Synthesis and biological evaluation of a novel series of 2,2-bisaminomethylated aurone analogues as anti-inflammatory and antimicrobial agents

Article abstract of DOI:10.1016/j.ejmech.2010.03.045

This is the first report on aurones as a new class of drugs with anti-inflammatory and antimicrobial agents. A series of 2,2-bisaminomethylated aurone analogues (4a-j) were synthesized by Mannich reaction from 1,3,5-trimethoxybenzene in three steps. The structures of the newly synthesized compounds were confirmed by IR, ¹H NMR and mass spectral analysis. All the synthesized compounds were screened against the pro-inflammatory cytokines (TNF-α, IL-6) and antimicrobial (antibacterial and antifungal) activity. Compounds 4a, 4b, 4c, 4d, and 4e showed promising results against IL-6 at 10 mM concentration (74-100%). Compounds 4a, 4b and 4c were found to be active against TNF-α (76-100%) at 10 μM. Interestingly, all compounds have shown good antimicrobial activity. Compounds 4d, 4e and 4f showed excellent antimicrobial activity as compared with standard drugs.

Full text of DOI:10.1016/j.ejmech.2010.03.045

European Journal of Medicinal Chemistry 45 (2010) 3223e3227
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and biological evaluation of a novel series of 2,2-bisaminomethylated
aurone analogues as anti-inflammatory and antimicrobial agents
,
b
,
b
b
b
c
Babasaheb P. Bandgar a , Sachin A. Patil , Balaji L. Korbad , Satish C. Biradar , Shivraj N. Nile ,
*
Chandrahasya N. Khobragade c
a Organic Chemistry Research Laboratory, School of Chemical Sciences, Solapur University, Solapur 413255, MS, India
b Organic Chemistry Research Laboratory, School of Chemical Sciences, Swami Ramanand Teerth Marathwada University, Nanded 431606, MS, India
c Biochemistry Research laboratory, School of Life Sciences, Swami Ramanand Teerth Marathawada University, Nanded 431606, MS, India
a r t i c l e i n f o
a b s t r a c t
Article history:
This is the first report on aurones as a new class of drugs with anti-inflammatory and antimicrobial
agents. A series of 2,2-bisaminomethylated aurone analogues (4aej) were synthesized by Mannich
reaction from 1,3,5-trimethoxybenzene in three steps. The structures of the newly synthesized
compounds were confirmed by IR, 1H NMR and mass spectral analysis. All the synthesized compounds
Received 5 November 2009
Received in revised form
25 March 2010
Accepted 29 March 2010
Available online 3 April 2010
were screened against the pro-inflammatory cytokines (TNF-
antifungal) activity. Compounds 4a, 4b, 4c, 4d, and 4e showed promising results against IL-6 at 10
concentration (74e100%). Compounds 4a, 4b and 4c were found to be active against TNF- (76e100%) at
10 M. Interestingly, all compounds have shown good antimicrobial activity. Compounds 4d, 4e and 4f
showed excellent antimicrobial activity as compared with standard drugs.
a, IL-6) and antimicrobial (antibacterial and
m
M
a
Keywords:
m
2,2-Bisaminomethylated aurones
Anti-inflammatory activity
Antimicrobial activity
Ó 2010 Elsevier Masson SAS. All rights reserved.
1. Introduction
agents has remained a significant hope in the mainstream of anti-
inflammatory drug development.
Tumour necrosis factor-alpha (TNF-
a
) and Interleukin-6 (IL-6)
Aurones, 2-benzylidenebenzofuran-3(2H)-ones, the naturally
occurring yellow pigments of the plants that are structurally
isomeric of flavones, are present in vegetables, and in flowers [9],
where they are responsible for the gold-yellow color of some
popular ornamental flowers such as snapdragon, cosmos and dahlia.
Aurones are biosynthesized from chalcones by the key enzyme
aureusidin synthase [10]. Representative naturally occurring
aurones are aureusidin [11], sulfuretin [12] and maritimetin [13].
