Studies on novel 2-imidazolidinones and tetrahydropyrimidin-2(1H)-ones as potential TACE inhibitors: Design, synthesis, molecular modeling, and preliminary biological evaluation

Article abstract of DOI:10.1016/j.bmc.2009.04.003

Compounds belonging to the class of 2-imidazolidinones and tetrahydropyrimidin-2(1H)-ones were synthesized and evaluated for their TACE inhibitory activity. Most of the compounds showed very good TACE inhibitory activity. Docking study clearly indicates importance of the P1′ group of the inhibitor for the TACE inhibitory activity. This work proves that these two classes of molecules could be used as potential leads for the development of TACE inhibitors.

Full text of DOI:10.1016/j.bmc.2009.04.003

Bioorganic & Medicinal Chemistry 17 (2009) 3604–3617
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Studies on novel 2-imidazolidinones and tetrahydropyrimidin-2(1H)-ones
as potential TACE inhibitors: Design, synthesis, molecular modeling,
and preliminary biological evaluation
*
Shirshendu DasGupta, Prashant R. Murumkar, Rajani Giridhar, Mange Ram Yadav
Pharmacy Department, Faculty of Technology and Engineering, Kalabhavan, The M. S. University of Baroda, Vadodara 390 001, Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Compounds belonging to the class of 2-imidazolidinones and tetrahydropyrimidin-2(1H)-ones were syn-
thesized and evaluated for their TACE inhibitory activity. Most of the compounds showed very good TACE
inhibitory activity. Docking study clearly indicates importance of the P10 group of the inhibitor for the
TACE inhibitory activity. This work proves that these two classes of molecules could be used as potential
leads for the development of TACE inhibitors.
Received 14 January 2009
Revised 31 March 2009
Accepted 1 April 2009
Available online 8 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
2-Imidazolidinones
Tetrahydropyrimidin-2(1H)-ones
TACE
TACE inhibitors
Molecular modeling
Me
1. Introduction
O
Me
H
N
Me
Me
O
Me
N
NH2
HO
N
H
Me
N
N
Tumor Necrosis Factor (TNF)-a is a pleitropic, pro-inflammatory
N
HO
O
cytokine produced by monocytes, macrophages, neutrophils, T
O
O
O
cells, mast cells, epithelial cells, osteoblasts, and dendritic cells.1,2
Over expression of TNF-a is responsible for a number of patholog-
(1) IK-682
(2) BMS-561392
ical conditions such as Crohn’s disease, ulcerative colitis,3 diabe-
tes,4 multiple sclerosis,5 and atherosclerosis.6 In addition to this,
In order to identify the structural requirements of
c
-lacta-
there are compelling data to support the fact that TNF-
a
plays a
mhydroxamates as selective TACE inhibitors, molecular modeling
studies have been performed. These studies revealed four binding
groups in this series of compounds:21,22
pivotal role in the origin and progression of Rheumatoid Arthritis
(RA) and other immune-mediated disorders.7–13 It has been
hypothesized that orally bioavailable small molecule TACE inhibi-
tors would have the potential to effectively treat RA by limiting the
1. The aromatic moiety, that is, quinoline nucleus here, occupies
the S10 site of the enzyme. The choice of aromatic moiety is of
prime importance as this is not only responsible for the selec-
tivity over MMPs but can also be modified suitably so that the
compound can become active in vivo,
2. The oxygen atom of the pyrrolidinone ring forms hydrogen
bonds with Leu348 and Gly349,
3. The methyl group of IK-682 (1) and the isobutyl group of BMS-
561392 (2) occupy the small hydrophobic pocket known as S20,
and
levels of soluble TNF-a.
3,14 It has also been demonstrated that inhi-
bition of TACE by small molecular weight orally bioavailable drugs
would be more effective than the biological agents in blocking
downstream cytokine production.15 Based on this hypothesis, sev-
eral research groups world-wide are actively pursuing for orally
bioavailable small size TACE inhibitors.16 Recently, Kenny et al.
have shown that TACE inhibitors might be useful for treating cer-
tain types of cancers.17,18
Work is in progress in this laboratory on designing and synthesis
of novel potential TACE inhibitors.19,20 It became evident from sur-
vey of the literature that IK-682 (1) and BMS-561392 (2) the two
4. The hydroxamic acid forms a stable five-membered ring with
the zinc atom, present in the catalytic site of the enzyme.
c-lactamhydroxamates, are potent and selective TACE inhibitors.
Taking the above-described four TACE binding groups of
tamhydroxamates into consideration, it was planned to replace the
asymmetric carbon of -lactam with achiral nitrogen to offer
c-lac-
* Corresponding author. Tel.: +91 02645 2434187; fax: +91 0265 2418927.
E-mail address: mryadav11@yahoo.co.in (M.R. Yadav).
c
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.04.003

S. DasGupta et al. / Bioorg. Med. Chem. 17 (2009) 3604–3617
3605
imidazolidinone ring structure in the designed compounds (I;
CO2H
O
n = 1). This change would not only remove the asymmetric
environment but could also change the overall electron density
in the ring. For the aryl group it was thought of having aryl/hetero-
aryl-substituted phenyl ether/thioether (II).
O
KOH
O
+
R
Me
N
EtOH
N
R
H
(4 - 6)
(3)
(7 - 9)
Me
O
Ar
SOCl2, MeOH
N
N
X
OH
n
CO2Me
n = 1, 2
NaBH4
-CONHOH
-COOH
X =
R
N
N
R
Ar =
Ar1
Y
(10 - 12)
(13 - 15)
R
Y = O,S
(I)
Ar1=
Me
Ar1 = Aryl/heteroaryl
(4, 7, 10, 13) =
(5, 8, 11, 14) =
(6, 9, 12, 15) =
N
R
(III)
(II)
Me
Me
It has been reported that during the development of IK-682 (1)
and BMS-561392 (2) inclusion of 4-quinolinyl group for the substi-
tuent ‘Ar1’ not only enhanced selectivity of the compounds for
TACE but also improved their potency.19 Hence, it was decided to
incorporate 4-quinolinyl moiety (III) in some of the compounds
for the ‘Ar1’ group. The R group was varied in the quinolinyl moiety
to observe the effect of size of substituents in this position.
In order to see the effect of ring size, six-membered ring (I;
n = 2) was also incorporated in place of five-membered imidazolid-
inone ring. For binding to the S20 site of TACE, methyl group of
IK-682 (1) was retained in the designed compounds.
A zinc binding motif was required in the designed molecules as
group ‘X’. The most effective zinc binding motif known till date is
hydroxamate. Hence, it was envisaged to incorporate hydroxamic
acid in the designed molecules, although hydroxamates have been
reported to pose toxicity problems due to their conversion to toxic
hydroxylamine. Though carboxylate is not that good a ligand for
zinc ions, but due to its non-controversial nature it was thought
of retaining this grouping in some of the molecules.
Scheme 1.
commercially (16–19)] were converted into chloro derivatives
(20–26) (Scheme 2) by thionyl chloride treatment in excellent
yields (more than 85%). Conversion of the alcohols into the chloro
derivatives was monitored by TLC and the products so obtained
were used as such for next step without characterization. The
chloro compounds (20–26) were then reacted with 4-nitrophenol
(27) in the presence of anhydrous potassium carbonate in DMF
at 80–90 °C to prepare the nitro derivatives (28–34). These nitro
compounds (28–34) were then treated with iron and aqueous
sodium chloride in methanol to obtain the desired ether-substi-
tuted amino compounds (35–41) as per Scheme 2. This reaction
took around 11–13 h to complete for all of the compounds. This
was a longer time than expected, probably due to the poor solubil-
ity of the nitro compounds in methanol.
2.1.2. Synthesis of thioether substituted phenylamine
1-(4-Aminothiophenoxymethyl)-4-methoxybenzene (43) was
synthesized from 4-methoxybenzyl chloride (17) and 4-amino-
thiophenol (42) in the presence of potassium carbonate as base
as per Scheme 3. The isolated compound was purified by column
chromatography on neutral alumina.
2. Results and discussions
2.1. Chemistry
In order to synthesize the proposed molecules, various aryl-
amines and isocyanates were required as the starting chemicals
or intermediates. Some of the amines were available commercially
while others were synthesized in the laboratory. Considering the
instability of isocyanates (B), these were prepared afresh whenever
required.
2.1.3. Synthesis of isocyanates
Isocyanates (46) were prepared in a two-step process24 accord-
ing to Scheme 4. The isocyanates are unstable at rt, sensitive to
light and moisture, and lachrymatory in nature. Hence, no efforts
were made to isolate or purify isocyanates (46). These isocyanates
were prepared afresh and used immediately for the next step. It
was observed that even if stored in a tightly closed amber colored
vial at ꢀ5 °C, they were unsuitable for synthetic purposes after a
week. The toluene solutions of isocynates were used for further
reactions in the next step. It was assumed that the yields of isocy-
anates were quantitative for the calculation purposes.
2.1.1. Synthesis of arylamines
The arylamines used for reacting isocyanates were ether/thioe-
ther-substituted arylamines. Their preparation involved the
synthesis of different intermediates which are discussed under dif-
ferent headings.
