Analogue-based design, synthesis and docking of non-steroidal anti-inflammatory agents. Part 2: Methyl sulfanyl/methyl sulfonyl substituted 2,3-diaryl-2,3-dihydro-1H-quinazolin-4-ones

Article abstract of DOI:10.1016/j.bmc.2012.09.069

A series of methyl sulfanyl/methyl sufonyl substituted 2,3-diaryl-2,3- dihydro-1H-quinazolin-4-one were designed using analogue-based design, scaffold hopping and shape similarity matching. The designed compounds were synthesized in 2-3 steps with simple chemistry and screened by ovine cyclooxygenases (COXs) inhibitory assay and carrageenan-induced rat paw edema assay. Among the screened compounds, two compounds exhibited 100% cyclooxygenase-2 (COX-2) inhibitory potency without showing cycloxygenase-1 (COX-1) inhibition at 20 μM. The compounds also showed promising in vivo anti-inflammatory potential. A structure-activity relationship within the dataset was established by correlating the effect of aromatic ring substituent constants, structural variables and physico-chemical descriptors with in vivo anti-inflammatory activity. Molecular docking studies were also performed on the title compounds to study the binding interactions to COX-2 active site residues. The experimentally determined COX-2 inhibitory activity was found moderately correlating with binding modes predicted for compounds by Glide XP dock scoring function. The 2,3-diaryl-2,3-dihydro-1H-quinazolin-4-one pharmacophore reported herein should be a new lead for further development of novel non-steroidal anti-inflammatory agents.

Full text of DOI:10.1016/j.bmc.2012.09.069

Bioorganic & Medicinal Chemistry xxx (2012) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Analogue-based design, synthesis and docking of non-steroidal
anti-inflammatory agents. Part 2: Methyl sulfanyl/methyl sulfonyl substituted
2,3-diaryl-2,3-dihydro-1H-quinazolin-4-ones
⇑
E. Manivannan , S. C. Chaturvedi
School of Pharmacy, Devi Ahilya Vishwavidyalaya, Ring Road, Indore 452017, (M.P.), India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of methyl sulfanyl/methyl sufonyl substituted 2,3-diaryl-2,3-dihydro-1H-quinazolin-4-one were
designed using analogue-based design, scaffold hopping and shape similarity matching. The designed
compounds were synthesized in 2–3 steps with simple chemistry and screened by ovine cyclooxygenases
(COXs) inhibitory assay and carrageenan-induced rat paw edema assay. Among the screened compounds,
two compounds exhibited 100% cyclooxygenase-2 (COX-2) inhibitory potency without showing cyclox-
Received 5 August 2012
Revised 26 September 2012
Accepted 27 September 2012
Available online xxxx
ygenase-1 (COX-1) inhibition at 20 lM. The compounds also showed promising in vivo anti-inflamma-
Keywords:
tory potential. A structure–activity relationship within the dataset was established by correlating the
effect of aromatic ring substituent constants, structural variables and physico-chemical descriptors with
in vivo anti-inflammatory activity. Molecular docking studies were also performed on the title
compounds to study the binding interactions to COX-2 active site residues. The experimentally
determined COX-2 inhibitory activity was found moderately correlating with binding modes predicted
for compounds by Glide XP dock scoring function. The 2,3-diaryl-2,3-dihydro-1H-quinazolin-4-one
pharmacophore reported herein should be a new lead for further development of novel non-steroidal
anti-inflammatory agents.
Anti-inflammatory activity
Cyclooxygenase-1
Cyclooxygenase-2
2,3-Diaryl-2,3-dihydro-1H-quinazolin-4-
ones
Pharmacophore
Structure–activity relationship
Docking
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
ical and homeostatic functions, whereas COX-2 is expressed in
pathological condition and triggers inflammatory signals, thus des-
Quinazolinone scaffold is a privileged structure for design and
development of novel non-steroidal anti-inflammatory drugs
(NSAIDs).1 Natural and synthetic quinazolinone derivatives have
been extensively studied for its anti-inflammatory potential
through different pharmacological mechanism and they are well
documented in the literature.2–7 Especially, the quinazolinone
based natural products; rutaecarpine8,9 and tryptanthrin10,11 have
demonstrated significant anti-inflammatory potential through
interfering prostaglandin pathway and cyclooxygenase (COX) inhi-
bition. Rutaecarpine inhibited COX-2 and COX-1 dependent phases
of PGD2 generation in BMMC in a concentration-dependent man-
ignated as an inducible enzyme. Both of these enzymes share more
than sixty percent of homology with respect to their structure.15
However, there is a small side pocket access in COX-2 because of
presence of valine 523, which is absent in COX-1 due to bulkier iso-
leucine 523.15 This single amino acid difference between COX-1
and COX-2 at position 523 made a huge impact in designing selec-
tive COX-2 inhibitors that can spare the gastric side effects associ-
ated with non-selective non-steroidal anti-inflammatory agents
(NSAIDs).15,16 The structure based inhibitors design on COX-2 en-
zyme identified a methyl sulfonyl or a sulphonamide group as
the best chemical feature in accessing the side pocket and thus
selectively inhibits COX-2.17 As a result of this discovery, a wide
variety of compounds having either a methyl sulfonyl or a sulph-
onamide substitution were synthesized, biologically evaluated
and reported for COX-2 specific inhibition.17–22
ner with an IC50 of 0.28 and 8.7 l
M, respectively.9 Tryptanthrin
inhibited COX-2 in lipopolysaccharide stimulated Mono Mac 6
cells assay with an IC50 of 64 nM.11
COX enzyme plays a crucial role in production of various pros-
tanoids involved in physiological and pathological functions espe-
cially inflammation.12,13 COX exists in two distinct forms as
cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).14 COX-
1 is designated as housekeeping enzyme because of its physiolog-
In our continuing effort towards the identification of gastric spar-
ring NSAIDs, wehave established the quantitative structure–activity
relationship (QSAR) of various central monocyclic ring (furanone23
and pyranone24,25), bicyclic scaffold (benzopyran-4-one25,26), fused
heterocycles (fused pyrazole27–29 and thiazolotriazole30
) and
straight chain molecules31 for selective COX-2 inhibition. In our pre-
vious communication, we also demonstrated the anti-inflammatory
⇑
Corresponding author. Tel.: +91 731 2100605, mobile: +91 8982677476.
E-mail address: drmanislab@gmail.com (E. Manivannan).
