2.90
2.39
6a
Ser 530
—
6b
6c
Ser 530
3.06
—
—
Ser 530
2.93
6d
6e
Ser 530, Arg 120
Ser 530
2.95, 2.69
2.53
—
c decreased the
6f
Ser 530
2.53
6g
Ser 530
2.93
—
6h
6i
Ser 530
3.10
more potent than the benzopyran derivatives.
Compounds 3a c showed more ulcerative effect than
Ser 530
3.10
—
6j
Ser 530
2.44
Diclofenac. On the other hand, furosalicylanilides 6d, 6i, 6k
and 6n were of much less ulcerogenic effect. The best results
6k
6l
Tyr 385, Ser 530
Ser 530
2.89, 2.46, 3.01
2.96
—
were for 12a,b and 16a b which showed lesser ulcerogenic
insults.
6m
6n
8a
Ser 530
2.54
Tyr 385, Ser 530
Ser 530
3.17, 2.66, 2.77
2.51
8b
8c
Ser 530
2.47
Experimental
Ser 530
—
2.35
—
Chemistry Melting points were determined on Electro
thermal Stuart 5MP3 digital melting point apparatus and were
uncorrected. Elemental microanalyses were performed at the
micro analytical centre, Faculty of Science, Cairo University.
IR spectra were recorded on a Bruker Fourier transform (FT)-
8d
8e
Ser 530
2.67
8f
Ser 530
2.73
12a
12b
16a
16b
16c
17a
17b
17c
Tyr 355, Ser 530
Tyr 385, Ser 530
Tyr 355
2.97, 2.79
2.87, 2.47, 3.12
2.79
1
IR spectrophotometer as KBr discs. H-NMR spectra were re-
corded in DMSO-d6 on a Varian Mercury spectrometer (200,
300MHz). Mass spectra were performed on HP MODEL:
MS_5988 mass spectrometer and on Shimadzu QP-2010 Plus
(EI, 70eV). Silica gel used for column chromatography was
obtained from Fluka, 70 230 mesh thin layer chromatogra-
phy was carried out on silica gel TLC plates with fluorescence
indicator (F254).
Arg 120
2.79
Tyr 385, Ser 530
Tyr 355
3.00, 2.40
2.99
Tyr 355, Tyr 385
Ser 530
2.59, 2.99
2.67
—
3,7-Dibromo-6-hydroxy-4-methoxy-1-benzofuran-5-car-
boxylic Acid (3a) To a solution of 2a (2.08g, 10mmol) in
interacted with Ser530 with one hydrogen bond, Table 3.
Cyclization of the anilides to their corresponding furoben- chloroform (50mL), a mixture of bromine (0.54mL, 1.58g,
—
zoxazines 8a f decreased the anti-inflammatory activity. All 10mmol) in chloroform (25mL) was added with stirring. The
these furobenzoxazines interacted with the amino acid Ser530 mixture was left for 24h and the solvent was evaporated un-
with only one hydrogen bond. Concerning 1-benzofuran- der reduced pressure. The residue was washed by ethanol and
—
3-arylprop-2-en-1-ones 12a,b and 6-(aryl-3-oxoprop-1-enyl)- crystallized from benzene, yield 60 65%.
1
—
— °
Yield 60%, mp 215 217 C. H-NMR (DMSO-d6) δ: 4.00
4H-chromen-4-ones 16a c, the benzofuran derivatives were
more potent than the benzopyran derivatives. Compound 12b (3H, s, OCH3), 7.97 (1H, s, furan H), 10.90 (1H, s, OH exch.
−
1
which showed the highest activity interacted with the 2 amino D2O), 16.00 (1H, s, COOH exch. D2O). IR (KBr) cm : 3150
acids Tyr385 and Ser530. The benzopyran chalcone 16b which (OH phenolic), 2850 broad (OH carboxylic), 1702 (C=O).
interacted with Arg120 showed better activity than its conge- MS m/z: 364 (M+), 366 (M++2), 368 (M++4). Anal. Calcd. for
ners 16a which interacted with Tyr355 by one hydrogen bond C10H6Br2O5 (365.96): C, 32.82; H, 1.65. Found: C, 32.62; H,
and 16c which interacted with Tyr385 and Ser530 by 2 hydro- 1.79.
gen bonds.
7-Bromo-6-hydroxy-4-methoxy-1-benzofuran-5-carbox-
Cyclization of 6-(aryl-3-oxoprop-1-enyl)-4H-chromen-4- ylic acid (3b) To a suspension of 4 (3.08g, 10mmol) in 5%
—
ones 16a
c
to 6-[6-aryl-2-thioxo-2,5-dihydropyrimidin- NaOH (50mL), 30% H2O2 (6mL) was added with stirring till
—
4-yl]-4H-chromen-4-ones 17a c was not of much benefit as dissolved. The solution was stirred at room temperature for
the anti-inflammatory activity decreased, 17a and 17c inter- 30min. and neutralized with acetic acid. The reaction mixture
acted with Tyr355 and Ser530 respectively with one hydrogen was left over night in the fridge, filtered, dried and crystal-
bond while 17b is the only derivative which interacted with lized from ethanol.
1
—
°
Tyr355 and Tyr385 by 2 hydrogen bonds.
Yield 65%, mp 204 206 C. H-NMR (DMSO-d6) δ: 4.02
(3H, s, OCH3), 7.27 (1H, d, furan H, J=2Hz), 7.94 (1H, d,
furan H, J=2Hz), 10.85 (1H, s, OH exch. D2O), 16.00 (1H, s,
Conclusion
−
1
All the newly synthesized compounds showed anti-inflam- COOH exch. D2O). IR (KBr) cm : 3140 (OH phenolic), 2955
matory activity, using carrageenan induced rat paw edema broad (OH carboxylic), 1751 (C=O). MS m/z: 286 (M+), 288

116
Vol. 60, No. 1
(M++2). Anal. Calcd for C10H7BrO5 (287.06): C, 41.84; H, 2.46. 1617 (NH bending). MS m/z: 361 (M+), 363 (M++2). Anal.
Found: C, 41.91; H, 2.37.
General Procedure for the Preparation of 6a
Calcd for C16H12BrNO4 (362.17): C, 53.06; H, 3.34; N, 2.87.
n To a Found: C, 53.00; H, 3.38; N, 2.87.