The 2-substituted quinolin-4-yl-methanols (13–15) synthe-
sized from isatin (3) in a three-step process is depicted in Scheme
1. In the first step, isatin was reacted with ketones (4–6) in the
presence of a strong base like potassium hydroxide in ethanol to
form 2-substituted quinoline-4-carboxylic acid as per the reported
procedure.23 These acids (7–9) were converted to esters (10–12)
and the esters were reduced to obtain the desired 2-substituted
quinolin-4-yl-methanols (13–15).
2.1.4. Synthesis of target compounds (I)
The aromatic amines [prepared as shown in Schemes 2 and 3
(35–41, 43) and those available commercially (47, 48)] were
converted to 2-imidazolidinone derivatives (60–69) via urea deriv-
atives (49–59) by reported method.25,26 In the next step, 2-imi-
dazolidinone derivatives (60–69) were converted to ester
derivatives (70–79) using ethyl 2-bromopropionate in the pres-
ence of sodium hydride. In order to have zinc binding ligands in
For the synthesis of required arylamines, the alcohols [synthe-
sized as shown in Scheme 1 (13–15) and alcohols available

3606
S. DasGupta et al. / Bioorg. Med. Chem. 17 (2009) 3604–3617
SOCl2
Ar CH2OH
Ar CH2Cl
(13 - 19)
(20 - 26)
K2CO3
NO2
(27)
OH
NH2
NO2
Ar
O
Ar
O
Fe/NaCl
(35 - 41)
(28 - 34)
Ar
Me
Me
(16, 23, 31, 38) =
(17, 24, 32, 39) =
N
(13, 20, 28, 35) =
(14, 21, 29, 36) =
N
N
MeO
Me
(18, 25, 33, 40) =
(19, 26, 34, 41) =
(15, 22, 30, 37) =
N
Scheme 2.
NH2
NH2
K2CO3
Cl
+
S
HS
MeO
MeO
(17)
(42)
(43)
Scheme 3.
O
O
NCO
Cl
Cl
Cl
+
NaN3
n
n
Cl
n
N3
(44)
(45)
(46)
(A) n = 2 ;
(B) n = 3
Scheme 4.
the targeted molecules, it was proposed to prepare carboxylic acid
derivatives. To achieve this, esters (70–79) were hydrolyzed in
basic medium to prepare the corresponding acids (80–89). Lithium
hydroxide or sodium hydroxide was used as the base in aqueous
medium in this reaction. To prepare hydroxamates (90–99) as zinc
binding ligands esters (70–79) were reacted with hydroxylamine
hydrochloride in basic conditions. The synthesis of the target com-
pounds is shown in Scheme 5. As shown in Scheme 6, compound
(58A) is treated with 4-nitrobenzyl bromide (100) in the presence
of potassium carbonate in DMF to provide compound (59A).
TNF converting enzyme. The cells were grown and cell lysate
was prepared according to the reported procedure.27 This cell
lysate was stored at ꢀ70 °C and was used as the source of TACE
in the enzyme inhibition studies as and when required in a span
of seven days.
To assess the TACE inhibitory activity of the synthesized com-
pounds, InnozymeTM TACE activity ELISA kit was procured from
Calbiochem, USA (Catalog No. CBA042). The method followed for
the assay was as given in the protocol supplied by the manufac-
turer.28 The kit contained 96-well plate and the wells were pre-
coated with a monoclonal antibody specific for human TACE that
captured the enzyme from the cell lysate. The diluted cell lysate
was added to the wells and incubated for 1 h at 25 °C. After the
enzyme was attached to the antibody, the wells were washed to
discard the unbound enzyme, and inhibitors (synthesized com-
pounds dissolved in DMSO) were added to the designated wells.
2.2. Biological activity and molecular modeling studies
In vitro biological studies were performed to evaluate the TACE
inhibitory activities of the synthesized final compounds. Human
monocytic acute leukemia (THP-1) cells were used for expressing

S. DasGupta et al. / Bioorg. Med. Chem. 17 (2009) 3604–3617
3607
H
H
N
N
NCO
Ar
Cl
n
Cl
+
Ar NH2
n
O
(35 - 41, 43, 47, 48)
(49 - 59)
(46)
NaH
Br
O
Me
OEt
OEt
O
Ar
Me
N
N
O
Ar
O
N
NH
n
n
NaH
(70 - 79)
(60 - 69)
-
HO
NH2OH, KOH
O
Me
H
N
O
Me
Ar
OH
N
N
OH
Ar
N
N
O
n
O
n
(90 - 99)
(80 - 89)
(A) n = 1; (B) n = 2
Ar
(35, 49, 60, 70, 80, 90) =
(40, 54, 65, 75, 85, 95) =
(41, 55, 66, 76, 86, 96) =
N
O
Me
Me
O
O
(36, 50, 61, 71, 81, 91) =
(37, 51, 62, 72, 82, 92 ) =
N
(43, 56, 67, 77, 87, 97) =
O
Me
MeO
S
(47, 57, 68, 78, 88, 98) =
N
O
O
O
Ph
(48, 58) =
(38, 52, 63, 73, 83, 93) =
(39, 53, 64, 74, 84, 94) =
O
HO
N
(59, 69, 79, 89, 99) =
MeO
O2N
O
Scheme 5.
H
N
H
N
Cl
H
N
H
N
Br
K2CO3
O
Cl
O
+
O2N
O
O2N
HO
(58A)
(100)
(59A)
Scheme 6.
In one of the wells no inhibitor was added, which was regarded as
blank and in one of the wells TAPI-1, a well known TACE inhibitor,
was added. The wells were again incubated for 2 h at 25 °C. In the
presence of an inhibitor, the enzyme would bind to it leading to a
decreased concentration of the free enzyme. Upon addition of an
internal fluorescent substrate (MCA-KPLGL-Dpa-AR-NH2), the free
enzyme would cleave the scissile amide bond of the substrate.
Fluorescence intensity of the cleaved product, MCA-KPLG was
measured at an excitation wavelength of 355 nm and emission
wavelength of 405 nm. The fluorescence intensity is indirectly
related to the inhibitory activity of the test compounds. The inhib-
itory activity of a test compound in a particular concentration was
calculated from the following equation:
%Inhibition ¼ ½1 ꢀ ðFluorescence intensity of test=
Fluorescence intensity of blankÞꢁ ꢂ 100

3608
S. DasGupta et al. / Bioorg. Med. Chem. 17 (2009) 3604–3617
Table 1
the zinc binding groups are active, hydroxamate has higher inhib-
Activity of the compounds along with their docking score
itory activity over the previous carboxylate moiety.
Compound (97A) having thioether linkage at P10 position is
more active than compound (94A) bearing ether linkage in the
Sr. No.
Compound ID
G-Score
% Inhibition at 0.1 l
M/L*
R-Isomer
S-Isomer
same position, at 0.1 lM concentration (42% inhibition by 97A in
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
80A
80B
81A
82A
82B
83A
83B
86A
86B
87A
90A
91A
91B
93A
93B
94A
94B
95A
95B
97A
98A
98B
99A
TAPI-1
IK-682
ꢀ7.75
ꢀ8.98
ꢀ8.48
ꢀ6.67
ꢀ5.43
ꢀ7.08
ꢀ8.53
ꢀ7.84
ꢀ7.25
ꢀ7.36
ꢀ10.01
ꢀ10.83
ꢀ7.56
ꢀ12.65
ꢀ10.47
ꢀ11.10
ꢀ8.76
ꢀ8.64
ꢀ11.13
ꢀ9.29
ꢀ9.49
ꢀ10.35
ꢀ12.04
ꢀ7.79
ꢀ7.67
ꢀ8.13
ꢀ6.83
ꢀ5.72
ꢀ7.08
ꢀ8.52
ꢀ7.52
ꢀ7.41
ꢀ9.97
ꢀ8.35
ꢀ12.51
ꢀ9.54
ꢀ11.85
ꢀ8.28
ꢀ12.31
ꢀ8.27
ꢀ7.99
ꢀ8.82
ꢀ9.97
ꢀ9.26
ꢀ8.42
ꢀ9.32
47
20
49
30
31
28
35
30
28
40
60
62
34
50
37
38
18
36
40
42
39
28
40
28
—
comparison to 38% inhibition by 94A). Both the compounds have
same structures except for this change. This fact might be consid-
ered while designing new TACE inhibitors in future.
The overall activity pattern of the compounds clearly shows
that heterocyclic quinolinyl or pyridinyl rings at P10 position is a
preferred ring system than simple phenyl or substituted phenyl
rings. It has also been indicated from the above activity data that
ethyl group is the group of choice at 2-position of quinolinyl ring.
The phenyl ring at this position is not favored from the SAR point-
of-view. From the compounds tested, 91A has shown the highest
activity (62% inhibition). Compound (90A) which has shown 60%
inhibition of TACE is also a very promising compound.