0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2012.09.069
Please cite this article in press as: Manivannan, E.; Chaturvedi, S. C. Bioorg. Med. Chem. (2012), http://dx.doi.org/10.1016/j.bmc.2012.09.069

2
E. Manivannan, S. C. Chaturvedi / Bioorg. Med. Chem. xxx (2012) xxx–xxx
potential of a series of rationally designed 2, 3 diaryl quinazolinones
acting through COX-2 inhibition.1 In this Letter, we report our recent
study, analogue-based design, scaffold hopping, shape matching,
structure–activity relationship and docking studies of methyl sulfa-
nyl and methyl sulfonyl substituted 2,3-diaryl-2,3-dihydro-1H-qui-
nazolin-4-ones as potential non-steroidal anti-inflammatory
agents.
designed compounds were then subjected to PHASE32,33 (Schro-
dinger software, NY, USA) shape query with a selective COX-2
inhibitor (SC-558) bound in complex with cycloxygenase-2 en-
zyme (pdb code: 1CX2). The high shape similarity index (SSI
>6.5) was obtained for all the designed compounds, which showed
good shape and surface complementarily of the compounds to
COX-2 enzyme binding pocket. All the designed compounds were
also computationally evaluated for their pharmacokinetic and drug
likeness property using molinspiration1 web-portal and shown in
Table 1.
2. Result and discussion
2.1. Analogue-based pharmacophore design
2.2. Chemistry
The novel quinazolinone based pharmacophore for selective
COX-2 inhibition was elucidated by analogue-based design that
uses two natural products (rutaecarpine and tryptanthrin) and
two well known synthetic selective COX-2 inhibitors (celecoxib
and rofecoxib) shown in Figure 1. To build a complete pharmaco-
phore, the common structural feature ‘quinazolinone’ present in
both natural compounds was chosen as central template. The ‘dia-
ryl’ system, which is common in celecoxib18 and rofecoxib19 was
considered for side arm attachment to central quinazolinone core.
Further, the secondary biophore feature ‘methyl sulfonyl’ group,
which is known for COX-2 selectivity was introduced at para posi-
tion of either of the side arm-aryl rings of quinazolinone. Finally,
the central template was hopped with its dihydro analog to derive
target compounds. Six compounds of methyl sulfanyl and six com-
pounds of methyl sulfonyl substituted 2,3-diaryl-2,3-dihydro-1H-
quinazolin-4-one analogues were designed for anti-inflammatory
activity evaluation based on the present pharmacophore. The
The target compounds, 2,3-diaryl-2,3-dihydro-1H-quinazolin-
4-one analogues were synthesized by either two or three steps,
according to methyl sulfanyl or methyl sulfonyl substitution pat-
tern and is shown in Scheme 1. First, a series of (4-methylsulfa-
nyl-benzylidene)-phenyl-amine derivatives 3a–f were prepared
by condensing various substituted anilines 1 with 4-thiomethyl
benzaldehyde 2 in ethanol medium with few drops of glacial acetic
acid at 78 °C. Further, Oxone34,35 mediated oxidation reaction of
these compounds provided (4-methyl sulfonyl-benzylidene)-phe-
nyl-amine 3g–l in moderate to good yields. Then these intermedi-
ate azomethines 3a–l and an equimolar mixture of isatoic
anhydride 4 reacted readily under microwave irradiation, without
solvent for less than 3 min, which afforded substituted 2,3-diaryl-
2,3-dihydro-1H-quinazolin-4-ones 5a–l with yields of 70–80%. The
proposed structures of intermediate azomethines and final
compounds were confirmed by elemental analysis, IR, ESI-MS,
O
O
O
N
N
TRYPTANTHRIN
O
N
O
H3CO2S
N
NATURAL PRODUCT PHARMACOPHORE
SYNTHETIC PHARMACOPHORE
H3C
O
N
HYBRIDIZED PHARMACOPHORE
N
N
CF3
N
RUTAECARPINE
H2NO2S
NH
SCAFFOLD HOPPING
O
N
N
H
SO2CH3
DIHYDRO ANALOGUE OF HYBRIDIZED PHARMACOPHORE
Figure 1. Design of novel anti-inflammatory pharmacophore template.
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E. Manivannan, S. C. Chaturvedi / Bioorg. Med. Chem. xxx (2012) xxx–xxx
3
Table 1
Rationally designed substituted 2,3-diaryl-2,3-dihydro-1H-quinazolin-4-ones and their physicochemical properties
R
R
1
2
O
N
N
H
R
3
Compound
Substitution
R2
Physico-chemical properties
R1
R3
ClogP
1.8368
CMR
TPSA
Molecular volume
Number of rotatable bonds
Molecular weight
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
H
H
H
F
H
H
H
H
H
F
H
OCH3
Cl
F
H
CH3
H
OCH3
Cl
F
H
SCH3
SCH3
SCH3
SCH3
SCH3
SCH3
SO2CH3
SO2CH3
SO2CH3
SO2CH3
SO2CH3
SO2CH3
10.5044
11.1213
10.9958
10.5199
10.5199
10.9682
10.5706
11.1875
11.0620
10.5861
10.5861
11.0344
32.34
41.57
32.34
32.34
32.34
32.34
66.48
75.71
66.48
66.48
66.48
66.48
315.750
341.295
329.285
320.681
320.681
332.311
329.053
354.598
342.588
333.984
333.984
345.614
3
4
3
3
3
3
3
4
3
3
3
3
345.467
375.493
379.912
363.457
363.457
359.494
377.465
407.491
411.910
395.455
395.455
391.492
2.9028
3.6968
3.1268
2.9568
3.4828
ꢀ0.3632
0.7028
1.4968
0.9268
0.7568
1.2828
5j
5k
5l
H
CH3
R3
NH2
OHC
R1
R3
N
(2)
a.
(3a-3f)
(3g-3l)
H
b.
R2
R1
R2
O
(1)
O
c.
O
N
H
(4)
R1
O
R2
N
N
H
(5a-5l)
R3
Scheme 1. Reagents and conditions: (a) EtOH, CH3COOH, reflux; (b) OxoneÒ, THF/MeOH, rt; (c) neat MW, 2–4 min.
and 1H NMR spectra and presented in experimental section. 1H
NMR spectra showed the signal attributable to CH3 of methyl sul-
fanyl in the region of 2.82 ppm. The signals appeared at 8.34–
8.40 ppm attributable to benzylidinimino proton. The aromatic
ring protons showed the chemical shifts of multiplet signals. For
the title compounds, the conversion of methyl sulfanyl (–SCH3)
to methyl sulfonyl (–SO2CH3) was detected by the d shift from
2.47 to 3.28 ppm for CH3 protons in the NMR spectrum. Other aro-
matic protons appeared as multiplets in d 6.1–8.2 ppm. Further the
mass spectrum [FAB-MS] showed a molecular ion peak (M+) for all
the compounds with different intensities and the base peaks for
most of the compounds. All the synthesized compounds were also
characterized by elemental analysis and its experimental values in
agreement with the calculated values.