—
—
solution of the appropriate furosalicylic acids 3a c (10mmol)
7-Bromo-6-hydroxy-4-methoxy-N-(4-chlorophenyl)-1-ben-
—
°
and the appropriate aniline derivative (10mmol) in chlo- zofuran-5-carboxamide (6g): Yield 63%, mp 249 251 C.
robenzene (50mL), phosphorus trichloride (1.37g, 1.27mL, 1H-NMR (DMSO-d6) δ: 4.13 (3H, s, OCH3), 6.74 (1H, d,
10mmol) was added. The solution was refluxed for 3h, filtered furan H, J=2.0Hz), 7.11 (2H, d, ArH, J=8Hz), 7.65 (2H, d,
while hot and the filtrate was evaporated till dryness. The ArH, J=8Hz), 7.88 (1H, d, furan H, J=2Hz), 10.44 (1H, s,
−
1
solid obtained was washed with ethanol and crystallized from NH exch. D2O), 11.20 (1H, s, OH exch. D2O). IR (KBr) cm :
—
benzene, yield 50 70%.
3332 (NH), 3150 (OH), 1641 (C=O), 1600 (NH bending). MS
3,7-Dibromo-6-hydroxy-4-methoxy-N-phenyl-1-benzofuran- m/z: 395 (M+), 397 (M++2). Anal. Calcd for C16H11BrClNO4
5-carboxamide (6a): Yield 60%, mp 212 214 C. 1H-NMR (396.62): C, 48.45; H, 2.80; N, 3.53. Found: C, 48.67; H, 3.01;
—
°
—
(DMSO-d6) δ: 4.16 (3H, s, OCH3), 7.09 7.70 (5H, m, ArH), N, 3.47.
7.98 (1H, s, furan H), 10.33 (1H, s, NH exch. D2O), 11.6 (1H, 7-Bromo-6-hydroxy-4-methoxy-N-(2,6-dichlorophenyl)-
−
1
—
s, OH exch. D2O). IR (KBr) cm : 3323 (NH), 3153 (OH), 1678 1-benzofuran-5-carboxamide (6h): Yield 69%, mp 276
−
1
(C=O), 1635 (NH bending). MS m/z: 439 (M+), 441 (M++2). 278 C. IR (KBr) cm : 3328 (NH), 3133 (OH), 1643 (C=O),
°
Anal. Calcd for C16H11Br2NO4 (441.07): C, 43.57; H, 2.51; N, 1605 (NH bending). MS m/z: 431 (M+). Anal. Calcd for
3.18. Found: C, 43.50; H, 2.79; N, 3.23.
C16H10BrCl2NO4 (431.06): C, 44.58; H, 2.34; N, 3.25. Found:
3,7-Dibromo-6-hydroxy-4-methoxy-N-(4-chlorophenyl)- C, 44.50; H, 2.64; N, 3.45.
—
1-benzofuran-5-carboxamide (6b): Yield 70%, mp 240
7-Bromo-6-hydroxy-4-methoxy-N-4-methoxyphenyl-1-ben-
1
1
°
—
°
243 C. H-NMR (DMSO-d6) δ: 4.03 (3H, s, OCH3), 7.03 (2H, zofuran-5-carboxamide (6i): Yield 50%, mp 219 221 C. H-
d, ArH, J=9.2Hz), 7.74 (2H, d, ArH, J=9.2Hz), 7.97 (1H, s, NMR (DMSO-d6) δ: 3.57 (3H, s, OCH3), 4.18 (3H, s, OCH3),
furan H), 10.44 (1H, s, NH exch. D2O), 11.0 (1H, s, OH exch. 6.37 (1H, d, furan H, J=2.2Hz), 6.92 (2H, d, ArH, J=9.2Hz),
−
1
D2O). IR (KBr) cm : 3331 (NH), 3142 (OH), 1680 (C=O), 7.58 (2H, d, ArH, J=9.2Hz), 8.14 (1H, d, furan H, J=2.2Hz),
1641 (NH bending). MS m/z: 473 (M+), 475 (M++2), 477 10.24 (1H, s, NH exch. D2O), 13.75 (s, 1H, OH exch. D2O). IR
−
1
(M++4). Anal. Calcd. for C16H10Br2ClNO4 (475.52): C, 40.41; (KBr) cm : 3315 (NH), 3196 (OH), 1682 (C=O), 1616 (NH
H, 2.12; N, 2.95. Found: C, 40.29; H, 2.29; N, 2.52. bending). Anal. Calcd for C17H14BrNO5 (392.20): C, 52.06; H,
3,7-Dibromo-6-hydroxy-4-methoxy-N-(2,6-dichlorophenyl)- 3.60; N, 3.57. Found: C, 51.54; H, 3.09; N, 3.14.
—
°
1-benzofuran-5-carboxamide (6c): Yield 70%, mp 273 275 C.
7-Bromo-6-hydroxy-4-methoxy-N-4-methoxyphenyl-1-ben-
1
1H-NMR (DMSO-d6) δ: 4.02 (3H, s, OCH3), 7.41 (1H, m, zofuran-5-carboxamide (6j): Yield 52%, mp 202 204 C. H-
—
°
ArH), 7.61 (1H, d, ArH, J=9.2Hz), 7.80 (1H, s, furan H), 8.01 NMR (DMSO-d6) δ: 3.35 (3H, s, CH3), 4.17 (3H, s, OCH3),
—
(1H, d, ArH, J=9.2Hz), 10.40 (1H, s, NH exch. D2O), 13.80 6.27 (1H, d, furan H, J=2.0Hz), 6.65 7.88 (4H, m, ArH),
−
1
(1H, s, OH exch. D2O). IR (KBr) cm : 3313 (NH), 3145 (OH), 8.12 (1H, d, furan H, J=2.0Hz), 10.27 (1H, s, NH exch. D2O),
1682 (C=O), 1645 (NH bending). MS m/z: 507 (M+), 509 13.72 (1H, s, OH exch. D2O). Anal. Calcd for C17H14BrNO4
(M++2), 511(M++4). Anal. Calcd for C16H9Br2Cl2NO4 (509.96): (376.20): C, 54,27; H, 3.75; N, 3.72. Found: C, 53.79; H, 3.58;
C, 37.68; H, 1.78; N, 2.75. Found: C, 37.80; H, 2.04; N, 2.31.
N, 3.25.