All the synthesized compounds were energy minimized and
docked in the active site of human TACE. Binding interactions of
only a few are discussed here. As all the synthesized compounds
are racemic mixtures, docking study was carried out for both the
isomers. Binding score differences between R and S isomers were
found to be marginal for majority of the docked compounds. How-
ever, most of the compounds having R-configuration showed
better G-score than S-isomers (Table 1). In compound IK-682, R-
isomer is also the active form. Compound 93A is the highest ranked
compound with R-isomer, whereas compound 91A with S-isomer
showed higher binding score (G-score ꢀ12.51) (Table 1). During
the binding studies it was observed that the conformation of
methyl group in the side chain in the molecules of both the series
changes as the aryl/heteroaryl substituents are varied. The binding
interaction of 2-{3-[4-(2-ethyl-4-quinolinylmethoxy)phenyl]-2-
oxo-1-imidazolidinyl}-N-hydroxypropionamide (91A, 62% TACE
inhibitory activity) was studied within the TACE binding site by
docking studies. P10 group of 91A (2-ethyl-4-quinolinyl)methoxy
is oriented toward larger S10 pocket of the TACE (Fig. 1) interacting
with active site (Glu398, Leu348, Leu350, Ala439, Val440, Lys432,
and Leu401). Central phenyl ring interacts with His405, Tyr436
as shown in Figure 2A. Catalytic zinc bonds with oxygen of NHOH
group along with carbonyl group of imidazolidin ring. Glu406 and
Leu348 residues interact with methylene group of imidazolidin
ring. Carbonyl group of CONHOH bonds with the His405 and
Leu350. This interaction study clearly reveals that compound 91A
perfectly interacts with the catalytic active site and also P10 group
orients toward S10 pocket giving excellent TACE inhibitory activity
along with best docking score (Gscore ꢀ12.51) (Table 1). Binding
ꢀ8.89
ꢀ9.39
*
Each value is an average of three determinations, and the standard errors for all
determinations are less than 10%.
The blank well contains solvent (DMSO) and the substrate.
The TACE inhibitory activity of only some of the selected com-
pounds was performed and the data are given in Table 1. TAPI-1,
a well-known inhibitor of TACE and MMP,29 was used as the posi-
tive control in the study.
From the activity data, the structure-activity relationship of this
series of compounds has been derived. It was noted that the five-
membered 2-imidazolidinone ring was more favored in the central
part of the molecule rather than the six-membered tetrahydropyr-
imidin-2(1H)-one ring. TACE inhibition was found to be 62% for
compound (91A) at 0.1 lM concentration while the inhibition
was only 34% for compound (91B) in the same concentration. Sim-
ilarly, TACE inhibition was found out to be 47% for compound
(80A) and it was only 20% for compound (80B). In the same man-
ner, compound (93A) showed an inhibition of 50% while com-
pound (93B) showed 37%. The same observation was noted for
compounds (94A) and (94B) as well. Compound (94A) showed an
inhibition of 38% in comparison to compound (94B) which showed
only 18% inhibition. Compounds (98A) and (98B) showed 39% and
28% inhibition of TACE, respectively, at 0.1 lM concentration.
Compound (83B) bearing carboxylic acid as the zinc binding
group shows activity in the same range in comparison to com-
pound (93B) at 0.1 lM concentration (35% and 37%, respectively).
Compound (87A) having carboxylate moiety shows 40% inhibition
of the enzyme, while compound (97A) having hydroxamate moiety
shows 42% inhibition at 0.1 lM concentration. In these cases, it
was observed that the hydroxamates were marginally more active
than the corresponding carboxylates. Compound (83A) bearing
carboxylate moiety showed 28% inhibition at 0.1 lM concentration
while compound (93A), having hydroxamate moiety showed 50%
inhibition in the same concentration. Similarly, it was noted from
the activities of compounds (81A) and (91A) that the hydroxa-
mates were more active than carboxylates (49% and 62% inhibition,
respectively). The same observation was also made from the activ-
ities of compounds (80A) and (90A) (TACE inhibitory activities
were 47% and 60%, respectively). From these observations, it could
be concluded that although compounds bearing carboxylates as
Figure 1. Positioning of the P10 group of compound (ball and stick) 2-{3-[4-(2-
ethyl-4-quinolinylmethoxy)phenyl]-2-oxo-1-imidazolidinyl}-N-hydroxypropiona-
mide (91A) in the active site of TACE.

S. DasGupta et al. / Bioorg. Med. Chem. 17 (2009) 3604–3617
3609
Figure 3. Docking of compound 83A (ball and stick) in the active site of TACE.
3. Experimental
3.1. Chemistry
3.1.1. General procedure for the synthesis of 2-substituted
quinolin-4-carboxylic acids (11–13)
Isatin (3) (13 mmol) was suspended in ethanol (9 mL). Potassium
hydroxide (65 mmol) was added to the above suspension and stirred
for5 min. Ketones(4–6)(26 mmol) wereadded to theabovemixture
and the reaction mixture was placed in a microwave reactor with the
given conditions (Power, 300 W; Temp., 100 °C; run time, 1.00 min;
hold time, 5.00 min; stirrer speed, high). After the reaction was over,
the reaction mixture was removed from the reactor and ethanol was
completely removed from the reaction mixture under vacuum. The
semi-solid mass thus obtained was dissolved in ice-water (20 mL).
The aqueous layer was acidified with concd HCl up to pH 4. The pre-
cipitated material was filtered and dried in oven. The crude product
thus obtained was purified by crystallization from methanol to af-
ford off-white solid.
Figure 2. Docking of compounds (ball and stick) in the active site of TACE (a) 2-{3-
[4-(2-ethyl-4-quinolinylmethoxy)phenyl]-2-oxo-1-imidazolidinyl}-N-hydroxypro-
pionamide (91A) and (b) N-hydroxy-2-{2-oxo-3-[4-(2-pyridinylmethoxy) phenyl]-
1-imidazolidinyl}propionamide (93A). Interactions are shown as dashed lines and
zinc is shown in yellow color.
mode of N-hydroxy-2-{2-oxo-3-[4-(2-pyridinylmethoxy)phenyl]-
1-imidazolidinyl}propionamide (93A, 50% TACE inhibitory activity)
was also examined (Fig. 2b). Leu401, Lys432, and Tyr433 residues
interact with pyridinylmethoxy as shown in Figure 2b. Central
phenyl ring interacts with Leu348 and Val402 residues. Imidazoli-
din ring is engaged with Glu406 residue through interaction with
oxygen of carbonyl group and both the methylene groups interact
with Pro437 residue. Oxygen of the NHOH group interacts with
His405 and Glu406 residues along with the zinc. Nitrogen of NHOH
is engaged with His415, Gly349, and Leu350 residues as shown in
Figure 2b. Thus, compound 93A interacts with all the amino acid
residues which are the part of the active sites such as Zn,
Glu406, Leu350, Gly439, His405, His415, Leu348, and Lys432. This
might be a reason for showing good inhibitory activity and having
highest ranked Glide score (ꢀ12.65) (Table 1).
3.1.1.1. 2-Isobutylquinoline-4-carboxylic acid (7). Yield: 42.0%,
Rf = 0.60 (50% EtOAc in n-hexane), mp 188–189 °C. (Lit.23 187–
189 °C).
3.1.1.2. 2-Ethylquinoline-4-carboxylic acid (8). Yield: 62.2%,
Rf = 0.51 (50% EtOAc in n-hexane), mp 225–227 °C, IR (KBr,
cmꢀ1): 3412, 1660, 1610, 1315, 1238, 854, 769, PMR (DMSO-d6):
d 7.93–7.95 (m, 1H), 7.76–7.78 (m, 1H), 7.64–7.68 (m, 1H), 7.51–
7.55 (m, 2H), 3.01–3.04 (q, 2H, J = 7.72 Hz), 1.37–1.41 (t, 3H,
J = 7.62 Hz).
3.1.1.3. 2-Phenylquinoline-4-carboxylic acid (9). Yield: 64.4%,
Rf = 0.18 (30% EtOAc in n-hexane), mp 209–210 °C (Lit.23 210–12 °C).
From the interaction study of compound (83A) (Fig. 3), it is
observed that the carboxylate end of the compound interacts with
TACE almost in a similar manner as the hydroxamate groups of com-
pound (91A, 93A). But the P10 group of the molecule interacts with
Leu401only. No other partof thecompound interactswith the active
site residues of S10 site of TACE, unlike compound (91A, 93A). More-
over, the orientation of P10 group of (83A) is not aligned toward the
S10 pocketof theenzyme(Fig. 3). Thismightexplainthepoordocking
score as well as biological activity of (83A). This proves that the ori-
entation of the P10 group is one of the most important factors for the
biological activity of TACE inhibitors, particularly in imidazolidin-2-
ones and tetrahydropyrimidin-2(1H)-ones scaffold-containing
compounds. For all the compounds docking score was found to be
in good correlation with the biological activity data.
3.1.2. General procedure for the synthesis of methyl 2-substi-
tuted quinolin-4-carboxylate (10–12)
2-Substituted quinoline-4-carboxylic acids (7–9) (5.4 mmol)
were dissolved in methanol (10 mL) and cooled to 0–5 °C. Thionyl
chloride (8.2 mmol) was added drop-wise to the above solution un-
der stirring. After the addition was over, the reaction mixture was re-
fluxed for 2 h. Excess methanol and thionyl chloride were removed
fromthe reaction mixture, which was pouredinto saturatedsolution
of sodium bicarbonate (50 mL). The aqueous layer was extracted
with chloroform (3 ꢂ 20 mL); the combined organic layer was dried
over anhydrous sodium sulfate and recovered to get the title com-
pound as off-white solid (0.97 g, 74.2%). Mp 46–48 °C.