2.3. Cyclooxygenases inhibition
The ability of methyl sulfanyl and methyl sulfonyl substituted
2,3-diaryl-2,3-dihydro-1H-quinazolin-4-ones and reference drug
celecoxib to inhibit the COX-1 and COX-2 isozymes was evaluated
using colorimetric COX (ovine) inhibitor screening assay and the
results obtained are listed in Table 2. The colorimetric COX (ovine)
inhibitor screening assay measures the peroxidase component of
COX. The peroxidase activity is assayed colorimetrically by
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E. Manivannan, S. C. Chaturvedi / Bioorg. Med. Chem. xxx (2012) xxx–xxx
Table 2
COX-1, COX-2 inhibitory activities and in vivo anti-inflammatory activity of substituted 2,3-diaryl-2,3-dihydro-1H-quinazolin-4-ones
Compound
Percentage inhibition
Percentage edema inhibition
COX-1 (20
lM)
COX-2 (20
lM)
Selectivity
90 Min
180 Min
270 Min
360 Min
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
—
—
5
—
—
—
49
41
NI
NI
15
NI
3
—
—
91
—
—
—
—
0.055
—
—
30 1.68⁄
33 1.94⁄⁄
38 1.82⁄
32 1.61⁄⁄
33 0.25
30 0.26⁄⁄
31 1.68⁄
39 1.94⁄⁄
37 1.18⁄
38 1.55⁄⁄
36 0.48
34 1.32⁄⁄
—
34 1.15⁄
35 0.24⁄
41 1.45⁄⁄⁄
39 1.08⁄
37 1.44⁄
34 0.28⁄
35 1.29⁄
43 0.74⁄
42 1.42⁄⁄
43 1.48⁄
39 0.29⁄
35 1.24⁄
—
37 1.58⁄
38 1.12⁄
46 0.52⁄
42 0.48⁄
39 0.27⁄⁄⁄
38 0.88⁄
38 0.48⁄
47 1.52⁄⁄
46 0.73⁄⁄
45 1.22⁄⁄
42 0.48
39 0.23⁄⁄
—
39 1.26⁄
40 1.63⁄⁄
47 1.22
44 1.64⁄⁄
41 1.62⁄
39 0.74⁄
40 1.86⁄
49 1.76⁄⁄
51 1.89⁄
48 1.62⁄
44 1.64⁄
40 1.04⁄
—
—
—
66
71
100
100
54
91
94
—
0.742
0.577
>0.001
>0.001
0.278
>0.01
0.032
—
Celecoxib
Indomethacin
—
41 0.48⁄
58 1.26⁄⁄
49 0.28⁄
13 0.24⁄
Significance levels ⁄p <0.05, ⁄⁄p <0.01 and ⁄⁄⁄p <0.001 as compared with the respective control. All the results were expressed as means SEM (standard error of estimate).
monitoring the appearance of oxidized N,N,N0,N0-tetramethyl-p-
phenylene diamine (TMPD) at 590 nm.
In regard to the COX-1 enzyme inhibition of target compounds,
the methyl sulfanyl/methyl sulphonyl substituted analogues 5g
and 5h were identified as weak COX-1 inhibitors as they have
methyl sulfonyl at R3 (ie., 2 phenyl ring of dihydro-1H-quinazo-
lin-4-ones) along with halogen substitution (Cl and F) at R2 (ie.,
para position of N-aryl ring of dihydro-1H-quinazolin-4-ones) pos-
sessed most promising anti-inflammatory activity. Surprisingly, 5h
also showed good anti-inflammatory activity with an electron
releasing group (–OCH3) substitution at R2 position and the reason
for the compound’s enhanced potency is not immediately appar-
ent. The results of the anti-inflammatory activity studies clearly
indicate that 2,3-diaryl-2,3-dihydro-1H-quinazolin-4-ones exhibit
comparable potency to Indomethacin. Mostly, the anti-inflamma-
tory activity pattern was observed similar to that of our previously
reported compound class 2,3-diaryl-quinazolin-4-ones.
shown 49% and 41% inhibition at 20
the screened compounds, 5i, 5j and 5l were proved to be practically
inactive for COX-1 as they have shown (0%) no inhibition at 20 M.
lM respectively. Among all
l
In COX-2 enzyme inhibition assay, 5c, 5i, 5j and 5l showed higher
COX-2 inhibitory activity with a range of 88–100% maximum. The
COX-1 and COX-2 inhibitory activity results indicate that overall
the methyl sulfonyl substitution on the target compounds increase
the COX-2 selectivity in slightly varying magnitude depending up
on the presence of other aromatic ring substitution. The moderate
to better level of COX-2 selectivity was observed with the com-
pounds, when substituted with electron withdrawing groups at
ortho and para position of the aromatic rings.
2.5. Structure–activity relationship analysis
The in vivo anti-inflammatory activity data expressed in edema
inhibition percentage was used for the present QSAR modelling.
For the purpose of QSAR study, the percentage edema inhibition
was converted into logarithm units. The converted anti-inflamma-
tory activity was considered as dependent variable and the calcu-
lated aromatic substituent constants, physicochemical properties,
structural variables, as independent variables for developing statis-
tically significant relationships to explore the structure-activity
requirements among these compounds.
Initially, a correlation matrix was built between dependant var-
iable and independent variables, and they are graphically repre-
sented in Figure 2. All molecular descriptors and substituent
constants were shown less correlation (r <0.5) with anti-inflamma-
tory activity except two variables, R2 (f) that is, inductive/field ef-
fect at R2 position (r = 0.769), and molecular weight (r = 0.769).
Interestingly, one of the 2D-molecular descriptors, topological po-
lar surface area (TPSA) was found moderately correlated (r = 0.458)
with anti-inflammatory activity. TPSA has been a widely used
molecular descriptor in the study of drug transport properties
and recently gained greater attention in QSAR modelling. TPSA, is
the sum of the contributions of the molecular surface area of polar
atoms such as oxygen, nitrogen and hydrogens. The positive corre-
lation (r = 0.445) of an indicator variable IR3(SO2CH3) shows the
methyl sulfonyl substitution in the title compounds favours the
anti-inflammatory activity than methyl sulfanyl substitution. The
statistically reliable QSAR models are discussed below:
2.4. In vivo anti-inflammatory activity
All the synthesized compounds were screened for in vivo anti-
inflammatory activities at 50 mg per kg body weight dose level
with carrageenan-induced rat paw edema assay using indometha-
cin as standard drug.1 The edema induced by subplantar injection
of carrageenan was observed more prominent in the group treated
with carboxymethyl cellulose sodium (CMC-Na:Vehicle), where in
case of indomethacin treated group exerted 58.16% anti-inflamma-
tory effect after 180 min. Among the tested 2,3-diaryl-2,3-dihydro-
1H-quinazolin-4-one analogues 5c, 5h, 5i and 5j exhibited more
than 45% edema inhibition and decreased the difference in paw
thickness comparable to that of a group received standard anti-
inflammatory drug indomethacin (p <0.05). The anti-inflammatory
effects of compounds 5h and 5i were 49 1.76⁄ and 51 1.89⁄%
respectively and were comparable to the effect observed with
indomethacin at 10 mg/kg dose. All test compounds of the series,
the anti-inflammatory activity was retained up to six hours unlike
indomethacin, in which a decrease in the activity was observed
after 4 h. The efficacy of test compounds was comparable to that
of indomethacin, but with a longer duration of action. As stated
in our previous communication, this phenomenon may partly be
due to the low systemic bioavailability of the test compounds fol-
lowing oral dosing, due to efficient first-pass metabolism and some
degree of intestinal metabolism.1
Model 1. log (AA) = 0.205 ( 0.052) R2 f + 0.002 ( 0.001)
Among the most active compounds, 5c is the only compound
with methyl sulfanyl at R3 substitution position and rest of the
compounds have methyl sulfonyl at R3. As expected, 2,3-diaryl-
2,3-dihydro-1H-quinazolin-4-ones 5i and 5j substituted with
MW ꢀ 0.926 ( 0.198)
n = 12, r = 0.919, r2 = 0.845, ra2dj ¼ 0:811, s = 0.03, F = 24.612,
p = 0.000,
DW = 2.564.