4,7-Dimethoxy-6-hydroxy-N-phenyl-1-benzofuran-5-carbox-
— °
amide (6k): Yield 58%, mp 210 212 C. H-NMR (DMSO-d6)
3,7-Dibromo-6-hydroxy-4-methoxy-N-(4-methoxyphenyl)-
1
—
1-benzofuran-5-carboxamide (6d): Yield 58%, mp 216
1
°
218 C. H-NMR (DMSO-d6) δ: 3.95 (3H, s, OCH3), 4.18 (3H, δ: 3.89 (3H, s, OCH3), 4.18 (3H, s, OCH3), 7.24 (1H, d, furan
s, OCH3), 6.89 (2H, d, ArH, J=9.2Hz), 7.51 (2H, d, ArH, H, J=2.1Hz), 7.41 (2H, m, ArH), 7.61 (3H, m, ArH), 7.93 (1H,
J=9.2Hz), 7.88 (1H, s, furan H), 10.22 (1H, s, NH exch. D2O), d, furan H, J=2.1Hz), 10.31 (1H, s, NH exch. D2O), 12.50
11.22 (1H, s, OH exch. D2O). IR (KBr) cm : 3340 (NH), (1H, s, OH exch. D2O). IR (KBr) cm : 3366 (NH), 3118 (OH),
3133 (OH), 1643 (C=O), 1600 (NH bending). MS m/z: 469 1646 (C=O), 1598 (NH bending). Anal. Calcd for C17H15NO5
(M+), 471 (M++2), 473 (M++4). Anal. Calcd for C17H13Br2NO5 (313.30): C, 65.17; H, 4.83; N, 4.47. Found: C, 65.39; H, 4.69;
(471.10): C, 43.34; H, 2.78; N, 2.97. Found: C, 43.80; H, 2.99; N, 4.45.
−
1
−
1
N, 2.86.
4,7-Dimethoxy-6-hydroxy-N-(4-chlorophenyl)-1-benzofuran-
3,7-Dibromo-6-hydroxy-4-methoxy-N-(4-methylphenyl)- 5-carboxamide (6l): Yield 63%, mp 226 228 C. 1H-NMR
—
°
—
°
1-benzofuran-5-carboxamide (6e): Yield 55%, mp 216 218 C. (DMSO-d6) δ: 3.90 (3H, s, OCH3), 3.98 (3H, s, OCH3), 7.09
1H-NMR (DMSO-d6) δ: 2.29 (3H, s, CH3), 4.18 (3H, s, OCH3), (1H, d, furan H, J=1.8Hz), 7.40 (2H, d, ArH, J=8.4Hz),
7.14 (2H, d, ArH, J=8.2Hz), 7.56 (2H, d, ArH, J=8.2Hz), 7.98 7.73 (2H, d, ArH, J=8.4Hz), 7.89 (1H, d, furan H, J=1.8Hz),
(1H, s, furan H), 10.26 (1H, s, NH exch. D2O), 11.95 (1H, s, 9.87 (1H, s, NH exch. D2O), 10.36 (1H, s, OH exch. D2O). IR
−
1
−
1
OH exch. D2O). IR (KBr) cm : 3350 (NH), 3150 (OH), 1673 (KBr) cm : 3366 (NH), 3118 (OH), 1646 (C=O), 1598 (NH
(C=O), 1605 (NH bending). Anal. Calcd for C17H13Br2NO4 bending). MS m/z: 347 (M+), 349 (M++2). Anal. Calcd for
(455.10): C, 44.87; H, 2.88; N, 3.08. Found: C, 45.05; H, 2.61; C17H14ClNO5 (347.75): C, 58.72; H, 4.06; N, 4.03. Found: C,
N, 2.95.
58.97; H, 4.19; N, 3.82.
7-Bromo-6-hydroxy-4-methoxy-N-phenyl-1-benzofuran-
4,7-Dimethoxy-6-hydroxy-N-(2,6-dichlorophenyl)-1-benzo-
1
5-carboxamide (6f): Yield 58%, mp 228 230 C. 1H-NMR furan-5-carboxamide (6m): Yield 69%, mp 258 260 C. H-
—
°
—
°
(DMSO-d6) δ: 4.00 (3H, s, OCH3), 6.80 (1H, d, furan H, NMR (DMSO-d6) δ: 3.89 (3H, s, OCH3), 4.18 (3H, s, OCH3),
—
J=2.0Hz), 7.00 7.70 (5H, m, ArH), 7.98 (1H, s, furan H, 7.14 (1H, d, furan H, J=2.1Hz), 7.41 (1H, t, ArH, J=8.7Hz),
J=2.0Hz), 10.13 (1H, s, NH exch. D2O), 11.5 (1H, s, OH exch. 7.61 (2H, d, ArH, J=8.7Hz), 7.93 (1H, d, furan H, J=2.1Hz),
−
1
D2O). IR (KBr) cm : 3206 (NH), 3159 (OH), 1680 (C=O), 10.31 (1H, s, NH exch. D2O), 12.51 (1H, s, OH exch. D2O). IR

January 2012
117
−
1
(KBr) cm : 3329 (NH), 3150 (OH), 1641 (C=O), 1598 (NH
4,7-Dimethoxy-5-{[(2,6-dichlorophenyl)amino]carbonyl}-
—
bending). Anal. Calcd for C17H13Cl2NO5 (382.19): C, 53.42; H, 1-benzofuran-6-yl Ethyl Carbonate (7f): Yield 70%, mp 254
1
°
3.43; N, 3.66. Found: C, 53.40; H, 3.50; N, 3.16.
256 C. H-NMR (DMSO-d6) δ: 1.20 (3H, t, CH2CH3), 3.90
4,7-Dimethoxy-6-hydroxy-N-(4-methoxyphenyl)-1-benzo- (3H, s, OCH3), 4.08 (3H, s, OCH3), 4.24 (2H, q, CH2CH3),
1
—
°
—
furan-5-carboxamide (6n): Yield 50%, mp 223 225 C. H- 7.14 (1H, d, furan H, J=2.0Hz), 7.33 7.90 (3H, m, ArH),
NMR (DMSO-d6) δ: 3.85 (3H, s, OCH3), 3.98 (3H, s, OCH3), 8.16 (1H, d, furan H, J=2.0Hz), 9.86 (1H, s, NH exch. D2O).
4.18 (3H, s, OCH3), 6.85 (1H, d, furan H, J=2.1Hz), 6.98 (2H, MS m/z: 453 (M+). Anal. Calcd for C20H17Cl2NO7 (454.62): C,
d, ArH, J=9.2Hz), 7.51 (2H, d, ArH, J=9.2Hz), 7.88 (1H, d, 52.83; H, 3.77; N, 3.08. Found: C, 53.10; H, 3.21; N, 3.35.