Aurones are obtained from chalcone by aurone synthase as well
as through the biosynthesis of other flavonoids [14]. Aurones have
been reported to possess insect antifeedent activity [15], anticancer
[16,17], antiparasitic [18], antileishmanial [19,20] and antifungal
activity [21]. Aurones can be used as potential cancer chemo-
therapy agents and as inhibitors of an enzyme involved in the
metabolism of thyroid hormones [22]. They have also been repor-
ted to be antiproliferative agents interfering with G2/M phase of
the cell cycle [16], tyrosinase inhibitors [23] and as potentially
are two major multifunctional pro-inflammatory mediators of
a variety of autoimmune diseases such as pain and joint destruction
characteristics of RA [1]. The inhibition of release of cytokines
becomes a major focus of current drug development and an
important method for evaluating the bioactivity of drugs [2]. Over-
expression of TNF-
a is responsible for a number of pathological
conditions like Crohn’s disease, ulcerative colitis [3], diabetes [4],
multiple sclerosis [5], atherosclerosis [6] and stroke [7]. In spite of
enormous efforts, no small molecule has yet been approved to
specifically inhibit TNF-a activity.
Amongst pro-inflammatory cytokines, the IL-6 is a multifunc-
tional cytokine produced by a variety of cells in response to infec-
tion, trauma, or immunological challenge. It appears to be the
central mediator of anemia of chronic disease in a range of
inflammatory diseases, including end-stage renal disease and
rheumatoid arthritis [8]. Till date, designing the IL-6 inhibitory
useful imaging agents for detecting b-amyloid plaques in Alzheimer’s
disease [24]. Recently, (Z)-2-(5-nitrofuran-2-yl-methylene)-3(2H)-
benzofuranones and (Z)-2-benzylidene-6,7-dihydroxy-3(2H)-benzo-
furanones exhibited very good in vitro antibacterial properties [25,26].
Recently, a novel class of “(Z)-2-(nitroimidazolylmethylene)-3(2H)-
benzofuranones possessing 1-methyl-5-nitroimidazole analogues
exhibited very good antibacterial agents [27].
* Corresponding author. Organic Chemistry Research Laboratory, School of
Chemical Sciences, Swami Ramanand Teerth Marathwada University, Nanded
431606, MS, India. Tel./fax: þ91 217 2351300.
E-mail address: bandgar_bp@yahoo.com (B.P. Bandgar).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.03.045

3224
B.P. Bandgar et al. / European Journal of Medicinal Chemistry 45 (2010) 3223e3227
O
O
O
O
O
Cl
b
a
O
O
O
O
OH
O
2
3
1
c
O
O
NR1R2
NR1R2
O
N
O
4
R1
R2
CH2CH3
CH2CH3
Where
(c)
N
N
N
(a)
(b)
N
CH3
N
O
(d)
(e)
=
N
CH3
CH2CH2CH2CH3
CH2CH3
CH3
(g)
N
N
(f)
(h)
(i)
N
N CH2CH3
N
CH3
CH2CH2CH2CH3
Scheme 1. Reagents and conditions: (a) ClCH2COCl, AlCl3, dry ether; (b) potassium acetate, EtOH, ref.; (c) Secondary amines, HCHO, isopropanol, conc. HCl, ref.
2. Chemistry
Sigma Chemical Co., St. Louis, MO) was added, at a final concen-
tration of 1
g/mL. Plates were incubated at 37 ꢁC for 24 h, 5% CO2.
Supernatants were harvested and assayed for TNF- and IL-6 by
ELISA as described by the manufacturer (BD Biosciences). The cells
were simultaneously evaluated for cytotoxicity [30] using CCK-8
from Dojindo Laboratories. Percent inhibition of cytokine release
compared to the control was calculated.
m
Compounds described in this study were prepared using
a straightforward chemistry (Scheme 1). 2-Chloro-1-(2-hydroxy-
4,6-dimethoxyphenyl)ethanone 2 was synthesized following the
method described in the literature with minor modifications [28].
2-Chloro-1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone (2) on
cyclisation with anhydrous potassium acetate in ethanol under
reflux yielded 4,6-dimethoxybenzofuran-3(2H)-one (3) [28]. 2,2-
Bis(aminomethyl)-4,6-dimethoxybenzofuran-3(2H)-ones (4aei)
were prepared by the Mannich reaction between 4,6-dimethox-
ybenzofuran-3(2H)-one (3) and a mixture of secondary amines
with formaldehyde in isopropanol with catalytic amount of conc.