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E. Manivannan, S. C. Chaturvedi / Bioorg. Med. Chem. xxx (2012) xxx–xxx
5
Figure 2. Graphical representation Hansch type structure–activity relationship; contribution of physicochemical constants, properties and structural variables to invivo anti-
inflammatory activity.
tory activity. R2 (f) is the field effect/inductive effect at R2 position
and molecular weight of the compounds show positive coefficient
and thus have favourable effect towards anti-inflammatory activ-
ity. The 2,3-diaryl-2,3-dihydro-1H-quinazolin-4-ones with either
an electron-withdrawing or electron-donating groups on one of
the phenyl rings (N-aryl) were found highly active. Thus, it can
be easily understood that the electronic effect plays a major role
in determining the anti-inflammatory activity. The structure–
activity models discussed above provide more specific analysis
and information about the electronic effects on this ring, showing
that para position field effect/inductive effect are important for en-
hanced activity.
The above QSAR model is a biparametric equation modelled
with all 12 compounds. Compound 5b (studentized resid-
ual = ꢀ3.093) was identified as an outlier while deriving the model
1. The substituent constant, R2 (f) and MW together explains 84.5%
variance in anti-inflammatory activity. R2 (f) is the field effect/
inductive effect at R2 position of the title compounds. MW is the
molecular weight of the compounds.
Model 2. log (AA) = 0.225 ( 0.038) R2 f + 0.002 ( 0.000)
MW ꢀ 0.861 ( 0.144)
n = 11, r = 0.962, r2 = 0.925, ra2dj ¼ 0:906, s = 0.02, F = 49.084,
p = 0.000,
DW = 2.287.
2.6. Cycooxygenase-2 binding interaction
Model 2 is developed for 11 compounds after eliminating com-
pound 5b as outlier, the reason for the outlying behaviour of this
compound is not immediately apparent. However, 5b is the only
compound with methoxy substitution at R2 position in the methyl
sulfonyl series. Model 2 explains 92.5% variance in anti-inflamma-
Figures 3 and 4 reports the binding mode of the 2,3-diaryl-2,3-
dihydro-1H-quinazolin-4-ones with methyl sulfanyl or methyl sul-
fonyl group in the R3 position respectively as compared to SC-558
complexed with COX-2. In the most favourable orientation found
Figure 3. Docking poses of methyl sulfanyl substituted 2,3-diaryl-2,3-dihydro-1H-quinazolin-4-ones (5a–f) with SC-558 in active site of COX-2 Enzyme.
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6
E. Manivannan, S. C. Chaturvedi / Bioorg. Med. Chem. xxx (2012) xxx–xxx
Figure 4. Docking poses of methyl sulfonyl substituted 2,3-diaryl-2,3-dihydro-1H-quinazolin-4-ones (5g–h) with SC-558 in active site of COX-2 Enzyme.
by the GLIDE XP docking program, the methyl sulfanyl/methyl sul-
fonyl moiety is projected towards the selectivity pocket and the
vicinal unsubstituted or substituted phenyl ring projected towards
the hydrophobic pocket very much similar to the binding mode of
SC-558. Though, it is surprising when compared to the docking re-
sults of 2,3-diaryl-3H-quinazolin-4-ones1 where only five com-
pounds attained a favourable disposition matching SC-558, it
should be noted that the ‘benzo ring’ of quinazolinone ring is
unsubstituted in 2,3-diaryl-2,3-dihydro-1H-quinazolin-4-ones. 4-
Fluoro substitution in the phenyl group oriented towards the
hydrophobic pocket appears to have positive influence in the
COX-2 binding affinity as indicated by their high Glide score. The
docking scores of the compounds are in moderate agreement with
the experimental potency determined against COX-2 enzyme. The
electronic effects on the aromatic ring, showing that para position
field effect/inductive effect are important for enhanced activity.
Docking studies of these compounds with cyclooxygenase-2 en-
zyme showed that these molecules are in good agreement with
the binding mode of inbound reference ligand SC-558. Thus, these
compounds seems to be the best candidate for being further eval-
uation for its pharmacokinetic profile and for its in vivo ulcero-
genic activity and toxicity model to validate the safe anti-
inflammatory potential.
4. Experimental
4.1. Materials
top scoring ligand 5j exhibit 100% percentage inhibition at 20 lM
The starting materials were procured from Merck and Sigma Al-
drich or prepared using known procedures. All commercially avail-
able solvents and reagents were used without further purification.
Column chromatographic separations were carried out by gradient
elution with hexane–ethyl acetate mixture, unless otherwise
mentioned and silica gel (60–120 mesh) used. TLC was performed
on E-Merck pre-coated 60 F254 plates and the spots were rendered
visible by exposing to UV light and iodine vapour. Melting points
were recorded using an electrothermal melting point apparatus
and are uncorrected. IR spectra were recorded using Shimadzu FTIR
or Jasco FT/IR-470 PLUS. NMR spectral study was carried out using
Brucker DRX 400. The FAB mass spectra were recorded on JEOL SX
102/DA-6000. Microanalytical data were obtained using a Carlo-
Erba CHNS-O EA 1108 Elemental Analyser. Elemental analyses ob-
served for all the newly synthesized compounds were within the
limits of accuracy ( 0.3%). Topological polar surface area (TPSA)
and molecular volume were calculated using the web-based pro-
gram Molinspiration.
concentration and the docking pose of the compound in the active
site of COX-2 enzyme is shown by Figure 4. It can also be appreci-
ated from Figure 4 that the methyl sulfonyl group of compound 5j
positioned into hydrophilic cavity forms hydrogen bonding with
Arg 513 and similar interaction is seen in all other compounds with
methyl sulfonyl group possessing 2,3-diaryl-2,3-dihydro-1H-qui-
nazolin-4-ones.