—
f To a
furan H, J=2.1Hz), 10.50 (1H, s, NH exch. D2O), 11.51 (1H, s,
General Procedure for the Preparation of 8a
−
1
—
OH exch. D2O). IR (KBr) cm : 3396 (NH), 3129 (OH), 1654 solution of the appropriate ethyl ester 7a f (10mmol) in ab-
(C=O), 1605 (NH bending). MS m/z: 343 (M+), 345 (M++2). solute ethanol (25mL), sodium metal (0.25g) was added; the
Anal. Calcd for C18H17NO6 (343.33): C, 62.79; H, 4.66; N, 4.08. mixture was stirred for 30min till no effervescence observed
Found: C, 62.60; H, 4.75; N, 4.43.
then refluxed for 24h. The solution was left aside to cool
—
General Procedure for the Preparation of 7a
f
To a down poured on ice/water and neutralized by dilute acetic
solution of the appropriate anilide 6b, 6c, 6g, 6h, 6l or 6m acid. The separated solid was filtered off, dried and crystal-
—
(10mmol) in dry pyridine (20mL), ethyl chloroformate (1.08g, lized from ethanol, yield 55 65%.
°
0.94mL, 10mmol) was added at 0 C and stirred for 30min.
6,9-Dibromo-5-methoxy-3-(4-chlorophenyl)-2H-furo[3,2-
The solution was refluxed for 1h, set aside to cool, poured on g][1,3]benzoxazine-2,4(3H)-dione (8a): Yield 60%, mp
1
—
°
ice/water and left for 24h in ice chest. The solid separated was 269 271 C. H-NMR (DMSO-d6) δ: 4.00 (3H, s, OCH3), 7.40
—
filtered, dried and crystallized from ethanol, yield 60 70%.
(2H, d, ArH, J=8.7Hz), 7.73 (2H, d, ArH, J=8.7Hz), 7.89 (1H,
−
1
3,7-Dibromo-4-methoxy-5-{[(4-chlorophenyl)amino]- s, furan H). IR (KBr) cm : 1770 (C=O ester), 1699 (C=O
carbonyl}-1-benzofuran-6-yl Ethyl Carbonate (7a): Yield amide). MS m/z: 501 (M++2). Anal. Calcd for C17H8Br2ClNO5
1
—
°
62%, mp 293 295 C. H-NMR (DMSO-d6) δ: 1.27 (3H, t, (501.51): C, 40.71; H, 1.61; N, 2.79. Found: C, 40.52; H, 1.89;
CH2CH3), 4.16 (3H, s, OCH3), 4.29 (2H, q, CH2CH3), 7.23 (2H, N, 2.65.
d, ArH), 7.51 (1H, t, ArH), 8.07 (1H, s, furan H), 9.8 (1H, s,
6,9-Dibromo-5-methoxy-3-(2,6-dichlorophenyl)-2H-
NH exch. D2O). I MS m/z: 545 (M+), 547 (M++2), 549 (M++4). furo[3,2g][1,3]benzoxazine-2,4(3H)-dione (8b): Yield 65%,
1
—
°
Anal. Calcd for C19H14Br2ClNO6 (547.58): C, 41.67; H, 2.58; N, mp 284 286 C. H-NMR (DMSO-d6) δ: 4.24 (3H, s, OCH3),
2.65. Found: C, 41.51; H, 2.19; N, 2.78.
7.37 (2H, d, ArH), 7.59 (1H, t, ArH), 7.95 (1H, s, furan H).
−
1
3,7-Dibromo-4-methoxy-5-{[(2,6-chlorophenyl)amino]- IR (KBr) cm : 1773 (C=O ester), 1692 (C=O amide). MS
carbonyl}-1-benzofuran-6-yl Ethyl Carbonate (7b): Yield m/z: 535 (M++2). Anal. Calcd for C17H7Br2Cl2NO5 (535.96): C,
1
—
°
60%, mp 302 304 C. H-NMR (DMSO-d6) δ: 1.27 (3H, t, 38.10; H, 1.32; N, 2.61. Found: C, 38.33; H, 1.52; N, 1.96.
—
CH2CH3), 4.16 (3H, s, OCH3), 4.29 (2H, q, CH2CH3), 7.23
9-Bromo-5-methoxy-3-(4-chlorophenyl)-2H-furo[3,2-g][1,3]-
—
°
7.51 (3H, m, ArH), 8.07 (1H, s, furan H), 9.8 (1H, s, NH exch. benzoxazine-2,4(3H)-dione (8c): Yield 63%, mp 263 265 C.
−
D2O). IR (KBr) cm : 3250 (NH), 1702 (C=O ester), 1605 1H-NMR (DMSO-d6) δ: 3.81 (3H, s, OCH3), 6.77 (1H, d,
(C=O amide). MS m/z: 579 (M+), 581 (M++2), 583 (M++4). furan H, J=2.1Hz), 7.27 (2H, d, ArH, J=8.7Hz), 7.49 (1H,
Anal. Calcd for C19H13Br2Cl2NO6 (582.02): C, 39.21; H, 2.25; d, furan H, J=2.1Hz), 7.71 (2H, d, ArH, J=8.7Hz). IR (KBr)
1
−
1
N, 2.41. Found: C, 38.99; H, 2.82; N, 2.45. cm : 1720 (C=O ester), 1672 (C=O amide). Anal. Calcd for
7-Bromo-4-methoxy-5-{[(4-chlorophenyl)amino]carbonyl}- C17H9BrClNO5 (422.61): C, 48.31; H, 2.15; N, 3.31. Found: C,
—
1-benzofuran-6-yl Ethyl Carbonate (7c): Yield 65%, mp 289
47.33; H, 2.65; N, 3.00.
9-Bromo-5-methoxy-3-(2,6-dichlorophenyl)-2H-furo[3,2-
−
1
°
291 C. IR (KBr) cm : 3404 (NH), 1762 (C=O ester), 1699
(C=O amide). MS m/z: 467 (M+), 469 (M++2). Anal. Calcd for g][1,3]benzoxazine-2,4(3H)-dione (8d): Yield 60%, mp 267
—
1
°
C19H15BrClNO6 (468.68): C, 48.69; H, 3.23; N, 2.99. Found: C, 269 C. H-NMR (DMSO-d6) δ: 4.31 (3H, s, OCH3), 7.40 (1H,
—
d, furan H, J=2.4Hz), 7.44 7.63 (3H, m, ArH), 8.02 (1H, d,
7-Bromo-4-methoxy-5-{[(2,6-dichlorophenyl)amino]- furan H, J=2.4Hz). IR (KBr) cm : 1768 (C=O ester), 1692
48.59; H, 3.01; N, 2.89.
−
1
carbonyl}-1-benzofuran-6-yl Ethyl Carbonate (7d): Yield (C=O amide). Anal. Calcd for C17H8BrCl2NO5 (457.06): C,
1
—
°
60%, mp 295 297 C. H-NMR (DMSO-d6) δ: 1.20 (3H, t, 44.76; H, 1.67; N, 3.06. Found: C, 44.79; H, 2.00; N, 2.73.