HCl under reflux for 12 h. The desired derivatives were obtained in
55% yield. All synthesized compounds 4aei were characterized by
using IR, 1H NMR and mass spectra.
a
3.2. Antibacterial studies
The newly synthesized compounds were screened for their
antibacterial activity against Bacillus subtilis (NCIM 2546), E. coli
(NCIM 2065), Staphylococcus aureus (NCIM 2120), Klebsiella pneu-
moniae (NCIM 5082), and Proteus vulgaris (NCIM 2813) bacterial
strains by disc diffusion method [31,32]. Disc measuring 6.25 mm in
diameter were punched from Whatmann no. 1 filter paper. Batches
of 10 discs were dispensed to each screw capped bottle and ster-
ilized by dry heat at 140 ꢁC for an hour. The test compounds were
prepared with a concentration 0.5% using dimethylsulfoxide. The
discs of each concentration were placed in triplicate in nutrient
agar medium seeded with fresh bacterial culture separately and
incubated at 37 ꢁC for 24 h. Penicillin and gentamycin were used as
The synthesized 2,2-bisaminomethylated aurone analogues
were assayed for their biological activities such as, anti-inflam-
matory activity (TNF-
a and IL-6), and antimicrobial (bacterial and
antifungal) activity.
3. Biological evaluation
3.1. Assay for TNF- and IL-6 inhibition
a
Table 1
Antinflammatory activity against TNF-
a
and IL-6.
Pro-inflammtory cytokine production by lipopolysaccharide
(LPS) in THP-1 cells was measured according to the method
described by Hwang et al. [29]. Briefly, THP-1 cells were cultured in
RPMI 1640 culture medium (Gibco BRL, Pasley, UK) containing
100 U/mL penicillin and 100 mg/mL streptomycin (100ꢀ solution,
Sigma Chemical Co. St. Louis, MO) containing 10% fetal bovine
serum (FBS, JRH). Cells were differentiated with phorbol myristate
acetate (PMA, Sigma). Following cell plating, the test compounds or
vehicle using 0.5% DMSO was added to each well and the plate was
incubated for 30 min at 37 ꢁC. Finally, LPS (Escherichia coli0127:B8,
Compounds
%Inhibition at 10
m
M concentration
IL-6
TNF-a
Cytotoxicity
4a
4b
4c
4d
4e
4f
76
89
35
100
28
17
97
100
82
100
74
29
66
21
83
37
65
00
37
90
DMS (1
m
M)
69
The results summarized are the mean values of n ¼ 2, DMS ¼ dexamethasone.

B.P. Bandgar et al. / European Journal of Medicinal Chemistry 45 (2010) 3223e3227
3225
Table 2
4. Results and discussion
Antibacterial activity of aurone analogues.
All the synthesized compounds were evaluated for anti-
inflammatory and antimicrobial activity. Anti-inflammatory activity
Compounds Esherichia Bacillius Staphylococcus Klebsiella
Proteus
coli
subtilis
aureus
pneumoniae vulgaris
4a
4b
4c
4d
4e
4f
4g
4h
4i
15 (50)
17 (25)
18 (25)
20 (25)
18 (25)
21 (25)
14 (50)
16 (25)
e
14 (50)
16 (25)
17 (25)
18 (25)
17 (25)
18 (25)
15 (50)
15 (50)
e
e
e
16 (25)
22 (25)
15 (50)
22 (25)
17 (25)
22 (25)
15 (50)
14 (50)
e
analysis against TNF-
out. Inhibitory activity results are summarized in Table 1.
Dexamethasone (1 M) was used as a reference compound. Aurone
analogues 4aef exhibited 17e100% inhibition of TNF- at 10 M.
Compounds 4a, 4b and 4d were found to be excellent TNF-
a and IL-6 at 10 mM concentrations was carried
15 (50)
16 (25)
15 (25)
16 (25)
18 (25)
14 (50)
15 (25)
e
e
18 (25)
20 (25)
17 (25)
21 (25)
15 (50)
17 (25)
e
m
a
m
a
inhibitors (76e100%).
Interestingly, all the synthesized aurone analogues were observed
to be promising leads, possessing excellent IL-6 inhibitory activity.
Compounds 4a, 4b, 4c, 4dand 4eshowed excellent inhibition of IL-6 at
Gentamycin 21 (25)
24 (25)
18 (25)
24 (25)
24 (25)
“e” Indicates bacteria are resistant to the compounds at concentrations >100
mL; MIC values are given in brackets; MIC (
g/mL) ¼ minimum inhibitory concen-
trations; zone of inhibition is expressed in mm.
mg/
10
a range of 21e37%, whereas compound 4b, 4d and 4f exhibited cyto-
toxicity of 66%, 83% and 65% respectively at 10 M. Compound 4e
mM (74e100%). Compound 4a, 4c and 4e showed cytotoxicity in
m
m
showed promising antibacterial and antifungal activity against all the
strains with less cytotoxicity, while compound 4c possesses good
antibacterial activity against E. coli, S. aureus and K. pneumonia and
moderate to poor antifungal activity with less cytotoxicity.
standard drugs. Solvent and growth controls were prepared and
kept. Zones of inhibition and minimum inhibitory concentrations
(MICs) were noted. The results of antibacterial studies are given in
Table 2.
