Synthesis and biological evaluation of novel piperazine derivatives of flavone as potent anti-inflammatory and antimicrobial agent

Article abstract of DOI:10.1016/j.bmcl.2012.08.071

A series of novel 6-methoxy-2-(piperazin-1-yl)-4H-chromen-4-one and 5,7-dimethoxy-2-(piperazin-1-ylmethyl)-4H-chromen-4-one derivatives of biological interest were prepared and screened for their pro-inflammatory cytokines (TNF-α and IL-6) and antimicrobial activity (antibacterial and antifungal). Among all the compound screened (5a-j and 10k-t), the compounds 5c, 5g, 5h, 10l, 10m, 10n and 10r found to have promising anti-inflammatory activity (up to 65-87% TNF-α and 70-93% IL-6 inhibitory activity) at concentration of 10 μM with reference to standard dexamethasone (71% TNF-a and 84% IL-6 inhibitory activities at 1 μM) while the compounds 5b, 5i, 5j, 10s and 10t found to be potent antimicrobial agent showing even 2 to 2.5-fold more potency than that of standard ciprofloxacin and miconazole at the same MIC value of 10 μg/mL.

Full text of DOI:10.1016/j.bmcl.2012.08.071

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6385–6390
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of novel piperazine derivatives of flavone
as potent anti-inflammatory and antimicrobial agent
Girish D. Hatnapure a, Ashish P. Keche a, Atish H. Rodge c, Satish S. Birajdar a, Rajesh H. Tale c,
,
⇑
Vandana M. Kamble a,b,
⇑
a Department of Chemistry, Maharashtra Udaygiri Mahavidayla, Udgir, India
b Department of Chemistry, The Institute of Science Bombay, India
c Dendrimer and Bio-organic Chemistry Laboratory, School of Chemical Science, S.R.T.M. University, Nanded, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2012
Revised 29 July 2012
Accepted 17 August 2012
Available online 24 August 2012
A series of novel 6-methoxy-2-(piperazin-1-yl)-4H-chromen-4-one and 5,7-dimethoxy-2-(piperazin-1-
ylmethyl)-4H-chromen-4-one derivatives of biological interest were prepared and screened for their
pro-inflammatory cytokines (TNF-
Among all the compound screened (5a–j and 10k–t), the compounds 5c, 5g, 5h, 10l, 10m, 10n and
10r found to have promising anti-inflammatory activity (up to 65–87% TNF- and 70–93% IL-6 inhibitory
activity) at concentration of 10 M with reference to standard dexamethasone (71% TNF-a and 84% IL-6
inhibitory activities at 1 M) while the compounds5b, 5i, 5j, 10s and 10t found to be potent antimicrobial
agent showing even 2 to 2.5-fold more potency than that of standard ciprofloxacin and miconazole at the
same MIC value of 10 g/mL.
a and IL-6) and antimicrobial activity (antibacterial and antifungal).
a
l
Keywords:
Piperazine derivatives
Flavone
l
l
Chrysin
Ó 2012 Elsevier Ltd. All rights reserved.