3. Conclusion
In this Letter, we described the rational design of non-steroidal
anti-inflammatory agents through analogue-based, scaffold hop-
ping and shape similarity search. Further, the designed compounds
were synthesized and biologically evaluated for in vitro and in vivo
anti-inflammatory activities. The influence of dihydro quinazoli-
none as central core and different small substituents on the phenyl
moieties of sidearm ring features was investigated. The structural
optimization of the starting compound quinazolinones led to this
new series with better cycloxygenase inhibitory activities and
anti-inflammatory potencies. In whole, two compounds 5i and 5j
were exhibited 100% COX-2 inhibitory potency without showing
4.2. Synthesis
4.2.1. Synthesis for the synthesis of (4-methylsulfanyl-
benzylidene)-phenyl-amine (3a–f)
COX-1 inhibition at 20 lM and promising in vivo anti-inflamma-
tory potential. The quantitative structure–activity model discussed
here give more specific analysis and information about the
Equimolar mixture of various substituted aniline (0.01 mol) and
4-thiomethyl benzaldehyde (0.01 mol), was refluxed in ethanol
Please cite this article in press as: Manivannan, E.; Chaturvedi, S. C. Bioorg. Med. Chem. (2012), http://dx.doi.org/10.1016/j.bmc.2012.09.069

E. Manivannan, S. C. Chaturvedi / Bioorg. Med. Chem. xxx (2012) xxx–xxx
7
with few drops of glacial acetic acid upto 10 h. The solvent was re-
moved and the crude product thus obtained was crystallized in
ethanol.
m/z [M+H]+: 365; Elemental Anal. Calcd. for C21H17FN2OS: C,
69.21; H, 4.70; N, 7.69. Found: C, 69.25; H, 4.76; N, 7.73.
4.2.1.8. 3-(2-Fluoro-phenyl)-2-(4-methylsulfanyl-phenyl)-2,3-
4.2.1.1.
amine (3a).
(4-Fluoro-phenyl)-(4-methylsulfanyl-benzylidene)-
dihydro-1H-quinazolin-4-one (5e).
Yield: 60%; mp 246–
Yield: 81%; mp 94–95 °C; Rf = 0.41 mobile phase
248 °C; Rf = 0.41 mobile phase hexane–ethyl acetate (6:4); IR
(KBr, cmꢀ1): 3298 (NH stretch), 1640 (C@O stretch), 1H NMR
(CDCl3): d 2.47 (s, 3H, SCH3), 4.71 (s, 1H), 6.04 (s, 1H), 6.57 (d,
J = 8 Hz, 1H), 6.88–7.40 (m, 10H), 8.14 (d, J = 7.9 Hz, 1H); ESI-MS
m/z [M+H]+: 365; Elemental Anal. Calcd. for C21H17FN2OS: C,
69.21; H, 4.70; N, 7.69. Found: C, 69.26; H, 4.62; N, 7.64.
hexane–ethyl acetate (6:4); 1H NMR (CDCl3): d 2.54 (s, 3H, SCH3),
7.08 (m, 2H), 7.20 (m, 2H), 7.31 (d, J = 9 Hz, 2H) 7.79 (J = 9 Hz,
2H), 8.38 (s, 1H); ESI-MS m/z [M+H]+: 246; Elemental Anal. Calcd.
for C14H12FNS: C, 68.54; H, 4.93; N, 5.71. Found: C, 68.56; H,
4.93; N, 5.72.
4.2.1.2. Synthesis for the synthesis of (4-methylsulfonyl-ben-
4.2.1.9. 2-(4-Methylsulfanyl-phenyl)-3-p-tolyl-2,3-dihydro-1H-
zylidene)-phenyl-amine (3g–l).
A solution of Oxone in H2O
quinazolin-4-one (5f).
Yield: 81%; mp 220–222 °C; Rf = 0.45
(6 ml) and methanol (4 ml) was added dropwise to a solution of
4-thiomethyl compounds (0.015 mol) in THF (10 ml) at 25 °C with
stirring. The reaction was allowed to proceed for 2–3 h prior to
addition of H2O (10 ml) and extraction with CH2Cl2 (4 ꢁ 30 ml).
The organic layer was separated and dried over anhydrous Na2SO4.
The solvent was removed in vacuo, and the residue was purified by
silica gel column chromatography.
mobile phase hexane–ethyl acetate (6:4); IR (KBr, cmꢀ1): 3302
(NH stretch); 1642 (C@O stretch); 1H NMR (CDCl3): d 2.49 (s, 3H,
SCH3), 2.78 (s, 3H), 4.76 (s, 1H), 6.10 (s, 1H), 6.76 (d, J = 8.1 Hz,
1H), 7.02–7.50 (m, 10H), 8.21 (d, J = 7.9 Hz, 1H); ESI-MS m/z
[M+H]+: 362; Elemental Anal. Calcd. for C22H20N2OS: C, 73.30; H,
5.59; N, 7.77. Found: C, 73.41; H, 5.63; N, 7.81.
4.2.1.10. 2-(4-Methanesulfonyl-phenyl)-3-phenyl-2,3-dihydro-
4.2.1.3. Synthesis of substituted 2,3-diaryl-2,3-dihydro-quinaz-
1H-quinazolin-4-one (5g).
Yield: 81%; mp 179–181 °C;
olin-4-ones (5a–l).
A mixture of isatoic anhydride (0.01 mol)
Rf = 0.41 mobile phase hexane–ethyl acetate (6:4); IR (KBr, cm
ꢀ1): 3295 (NH stretch); 1641 (C@O stretch); 1H NMR (CDCl3): d
3.29 (s, 3H, SO2CH3), 4.75 (s, 1H), 6.11 (s, 1H), 6.78 (d, J = 8.1 Hz,
1H), 6.98–7.41 (m, 11H), 8.16 (d, J = 7.9 Hz, 1H); ESI-MS m/z
[M+H]+: 379; Elemental Anal. Calcd. for C21H18N2O3S: C, 66.65;
H, 4.79; N, 7.40. Found: C, 66.60; H, 4.82; N, 7.42.
and substituted azomethines (3a–l) were transferred in to a clean
50 ml vial. The reaction mixture was then microwave irradiated for
2–4 min. After cooling to room temperature, the reaction mixture
was extracted with dichloromethane (15 ml) and filtered to re-
move all the unreacted and insoluble materials. The clear extract
was concentrated and cooled to obtain appropriate 2,3-diaryl-
2,3-dihydro-quinazolin-4-ones.
4.2.1.11. 2-(4-Methanesulfonyl-phenyl)-3-(4-methoxy-phenyl)-
2,3-dihydro-1H-quinazolin-4-one (5h).