The antibacterial screening data revealed that all the tested
compounds showed moderate to good antibacterial activity as
compared to standard. Compounds 4b, 4c, 4d, 4e, 4f and 4h showed
effective activity against E. coli, and compounds 4b, 4c, 4d, 4e and 4f
showed good zone of inhibition against B. subtilis and P. vulgaris.
Compounds 4c, 4d, 4e, 4f and 4h showed good inhibitory activity
against S. aureus and K. pneumoniae. Compounds 4d, 4e and 4f
showed excellent inhibitory activity against all bacterial strains,
whereas compounds 4a, 4g and 4i displayed less inhibitory activity
against all bacterial strains.
3.3. Antifungal studies
Newly synthesized compounds were screened for their anti-
fungal activity against Aspergillus fumigatus (NCIM 902), Aspergillus
niger (NCIM 545), Trichoderma viridie (TT), Candida albicans (NCIM
3100) and Penicillium chrysogenum (NCIM 707). Antifungal activity
was assessed by disc diffusion method in a modified condition
[33,34]. Fluconazole (200 mg/disc) was used as standard fungicide.
Potato dextrose agar (PDA) was used as basal medium for test fungi.
Glass Petridishes used were sterilized. Sterilized melted PDA
medium (w45 ꢁC) was poured at the rate of 15 mL into each Pet-
ridish (90 mm). After solidification of the medium, small portions of
the mycelium of each fungus werespreadcarefullyover the centreof
each PDA plate with the help of sterilized needles. Thus, each fungus
was transferred to a number of PDA plates, which were then incu-
bated at (25 ꢂ 2) ꢁC and ready for use after five days of incubation.
Prepared discs of samples were placed gently on solidified agar
plates, freshly seeded with the test organisms with sterile forceps.
A control disc was also placed on the test plates to compare the
effect of the test samples and to nullify the effect of solvent
respectively. The plates were then kept in a refrigerator at 4 ꢁC for
24 h so that the materials had sufficient time to diffuse over
a considerable area of the plates. After this, the plates were incu-
bated at 37 ꢂ 5 ꢁC for 72 h. Dimethylsulfoxide (0.5%) was used as
solvent to prepare desired solutions of the compounds initially and
also to maintain proper control. The results of the antifungal studies
are given in Table 3.
The antifungal screening data revealed that all the tested
compounds showed good fungal inhibition at concentration 25 mg/
mL. Compounds 4d, 4e, and 4f showed very good activity against
A. fumigatus and A. niger. Compounds 4e, 4f and 4g displayed prom-
ising activity against Trichoderma virdie and C. albicans. Compounds
4b, 4c, 4d, 4f and 4h showed good inhibitory activity against P.
chrysogenum. Compounds 4d, 4e, 4f and 4g showed promising
inhibitory activity against all fungal strains, whereas compounds 4a,
4c, 4h and 4i showed less inhibitory activity against all fungal strains.
5. Conclusion
In conclusion, a new series of 2,2-bisaminomethylated aurone
analogues exhibiting anti-inflammatory and antimicrobial activity
were synthesized. From the anti-inflammatory activity results of
the tested compounds, 4a showed promising activity against TNF-
a
and IL-6 with less cytoxicity. The results of the other compounds
as inhibitors of TNF- and IL-6 are certainly encouraging, but the
a
cytoxicity of these compounds limits the therapeutic applications.
The results of antibacterial activity of the tested compounds, 4d, 4e
and 4f showed promising activity against the bacterial strains. In
the case of antifungal results of the tested compounds, 4d, 4e and 4f
showed promising activity against the fungal strains. However the
basic nitrogen-containing aurone analogues can be considered as
one of the scaffolds for design and development of anti-inflam-
matory (TNF-a and IL-6) and antimicrobial agents. The importance
of the compounds 4a, 4d, 4e, 4f and 4g cannot be ignored as one of
the intermediates in the lead optimization process.