Anti-inflammatory
Antibacterial
Antifungal activity
Cytokines are intercellular messengers responsible for host de-
fense mechanisms as inflammatory, immune and hematogenic re-
sponses. Although many of them are transient, they are produced
by various cells act as urgent response mediators in cases of invasive
interventions. Disruption of this biological defense mechanism and
continuous excessive cytokine production contributes to pathogen-
esis of inflammatory diseases. One of the key pro-inflammatory
cally important molecular targets for the treatment of the above-
mentioned diseases. The available biopharmaceuticals (TNF soluble
receptor (EnbrelTM) and TNF antibody (RemicadeTM) are expensive,
difficult to administer orally and have major side effects on pro-
longed clinical use. Therefore, there is an urgent medical need to dis-
cover small molecule agents to deal with higher levels production of
TNF-a. Many compounds have been reported to have inhibitory
cytokine Tumor necrosis factor-
a
(TNF-
a
) is mainly produced by
activity against inflammation. Historically, natural products have
provided the most consistent source of new scaffolds to design
new therapeutic agents, and a number of naturally occurring pheno-
lic compounds have been discovered as potent anti-inflammatory
agent.8 For instance, flavonoid is a group of natural products present
in a wide variety of plants9,10 reported to have potent anti-inflam-
matory activity in both (in vitro and in vivo). Although not fully
understood, several mechanisms for proposed to explain their
in vivo anti-inflammatory action. Recent studies have also shown
that certain flavonoids, especially, viz.; Chrysin derivatives, express
their anti-inflammatory activity at least in part by modulation of
proinflammatory gene expression such as cyclooxygenase-2, induc-
ible nitric oxide synthase and several pivotal cytokines. Due to these
unique action mechanisms and significant in vivo activity, flavo-
noids are considered to be reasonable candidates for new
anti-inflammatory drugs. Flavonoidsexhibit a broad range ofbiolog-
ical activities, including antiviral, anti-inflammatory, antioxidant,
antiallergic, hepatoprotective, antithrombotic and antitumoral
actions.11–13
the activated macrophages and monocytes, which further induces
the production of the several inflammatory cytokines such as inter-
leukin-1b (IL-1b), interleukin-6 (IL-6) and granulocyte-macrophage
colony-stimulating factor (GM-CSF). It is also a multitude of biolog-
ical activities linked to pathology of autoimmune diseases such as
rheumatoid arthritis (RA),1 Crohn’s disease,2 systemic lupus erythe-
matosus,3 and multiple sclerosis,4 septic shock,5 and AIDS.6 On the
other hand, cytokine interleukin-6 (IL-6) (from the series of cytokine
signaling pathway) contributes to the initiation and extension of the
inflammatory process and considered as a central mediator in a
range of inflammatory diseases but has not received the desired
attention in drug discovery7 TNF-
a and IL-6 are thus pharmaceuti-
⇑
Corresponding authors. Tel.: +91 022 22829293; fax: + 91 022 22047962
(R.H.T.); tel.: +91 02462 229346; fax: +91 02462 229245 (V.M.K.).
E-mail addresses: rkht_2008@rediffmail.com (R.H. Tale), m.vandana248@gmail.
com (V.M. Kamble).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.08.071

6386
G. D. Hatnapure et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6385–6390
One of the acknowledged functions of flavonoids in plants is
recent years, the nitrogen containing flavones reported to have
considerable antimicrobial and anti-oxidant activities. Although
numerous other nitrogen containing structural classes (e.g., pyr-
roles, pyrimidines, pyridines, pyrimidones, indoles, oxyindoles, ur-
eas, and various fused bicyclic heterocycles) have been reported for
their proinflammatory cytokine inhibitory activity,17 the flavone
derivatives have not hitherto tested as anti-inflammatory agents,
their protective role against microbial invasion. This involves their
presence in plants as constitutive agents as well as their accumu-
lation as phytoalexins in response to microbial attack.14 Because
of this protective role, it is not surprising that plants rich in flavo-
noids have been used for many years in traditional medicine to
treat infectious diseases.15 Recently, possible modes of antimicro-
bial action of flavonoids have been discussed in a review.16 In
in particular against the TNF-a and IL-6 and so also their antimi-
crobial activities. In order to improve the anti-inflammatory and
antimicrobial activity of the compound based on crysin18 core
and related scaffold19 (Fig. 1); we envisage that hybrid compound
incorporating a flavonoid core and amine linkage in single molec-
ular frame could lead to the novel potent anti-inflammatory and
antimicrobial agents. We set out to test our notion by design, syn-
thesis and biological evaluation of novel flavone derivatives con-
taining piperazine moiety. Herein, we disclose our report on the
synthesis , anti-inflammatory and antimicrobial activity evaluation
of novel flavone derivatives bearing N-substituted piperazines viz.
6-methoxy-2-(piperazin-1-yl)-4H-chromen-4-one and 5,7-dime-
thoxy-2-(piperazin-1-ylmethyl)-4H-chromen-4-one derivatives.