Yield: 75%; mp 219–
4.2.1.4. 2-(4-Methylsulfanyl-phenyl)-3-phenyl-2,3-dihydro-1H-
221 °C; Rf = 0.39 mobile phase hexane–ethyl acetate (6:4); IR (KBr,
cmꢀ1): 3294 (NH stretch), 1636 (C@O stretch); 1H NMR (CDCl3): d
3.29 (s, 3H, SO2CH3), 3.71 (s, 3H), 4.70 (s, 1H), 6.10 (s, 1H), 6.75 (d,
J = 8.1Hz, 1H), 6.88–7.40 (m, 10H), 8.13 (d, J = 7.9Hz, 1H); ESI-MS
m/z [M+H]+: 409; Elemental Anal. Calcd. for C22H20N2O4S: C, 64.69;
H, 4.94 (4.81); N, 6.86 (6.82). Found: C, 64.74, H, 4.81; N, 6.86 6.82.
quinazolin-4-one (5a).
Yield, 76%; mp 203–205 °C; Rf = t0.54
mobile phase hexane–ethyl acetate (6:4); IR (KBr, cmꢀ1): 3299 (NH
stretch); 1641 (C@O stretch); 1H NMR (CDCl3): d 2.49 (s, 3H, S-
CH3), 4.75 (s, 1H), 6.20 (s, 1H), 6.55(d, J = 8 Hz, 1H), 6.88–7.35 (m,
11H), 8.14 (d, J = 7.9 Hz, 1H); ESI-MS m/z [M+H]+: 347; Elemental
Anal. Calcd. for C21H18N2OS: C, 72.80; H, 5.24; N, 8.09. Found: C,
72.82; H, 5.29; N, 8.07.
4.2.1.12.
3-(4-Chloro-phenyl)-2-(4-methanesulfonyl-phenyl)-
Yield: 71%; mp 192–
2,3-dihydro-1H-quinazolin-4-one (5i).
4.2.1.5.
3-(4-Methoxy-phenyl)-2-(4-methylsulfanyl-phenyl)-
Yield: 71%; mp
194 °C; Rf = 0.44 mobile phase hexane–ethyl acetate (6:4); IR
(KBr, cmꢀ1): 3294 (NH stretch); 1636 (C@O stretch); 1H NMR
(CDCl3): d 3.29 (s, 3H, SO2CH3), 4.76 (s, 1H), 6.19 (s, 1H), 6.73 (d,
J = 8.1 Hz, 1H), 6.94–7.42 (m, 10H), 8.16 (d, J = 7.9 Hz, 1H); ESI-
MS m/z [M+H]+: 413; Elemental Anal. Calcd. for C21H17ClN2O3S:
C, 61.09; H, 4.15; N, 6.78. Found: C, 61.88; H, 4.20; N, 6.86.
2,3-dihydro-1H-quinazolin-4-one (5b).
245–247 °C; Rf = 0.38 mobile phase hexane–ethyl acetate (6:4);
IR (KBr, cmꢀ1): 3301 (NH stretch); 1639 (C@O stretch); 1H NMR
(CDCl3): d 2.49 (s, 3H, SCH3), 3.76 (s, OCH3), 4.70 (s, 1H), 6.05 (s,
1H), 6.61 (d, J = 8 Hz, 1H), 6.84–7.38 (m, 10H), 8.06 (d, J = 7.9 Hz,
1H); ESI-MS m/z [M+H]+: 377; Elemental Anal. Calcd. for
C
22H20N2O2S: C, 70.19; H, 5.35; N, 7.44. Found: C, 70.24; H, 5.38;
4.2.1.13.
3-(4-Fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-
Yield: 70%; mp 229–
N, 7.46.
2,3-dihydro-1H-quinazolin-4-one (5j).
231 °C; Rf = 0.41 mobile phase hexane–ethyl acetate (6:4); IR
(KBr, cmꢀ1): 3298 (NH stretch); 1636 (C@O stretch); 1H NMR
(CDCl3): d 3.28 (s, 3H, SO2CH3), 4.74 (s, 1H), 6.16 (s, 1H), 6.69 (d,
J = 8.1 Hz, 1H), 6.91–7.38 (m, 10H), 8.14 (d, J = 7.9 Hz, 1H); ESI-
MS m/z [M+H]+: 397; Elemental Anal. Calcd for C21H17FN2O3S: C,
63.62; H, 4.32; N, 7.07. Found: C, 63.71; H, 4.40; N, 7.12.
4.2.1.6. 3-(4-Chloro-phenyl)-2-(4-methylsulfanyl-phenyl)-2,3-
dihydro-1H-quinazolin-4-one (5c).
Yield: 78%; mp 232–
234 °C; Rf = 0.42 mobile phase hexane–ethyl acetate (6:4); IR
(KBr, cmꢀ1): 3303 (NH stretch); 1643 (C@O stretch); 1H NMR
(CDCl3): d 2.50 (s, 3H, SCH3), 4.76 (s, 1H), 6.08 (s, 1H), 6.65 (d,
J = 8 Hz, 1H), 6.90–7.44 (m, 10H), 8.12 (d, J = 7.9 Hz, 1H); ESI-MS
m/z [M+H]+: 381; Elemental Anal. Calcd. for C21H17ClN2OS: C,
66.22; H, 4.50; N, 7.35. Found: C, 66.28; H, 4.48; N, 7.38.
4.2.1.14.
3-(2-Fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-
Yield: 72%; mp
2,3-dihydro-1H-quinazolin-4-one (5k).
225–227 °C; Rf = 0.40 mobile phase hexane–ethyl acetate (6:4);
IR (KBr, cmꢀ1): 3302 (NH stretch); 1638 (C@O stretch); 1H NMR
(CDCl3): d 3.28 (s, 3H, SO2CH3), 4.75 (s, 1H), 6.18 (s, 1H), 6.71 (d,
J = 8.0 Hz, 1H), 6.89–7.37 (m, 10H), 8.14 (d, J = 8 Hz, 1H); ESI-MS
m/z [M+H]+: 397; Elemental Anal. Calcd. for C21H17FN2O3S: C,
63.62; H, 4.32; N, 7.07. Found: C, 63.65; H, 4.28; N, 7.15.
4.2.1.7. 3-(4-Fluoro-phenyl)-2-(4-methylsulfanyl-phenyl)-2,3-
dihydro-1H-quinazolin-4-one (5d).
Yield: 69%; mp 241–
243 °C; Rf = 0.41 mobile phase hexane–ethyl acetate (6:4); IR
(KBr, cmꢀ1): 3298 (NH stretch); 1640 (C@O stretch); 1H NMR
(CDCl3): d 2.48 (s, 3H, SCH3), 4.70 (s, 1H), 6.05 (s, 1H), 6.57 (d,
J = 8 Hz, 1H), 6.89–7.41 (m, 10H), 8.14 (d, J = 7.9 Hz, 1H); ESI-MS
Please cite this article in press as: Manivannan, E.; Chaturvedi, S. C. Bioorg. Med. Chem. (2012), http://dx.doi.org/10.1016/j.bmc.2012.09.069

8
E. Manivannan, S. C. Chaturvedi / Bioorg. Med. Chem. xxx (2012) xxx–xxx
4.2.1.15.