CH2CH3), 4.00 (3H, s, OCH3), 4.20 (2H, q, CH2CH3), 6.80
5,9-Dimethoxy-3-(4-chlorophenyl)-2H-furo[3,2-g][1,3]ben-
1
—
—
°
(1H, d, furan H, J=2.1Hz), 7.23 7.95 (4H, m, ArH, furan H), zoxazine-2,4(3H)-dione (8e): Yield 63%, mp 222 224 C. H-
10.1 (1H, s, NH exch. D2O). I Anal. Calcd for C19H14BrCl2NO6 NMR (DMSO-d6) δ: 3.89 (3H, s, OCH3), 3.98 (3H, s, OCH3),
(503.13): C, 45.36; H, 2.80; N, 2.78. Found: C, 45.21; H, 2.99; 7.13 (1H, d, furan H, J=2.1Hz), 7.39 (2H, d, ArH, J=8.4Hz),
N, 2.78.
7.76 (2H, d, ArH, J=8.4Hz), 7.88 (1H, d, furan H, J=2.1Hz).
−
1
4,7-Dimethoxy-5-{[(4-chlorophenyl)amino]carbonyl}-1-ben- IR (KBr) cm : 1770 (C=O ester), 1693 (C=O amide). MS
—
zofuran-6-yl Ethyl Carbonate (7e): Yield 67%, mp 238
m/z: 373 (M+). Anal. Calcd for C18H12ClNO6 (373.74): C, 57.85;
1
°
240 C. H-NMR (DMSO-d6) δ: 1.23 (3H, t, CH2CH3), 3.90 H, 3.24; N, 3.75. Found: C, 57.35; H, 3.84; N, 3.25.
(3H, s, OCH3), 4.09 (3H, s, OCH3), 4.22 (2H, q, CH2CH3), 7.07 5,9-Dimethoxy-3-(2,6-dichlorophenyl)-2H-furo[3,2-g][1,3]-
—
°
(1H, d, furan H, J=1.8Hz), 7.34 (2H, d, ArH, J=8.5Hz), 7.68 benzoxazine-2,4(3H)-dione (8f): Yield 55%, mp 229 231 C.
(2H, d, ArH, J=8.5Hz), 8.15 (1H, d, furan H, J=1.8Hz), 9.86 1H-NMR (DMSO-d6) δ: 3.88 (3H, s, OCH3), 4.17 (3H, s,
−
1
—
(1H, s, NH exch. D2O). IR (KBr) cm : 3210 (NH), 1702 (C=O OCH3), 7.24 (1H, d, furan H, J=2.4Hz), 7.41 7.61 (3H, m,
−
1
ester), 1607 (C=O amide). MS m/z: 419 (M+). Anal. Calcd for ArH), 7.93 (1H, d, furan H, J=2.4Hz). IR (KBr) cm : 1768
C20H18ClNO7 (419.81): C, 57.22; H, 4.32; N, 3.34. Found: C, (C=O ester), 1700 (C=O amide). MS m/z: 407 (M+). Anal.
57.35; H, 3.94; N, 3.35.
Calcd for C18H11Cl2NO6 (408.19): C, 52.96; H, 2.72; N, 3.34.

118
Vol. 60, No. 1
Found: C, 53.16; H, 3.02; N, 3.11.
solution of 13 (2.34g, 10mmol) in ethanol (20mL). 5% NaOH
General Procedure for the Preparation of 11a,b A so- (10mL) and the appropriate acetophenone (10mmol) were
lution of aniline (0.93mL, 10mmol) in conc. HCl (8mL) and added and stirred for 24h at room temperature. The red solu-
water (8mL) was stirred in ice bath and NaNO2 (2g) in water tion was then neutralized by drops of dilute acetic acid and
(5mL) was added in portions to the stirred solution during the separated solid was filtered off, washed by ethanol, dried
30min till red fumes appear. The previous solution was added and crystallized from N,N-dimethylformamide (DMF)/water,
—
in portions to a solution of the appropriate chalchone 10a,b yield 78 85%.
(10mmol) in ethanolic 10% NaOH (20mL). The mixture was
6-[(1E)-3-Oxo-3-phenylprop-1-en-1-yl]-7-hydroxy-5-meth-
kept in ice chest for 1h and neutralized with dilute acetic acid. oxy-2-methyl-4H-chromen-4-one (14a): Yield 78%, mp
1
—
°
The deeply colour solid was filtered off, washed with water, 260 262 C. H-NMR (DMSO-d6) δ: 2.09 (3H, s, CH3), 3.79
—
dried and crystallized from ethanol, yield 55 60%.
(3H, s, OCH3), 6.00 (1H, s, γ-pyrone H), 6.75 (1H, s, ArH),
—
(2E)-1-{6-Hydroxy-4-methoxy-7-[(E)-phenyldiazenyl]-1- 7.41 7.68 (5H, m, ArH), 7.99 (1H, d, CH=CH, J=16Hz), 8.14
benzofuran-5-yl}-3-phenylprop-2-en-1-one (11a): Yield 60%, (1H, d, CH=CH, J=16Hz), 11.70 (1H, s, OH, exch. D2O). IR
−
1
−
1
—
°
mp 165 167 C. IR (KBr) cm : 3155 (OH), 1630 (C=O), 1575 (KBr) cm : 3100 (OH), 1655 (C=O) chalcone, 1631 (C=O)
(N=N). MS m/z: 399 (M++1). Anal. Calcd for C24H18N2O4 chromone. MS m/z: 337 (M++1). Anal. Calcd for C20H16O5
(398.41): C, 72.35; H, 4.55; N, 7.03. Found: C, 72.53; H, 4.24; (336.34): C, 71.42; H, 4.79. Found: C, 71.64; H, 4.64.
N, 7.42.