Our synthetic strategy for novel 6-methoxy-2-(piperazin-1-yl)-
4H-chromen-4-one 5a–j and 5,7-dimethoxy-2-(piperazin-1-yl-
methyl)-4H-chromen-4-one 10k–t was outlined in Scheme 1 and
2. Thus as show in scheme 1, a commercially available 1-(2-hydro-
xyl-5-methoxyphenyl) ethanone, compound 1 treated with CS2
under basic conditions to give the 4-hydroxy-6-methoxy-2H-chro-
mene-2-thione 2. S-alkylation of (2) with ethyl iodide under basic
conditions followed by the oxidation of the resultant 2-(ethyl-
thio)-6-methoxy-4H-chromen-4-one 3 with m-CPBA leads to 2-
(ethylsulfonyl)-6-methoxy-4H-chromen-4-one 4. The reaction of
4 with appropriate N-substituted piperazine at ambient conditions
afforded 6-methoxy-2-(piperazin-1-yl)-4H-chromen-4-one 5a–j in
OCH3
HO
O
O
HO
O
OH
Chrysin
OH
O
Wogonin
R
N
O
O
O
N
O
Hybride structure
N
N
N
11
H2N
S
Figure 1.
OH
O
S
O
O
S
b
a
O
O
O
O
OH
3
2
1
c
R
N
O
S
O
O
O
N
d
O
O
O
O
4
5
Scheme 1. Synthesis of 6-methoxy-2-(piperazin-1-yl)-4H-chromen-4-one derivatives. Reagents and conditions: (a) KOtBu, CS2, toluene, 16 h, H2SO4; (b) Etl, K2CO3, acetone,
reflux; (c)m-CPBA, DCM, 3 h; (d) piperazine, Et3N, DCM 25 °C.
O
O
O
O
OH
O
O
OH
a
b
O
O
O
O
O
8
7
6
O
O
O
O
O
O
N
Br
c
d
NH
O
O
10
9
Scheme 2. Synthesis of 5,7-dimethoxy-2-(piperazin-1-ylmethyl)-4H-chromen-4-one derivatives. Reagents and conditions: (a) NaH, Ethylacetate, THF, 48 h; (b) gla. acetic
acid, cat. con HCl 60 °C, 30 min; (c) NBS, CCl4, benzoyl peroxide, refluxed 6 h; (d) piperazine, Et3N, DCM 25 °C.

G. D. Hatnapure et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6385–6390
6387
good to high yields. For the synthesis of 2-(piperazin-1-ylmethyl)
flavone derivatives (Scheme 2), the diketone, 1-(2-hydroxy-4, 6-
dimethoxyphenyl) butane-1, 3-dione (7) constitutes the key inter-
mediate. The latter was obtained by the treatment of commercially
available, 1-(2-hydroxy-4, 6-dimethoxyphenyl) ethanone (6) with
ethyl acetate in the presence of NaH. Cyclisation of 7 uisng glacial
acetic acid afforded 5, 7-dimethoxy-2-methyl-4H-chromen-4-one
(8) in good yield. The side chain bromination of 8 with NBS afforded
inhibitory activity data (Tables 1 and 2), it is observed that the
compounds 5c, 5g, 5h, 10l, 10m, 10n and 10r found to be highly
active as TNF-a and IL-6 inhibitor (up to 65–87% TNF-a and 70–
93% IL-6 inhibitory activity) with compounds 5c (82% , and 87%)
and 10n (87% and 93%) exhibiting highest inhibition against TNF-
a
and IL-6 respectively at 10 lM. It is to be noted that almost all
of these compound (5c, 5g, 5h, 10l, 10m, 10n and 10r) either found
to be equally potent or more potent that the standard dexametha-
the
2-(bromomethyl)-5,7-dimethoxy-4H-chromen-4-one
(9)
sone at MIC 1 lM. Compounds 5a, and 10k exhibited moderate
which further reacted with different N-substituted piperazine to
give the desired 5,7-dimethoxy-2-(piperazin-1-ylmethyl)-4H-chro-
men-4-one derivatives in good yields.
activity (45–60% inhibition) while other compounds 5e, 5f, 10q
and 10s exhibited low to very low or no activity all at same level
of concentration.