Table 3
Antifungal activity of aurone analogues.
Compounds Aspergillus Aspergillus Trichoderma Candida Penicillium
fumigatus
niger
virdie
albicans chrysogenum
4a
4b
4c
4d
4e
4f
4g
4h
15 (50)
18 (25)
16 (50)
22 (25)
17 (25)
22 (25)
18 (25)
14 (50)
14 (50)
21(25)
14 (50)
24 (25)
17 (25)
21(25)
17 (25)
26 (25)
16 (50)
14 (50)
e
e
e
14 (50)
23 (25)
18(25)
16 (25)
15 (50)
24 (25)
15 (50)
16 (25)
15 (50)
24 (25)
15 (25)
14(50)
15 (50)
16(25)
16 (25)
15 (25)
13 (50)
e
15 (50)
e
14 (50)
16 (25)
17 (25)
16 (25)
13 (50)
e
6. Experimental
4i
6.1. Chemistry
Fluconazole
24 (25)
18(25)
24 (25)
“e” Indicates fungi are resistant to the compounds at concentrations >100
MIC values are given in brackets; MIC (
g/mL) ¼ minimum inhibitory concentra-
tions; zone of inhibition is expressed in mm.
mg/mL;
Chemicals were purchased from Aldrich Chemical Co., USA.
Melting points were determined with a digital thermometer. IR
m

3226
B.P. Bandgar et al. / European Journal of Medicinal Chemistry 45 (2010) 3223e3227
spectra were recorded on FT-IR Shimadzu 8300 spectrophotometer
and 1H NMR spectra were recorded on a Bruker 300 MHz spec-
trometer in CDCl3 using tetramethylsilane as internal standard and
198.93, 173.32, 168.95, 158.53, 105.72, 95.72, 92.464, 88.23, 59.89,
56.09, 55.75, 55.47, 26.74. Anal. Calcd for C20H28N2O4: C, 66.64; H,
7.83; N, 7.70%. Found: C, 66.66; H, 7.85; N, 7.72%.
chemical shifts are reported in d units. Mass spectra were obtained
with a Shimadzu LCMS-2010EV. Thin layer chromatography was
performed on pre-coated silica plates (Merck Kiesegel 60 F254) and
column chromatography using silica gel (mesh 100e200). The
spots could be visualized easily under ultraviolet light.
6.2.5. 2,2-Bis((diethylamino)methyl)-4,6-dimethoxybenzofuran-3
(2H)-one (4e)
Yield (29%), IR (Nujol): 2945, 2889, 1701, 1615, 1590, 1115,
817 cmꢃ1; 1H NMR (300 MHz, CDCl3,
d ppm): 6.01 (s, 1H, Ar-H), 5.95
(s, 1H, Ar-H), 3.91 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 2.87 (s, 2H,
AreCH2eNe), 2.78 (s, 2H, AreCH2eNe), 2.63e2.54 (q, 8H,
eCH2eNeCH2e ꢀ 2), 1.12e1.10 (t, 12 H, CH3 ꢀ 4). MS: 365 (M þ 1);
13C NMR (CDCl3, 400 MHz): 198.78, 173.01, 167.97, 162.82, 104.37,
96.01, 92.62, 88.33, 60.87, 55.99, 55.69, 52.98, 17.74. Anal. Calcd for
C20H32N2O4: C, 65.91; H, 8.85; N, 7.69%. Found: C, 65.97; H, 8.81; N,
7.75%.
6.2. Procedure for the synthesis of 4,6-dimethoxy-2,2-bis((4-
methylpiperazin-1-yl)methyl)benzofuran-3(2H)-one (4a)
4,6-Dimethoxybenzofuran-3(2H)-one (3) on Mannich reaction
with formaldehyde and N-methyl piperazine in the presence of
conc. HCl in isopropanol under reflux condition yielded the desired
product. This crude product was purified by column chromatog-
raphy (100e200 mesh size), using chloroform þ 1% MeOH as
eluting system.