1H-quinazolin-4-one (5l).
2-(4-Methylsulfonyl-phenyl)-3-p-tolyl-2,3-dihydro-
Yield: 80%; mp 183–185 °C;
particular chemical feature is present and to 0 if the same is absent.
Physicochemical substituent constants—hydrophobic ( ), molar
), resonance effect
p
Rf = 0.46 mobile phase hexane–ethyl acetate (6:4); IR (KBr, cmꢀ1):
3299 (NH stretch); 1640 (C@O stretch); 1512; 1H NMR (CDCl3): d
3.28 (s, 3H, SO2CH3), 4.75 (s, 1H), 6.18 (s, 1H), 6.71 (d, J = 8.0 Hz,
1H), 6.89–7.37 (m, 10H), 8.14 (d, J = 8 Hz, 1H); ESI-MS m/z [M+H]+:
393; Elemental Anal. Calcd. for C22H20N2O3S: C, 67.33 (67.39); H,
5.14 (5.12); N, 7.14 (7.08). Found: C, 67.39; H, 5.12; N, 7.08.
refractivity (MR), hammet electronic constant (r
(R) and field/inductive effect (f) were taken from the literature.39 In
addition, some physico–chemical properties like Calculated loga-
rithm of partition co-efficient, (ClogP), calculated molar refractiv-
ity (CMR), molecular weight (MW) and toplogical polar surface
area were calculated by Chemoffice 2008 software package.40,41
A
correlation matrix was constructed to correlate the biological
activity with the various physicochemical and structural predictor
variables. QSAR models were built using the regression analysis
module of systat version 11.42 The correlation matrix was used
to correlate the biological activity with the various predictor vari-
ables. Descriptors with inter correlation above r >0.5 are not con-
sidered while deriving QSAR models. The predictor variables with
p value greater than 0.05 were eliminated whilst deriving the QSAR
models in order to assure their statistical reliability. The QSAR
models were evaluated by using the statistical parameters viz., cor-
relation coefficient (r) or coefficient of determination (r2), adjusted
r2 (r2adj), standard error of estimate (s), Fischer F-value and stu-
dent_s t-distribution. The figures within the parentheses following
the coefficient terms are the standard error of the regression terms
and the constants.
4.3. Pharmacological evaluation
4.3.1. COX-1 and COX-2 inhibition assay
The in vitro ability of the synthesized compounds and the refer-
ence drug celecoxib to inhibit the COX-1 and COX-2 isozymes was
carried out using cayman colorimetric COX (ovine) inhibitor screen-
ing assay kit (Catalog No. 760111) supplied by Caymen chemicals,
USA. The calculations were performed as per the kit guidelines.36,37
4.3.2. Animals
Animals were assigned into different groups randomly and each
group consists of six animals. The animals were kept in appropriate
cages at temperature controlled (25 2 °C) rooms, under a 12 h light
and dark cycle and they were fed standard rodent pellet. All the ani-
mals were acclimatized for a week before the experiment. Standard
ethical guidelines of Committee for the Purpose of Control and
Supervision of Experiments on Animals (CPCSEA), Ministry of Social
Justice and Empowerment, Government of India were followed.
4.5. Molecular docking
Docking studies of the compounds were performed using crys-
tal structure of COX-2 enzyme (PDB ID: 1CX2) obtained from the
RCSB Protein Data Bank, which in-houses the selective COX-2
inhibitor SC-558 in its active site.1,43 All the docking simulations
were carried out using the program GLIDE (Grid-based Ligand
Docking with Energetics) module version 4.5, Schrödinger, LLC,
New York, NY, 2007 (Schrodinger Inc.).44,45 The protein residue
was prepared for grid generation by running the protein prepara-
tion wizard of Maestro. The impref minimizations were run until
the average root mean square deviation (rmsd) of the non-hydro-
gen atoms reached 0.3 Å. Grid files were generated using the co-
crystallized ligand at the centre of the two boxes. The size of the
binding box was set at 20 Å in order to explore a large region of
the protein. The three-dimensional structures of the compounds
were constructed using the Maestro interface. The initial geometry
of the structures was optimized using the OPLS-2005 force field
performing 1000 steps of conjugate gradient minimization. The
compounds were subjected to flexible docking using the pre-com-
puted grid files. For each compound the 100 top-scored poses were
saved and analyzed and only the best scoring poses were selected
for the study.
4.3.3. Carrageenan-induced rat paw edema assay
The test compounds and the standard drugs were administered
orally in the form of a suspension in 1% or 0.5% carboxy methylcel-
lulose sodium (CMC-Na). Anti-inflammatory activity was deter-
mined using carrageenan induced foot paw edema assay method
in rats using indomethacin 10 mg/kg as standard drug.38 The test
compounds were administered orally at a dose of 50 mg/kg. Ede-
mas were produced by injecting 0.1 ml of a solution of carrageenan
in the hind paw. Paw volumes were measured using the mercury
displacement technique with the help of a plethysmograph imme-
diately before and 90, 180, 270 and 360 min after carrageenan
injection. The percentage of edema inhibition was calculated using
the following formula.1
Percentage of edema inhibition ¼ 100½1 ꢀ ðA ꢀ XÞ=ðB ꢀ YÞꢂ
Where, X is the mean paw volume of rats before the administra-
tion of carrageenan and test compounds or reference drugs; A and
B is the mean paw volume of rats after the administration of carra-
geenan in the test group and control group, respectively; Y is the
mean paw volume of rats before the administration of carrageenan
in the control group.
Acknowledgements
4.3.4. Statistical calculations
This study was financially supported in part by University
Grants Commission through JRF and All India Council for Technical
Education through CAYT scheme to E.M.
Statistical significance of anti-inflammatory activity of the com-
pounds on rat paw edema model was analyzed using one-way
analysis of variance (ANOVA) followed by Dunnett’s multiple com-
parison test. A significance level of p <0.05 was considered as
acceptable in all cases. All the results were expressed as mean-
References and notes
1. Manivannan, E.; Chaturvedi, S. C. Bioorg. Med. Chem. 2011, 19, 4520.
2. Moon, T. C.; Murakami, M.; Kudo, I.; Son, K. H.; Kim, H. P.; Kang, S. S.; Chang, H.
W. Inflamm. Res. 1999, 48, 621.
s
SEM (standard error of estimate).
4.4. Physico-chemical constants, structural properties and
correlation
3. Danz, H.; Stoyanova, S.; Wippich, P.; Brattström, A.; Hamburger, M. Planta Med.
2001, 67, 411.
4. Abbas, S. E.; Awadallah, F. M.; Ibrahin, N. A.; Said, E. G.; Kamel, G. M. Eur. J. Med.
Chem. 2012, 53C, 141.