Having secured the series of the novel 6-methoxy-2-(piperazin-
1-yl)-4H-chromen-4-one and 5,7-dimethoxy-2-(piperazin-1-yl-
methyl)-4H-chromen-4-one derivatives, next in order to search
for the potent compounds from these newly synthesized flavone
derivatives, compounds 5a–j and 10k–t were evaluated for
in vitro anti-inflammatory activity against the pro-inflammatory
The SAR of the anti-inflammatory activity for 6-methoxy-2-
(piperazin-1-yl)-4H-chromen-4-one derivatives is shown in Table
1. It is observed that electronic nature of piperazine moiety on
4H-chromen-4-one has profound effect on the activity. It is very
clear from our results that the high electron donating ability of
the piperazine moiety can be explicitly correlated to high activity.
For instance, the compound 5a bearing 4-phenylpiperazine unit
cytokines (TNF-
a and IL-6) by TNF-a
and IL-6 inhibition assay20
and antimicrobial activity against various gram-positive, gram-
exhibited 45% TNF-a and 60% IL-6 inhibitory activity, however
negative bacteria and fungal strains by using an agar well diffusion
incorporation of CN group in the piperazine structure resulting into
the compound 5b, found to exhibit very low TNF-a inhibitoty
method with little modifications.21 Thus, from the TNF-
a
and IL-6
Table 2
Table 1
Anti-inflammatory activity of 5, 7-dimethoxy-2-(piperazin-1-ylmethyl)-4H-chro-
men-4-one derivatives
Anti-inflammatory activity of 6-methoxy-2-(piperazin-1-yl)-4H-chromen-4-one
derivatives
O
O
O
R
N
N
N
O
O
N
R
O
O
Compound 10(k–t)
(R)
% Inhibition at 10 lM
TNF-a
IL-6%
Compound 5(a–j)
(R)
% Inhibition at 10 lM
TNF-
a
IL-6
N
N
N
N
k
l
45
50
93
a
b
c
45
60
0
N
N
85
N
O
10
82
N
N
N
N
N
N
N
N
N
N
N
m
n
65
87
0
70
93
0
87
N
N
N
N
N
N
d
e
f
0
0
N
N
N
N
O
30
25
40
35
o
N
N
N
N
O
p
q
r
10
20
85
10
0
N
N
O
N
g
79
83
N
O
30
91
25
N
N
h
i
80
5
84
20
HN
s
N
N
HN
t
20
35
j
10
15
HN
N
Ref.1
Dexamethasone (1
Compound-12 (10
l
M)
71
68
84
92
Ref.1
Dexamethasone(1
Compound-12 (10 l
l
M)
M)
71
68
84
92
Ref.2a
lM)
Ref.2a
a
a
Potent compound from (Bioorg. Med. Chem. Lett. 2011, 21, 4648.)
Potent compound from (Bioorg. Med. Chem. Lett. 2011, 21, 4648.)

6388
G. D. Hatnapure et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6385–6390
activity (10% inhibition) and completely failed as IL-6 inhibitor (Ta-
ble 1, compounds 5a vs 5b). This is further supported by the fact
the presence of more electron rich N-pyrimidyl piperazine moiety
on the flavone core resulted into compound 5c having highest TNF-
thoxy-2-(piperazin-1-ylmethyl)-4H-chromen-4-one
derivaties.
This increase in activity on homologation is noticeable in case of
compounds with highly electron rich group such as OMe, pyrim-
idyl, morpholine (compound 5c vs 10n, 5g vs 10l and 5h vs 10r
etc). Surprisingly, in case of phenyl substituents (compound 5a
a
and IL-6 inhibitory activity. This trend is further consistence with
compounds 5g and 5h bearing intermediate electron donating 4-
methoxyphenyl and morpholine on the piperazine moiety. Surpris-
ingly, compound 5d containing 4-benzylpiperazine, the immediate
vs 10k) the TNF-a inhibitory activity was retained but IL-6 inhibi-
tory activity reduced significantly. The exact cause of this contrast
result is unclear at this time. The presence of benzylic, alkyl and
allylic group found to have similar effect on activity as for the pre-
vious series. As in case of highly electron deficient flavone deriva-
tive 5b, the compound 10o with N-acetyl group on piperazine ring
exhibited no activity at all. Explicitly, it is the electronic effect of
the substituent on piperazine ring which mainly influences the
anti-inflammatory activity.