6-[(1E)-3-(3-Methoxyphenyl)-3-oxoprop-1-en-1-yl]-7-hy-
(2E)-1-{6-Hydroxy-4-methoxy-7-[(E)-phenyldiazenyl]-1- droxy-5-methoxy-2-methyl-4H-chromen-4-one (14b): Yield
1
—
°
benzofuran-5-yl}-3-(4-methoxyphenyl)prop-2-en-1-one (11b): 80%, mp 272 274 C. H-NMR (DMSO-d6) δ: 2.24 (3H, s,
1
—
°
Yield 55%, mp 172 174 C. H-NMR (DMSO-d6) δ: 3.89 (3H, CH3), 3.75 (3H, s, OCH3), 3.84 (3H, s, OCH3), 5.99 (1H, s,
—
s, OCH3), 3.90 (3H, s, OCH3), 6.66 (1H, d, furan H, J=2Hz), γ-pyrone H), 6.72 (1H, s, ArH), 7.22 7.52 (4H, m, ArH), 7.96
—
6.79 7.40 (9H, m, ArH), 7.60 (1H, d, furan H, J=2Hz), 7.80 (1H, d, CH=CH, J=16Hz), 8.11 (1H, d, CH=CH, J=16Hz),
−
1
(1H, d, CH=CH, J=15Hz), 8.20 (1H, d, CH=CH, J=15Hz), 12.00 (1H, s, OH, exch. D2O). IR (KBr) cm : 3076 (OH), 1654
10.00 (1H, s, OH exch. D2O). MS m/z: 429 (M+ +1). Anal. Cal- (C=O) chalcone, 1645 (C=O) chromone. MS m/z: 366 (M+).
cd for C25H20N2O5 (428.44): C, 70.08; H, 4.81; N, 6.54. Found: Anal. Calcd for C21H18O6 (366.36): C, 68.85; H, 4.95. Found:
C, 69.78; H, 4.48; N, 6.73.
C, 69.02; H, 4.81.
General Procedure for the Preparation of 12a,b To a
6-[(1E)-3-(4-Bromophenyl)-3-oxoprop-1-en-1-yl]-7-hydroxy-
solution of the appropriate azo derivative 11a,b (10mmol) in 5-methoxy-2-methyl-4H-chromen-4-one (14c): Yield 85%, mp
1
—
°
70% ethanol (30mL) a solution of sodium dithionite (8.4g, 279 281 C. H-NMR (DMSO-d6) δ: 2.26 (3H, s, CH3), 3.91
40mmol) in water (25mL) was added in portions while re- (3H, s, OCH3), 5.97 (1H, s, γ-pyrone H), 6.68 (1H, s, ArH),
—
fluxing for 1h. The deep intense color disappeared and the 7.76 7.89 (4H, m, ArH), 8.04 (1H, d, CH=CH, J=16Hz),
solution was kept aside to cool, filtered and the filtrate was 8.21 (1H, d, CH=CH, J=16Hz), 12.00 (1H, s, OH, exch. D2O).
−
1
concentrated to half its volume. The filtrate was poured into IR (KBr) cm : 3100 (OH), 1653 (C=O) chalcone, 1600 (C=O)
3 times its volume of cold water. The separated solid was fil- chromone. MS m/z: 415 (M+). Anal. Calcd for C20H15BrO5
—
tered off, dried and crystallized from ethanol, yield 35 40%. (415.23): C, 57.85; H, 3.64. Found: C, 58.09; H, 3.67.
—
(2E)-1-(7-Amino-6-hydroxy-4-methoxy-1-benzofuran-5-yl)- General Procedure for the Preparation of 15a
c
A
—
°
3-phenylprop-2-en-1-one (12a): Yield 40%, mp 176 178 C. solution of aniline (0.93mL, 10mmol) in conc. HCl (8mL) and
1H-NMR (DMSO-d6) δ: 3.90 (2H, broad, NH2 exch. D2O), water (8mL) was stirred in ice bath and NaNO2 (2g) in water
—
4.00 (3H, s, 3H, OCH3), 6.70 8.20 (m, 9H, ArH, furan H, (5mL) was added to the stirred solution during 30min till red
−
1
CH=CH), 13.20 (s, 1H, OH exch. D2O). IR (KBr) cm : fumes appear. The previous solution was added to a solution
—
—
3357 3200 (broad, NH2, OH), 1600 (C=O) chalcone. MS of the appropriate chalchone 14a c (10mmol) in ethanolic
m/z: 311 (M++2). Anal. Calcd for C18H15NO4 (309.32): C, 69.89; 10% NaOH (20mL). The mixture was kept in ice chest for 1h
H, 4.89; N, 4.53. Found: C, 69.65; H, 4.81; N, 4.62.
and neutralized with acetic acid. The deeply colure solid was
(2E)-1-(7-Amino-6-hydroxy-4-methoxy-1-benzofuran-5-yl)- filtered off, washed with water, dried and crystallized from
—
3-(4-methoxyphenyl)prop-2-en-1-one (12b): Yield 35%, mp ethanol, yield 50 55%.
189 191 C. 1H-NMR (DMSO-d6) δ: 3.79 (2H, broad,
NH2 exch. D2O), 3.91 (3H, s, OCH3), 4.15 (3H, s, OCH3), oxy-2-methyl-8-((E)-phenyldiazenyl)-4H-chromen-4-one
6-[(1E)-3-Phenyl-3-oxoprop-1-en-1-yl]-7-hydroxy-5-meth-
—
°
1
—
—
°
6.80 8.20 (8H, m, ArH, furan H, CH=CH), 14.00 (1H, (15a): Yield 55%, mp 180 182 C. H-NMR (DMSO-d6) δ:
−
1
s, OH exch. D2O). IR (KBr) cm : 3156, 3129 (NH2), 3074 2.24 (3H, s, CH3), 3.81 (3H, s, OCH3), 6.04 (1H, s, γ-pyrone
(OH), 1691 (C=O) chalcone. MS m/z: 339 (M+). Anal. Calcd H), 6.81 6.94 (4H, m, ArH), 7.35 7.67 (6H, m, ArH),7.95
for C19H17NO5 (339.34): C, 67.25; H, 5.05; N, 4.13. Found: C, (d, 1H, CH=CH, J=15Hz), 8.16 (d, 1H, CH=CH, J=15Hz),
—
—
−
1
67.45; H, 5.09; N, 4.27.
11.91 (1H, s, OH, exch. D2O). IR (KBr) cm : 3178 (OH), 1705
7-Hydroxy-5-methoxy-2-methyl-4-oxo-4H-chromene- (C=O) chalcone, 1640 (C=O) chromone. MS m/z: 440 (M+).
6-carbaldehyde (13) To a solution of visnagin 1 (2.3g, Anal. Calcd for C26H20N2O5 (440.45): C, 70.90; H, 4.58; N,
10mmol) in 10% w/v hot sulphuric acid (60mL), 10% w/v 6.36. Found: C, 71.20; H, 4.89; N, 6.78.
potassium dichromate solution (40mL) was gradually added
6-[(1E)-3-(3-Methoxyphenyl)-3-oxoprop-1-en-1-yl]-7-
—
°
at a temprature (70 80 C). The mixture was left at room hydroxy-5-methoxy-2-methyl-8-((E)-phenyldiazenyl)-4H-
1
—
°
temprature for 30min. The white ppt was filtered washed with chromen-4-one (15b): Yield 50%, mp 188 190 C. H-NMR
—
water, dried and crystallized from hot water. Yield 65 70%, (DMSO-d6) δ: 2.21 (3H, s, CH3), 3.81 (3H, s, OCH3), 4.19
18)
°
mp 189 C (as reported).