3610
S. DasGupta et al. / Bioorg. Med. Chem. 17 (2009) 3604–3617
3.1.2.1. Methyl 2-isobutylquinoline-4-carboxylate (10). Yield:
74.2%, Rf = 0.82 (30% EtOAc in n-hexane), mp 46–48 °C, IR (KBr,
cmꢀ1): 2956, 1724, 1591, 1508, 1433, 1246, 1147, 1022, 800.
3.1.4.4. 2-Chloromethylpyridine (23). Yield: 90.9%, Rf = 0.77 (30%
EtOAc in n-hexane).
3.1.4.5. 4-Methoxybenzyl chloride (24). Yield: 85.2%, Rf = 0.60
(30% EtOAc in n-hexane).
3.1.2.2. Methyl
2-ethylquinoline-4-carboxylate
(11). Yield:
65.9%, Rf = 0.52 (30% EtOAc in n-hexane).
3.1.4.6. 1-Chloromethylnapthalene (25). Yield: 98.4%, Rf = 0.62
(10% EtOAc in n-hexane).
3.1.2.3. Methyl 2-phenylquinoline-4-carboxylate (12). Yield:
84.9%, Rf = 0.79 (30% EtOAc in n-hexane), mp 68–70 °C, PMR
(CDCl3): d 8.73–8.75 (m, 1H), 8.40 (s, 1H), 8.18–8.23 (m, 3H),
7.74–7.78 (m, 1H), 7.59–7.64 (m, 1H), 7.50–7.56 (m, 2H), 7.46–
7.49 (m, 1H), 4.06 (s, 3H).
3.1.4.7. 4-Chloromethylbiphenyl (26). Yield: 77.9%, Rf 0.83 (30%
EtOAc in n-hexane), mp 73–76 °C. (Lit.30 71–73 °C).
3.1.5. General procedure for the synthesis of nitro derivatives
(28–34)
3.1.3. General procedure for the synthesis of methyl 2-
substituted quinolin-4-methanol (13–15)
4-Nitrophenol (27) (38 mmol) was dissolved in dry DMF
(10.5 mL). Anhydrous potassium carbonate (63 mmol) was added
to the above solution under stirring followed by 1-aryl chloro-
methanol (20–26) (31.5 mmol). The reaction mixture was heated
to 80 °C for 4 h and poured into ice-water (250 mL) under stirring.
The solid so separated was filtered and washed with cold methanol
(30 mL) to afford pure desired compound as white solids.
Methyl
2-substituted
quinoline-4-carboxylates
(10–12)
(2.1 mmol) were dissolved in methanol (15 mL) and cooled to 0–
5 °C. Sodium borohydride (21 mmol) was added in fractions to
the above solution under stirring in such a manner that the tem-
perature of the reaction mixture did not rise above 10 °C. The reac-
tion mixture was stirred overnight at rt (about 35 °C). Methanol
was recovered from the reaction mixture and cold water (10 mL)
was added to it. The solid so precipitated was filtered and dried
to get the desired compound as white solid.
3.1.5.1. 2-Isobutyl-4-(4-nitrophenoxymethyl)quinoline (28). Yield:
61.7%, Rf = 0.67 (30% EtOAc in n-hexane), mp 95–97 °C, PMR (CDCl3): d
8.23–8.25 (d, 2H), 8.12–8.14 (m, 1H), 7.90–7.92 (m, 1H), 7.72–7.76 (m,
1H), 7.54–7.58 (m, 1H), 7.38 (s, 1H), 7.10–7.12 (d, 2H), 5.62 (s, 2H),
2.84–2.86 (d, 2H), 2.22–2.28 (m, 1H), 0.95–0.97 (d, 6H).
3.1.3.1. 4-Hydroxymethyl-2-isobutylquinoline (13). Yield: 99.7%,
Rf = 0.27 (30% EtOAc in n-hexane), mp 85–88 °C, PMR (CDCl3): d
8.06–8.09 (m, 1H), 7.89–7.91 (m, 1H), 7.64–7.66 (m, 1H), 7.47–
7.51 (m, 1H), 7.41 (s, 1H), 5.20 (s, 2H), 2.80–2.82 (d, 2H), 2.16–
2.23 (m, 1H), 0.94–0.96 (d, 6H).
3.1.5.2. 2-Ethyl-4-(4-nitrophenoxymethyl)quinoline (29). Yield:
55.9%, Rf = 0.56 (30% EtOAc in n-hexane), mp 145–148 °C, IR (KBr,
cmꢀ1): 1604, 1502, 1446, 1338, 1267, 1172, 1109, 846, 754, PMR
(DMSO-d6): d 8.23–8.25 (d, 2H, J = 8.84 Hz), 7.98–8.07 (m, 2H),
7.70–7.75 (m, 1H), 7.55–7.59 (m, 1H), 7.50 (s, 1H), 7.21–7.23 (d,
2H, J = 8.88 Hz), 5.67 (s, 2H), 2.98–3.03 (q, 2H, J = 7.51 Hz), 1.37–
1.41 (t, 3H, J = 7.50 Hz).
3.1.3.2. 2-Ethyl-4-hydroxymethylquinoline (14). Yield: 93.8%,
Rf = 0.15 (50% EtOAc in n-hexane), mp 113–114 °C, IR (KBr,
cmꢀ1): 3124, 2968, 1604, 1566, 1446, 1134, 1089, 883, 754, PMR
(CDCl3): d 8.06–8.08 (m, 1H), 7.89–7.91 (m, 1H), 7.66–7.70 (m,
1H), 7.52–7.58 (m, 1H), 7.46 (s, 1H), 5.21 (s, 2H), 2.96–3.02 (q,
2H, J = 7.64 Hz), 1.37–1.41 (t, 3H, J = 7.66 Hz).
3.1.5.3. 2-Phenyl-4-(4-nitrophenoxymethyl)quinoline(30). Yield:
71.3%, Rf = 0.83 (50% EtOAc in n-hexane), mp 155–157 °C, PMR
(CDCl3): d 8.25–8.28 (m, 3H), 8.14–8.16 (m, 2H), 8.00 (s, 1H), 7.95–
7.97 (m, 1H), 7.77–7.81 (m, 1H), 7.59–7.61 (m, 1H), 7.48–7.56 (m,
3H), 7.14–7.16 (d, 2H), 5.69 (s, 2H).
3.1.3.3. 4-Hydroxymethyl-2-phenylquinoline (15). Yield: 93.2%,
Rf = 0.65 (30% EtOAc in n-hexane), mp 102–104 °C, PMR (CDCl3):
d 8.17–8.21 (m, 3H), 8.10 (s, 1H), 7.95–7.97 (m, 1H), 7.69–7.74
(m, 1H), 7.50–7.56 (m, 3H), 7.43–7.48 (m, 1H), 5.21 (s, 2H), 4.90
(br s, 1H).
3.1.5.4. 2-(4-Nitrophenoxymethyl)pyridine (31). Yield: 54.3%,
Rf = 0.43 (30% EtOAc in n-hexane), mp 138–140 °C, PMR (CDCl3):
d 8.62–8.63 (m, 1H), 8.19–8.23 (d, 2H), 7.72–7.77 (m, 1H), 7.47–
7.49 (m, 1H), 7.26–7.29 (m, 1H), 7.04–7.08 (d, 2H), 5.30 (s, 2H).
3.1.4. General procedure for the synthesis of 1-aryl chloromet-
hanol (20–26)
1-Aryl methanols (13–19) (28.5 mmol) were dissolved in dry
chloroform (20 mL) and cooled to 5 °C. Thionyl chloride
(42.8 mmol) was added to this solution at such a rate that the tem-
perature of the reaction mixture did not rise above 10 °C. After the
addition was over, the temperature of the reaction mixture was al-
lowed to rise to rt (30 °C) and stirred further for about 30 min. The
reaction mixture was basified to pH 8 by slow and careful addition
of saturated sodium bicarbonate solution, extracted with chloro-
form (3 ꢂ 30 mL); the combined organic layer was washed with
water (3 ꢂ 20 mL), dried over anhydrous sodium sulfate, and the
solvent removed to get the title product as an oil (3.8 g, 85.2%).
3.1.5.5. 1-(4-Nitrophenoxymethyl)-4-methoxybenzene (32). Yield:
87.0%, Rf = 0.53 (30% EtOAc in n-hexane), mp 102–104 °C, IR (KBr,
cmꢀ1): 2926, 1591, 1516, 1454, 1336, 1249, 1176, 1028.
3.1.5.6. 1-(4-Nitrophenoxymethyl)naphthalene (33). Yield: 99.1%,
Rf = 0.68 (30% EtOAc in n-hexane), mp 142–145 °C, PMR (DMSO-d6):
d 8.22–8.24 (d, 2H), 8.01–8.03 (m, 1H), 7.89–7.94 (m, 2H), 7.59–7.63
(m, 1H), 7.48–7.58 (m, 3H), 7.15–7.18 (d, 2H), 5.62 (s, 2H).