The antimicrobial activity data is represented in ( Tables 3a/b
and 4a/b). As shown in our results, some analogues of this series
were found to potent antibacterial and antifungal agents. Interest-
ingly none of compound with high anti-inflammatory activity
found to be potent antibacterial or antifungal agents. It is clear
from our results that the presence of C–C or C–N multiple bond
or H-bond donor type group seems to be favorable for the high
antimicrobial activity. Thus the compounds, bearing amino alkyl,
cyano or alkenylalkyl group on piperazine to be the only potent
antibacterial and antifungal agents. Thus the compound 5b, 5i, 5j
homologue of compound 5a found to have no TNF-a and IL-6 activ-
ity at all. This further confirms the pivotal role of electronic factor
on the anti-inflammatory activity. Regarding the structure activity
relationship of 5,7-dimethoxy-2-(piperazin-1-ylmethyl)-4H-chro-
men-4-one derivatives 10k–t, with carbon linker between pipera-
zine and chromone unit and additional methoxy group at 7
position, similar trend as that of 6-methoxy-2-(piperazin-1-yl)-
4H-chromen-4-one derivatives was observed albeit with corre-
sponding higher activities. Thus the highly electron rich group on
the piperazine ring found to impart high activity, as a result com-
pound10l, 10m, 10n and 10r found to be the active anti-inflamma-
tory agents with compound bearing pyrimidyl group on the
piperazine ring to be the most active member among this series.
It can be seen that (Tables 1 vs 2) for a given substituent, there is
significant increase in the anti-inflammatory activity in going from
6-methoxy-2-(piperazin-1-yl)-4H-chromen-4-one and 5,7-dime-
Table 3b
Table 3a
Antibacterial activity of 5,7-dimethoxy-2-(piperazin-1-ylmethyl)-4H-chromen-4-one
derivatives (MIC values
l
g/mLb)
Antibacterial activity of 6-methoxy-2-(piperazin-1-yl)-4H-chromen-4-one deriva-
tives (MIC values
l
g/mLb)
Compound (R)
10 (k–t)
Gram-positive
Gram-negative
Compound (R)
5(a–j)
Gram-positive
Gram-negative
Staphylo- Bacillus Esche- Salmonella
Staphylo- Bacillus Escherichia Salmonella
coccus
aureus
subtilis richia typhimurium
coli
coccus
aureus
subtilis coli
typhimurium
N
N
N
k
90
65
90
40
90
70
90
65
a
75
40
80
50
30
65
80
45
80
80
50
80
N
N
N
N
l
b
c
N
O
N
N
N
N
N
N
m
0
85
0
0
0
N
N
N
N
N
N
N
N
N
N
d
e
f
70
90
50
55
80
45
65
00
40
65
00
65
N
n
0
90
95
90
90
N
O
N
N
o
80
60
O
N
p
60
75
0
45
65
90
10
90
70
0
90
70
00
10
N
N
g
60
45
75
80
N
N
N
q
O
h
i
95
20
75
10
90
15
90
10
N
N
r
O
N
HN
N
N
s
20
15
HN
N
j
10
10
10
10
N
t
10
10
10
15
HN
Ref
Ciprofloxacin (1
l
g/ml) 25
Compound-3 (10 lg/ 10
25
15
15
10
25
40
Refa
Ref.
Ciprofloxacin (1
Compound-3 (10 lg/ml)
l
g/ml)
25
10
25
15
15
10
25
40
Ref.a
ml)
a
a
Potent compound from (Bioorg. Med. Chem. Lett. 2011, 21, 4648.)
Values are the average of three reading.
Potent compound from (Bioorg. Med. Chem. Lett. 2011, 21, 4648.)