(3H, s, OCH3), 5.97 (1H, s, γ-pyrone H), 6.42 (1H, s, ArH),
—
—
To a 7.22 7.52 (8H, m, ArH), 7.96 (1H, d, CH=CH, J=16Hz),
General Procedure for the Preparation of 14a
c

January 2012
119
8.10 (1H, d, CH=CH, J=16Hz), 12.00 (1H, s, OH, exch. D2O). (2H, d, pyrimid.C5-H), 3.73 (1H, m, pyrimid.C6-H), 3.92 (3H,
−
1
—
IR (KBr) cm : 3100 (OH), 1682 (C=O) chalcone, 1664 (C=O) s, OCH3), 6.03 (1H, s, γ-pyrone H), 7.39 7.92 (7H, m, ArH
−
1
chromone. Anal. Calcd for C27H22N2O6 (470.74): C, 68.93; H, and NH). IR (KBr) cm : 3421 (NH), 3061 (OH), 1654 (C=O)
4.71; N, 5.95. Found: C, 69.43; H, 4.73; N, 6.33.
+
−
pyrone, 1112 (C=S). MS m/z: 392 (M 2). Anal. Calcd for
6-[(1E)-3-(4-Bromophenyl-3-oxoprop-1-en-1-yl]-7-hydroxy- C21H18N2O4S (394.44): C, 63.94; H, 3.06; N, 7.10. Found: C,
5-methoxy-2-methyl-8-((E)-phenyldiazenyl)-4H-chromen-4- 64.32; H, 3.72; N, 7.45.
1
—
°
one (15c): Yield 50%, mp 279 281 C. H-NMR (DMSO-d6)
6-[6-(3-Methoxyphenyl)-2-thioxo-2,5-dihydropyrimidin-
δ: 2.24 (3H, s, CH3), 4.12 (3H, s, OCH3), 5.90 (1H, s, γ-pyrone 4-yl]-7-hydroxy-5-methoxy-2-methyl-4H-chromen-4-one (17b):
−
1
—
°
H), 7.05 7.50 (5H, m, ArH), 7.75 (2H, d, ArH, J=8Hz), 7.86 Yield 62%, mp >350 C. IR (KBr) cm : 3430 (NH), 3080
+
−
(d, 2H, ArH, J=8Hz), 8.13 (d, 1H, CH=CH, J=15Hz), 8.77 (OH), 1650 (C=O) pyrone, 1115 (C=S). MS m/z: 422 (M 2).
(d, 1H, CH=CH, J=15Hz), 14.20 (1H, s, OH, exch. D2O). Anal. Calcd for C22H20N2O5S (424.47): C, 62.25; H, 4.75; N,
Anal. Calcd for C26H19BrN2O5 (519.34): C, 60.13; H, 3.69; N, 6.60. Found: C, 61.62; H, 4.31; N, 6.23.
5.39. Found: C, 60.43; H, 3.69; N, 5.59.
General Procedure for the Preparation of 16a
6-[6-(4-Bromophenyl)-2-thioxo-2,5-dihydropyrimidin-4-yl]-
To a 7-hydroxy-5-methoxy-2-methyl-4H-chromen-4-one (17c):
—
c
1
—
°
solution of the appropriate azo derivative 15a c (10mmol) Yield 60%, mp >350 C. H-NMR (DMSO-d6) δ: 2.27 (3H, s,
in 70% ethanol (50mL) a solution of sodium dithionite (8.4g, CH3), 2.89 (2H, d, pyrimid.C5-H), 3.77 (1H, m, pyrimid.C6-H),
40mmol) in water (25mL) was added in portions while reflux- 3.98 (3H, s, OCH3), 6.03 (1H, s, γ-pyrone H), 6.49-8.00 (6H,
ing for 1h. The deep intense color of azo dye disappeared and m, ArH, NH). IR (KBr) cm : 3446 (NH), 3099 (OH), 1654
the solution was kept aside to cool, filtered and the filtrate was (C=O) pyrone and 1114 (C=S). MS m/z: 475 (M++2). Anal.
concentrated to half its volume. The filtrate was poured into Calcd for C21H17BrN2O4S (473.34): C, 53.29; H, 3.62; N, 5.92.
3 times its volume of cold water. The separated solid was fil- Found: C, 53.34; H, 3.85; N, 6.02.
−
1
—
tered off, dried and crystallized from ethanol, yield 45 55%.
Pharmacological Studies. Animals Male Wister rats,
—
(E)-8-Amino-6-(phenyl-3-oxoprop-1-enyl)-7-hydroxy-5- each weighing 120 180g, were purchased from the animal
methoxy-2-methyl-4H-chromen-4-one (16a): Yield 50%, mp breeding unit of the National Ophthalmology Institute, Egypt.
1
—
°
—
172 174 C. H-NMR (DMSO-d6) δ: 2.25 (3H, s, CH3), 3.56
They were housed under appropriate conditions of controlled
3.66 (2H, broad, NH2 exch. D2O), 3.81 (3H, s, OCH3), 6.00 humidity, temperature and light. The animals were allowed
—
(1H, s, γ-pyrone H), 6.66 7.85 (7H, m, ArH and CH=CH), free access to water and were fed a standard pellet rat diet.
−
1
± °
11.80 (1H, s, OH, exch. D2O). IR (KBr) cm : 3168, 3144 The animals were kept at an ambient temperature of 22 2 C
—
(NH2), 3081 (OH), 1695 (C=O) chalcone, 1619 (C=O) chr- and a humidity of 65 70%. The study was conducted accord-
omone. MS m/z: 351 (M+). Anal. Calcd for C20H17NO5 (351.35): ing to the guidelines for animal experiments set by Faculty of
C, 68.37; H, 4.88; N, 3.99. Found: C, 68.43; H, 4.68; N, 4.08.