3.1.5.7. 4-(4-Nitrophenoxymethyl)biphenyl (34). Yield: 50.3%,
Rf = 0.74(30% EtOAc in n-hexane), mp 158–160 °C, IR (KBr, cmꢀ1):
3072, 1587, 1512, 1491, 1384, 1338, 1251, 1170, 1109, 955.
3.1.4.1. 4-Chloromethyl-2-isobutylquinoline (20). Yield: 71.4%,
Rf = 0.83 (30% EtOAc in n-hexane).
3.1.6. General procedure for the synthesis of amino derivatives
(35–41)
To the refluxing solutions of nitro derivatives (28–34)
(17.1 mmol) in methanol (700 mL), iron powder (17.1 mmol) and
saturated solution of sodium chloride (17.1 mmol) were added
every 30 min in fractions. The reaction was complete after 11 h.
3.1.4.2. 4-Chloromethyl-2-ethylquinoline (21). Yield: 96.1%,
Rf = 0.53 (30% EtOAc in n-hexane).
3.1.4.3. 4-Chloromethyl-2-phenylquinoline (22). Yield: 92.9%,
Rf = 0.84 (30% EtOAc in n-hexane), mp 82–85 °C.

S. DasGupta et al. / Bioorg. Med. Chem. 17 (2009) 3604–3617
3611
The reaction mixture was filtered through filtering aid (hyflosuper-
cel) to remove iron powder. The filtrate so obtained was evapo-
rated under vacuum and saturated sodium bicarbonate solution
was added (until the pH was about 8) to the reaction mass. The
slurry was extracted with chloroform (4 ꢂ 50 mL); the combined
organic layer was dried over anhydrous sodium sulfate and the sol-
vent removed to get the desired compound.
3.55–3.59 (m, 2H), 2.84–2.86 (d, 2H), 2.17–2.21 (m, 1H), 0.94–
0.96 (d, 6H).
3.1.8.2. 1-(3-Chloropropyl)-3-[4-(2-isobutyl-4-quinolinylmeth-
oxy)phenyl]urea (49B). Yield: 89.7%, Rf = 0.48 (50% EtOAc in n-
hexane), mp 115–116 °C, IR (KBr, cmꢀ1): 3358, 3292, 2955, 1637,
1600, 1510, 1236, 1170, 1070, 842, 761, PMR (DMSO-d6): d 8.14–
8.15 (m, 1H), 8.00–8.03 (m, 2H), 7.68–7.72 (m, 1H), 7.52 (s, 1H),
7.45 (br s, 1H), 7.32–7.34 (d, 2H, J = 8.96 Hz), 6.93–6.95 (d, 2H,
J = 8.80 Hz), 6.09–6.12 (t, 1H), 5.48 (s, 2H), 3.61–3.65 (m, 2H),
3.29–3.33 (m, 2H), 2.81–2.83 (d, 2H), 2.19–2.23 (m, 1H), 1.92–
1.99 (m, 2H), 0.95–0.96 (d, 6H).
3.1.6.1. 4-(2-Isobutyl-4-quinolinylmethoxy)aniline (35). Yield:
80.3%, Rf = 0.28 (30% EtOAc in n-hexane), mp 78–80 °C, IR (KBr,
cmꢀ1): 3390, 3323, 2955, 1608, 1512, 1232, 1182, 1018, 813, 748.
3.1.6.2. 4-(2-Ethyl-4-quinolinylmethoxy)aniline (36). Yield: 83.2%,
Rf = 0.30 (30% EtOAc in n-hexane).
3.1.8.3. 1-(2-Chloroethyl)-3-[4-(2-ethyl-4-quinolinylmethoxy)-
phenyl]urea (50A). Yield: 65.2%, Rf = 0.32 (50% EtOAc in n-hex-
ane), mp 148 °C (dec.), IR (KBr, cmꢀ1): 3329, 2964, 1633, 1610,
1508, 1251, 1170, 1020, 833, 759, PMR (DMSO-d6): d 8.20–8.22
(m, 1H), 8.08–8.10 (m, 1H), 7.98–8.00 (m, 1H), 7.70–7.74 (m,
1H), 7.52–7.59 (m, 2H), 7.32–7.36 (d, 2H), 6.94–6.98 (d, 2H),
6.24–6.27 (t, 1H), 5.49 (s, 2H), 3.62–3.65 (m, 2H), 3.52–3.56 (m,
2H), 2.99–3.05 (q, 2H, J = 7.61 Hz), 1.37–1.41 (t, 3H, J = 7.62 Hz).
3.1.6.3. 4-(2-Phenyl-4-quinolinylmethoxy)aniline
(37). Yield:
72.3%, Rf = 0.50 (50% EtOAc in n-hexane), mp 128–131 °C, IR (KBr,
cmꢀ1): 3423, 3331, 1604, 1514, 1238, 1078, 815, 769.
3.1.6.4. 4-(2-Pyridinylmethoxy)aniline (38). Yield: 76.9%, Rf = 0.27
(50% EtOAc in n-hexane).
3.1.6.5. 4-(4-Methoxybenzyloxy)aniline (39). Yield: 100%, Rf = 0.37
(50% EtOAc in n-hexane), mp 97–99 °C, IR (KBr, cmꢀ1): 3419, 3346,
3010, 1610, 1510, 1249, 1178, 1028.
3.1.8.4. 1-(3-Chloropropyl)-3-[4-(2-ethyl-4-quinolinylmeth-
oxy)phenyl]urea (50B). Yield: 70.1%, Rf = 0. 34 (50% EtOAc in n-
hexane), mp 130–132 °C, IR (KBr, cmꢀ1): 3313, 1635, 1606,
1508, 1244, 1172, 1020, 756.
3.1.6.6. 1-(4-Aminophenoxymethyl)naphthalene (40). Yield:
97.3%, Rf = 0.23 (30% EtOAc in n-hexane), mp 78–81 °C.
3.1.8.5. 1-(2-Chloroethyl)-3-[4-(2-phenyl-4-quinolinylmeth-
oxy)phenyl]urea (51A). Yield: 78.2%, Rf = 0.35 (50% EtOAc in n-
hexane), mp 168–170 °C, PMR (CDCl3): d 8.24–8.26 (m, 1H),
8.15–8.17 (m, 2H), 8.07 (s, 1H), 8.01–8.03 (m, 1H), 7.75–7.80
(m, 3H), 7.58–7.60 (m, 1H), 7.46–7.56 (m, 3H), 7.35–7.37 (m,
2H), 6.24–6.26 (t, 1H), 5.45 (s, 2H), 3.63–3.65 (m, 2H), 3.52–3.56
(m, 2H).
3.1.6.7. 4-(4-Aminophenoxymethyl)biphenyl (41). Yield: 96.1%,
Rf = 0.53 (50% EtOAc in n-hexane), mp 132–135 °C, IR (KBr,
cmꢀ1): 3460, 3385, 1240, 1182, 1020, 848.
3.1.7. Preparation of 1-(4-aminothiophenoxymethyl)-4-metho-
xybenzene (43)
4-Aminothiophenol (42) (1.1 g, 8.7 mmol) was dissolved in dry
DMF (3 mL). Potassium carbonate (1.2 g, 17 mmol) was added to
the above solution under stirring followed by 4-methoxybenzyl
chloride (17) (1.5 g, 9.6 mmol). The reaction mixture was stirred
at rt (around 35 °C) for 1 h, poured into ice-water (100 mL) under
stirring, and extracted with chloroform (3 ꢂ 50 mL). The combined
organic layer was dried over anhydrous sodium sulfate and the sol-
vent removed under vacuum to get a sticky compound. The crude
compound thus obtained was purified by column chromatography
over neutral alumina using 10–25% ethyl acetate in n-hexane as
eluant to afford the desired product as off-white solid. Yield:
48.9%, Rf = 0.42 (50% EtOAc in n-hexane), mp 78–80 °C, PMR
(CDCl3): d 7.09–7.25 (m, 4H), 6.76–6.79 (m, 2H), 6.51–6.57 (m,
2H), 4.23 (s, 2H), 3.77 (s, 3H), 3.68 (br s, 2H).
3.1.8.6. 1-(3-Chloropropyl)-3-[4-(2-phenyl-4-quinolinylmeth-
oxy)phenyl]urea (51B). Yield: 86.9%, Rf = 0.22 (50% EtOAc in n-
hexane), mp 170–172 °C, IR (KBr, cmꢀ1): 3316, 2985, 1640,
1592, 1281, 1252, 1052, 835, PMR (CDCl3): d 8.16–8.19 (m,
2H), 7.98–8.06 (m, 3H), 7.73–7.77 (m, 1H), 7.44–7.60 (m, 4H),
7.32–7.36 (d, 2H), 6.96–6.99 (d, 2H), 5.98–6.01 (t, 1H), 5.55 (s,
2H), 3.61–3.64 (m, 2H), 3.32–3.37 (m, 2H), 1.94–2.01 (m, 2H).
3.1.8.7. 1-(2-Chloroethyl)-3-[4-(2-pyridinylmethoxy)phenyl]urea
(52A). Yield: 84.1%, Rf = 0.25 (50% EtOAc in n-hexane), mp 145–
146 °C, PMR (CDCl3): d 8.57–8.59 (m, 1H), 8.09–8.11 (m, 1H), 7.72–
7.76 (m, 1H), 7.51–7.53 (m, 1H), 7.24–7.32 (m, 3H), 6.86–6.90 (m,
2H), 6.19–6.21 (t, 1H), 5.15 (s, 2H), 3.62–3.65 (m, 2H), 3.51–3.56
(m, 2H).