Values are the average of three reading.
b
b

G. D. Hatnapure et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6385–6390
6389
Table 4a
Table 4b
Antifungal activity of 6-methoxy-2-(piperazin-1-yl)-4H-chromen-4-one derivatives
Antifungal activity of 5,7-dimethoxy-2-(piperazin-1-ylmethyl)-4H-chromen-4-one
(MIC values
l
g/mLb)
derivatives (MIC values
l
g/mLb)
Compound (R)
Candida Aspergillus Fusarium Aspergillus
Com-
(R)
Candida Aspergillus Fusarium Aspergillus
5(a–j)
albicans niger
solani
flavus
pound
10(k–t)
albicans niger
solani
flavus
N
N
a
90
15
85
85
10
70
80
95
N
N
N
k
l
80
95
90
80
95
85
N
N
b
c
15
95
30
85
N
75
85
N
N
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
m
n
85
90
75
95
75
60
90
65
85
95
95
90
d
e
f
55
75
90
30
60
90
45
70
0
65
70
0
N
o
O
O
g
95
75
85
90
N
N
N
N
N
p
q
r
70
55
85
90
55
35
80
0
75
45
85
0
75
60
90
0
N
N
N
O
N
O
h
i
0
90
10
10
0
0
N
HN
N
10
10
15
HN
s
j
15
10
15
N
N
Ref
Miconazole (1
Compound-3 (10
l
g/ml)
25
10
20
10
15
15
20
10
t
10
10
15
10
Refa
lg/
HN
ml)
Ref
Miconazole (1
Compound-3 (10
l
g/ml)
g/ml)
25
10
20
10
15
15
20
10
Refa
l
a
Potent compound from (Bioorg. Med. Chem. Lett. 2011, 21, 4648.)
b
Values are the average of three reading.
a
Potent compound from (Bioorg. Med. Chem. Lett. 2011, 21, 4648).
Values are the average of three reading.
b
10s and 10t bearing N-methyl-2-(pyrrolidin-1-yl) ethanamine,
benzyl-N-methylpiperidin-4-amine and N-benzyl-N-ethylpiperi-
din-4-amine respectively have shown higher potency. Thus the
mere presence of electron donor group on the piperazine ring
has very little or nothing to do with antimicrobial activity as com-
pounds 5a, 5c, 5d, 5e, 5g, 5h, 10k, 10l, 10m, 10n, 10o, 10q, 10r
bearing such a groups exhibited very low or no antimicrobial activ-
activity while the compounds 5b, 5i, 5j 10s and 10t found to be
the potent antimicrobial agent, showing even 2 to 2.5-fold more
activity than that of standard ciprofloxacin and miconazole at the
same MIC value of 10 lg/mL. Thus the presence of highly electron
rich group such as OMe, pyrimidyl, morpholine on piperazine as
well as homologation of chromone and piperazine moiety have
strong relevance to the anti-inflammatory activity while the amino
alkyl, cyano or alkenylalkyl group either on piperazine or chro-
mone found to be effective potent antimicrobial agents.
ity with respect to standard drug up to concentration of 200
against some bacteria and fungi.
lg/mL
It is clear from our results (Tables 3 vs Table 4) that the SAR of
6-methoxy-2-(piperazin-1-yl)-4H-chromen-4-one and 5,7-dime-
Acknowledgments
thoxy-2-(piperazin-1-ylmethyl)-4H-chromen-4-one
derivatives
for antibacterial activity strongly correlates with their SAR of anti-
fungal activity except that instead compounds 5j and 5b shows
higher potency. Notably all these active antimicrobial agents found
to have 2 to 2.5-fold more potency than the standard drug cipro-
We are grateful to the Department of Chemistry, Maharashtra
Udaygiri Mahavidayla, Udgir for providing necessary facilities.
Supplementary data
floxacin and miconazole at same level of concentration 10 lg/mL.
In conclusion, we have synthesized the chrysin based novel
6-methoxy-2-(piperazin-1-yl)-4H-chromen-4-one (5a–j) and 5,
7-dimethoxy-2-(piperazin-1-ylmethyl)-4H-chromen-4-one deriv-
atives (10k–t) and evaluated for their anti-inflammatory (against
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
08.071.
TNF-a and IL-6) as well as antimicrobial activities against different
gram positive and gram negative bacterial and fungal strain.