6.2.6. 2,2-Bis((dibutylamino)methyl)-4,6-dimethoxybenzofuran-3
(2H)-one (4f)
Yield (27%), IR (Nujol): 2935, 2858, 1705, 1616, 1590, 1155,
6.2.1. 4,6-Dimethoxy-2,2-bis((4-methylpiperazin-1-yl)methyl)
benzofuran-3(2H)-one (4a)
816 cmꢃ1; 1H NMR (300 MHz, CDCl3,
d ppm): 6.00 (s,1H, Ar-H), 5.99
(s, 1H, Ar-H), 3.98 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 2.86 (s, 2H,
AreCH2eNe), 2.75 (s, 2H, AreCH2eNe), 2.58 (t, 8H,
eCH2eNeCH2e ꢀ 2), 1.67e1.59 (m, 8H), 0.98 (t, 12 H). MS: 477
(M þ 1). Anal. Calcd for C28H48N2O4: C, 70.55; H, 10.15; N, 5.88%.
Found: C, 70.48; H, 10.27; N, 5.79%.
Yield (55%), off white compound mp IR (KBr, cmꢃ1): 2937, 2842,
2795, 1703, 1616, 1593, 1250, 1160, 817 cmꢃ1 1H NMR (300 MHz,
;
CDCl3,
d ppm): 6.13 (s, 1H, Ar-H), 6.00 (s, 1H, Ar-H), 3.91 (s, 3H,
OCH3), 3.88 (s, 3H, OCH3), 2.87 (s, 2H, AreCH2eNe), 2.72 (s, 2H,
AreCH2eNe), 2.54 (bs, 8H, eCH2eNeCH2e ꢀ 2), 2.26 (bs, 8H,
eCH2eNeCH2e ꢀ 2), 2.19 (s, 6H, eNeCH3 ꢀ 2). MS: 419 (M þ 1);
13C NMR (CDCl3, 400 MHz): 198.05, 174.93, 169.44, 158.50, 105.51,
95.69, 92.30, 88.33, 60.44, 55.91, 55.76, 55.21, 54.35, 45.88. Anal.
Calcd for C22H32N4O4: C, 63.13; H, 8.19; N, 13.33%. Found: C, 63.21;
H, 8.30; N, 13.41%.
6.2.7. 2,2-Bis((dimethylamino)methyl)-4,6-dimethoxybenzofuran-
3(2H)-one (4g)
Yield (31%), off white sticky compound, IR (Nujol): 2938, 1707,
1616, 1593, 1219, 820 cmꢃ1; 1H NMR (300 MHz, CDCl3,
d ppm): 6.10
(s, 1H, Ar-H), 6.00 (s, 1H, Ar-H), 3.84 (s, 3H, OCH3), 3.80 (s, 3H,
OCH3), 2.85 (s, 2H, AreCH2eNe), 2.76 (s, 2H, AreCH2eNe), 2.52
(s, 12 H, eNeCH3 ꢀ 4). MS: 309 (M þ 1). Anal. Calcd for C16H24N2O4:
C, 62.32; H, 7.84; N, 9.08%. Found: C, 62.39; H, 7.94; N, 10.08%.
6.2.2. 4,6-Dimethoxy-2,2-bis(morpholinomethyl)benzofuran-3
(2H)-one (4b)
Yield (57%), pure white compound, mp IR (KBr, cmꢃ1): 2942,
2851, 1701, 1619, 1590, 1217, 1116, 818 cmꢃ1
;
1H NMR (300 MHz,
6.2.8. 2,2-Bis((4-ethylpiperazin-1-yl)methyl)-4,6-
dimethoxybenzofuran-3(2H)-one (4h)
CDCl3,
d ppm): 6.10 (s, 1H, Ar-H), 6.00 (s, 1H, Ar-H), 3.90 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 3.50 (t, 8H, eCH2eOeCH2e ꢀ 2), 2.83
(s, 2H, AreCH2eNe), 2.70 (s, 2H, AreCH2eNe), 2.52e2.46 (m, 8H,
eCH2eNeCH2e ꢀ 2). MS: 393 (M þ 1); 13C NMR (CDCl3, 400 MHz):
197.57, 175.15, 169.57, 158.74, 104.85, 94.89, 92.51, 88.75, 72.58,
60.08, 55.71, 55.56, 55.01. Anal. Calcd for C20H28N2O6: C, 61.21; H,
7.19; N, 7.14%. Found: C, 61.27; H, 7.26; N, 7.22%.