3.1.8. General procedure for the synthesis of urea derivatives
(49–59)
3.1.8.8. 1-(3-Chloropropyl)-3-[4-(2-pyridinylmethoxy)phenyl]urea
(52B). Yield: 76.5%, Rf = 0.64 (EtOAc), mp 133–134 °C, IR (KBr, cmꢀ1):
3312, 2980, 1648, 1596, 1282, 1252, 1048, 827, PMR (CDCl3): d
8.49–8.59 (m, 1H), 7.69–7.74 (m, 1H), 7.49–7.51 (m, 1H), 7.22–7.25
(m, 1H), 7.15–7.19 (d, 2H), 6.92–6.95 (d, 2H), 6.51 (br s, 1H), 5.17 (s,
2H), 5.01–5.03 (t, 1H), 3.55–3.58 (m, 2H), 3.34–3.39 (m, 2H), 1.94–
2.00 (m, 2H).
Aniline derivatives (35–41, 43, 47, 48) (6.6 mmol) were dis-
solved in dry benzene (7 mL). Isocyanate (46) (7.0 mmol) was
added to the above solution under stirring. The reaction mixture
was stirred for 30 min. The precipitated material was filtered and
dried to get the desired compound as white solid.
3.1.8.1. 1-(2-Chloroethyl)-3-[4-(2-isobutyl-4-quinolinylmeth-
oxy)phenyl]urea (49A). Yield: 89.7%, Rf = 0.86 (80% EtOAc in n-
hexane), mp 130–131 °C, IR (KBr, cmꢀ1): 3325, 2956, 1641,
1602, 1510, 1236, 1172, 1018, 827, 763, PMR (CDCl3): d 8.11–
8.13 (m, 1H), 7.91–7.93 (m, 1H), 7.69–7.73 (m, 1H), 7.51–7.55
(m, 1H), 7.41 (s, 1H), 7.22–7.26 (m, 2H), 6.97–7.0 (m, 2H), 6.77
(br s, 1H), 5.47 (s, 2H), 5.38–5.41 (t, 1H), 3.62–3.65 (m, 2H),
3.1.8.9. 1-(2-Chloroethyl)-3-[4-(4-methoxybenzyloxy)phenyl]urea
(53A). Yield: 67.6%, Rf = 0.32 (50% EtOAc in n-hexane), mp 135–138 °C,
IR (KBr, cmꢀ1): 3292, 2958, 1653, 1599, 1508, 1242, 1178, 1006, 827.
3.1.8.10. 1-(3-Chloropropyl)-3-[4-(4-methoxybenzyloxy) phenyl]-
urea (53B). Yield: 65.2%, Rf = 0.69 (70% EtOAc in n-hexane), mp 134–
136 °C, IR (KBr, cmꢀ1): 3317, 1635, 1518, 1242, 1178, 1031, 825.

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S. DasGupta et al. / Bioorg. Med. Chem. 17 (2009) 3604–3617
3.1.8.11. 1-(2-Chloroethyl)-3-[4-(1-naphthylmethoxy)phenyl]urea
(54A). Yield: 65.6%, Rf = 0.41 (50% EtOAc in n-hexane), mp 150–151 °C,
PMR (DMSO-d6): d 8.04–8.06 (m, 2H), 7.84–7.90 (m, 2H), 7.51–7.57
(m, 3H), 7.46–7.50 (m, 1H), 7.31–7.35 (m, 2H), 6.93–6.99 (m, 2H),
6.15–6.18 (t, 1H) 5.44 (s, 2H), 3.64–3.66 (m, 2H), 3.53–3.57 (m, 2H).
3.85–3.89 (m, 2H), 3.48–3.50 (m, 2H), 2.82–2.84 (d, 2H), 2.14–
2.21 (m, 1H), 0.95–0.97 (d, 6H).
3.1.9.2. 1-[4-(2-Isobutyl-4-quinolinylmethoxy)phenyl]tetrahy-
dropyrimidin-2(1H)-one (60B). Yield: 58.8%, Rf = 0.25 (EtOAc), mp
139–140 °C, IR (KBr, cmꢀ1): 3225, 2978, 1671, 1498, 1438, 1241,
1182, 1045, 835, PMR (DMSO-d6): d 8.07–8.09 (m, 1H), 7.95–7.98
(m, 1H), 7.69–7.73 (m, 1H), 7.52–7.56 (m, 2H), 7.48 (s, 1H), 7.23–
7.25 (m, 1H), 7.00–7.06 (m, 2H), 5.56 (s, 2H), 3.83–3.87 (m, 2H),
3.63–3.66 (m, 1H), 3.40–3.41 (m, 1H), 2.84–2.85 (d, 2H), 2.15–
2.23 (m, 2H), 2.06–2.09 (m, 2H), 0.95–0.97 (d, 6H).
3.1.8.12. 1-(3-Chloropropyl)-3-[4-(1-naphthylmethoxy) phenyl]
urea (54B). Yield: 73.3%, Rf = 0.14 (30% EtOAc in n-hexane), mp
143–145 °C, IR (KBr, cmꢀ1): 3309, 1639, 1510, 1249, 1224, 1024,
794.
3.1.8.13. 1-[4-(4-Biphenylmethoxy)phenyl]-3-(2-chloroethyl)
urea (55A). Yield: 64.8%, Rf = 0.41 (50% EtOAc in n-hexane), mp
190–192 °C, IR (KBr, cmꢀ1): 3309, 3034, 1639, 1573, 1512,
1236, 1174, 1041, 825, 754.
3.1.9.3. 1-[4-(2-Ethyl-4-quinolinylmethoxy)phenyl]imidazolidin-
2-one (61A). Yield: 82.3%, Rf = 0.17 (50% EtOAc in n-hexane), mp
159–161 °C, IR (KBr, cmꢀ1): 3209, 2964, 1701, 1512, 1487, 1267,
1188, 1022, 825.
3.1.8.14. 1-[4-(4-Biphenylmethoxy)phenyl]-3-(3-chloropropyl)
urea (55B). Yield: 79.8%, Rf = 0.61 (50% EtOAc in n-hexane), mp
145–148 °C.
3.1.9.4. 1-[4-(2-Ethyl-4-quinolinylmethoxy)phenyl]tetrahydro-
pyrimidin-2(1H)-one (61B). Yield: 86.6%, Rf = 0.1 (EtOAc), mp
189–190 °C, IR (KBr, cmꢀ1): 3213, 1658, 1606, 1508, 1244, 1224,
1174, 885, 835, 759.
3.1.8.15. 1-(2-Chloroethyl)-3-[4-(4-methoxythiobenzyloxy) pheny-
l]urea (56A). Yield: 76.0%, Rf = 0.43 (50% EtOAc in n-hexane), mp 158–
159 °C, IR (KBr, cmꢀ1): 3304, 1637, 1604, 1514, 1253, 1033, 819, 744.
3.1.9.5. 1-[4-(2-Phenyl-4-quinolinylmethoxy)phenyl]imidazoli-
din-2-one (62A). Yield: 84.3%, Rf = 0.48 (EtOAc), mp 159–161 °C,
PMR (CDCl3): d 8.22–8.24 (m, 1H), 8.15–8.17 (m, 2H), 8.04 (s,
1H), 7.97–7.99 (m, 1H), 7.74–7.78 (m, 1H), 7.44–7.60 (m, 6H),
7.03–7.07 (m, 2H), 5.57 (s, 2H), 4.72 (br s, 1H), 3.89–3.93 (m,
2H), 3.54–3.58 (m, 2H).
3.1.8.16. 1-(4-Benzyloxyphenyl)-3-(2-chloroethyl)urea (57A). Yield:
52.5%, Rf = 0.50 (50% EtOAc in n-hexane), mp 168–170 °C, IR (KBr,
cmꢀ1): 3310, 1639, 1600, 1508, 1382, 1236, 1006, PMR (DMSO-d6): d
8.46 (br s, 1H), 7.40–7.44 (m, 2H), 7.36–7.38 (m, 2H), 7.31–7.33 (m,
1H), 7.27–7.29 (m, 2H), 6.88–6.90 (m, 2H), 6.29–6.33 (t, 1H), 5.03 (s,
2H), 3.62–3.65 (m, 2H), 3.35–3.41 (m, 2H).
3.1.9.6. 1-[4-(2-Phenyl-4-quinolinylmethoxy)phenyl]tetrahydro-
pyrimidin-2(1H)-one (62B). Yield: 100%, Rf = 0.33 (10% MeOH in
CHCl3), mp 200–201 °C, IR (KBr, cmꢀ1): 3223, 2987, 1670, 1494,
1444, 1249, 1179, 1039, 837, PMR (DMSO-d6): d 8.17–8.19 (m, 3H),
8.08–8.06 (m, 1H), 8.02–8.04 (m, 1H), 7.75–7.78 (m, 1H), 7.45–7.61
(m, 4H), 7.24–7.26 (d, 2H), 7.05–7.07 (d, 2H), 5.78 (br s, 1H), 5.59 (s,
2H), 3.63–3.66 (m, 2H), 3.37–3.41 (m, 2H), 2.04–2.09 (m, 2H).