(E)-8-Amino-6-(3-methoxyphenyl-3-oxoprop-1-enyl)-7-hy- tional guidelines.
droxy-5-methoxy-2-methyl-4H-chromen-4-one (16b): Yield Anti-inflammatory Activity A suspension (1%) of carra-
55%, mp 179 181 C. H-NMR (DMSO-d6) δ: 2.24 (3H, s, geenan was prepared by sprinkling 1g carrageenan powder in
Pharmacy, Cairo University in accordance with the interna-
1
—
°
—
CH3), 3.59 3.65 (2H, broad, NH2 exch. D2O), 3.76 (3H, s, small amounts over the surface of 100mL saline (NaCl 0.9%
—
OCH3), 3.84 (3H, s, OCH3), 6.00 (1H, s, γ-pyrone H), 6.68
w/v) and the particles allowed to soak between additions. The
°
—
7.91 (6H, m, ArH and CH=CH), 11.70 (1H, s, OH, exch. D2O). suspension was then left at 37 C for 2 3h before use. Right
−
1
IR (KBr) cm : 3156, 3129 (NH2), 3074 (OH), 1691 (C=O) paw is marked with ink at the level of lateral malleolus; basal
chalcone, 1676 (C=O) chromone. Anal. Calcd for C21H19NO6 paw volume is measured plethysmographically by volume
(381.83): C, 66.13; H, 5.02; N, 3.67. Found: C, 66.45; H, 4.88; displacement method using Plethysmometer (UGO Basile
N, 3.26.
7140) by immersing the paw till the level of lateral malleolus.
(E)-8-Amino-6-(4-bromophenyl-3-oxoprop-1-enyl)-7-hy- 0.05mL of this suspension was injected into the subplantar
droxy-5-methoxy-2-methyl-4H-chromen-4-one (16c): Yield surface of the right hind paw of the rat. The paw volume is
1
—
°
45%, mp 196 198 C. H-NMR (DMSO-d6) δ: 2.29 (3H, s, measured again at 1, 2, 3 and 4h after challenge. The increase
CH3), 3.68 (2H, s, NH2 exch. D2O), 3.86 (3H, s, OCH3), 5.92 in paw volume is calculated as percentage compared with the
—
(1H, s, γ-pyrone H), 6.60 8.07 (6H, m, ArH and CH=CH), basal volume. The animals were randomized and divided into
−
1
11.70 (1H, s, OH, exch. D2O). IR (KBr) cm : 3156, 3126 groups consists of 6 animals per group. The tested compounds
(NH2), 3074 (OH), 1690 (C=O) chalcone, 1625 (C=O) chro- and the reference drug (Diclofenac) were given orally 30min
mone. MS m/z: 429 (M+). Anal. Calcd for C20H16BrNO5 prior to the intraplatar injection of carrageenan. The differ-
(430.25): C, 55.83; H, 3.75; N, 3.26. Found: C, 55.35; H, 3.81; ence of average values between treated animals and control
N, 3.11.
General Procedure for the Preparation of 17a
group is calculated for each time interval and evaluated statis-
To a tically. The percent Inhibition is calculated using the formula
—
c
—
solution of the appropriate chalcone 16a c (10mmol) in dry as follows.
DMF (30mL), thiourea (0.76g, 10mmol) and H2SO4 (0.5mL)
were added. The solution was refluxed for 6h, cooled and
−
×
% edema inhibition=[1 (Vt/Vc)] 100
poured into ice-water. The separated solid was filtered off, Vt and Vc are edema volume in the drug treated and control
washed with ethanol, dried and crystallized from DMF/water, groups respectively.
—
yield 60 65%.
PGE2 Inhibition Activity PGE2 concentrations were
6-[6-Phenyl-2-thioxo-2,5-dihydropyrimidin-4-yl]-7-hydroxy- measured in serum samples prepared by centrifugation of
5-methoxy-2-methyl-4H-chromen-4-one (17a): Yield 65%, blood of the injected animals using rat specific immunoassay
1
mp >350 C. H-NMR (DMSO-d6) δ: 2.27 (3H, s, CH3), 2.88 kit.26) The assay was performed following the instructions in
°

120
Vol. 60, No. 1
7) Yamamoto Y., Toyohara J., Ishiwata K., Sano K., Yamamoto F., Mu-
the leaflet of the kit. The duplicate readings for each stan-
dard, control and sample were averaged and subtracted from
the average zero standard optical density. A standard curve
was constructed by plotting the mean optical density on a
logarithmic y-axis against the concentrations (pg/mL) on a
logarithmic x-axis. The best fitting line was then determined
using regression analysis. These standard curves were used to
determine the concentration of PGE2 (pg/mL) in the samples.
Ulcerogenic Effect Male albino rats (100–120g) were
fasted for 12h prior to the administration of the compounds.
The animals were divided into 14 groups, each of 6 animals.
The control group received 1% gum acacia orally. Other
groups received Diclofenac or the tested compounds orally in
2 equal doses at 0 and 12h for 3 successive days at a dose of
100mg/kg per day. Animals were sacrificed by diethyl ether
6h after the last dose and the stomach was removed. An open-
ing at the greater curvature was made and the stomach was
cleaned by washing with cold saline and inspected with a 3Å
magnifying lens for any evidence of hyperaemia, haemor-
rhage, definite hemorrhagic erosion, or ulcer. An arbitrary
scale was used to calculate the ulcer index which indicates
the severity of the stomach lesions. Ulcers were classified into
levels: level I, in which the ulcer area is less than 1mm2; level
II, in which the ulcer area is in the range from 1 to 3mm2;
and level III, in which the ulcer area equals 3mm2.27) The
—
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—
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—
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—
Azimzadeh B. S., Pak. J. Pharm. Sci., 22, 395 401 (2009).
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—
Bull., 58, 579 581 (2010).
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—
Boyce J. P., Bioorg. Med. Chem., 16, 8760 8764 (2008).
—
14) Giitschow M., Neumann U., Bioorg. Med. Chem., 5, 1935 1942
(1997).
’
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—
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—
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—
Bioorg. Med. Chem., 15, 2952 2962 (2007).
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—
4992 4995 (1953).
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—
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×
ulcer index was calculated as 1 (number of ulcers of level
20) Hassan G. S., Hegazy G. H., Safwat H. M., Arch. Pharm. Chem.
×
×
I)+2 (number of ulcers of level II)+3 (number of ulcers of
level III).
—
Life Sci., 339, 448 455 (2007).
21) Waisser K., Hladuvková J., Gregor J., Rada T., Kubicová L.,
—
6
Statistical Analysis of Data Data obtained from ani-
Klimesová V., Kaustová J., Arch. Pharm. (Weinheim), 331, 3
(1998).
±
mal experiments were expressed as mean standard error
22) Waisser K., Gregor J., Kubicová L., Klimesová V., Kunes J.,
±
( S.E.M.). Statistical differences between the treatments
—
Machácek M., Kaustová J., Eur. J. Med. Chem., 35, 733 741
and the control were tested by one-way analysis of variance
(ANOVA) followed by post hoc test using SPSS 11.0 software.
A value of p<0.05 was considered to be significant.
(2000).
—
23) Schonberg A., Sina A., J. Am. Chem. Soc., 72, 1611 1616 (1950).
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—
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