Yield (37%), IR (Nujol): 2955, 2767, 1705, 1616, 1590, 1250, 1155,
817 cmꢃ1; 1H NMR (300 MHz, CDCl3,
d ppm) 6.01 (s, 1H, Ar-H), 5.99
(s, 1H, Ar-H), 3.94 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 2.88 (s, 2H,
AreCH2eNe), 2.75 (s, 2H, AreCH2eNe), 2.64e2.59 (bs, 8H,
eCH2eNeCH2e ꢀ 2), 2.56e2.51 (bs, 8H, eCH2eNeCH2e ꢀ 2), 2.48
(q, 8H), 1.10 (t, 12H). MS: 447 (M þ 1). Anal. Calcd for C24H38N4O4: C,
64.55; H, 8.58; N, 12.56%. Found: C, 64.61; H, 8.51; N, 12.50%.
6.2.3. 4,6-Dimethoxy-2,2-bis((piperidin-1-yl)methyl)benzofuran-3
(2H)-one (4c)
6.2.9. 2,2-Bis((ethylmethylamino)methyl)-4,6-
dimethoxybenzofuran-3(2H)-one(4i)
Yield (43 %), mp 117e120 ꢁC; IR (KBr, cmꢃ1): 2939, 2875, 1703,
1619,1590, 1217,1120, 820 cmꢃ1; 1H NMR (300 MHz, CDCl3,
d
ppm):
Yield (29%), IR (Nujol): 2945, 2879, 1704, 1619, 1590, 1120,
6.10 (s, 1H, Ar-H), 6.00 (s, 1H, Ar-H), 3.84 (s, 3H, OCH3), 3.80 (s, 3H,
OCH3), 2.85 (s, 2H, AreCH2eNe), 2.76 (s, 2H, AreCH2eNe),
2.52e2.46 (m, 8H, eCH2eNeCH2e ꢀ 2), 1.59e1.57 (t, 12 H,
eCH2eCH2eCH2e ꢀ 2). MS: 389 (M þ 1); 13C NMR (CDCl3,
400 MHz): 198.53, 174.68, 169.04, 159.03, 106.72, 95.52, 92.76,
89.06, 59.95, 56.24, 55.75, 55.09, 25.74, 21.57; Anal. Calcd for
C22H32N2O4: C, 68.01; H, 8.30; N, 7.21%. Found: C, 68.04; H, 8.32; N,
7.23%.
817 cmꢃ1; 1H NMR (300 MHz, CDCl3,
d ppm): 6.01 (s, 1H, Ar-H), 5.95
(s, 1H, Ar-H), 3.91 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 2.87 (s, 2H,
AreCH2eNe), 2.77 (s, 2H, AreCH2eNe), 2.64 (q, 4H,
eCH2eNe ꢀ 2), 1.13e1.11 (t, 6 H, CH3 ꢀ 2). MS: 337 (M þ 1); 13C
NMR (CDCl3, 400 MHz): 198.75, 172.38, 168.87, 158.59, 104.92,
95.98, 92.75, 88.85, 60.89, 58.65, 55.97, 55.529, 16.78. Anal. Calcd
for C18H28N2O4: C, 64.26; H, 8.39; N, 8.33%. Found: C, 64.10; H, 8.29;
N, 8.26%.
6.2.4. 4,6-Dimethoxy-2,2-bis((pyrrolidin-1-yl)methyl)benzofuran-3
(2H)-one (4d)
Acknowledgement
Yield (37%), mp 109e112 ꢁC; IR (KBr, cmꢃ1): 2929, 2837, 2782,
The authors are thankful to Mr. Mahesh Nambiar and Mrs. Asha
Almeida, Piramal Life Sciences Ltd., Mumbai for screening of the
1709, 1617, 1590, 1240, 1152, 820 cmꢃ1 1H NMR (300 MHz, CDCl3,
;
d
ppm): 6.00 (s, 1H, Ar-H), 5.99 (s, 1H, Ar-H), 3.97 (s, 3H, OCH3), 3.89
compounds against TNF-a and IL-6 and Council of Scientific and
(s, 3H, OCH3), 2.87 (s, 2H, AreCH2eNe), 2.75 (s, 2H, AreCH2eNe),
2.58 (m, 8H, eCH2eNeCH2e ꢀ 2), 1.67e1.59 (m, 8H,
eCH2eNeCH2e ꢀ 2). MS: 361 (M þ 1); 13C NMR (CDCl3, 400 MHz):
Industrial Research (CSIR), New Delhi, for financial assistance
[Project No. 01(2023)/05/EMR-II], SAP thanks CSIR for Senior
Research Fellowship.

B.P. Bandgar et al. / European Journal of Medicinal Chemistry 45 (2010) 3223e3227
3227
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