3.1.8.17. 1-(4-Benzyloxyphenyl)-3-(3-chloropropyl)urea (57B).
Yield: 94.2%, Rf = 0.59 (50% EtOAc in n-hexane), mp 155–156 °C, IR
(KBr, cmꢀ1): 3310, 2982, 1638, 1598, 1288, 1248, 1036, 831.
3.1.8.18. 1-(2-Chloroethyl)-3-(4-hydroxyphenyl)urea (58A). Yield:
87.6%, Rf = 0.68 (EtOAc), mp 135–137 °C, IR (KBr, cmꢀ1): 3307,
3031, 1635, 1585, 1508, 1465, 1238, 835.
3.1.9.7. 1-[4-(2-Pyridinylmethoxy)phenyl]imidazolidin-2-one
(63A). Yield: 81.1%, Rf = 0.13 (50% EtOAc in n-hexane), mp 184–
185 °C, PMR (CDCl3): d 8.58–8.60 (m, 1H), 7.68–7.72 (m, 1H),
7.50–7.52 (m, 1H), 7.40–7.44 (m, 2H), 7.20–7.23 (m, 1H), 6.95–
6.99 (m, 2H), 5.19 (s, 2H), 4.95 (br s, 1H), 3.87–3.91 (m, 2H),
3.53–3.57 (m, 2H).
3.1.8.19. 1-(2-Chloroethyl)-3-[4-(4-nitrobenzyloxy)phenyl]urea
(59A). Yield: 62.2%, Rf = 0.31 (50% EtOAc in n-hexane), mp 191–
193 °C, IR (KBr, cmꢀ1): 3301, 1629, 1595, 1527, 1515, 1452, 1344,
1244, 1174, 1109, 1047, 835, 736, PMR (CDCl3): d 8.20–8.23 (d,
2H), 8.15 (br s, 1H), 7.61–7.64 (d, 2H), 7.30–7.32 (d, 2H), 6.85–
6.87 (d, 2H), 6.22–6.24 (t, 1H), 5.14 (s, 2H), 3.62–3.65 (m, 2H),
3.51–3.55 (m, 2H).
3.1.9.8. 1-[4-(2-Pyridinylmethoxy)phenyl]tetrahydropyrimidin-
2(1H)-one (63B). Yield: 56.1%, Rf = 0.57 (EtOAc), mp 211–212 °C, IR
(KBr, cmꢀ1): 3223, 2987, 1670, 1494, 1444, 1249, 1179, 1039, 837,
PMR (DMSO-d6): d 8.58–8.59 (m, 1H), 7.68–7.73 (m, 1H), 7.50–
7.52 (m, 1H), 7.18–7.23 (m, 3H), 6.94–6.97 (m, 2H), 5.19 (s, 2H),
4.87 (br s, 1H), 3.62–3.65 (m, 2H), 3.40–3.43 (m, 2H), 2.04–2.17
(m, 2H).
3.1.9. General procedure for the synthesis of cyclic urea deriva-
tives (60–69)
Linear urea derivatives (49–59) (2.3 mmol) were dissolved in
dry THF (10 mL) and cooled to 0–5 °C. Sodium hydride (4.6 mmol)
was added to the above solution in fractions at such a rate that the
temperature of the reaction mixture did not rise above 10 °C. After
the addition was over the reaction mixture was stirred at rt (about
30 °C) for 1 h. The reaction mixture was poured into ice-water
(150 mL) and the solid so appeared was filtered and dried to get
the title compound as solid.
3.1.9.9. 1-[4-(4-Methoxybenzyloxy)phenyl]imidazolidin-2-one
(64A). Yield: 72.9%, Rf = 0.64 (70% EtOAc in n-hexane), mp 192–
193 °C, IR (KBr, cmꢀ1): 3265, 2912, 1681, 1516, 1246, 1020, 827,
PMR (DMSO-d6): d 7.91 (br s, 1H), 7.40–7.46 (m, 2H), 7.33–7.38
(m, 2H), 7.21–7.23 (m, 1H), 6.85–6.93 (m, 3H), 4.96 (s, 2H),
3.74–3.84 (m, 5H), 3.30–3.35 (m, 2H).
3.1.9.1. 1-[4-(2-Isobutyl-4-quinolinylmethoxy)phenyl]imidaz-
olidin-2-one (60A). Yield: 52.0%, Rf = 0.39 (70% EtOAc in n-hex-
ane), mp 154–155 °C, IR (KBr, cmꢀ1): 3242, 2955, 1685, 1606,
1516, 1292, 1240, 1024, 827, PMR (DMSO-d6): d 8.00–8.04 (m,
2H), 7.80 (s, 1H), 7.69–7.73 (m, 1H), 7.54–7.57 (m, 1H), 7.44–
7.48 (m, 2H), 7.01–7.03 (m, 2H), 6.44 (br s, 1H), 5.51 (s, 2H),
3.1.9.10. 1-[4-(4-Methoxybenzyloxy)phenyl]tetrahydropyrimi-
din-2(1H)-one (64B). Yield:80.1%,Rf = 0.64(70%EtOAcinn-hexane),
mp 218–220 °C, IR (KBr, cmꢀ1): 3217, 2955, 1647, 1585, 1510, 1244,
1174, 1030, 827, 810, PMR (DMSO-d6): d 7.33–7.35 (d, 2H), 7.14–
7.16 (d, 2H), 6.88–6.90 (m, 4H), 6.27 (br s, 1H), 4.96 (s, 2H), 3.79 (s,
3H), 3.58–3.61 (m, 2H), 3.30–3.330 (m, 2H), 2.00–2.02 (m, 2H).

S. DasGupta et al. / Bioorg. Med. Chem. 17 (2009) 3604–3617
3613
3.1.9.11. 1-[4-(1-Naphthylmethoxy)phenyl]imidazolidin-2-one
(65A). Yield: 98.1%, Rf = 0.64 (70% EtOAc in n-hexane), mp 190–
191 °C, PMR (CDCl3): d 8.04–8.07 (m, 1H), 7.87–7.91 (m, 2H),
7.59–7.61 (m, 1H), 7.52–7.55 (m, 2H), 7.44–7.49 (m, 3H), 6.99–
7.02 (m, 2H), 6.29 (br s, 1H), 5.46 (s, 2H), 3.85–3.89 (m, 2H),
3.49–3.53 (m, 2H).
3.1.10.1. Ethyl 2-{3-[4-(2-isobutyl-4-quinolinylmethoxy)phenyl]-
2-oxo-1-imidazo- lidinyl}propionate (70A). Yield: 48.5%, Rf = 0.39
(50% EtOAc in n-hexane), mp 122–123 °C, IR (KBr, cmꢀ1): 2953, 1739,
1689, 1518, 1278, 1245, 1182, 1076, 831, 769.
3.1.10.2. Ethyl 2-{3-[4-(2-isobutyl-4-quinolinylmethoxy)phenyl]-
2(1H)-oxotetrahydro-1-pyrimidinyl}propionate
(70B). Yield:
3.1.9.12. 1-[4-(1-Naphthylmethoxy)phenyl]tetrahydropyrimidin-
2(1H)-one (65B). Yield: 83.7%, Rf =0.54 (70% EtOAc in n-hexane), mp
214–217 °C, PMR (DMSO-d6): d 8.02–8.04 (m, 1H), 7.85–7.91 (m,
2H), 7.69–7.71 (m, 1H), 7.54–7.59 (m, 2H), 7.50–7.52 (m, 1H), 7.20–
7.24 (m, 2H), 6.98–7.02 (m, 2H), 5.92 (br s, 1H), 5.47 (s, 2H), 3.61–
3.65 (m, 2H), 3.36–3.40 (m, 2H), 2.03–2.09 (m, 2H).
79.7%, Rf = 0.38 (50% EtOAc in n-hexane), mp 78–80 °C.
3.1.10.3. Ethyl 2-{3-[4-(2-ethyl-4-quinolinylmethoxy)phenyl]-
2-oxo-1-imidazolidinyl}propionate (71A). Yield: 56%, Rf = 0.53
(50% EtOAc in n-hexane), IR (KBr, cmꢀ1): 2926, 1739, 1701, 1518,
1437, 1280, 1242, 1180, 1020, 835, 763.
3.1.9.13. 1-[4-(4-Biphenylmethoxy)phenyl]imidazolidin-2-one
(66A). Yield: 98.0%, Rf = 0.17 (50% EtOAc in n-hexane), mp
262–263 °C, IR (KBr, cmꢀ1): 3257, 2924, 1681, 1516, 1246, 1153,
1016, 825.
3.1.10.4. Ethyl 2-{3-[4-(2-ethyl-4-quinolinylmethoxy)phenyl]-
2(1H)-oxotetrahydro-1-pyrimidinyl}propionate
65.1%, Rf = 0.29 (50% EtOAc in n-hexane).
(71B). Yield:
3.1.10.5. Ethyl
2-{2-oxo-3-[4-(2-phenyl-4-quinolinmeth-
oxy)phenyl]-1-imidazolidinyl}propionate (72A). Yield: 61%,
Rf =0.32 (30% EtOAc in n-hexane).