Hansch 2D-QSAR analysis was performed using two types of
predictor descriptors, physicochemical constants and indicator
variables. An indicator variable was assigned for any structural
variations between the compounds as I with a relevant subscript
of the specific chemical feature. I was assigned a value of 1 if a
5. Mosaad, M. S.; Mohsen, K. M.; Emad, K. M.; Abotaleb, N.; Salwa, N. M.; Marwa,
A. F. Acta Pol. Pharm. 2010, 67, 159.
6. Rörsch, F.; Buscató, E. L.; Deckmann, K.; Schneider, G.; Zsilavecz, M. S.;
Geisslinger, G.; Proschak, E.; Grösch, S. J. Med. Chem. 2012, 55, 3792.
7. Ozaki, K. I.; Yamada, Y.; Oine, T.; Ishizuka, T.; Iwasawa, Y. J. Med. Chem. 1985,
28, 568.
Please cite this article in press as: Manivannan, E.; Chaturvedi, S. C. Bioorg. Med. Chem. (2012), http://dx.doi.org/10.1016/j.bmc.2012.09.069

E. Manivannan, S. C. Chaturvedi / Bioorg. Med. Chem. xxx (2012) xxx–xxx
9
8. Chiou, W. F.; Liao, J. P.; Chen, C. F. J. Nat. Prod. 1996, 59, 374.
9. Lee, S. H.; Son, J. K.; Jeong, B. S.; Jeong, T. C.; Chang, H. W.; Lee, E. S.; Jahng, Y. D.
Molecule 2008, 13, 272.
25. Prasanna, S.; Manivannan, E.; Chaturvedi, S. C. QSAR Comb. Sci. 2004, 23, 621.
26. Prasanna, S.; Manivannan, E.; Chaturvedi, S. C. Bioorg. Med. Chem. Lett. 2004, 14,
4005.
10. Wu, X. Y.; Qin, G. W.; Cheung, K. K.; Cheng, K. F. Tetrahedron 1997, 53, 13323.
11. Hartleb, I.; Seifert, K. Planta Med. 1994, 60, 578.
27. Prasanna, S.; Manivannan, E.; Chaturvedi, S. C. Arch. Pharm. (Weinheim) 2004,
337, 440.
12. Vane, J. R. Nat. New Biol. 1971, 231, 232.
13. Vane, J. R.; Bakhle, Y. S.; Botting, R. M. Annu. Rev. Pharmacol. Toxicol. 1998, 38,
97.
28. Prasanna, S.; Manivannan, E.; Chaturvedi, S. C. Bioorg. Med. Chem. Lett. 2005, 15,
2097.
29. Manivannan, E.; Chaturvedi, S. C. Med. Chem. Res. 2009, 18, 396.
30. Manivannan, E.; Prasanna, S.; Chaturvedi, S. C. Indian J. Biochem. Biophys. 2004,
41, 179.
31. Manivannan, E.; Chaturvedi, S. C. Med. Chem. 2009, 440.
32. Phase, version 3.3, Schrödinger, LLC., New York, NY, 2011.
33. Sastry, G. M.; Dixon, S. L.; Sherman, W. J. Chem. Inf. Model. 2011, 51, 2455.
34. Wüst, F. R.; Höhne, A.; Metz, P. Org. Biomol. Chem. 2005, 3, 503.
35. Uddin, Md. J.; Rao, P. N. P.; Knaus, E. E. Bioorg. Med. Chem. 2004, 12, 5929.
36. Takeda, S.; Misawa, K.; Yamamoto, I.; Watanabe, K. Drug Metab. Dispos. 2008,
36, 1917.
14. Botting, J. H. Drugs Today 1999, 35, 225.
15. Kurumbail, R. G.; Stevens, A. M.; Gierse, J. K.; McDonald, J. J.; Stegeman, R. A.;
Pak, J. Y.; Gildehaus, D.; Miyashiro, J. M.; Penning, T. D.; Seibert, K.; Isakson, P.
C.; Stallings, W. C. Nat. New Biol. 1996, 384, 644.
16. Kalgutkar, A. S.; Zhao, Z. Curr. Drug Targets 2001, 2, 79.
17. Dannhardt, G.; Kiefer, W. Eur. J. Med. Chem. 2000, 36, 109.
18. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Doctor,
S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rojers, R. S.; Rogier,
D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.;
Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.;
Isakson, P. C. J. Med. Chem. 1997, 40, 1347.
37. Lee, S. H.; Son, M. J.; Ju, H. K.; Lin, C. X.; Moon, T. C.; Choi, H. G.; Son, J. K.; Chang,
H. W. Biol. Pharm. Bull. 2004, 27, 786.
19. Bertenshaw, S. R.; Talley, J. J.; Rogier, D. J.; Graneto, M. J.; Koboldt, C. M.; Zhang,
Y. Bioorg. Med. Chem. Lett. 1996, 6, 2827.
20. Talley, J. J.; Bertenshaw, S. R.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Kellogg,
M. S.; Koboldt, C. M.; Yuan, J.; Zhang, Y. Y.; Seibert, K. J. Med. Chem 2000, 43,
1661.
21. Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C. M.; Masferrer, J.
L.; Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert,
K. J. Med. Chem. 2000, 43, 775.
22. Garg, R.; Kurup, A.; Mekapati, S. B.; Hansch, C. Chem. Rev. 2003, 103, 703.
23. Prasanna, S.; Manivannan, E.; Chaturvedi, S. C. Indian J. Chem. 2004, 43, 2249.
24. Prasanna, S.; Manivannan, E.; Chaturvedi, S. C. Bioorg. Med. Chem. Lett. 2005, 15,
313.
38. Winter, C. A.; Risley, E. A.; Nuss, G. W. Proc. Soc. Exp. Biol. Med. 1962, 111, 544.
39. Hansch, C.; Leo, A. Substituent Constants for Correlation Analysis in Chemistry and
Biology; John Wiley and Sons, 1979.
40. Prasanna, S.; Manivannan, E.; Chaturvedi, S. C. Drug Dev. Res. 2005, 64, 220.
41. Chem Draw ultra version 11.0 supplied by Cambridgesoft Corporation, USA.
42. Systat 11, Systat Software Inc., 2002.
43. Geronikaki, A. A.; Lagunin, A. A.; Hadjipavlou-Litina, D. I.; Eleftheriou, P. T.;
Filimonov, D. A.; Poroikov, V. V.; Alam, I.; Saxena, A. K. J. Med. Chem. 2008, 51,
1601.
44. Glide, version 5.5, Schrödinger, Inc., New York, NY, 2009.
45. Friesner, R. A.; Murphy, R. B.; Repasky, M. P.; Frye, L. L.; Greenwood, J. R.;
Halgren, T. A.; Sanschagrin, P. C.; Mainz, D. T. J. Med. Chem. 2006, 49, 6177.
Please cite this article in press as: Manivannan, E.; Chaturvedi, S. C. Bioorg. Med. Chem. (2012), http://dx.doi.org/10.1016/j.bmc.2012.09.069