References and notes
Among all the compound screened (5a–j and 10k–t), compounds
1. (a) Macnaul, K. L.; Hutchinson, N. I.; Parsons, J. N.; Bayne, E. K.; Tocci, M. J. J.
Immunol. 1990, 145, 4154; (b) Brennan, F. M.; Gibbons, D. L.; Mitchell, T.; Cope,
A. P.; Maini, R. N.; Feldmann, M. Eur. J. Immunol. 1907, 1992, 22.
5c, 5g, 5h, 10l, 10m, 10n and 10r showed promising TNF-
a and
IL-6 inhibitory activity with compound 10n exhibiting highest

6390
G. D. Hatnapure et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6385–6390
2. Dullemen, H. M. V.; Deventer, S. J. H. V.; Hommes, D. W.; Bijl, H. A.; Jansen, J.;
Tytgat, G. N. J.; Woody, J. Gastroenterology 1995, 109, 129.
3. Maury, C. P. J.; Teppo, A. M. Arthritis Rheum. 1989, 32, 146.
4. (a) Sharief, M. K.; Hentges, R. N. Engl. J. Med. 1991, 325, 467; (b) Beck, J.; Rondot,
P.; Catinot, L.; Falcoff, E.; Kirchner, H.; Wietzerbin, J. Acta Neurol. Scand. 1988,
78, 318; (c) Hofmann, F. M.; Hinton, D. R.; Merrill, J. E. J. Exp. Med. 1989, 170,
607; (d) Gallo, P.; Piccinno, M. G.; Krzalic, L.; Tavolato, B. J. Neuroimmunol. 1989,
23, 41.
11. Manthey, J. A.; Grohmann, K.; Guthrie, N. Curr. Med. Chem. 2001, 8, 135.
12. Rice-Evans, C. A.; Miller, N. J. Biochem. Soc. Trans. 1996, 24, 790.
13. Hollman, P. C. H.; Hertog, M. G. L.; Katan, M. B. Biochem. Soc. Trans. 1996, 24,
785.
14. Harborne, J. B.; Williams, C. A. Phytochemistry 2000, 55, 481.
15. Cushnie, T. P.; Lamb, A. J. Antimicrobial activity of flavonoids Int. J. Antimicrob.
Agents 2005, 26, 343.
16. Havsteen, B. H. Pharmacol. Ther. 2002, 96, 67.
5. Lechner, A. J.; Tredway, T. L.; Brink, D. S.; Klein, C. A.; Matuschak, G. M. Am. J.
Physiol. 1992, 263, 526.
6. Makonkawkeyoon, S.; Limson-Pombre, R. N. R.; Moreira, A. L.; Schauf, V.;
Kaplan, G. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 5974.
7. Dominic, S. C.; Raj, M. D. Semin. Arthritis Rheum. 2009, 38, 382.
8. Lin, Y. L.; Lin, J. K. Mol. Pharmacol. 1997, 52, 465.
9. Harborne, J. B.; Williams, C. A. Phytochemistry 2000, 55, 481.
10. Middleton, E., Jr.; Kandaswami, C.; Theoharides, T. C. Pharmacol. Rev. 2000, 52,
673.
17. Boehm, J. C.; Adams, J. L. Expert Opin. Ther. Patents 2000, 10, 25.
18. Tran, T. D.; Yeon, S. C.; Jeongsoo, K.; Hyun, P. K.; Sanghee, K.; Haeil, P. Bioorg.
Med. Chem. Lett. 2004, 14, 1165.
19. Tokushi, H.; Kunitomo, A.; Yoshiyuki, A.; Hiroshi, M.; Yoichi, N.; Masao, H.;
Tetsuko, F.; Hiroshi, S. Bioorg. Med. Chem. Lett. 2000, 10, 875.
20. Hwang, C.; Gatanaga, M.; Granger, G. A.; Gatanaga, T. J. J. Immunol. 1993, 151,
5631.
21. Sridhar, R.; Perumal, P. T.; Etti, S.; Shanmugam, G.; Ponnuswamy, M. N.;
Prabavathyc, V. R.; Mathivanan, N. Bioorg. Med. Chem. Lett. 2004, 14, 6035.