3.1.9.14. 1-[4-(4-Biphenylmethoxy)phenyl]tetrahydropyrimidin-
2(1H)-one (66B). Yield: 83.8%, Rf = 0.17 (EtOAc), mp 248–250 °C, IR
(KBr, cmꢀ1): 3221, 1645, 1510, 1242, 1224, 1033, 829, 758, 698.
3.1.10.6. Ethyl 2-{3-[4-(2-phenyl-4-quinolinylmethoxy)phenyl]-
2(1H)-oxotetrahydro-1-pyrimidinyl}propionate
56.6%, Rf = 0.42 (EtOAc).
(72B). Yield:
3.1.9.15. 1-[4-(4-Methoxythiobenzyloxy)phenyl]imidazolidin-
2-one (67A). Yield: 100%, Rf = 0.14 (50% EtOAc in n-hexane), mp
190–193 °C, IR (KBr, cmꢀ1): 3265, 2924, 1685, 1608, 1500, 1483,
1251, 1151, 1031, 835, 812.
3.1.10.7. Ethyl 2-{2-oxo-3-[4-(2-pyridinylmethoxy)phenyl]-1-
imidazolidinyl}propionate (73A). Yield: 58.9%, Rf = 0.28 (50%
EtOAc in n-hexane), mp 80–83 °C, PMR (CDCl3): d 8.56–8.60 (m,
1H), 7.68–7.72 (m, 1H), 7.50–7.52 (m, 1H), 7.42–7.46 (m, 2H),
7.20–7.22 (m, 1H), 6.94–6.98 (m, 2H), 5.19 (s, 2H), 4.69–4.75 (q,
1H, J = 7.51 Hz), 4.16–4.21 (m, 2H), 3.76–3.86 (m, 2H), 3.61–3.68
(m, 1H), 3.48–3.54 (m, 1H), 1.45–1.47 (d, 3H, J = 7.48 Hz), 1.25–
1.29 (t, 3H).
3.1.9.16. 1-(4-Benzyloxyphenyl)imidazolidin-2-one (68A). Yield:
99.3%, Rf = 0.24 (50% EtOAc in n-hexane), mp 216–219 °C, IR (KBr,
cmꢀ1): 3259, 1681, 1514, 1245, 1150, 1004, 827, PMR (CDCl3): d
7.40–7.48 (m, 4H), 7.35–7.39 (m, 2H), 7.29–7.33 (m, 1H), 6.91–
6.94 (m, 2H), 6.29 (br s, 1H), 5.04 (s, 2H), 3.83–3.89 (m, 2H),
3.47–3.53 (m, 2H).
3.1.10.8. Ethyl 2-{3-[4-(2-pyridinylmethoxy)phenyl]-2(1H)-oxo-
3.1.9.17. 1-(4-Benzyloxyphenyl)tetrahydropyrimidin-2(1H)-one
(68B). Yield: 93.5%, Rf = 0.53 (70% EtOAc in n-hexane), mp 230–
231 °C, IR (KBr, cmꢀ1): 3222, 2979, 1666, 1490, 1448, 1248, 1178,
1036, 833, PMR (DMSO-d6): d 7.35–7.42 (m, 4H), 7.28–7.32 (m,
1H), 7.16–7.19 (d, 2H, J = 8.84 Hz), 6.89–6.93 (d, 2H, J = 8.88 Hz),
6.01 (br s, 1H), 5.04 (s, 2H), 3.60–3.63 (m, 2H), 3.34–3.37 (m,
2H), 2.01–2.07 (m, 2H).
tetrahydro-1-pyrimi-
dinyl}propionate
(73B). Yield:
82.2%,
Rf = 0.17 (50% EtOAc in n-hexane).
3.1.10.9. Ethyl 2-{3-[4-(4-methoxybenzyloxy)phenyl]-2-oxo-1-
imidazolidinyl}propionate (74A). Yield: 64.2%, Rf =0.55 (50%
EtOAc in n-hexane).
3.1.10.10. Ethyl 2-{3-[4-(4-methoxybenzyloxy)phenyl]-2(1H)-
oxotetrahydro-1-pyrimidinyl}propionate (74B). Yield: 56.7%,
Rf = 0.21 (30% EtOAc in n-hexane), IR (KBr, cmꢀ1): 2955, 1737,
1645, 1514, 1249, 1180, 1026, 829, 756.
3.1.9.18. 1-[4-(4-Nitrobenzyloxy)phenyl]imidazolidin-2-one
(69A). Yield: 85.2%, Rf = 0.37 (EtOAc), mp 200–201 °C, IR (KBr,
cmꢀ1): 3273, 2929, 1693, 1583, 1514, 1433, 1350, 1257,
1232, 1186, 1051, 827.
3.1.10.11. Ethyl 2-{3-[4-(1-naphthylmethoxy)phenyl]-2-oxo-1-
imidazolidinyl}propionate (75A). Yield: 58%, Rf = 0.31 (30% EtOAc
in n-hexane).
3.1.10. General procedure for the synthesis of ester derivatives
(70–79)
Imidazolidin-2-ones (60–69) (2.5 mmol) were dissolved in dry
THF (10 mL) and cooled to 0–5 °C. Sodium hydride (0.34 g,
7.5 mmol) was added at this temperature to the reaction mixture.
The reaction mixture was refluxed for 2 h. Ethyl 2-bromopropio-
nate (5.0 mmol) was added to the reaction mixture drop-wise
and it was further refluxed for 2 h. The reaction mixture was al-
lowed to cool to rt and poured into ice-water (100 mL). The aque-
ous solution was extracted with chloroform (4 ꢂ 25 mL); the
combined organic layer was dried over anhydrous sodium sulfate
and the solvent removed to get crude oily product. The crude prod-
uct thus obtained was purified by column chromatography over
silica gel using ethyl acetate in n-hexane as eluant to afford the de-
sired compound.
3.1.10.12. Ethyl
2-{3-[4-(1-naphthylmethoxy)phenyl]-2(1H)-
oxotetrahydro-1-pyrimidinyl}propionate (75B). Yield: 61.7%,
Rf = 0.55 (50% EtOAc in n-hexane), PMR (CDCl3): d 7.94–7.97 (m,
1H), 7.80–7.83 (m, 1H), 7.63–7.71(m, 1H), 7.45–7.52 (m, 2H),
7.25–7.31 (m, 1H), 7.13–7.18 (m, 2H), 6.95–6.98 (m, 1H), 6.75–
6.78 (m, 2H), 5.39 (s, 2H), 4.45–4.49 (q, 1H), 4.07–4.15 (m, 2H),
3.57–3.60 (m, 2H), 3.30–3.34 (m, 2H), 2.05–2.13 (m, 2H), 1.36–
1.38 (d, 3H), 1.19–1.22 (t, 3H).
3.1.10.13. Ethyl 2-{3-[4-(4-biphenylmethoxy)phenyl]-2-oxo-1-
imidazolidinyl}propionate (76A). Yield: 55.8%, Rf = 0.63 (50%
EtOAc in n-hexane), mp 163–164 °C, IR (KBr, cmꢀ1): 2982, 1739,
1689, 1514, 1278, 1242, 1182, 1014, 825, 744.

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S. DasGupta et al. / Bioorg. Med. Chem. 17 (2009) 3604–3617
3.1.10.14. Ethyl
2-{3-[4-(4-biphenylmethoxy)phenyl]-2(1H)-
1H), 7.51–7.55 (m, 2H), 7.08–7.11 (m, 2H), 5.74 (s, 2H), 4.58–
4.62 (q, 1H, J = 7.58 Hz), 3.81–3.91 (m, 2H), 3.65–3.71 (m, 1H),
3.51–3.58 (m, 1H), 3.42–3.46 (q, 2H, J = 7.61 Hz), 1.52–1.55 (t,
3H, J = 7.60 Hz), 1.46–1.48 (d, 3H, J = 7.52 Hz). Anal. Calcd for
C24H25N3O4: C, 68.72, H, 6.01, N, 10.02. Found: C, 68.44, H, 6.41,
N, 10.13.
oxotetrahydro-1-pyrim- idinyl}propionate (76B). Yield: 83.2%,
Rf = 0.39 (50% EtOAc in n-hexane), mp 119–120 °C, IR (KBr,
cmꢀ1): 2966, 1735, 1645, 1508, 1240, 1188, 1016, 840, 765.
3.1.10.15. Ethyl 2-{3-[4-(4-methoxythiobenzyloxy)phenyl]-2-
oxo-1-imidazolidinyl}propionate (77A). Yield: 60.4%, Rf = 0.49
(50% EtOAc in n-hexane), mp 90–95 °C, IR (KBr, cmꢀ1): 2924,
1732, 1701, 1514, 1273, 1199, 1031, 842, 754.
3.1.11.4. 2-{3-[4-(2-Ethyl-4-quinolinylmethoxy)phenyl]-2(1H)-
oxotetrahydro-1-pyrimidinyl}propionic acid (81B). Yield: 73.7%,
Rf = 0.12 (EtOAc), mp 182–183 °C, IR (KBr, cmꢀ1): 3448, 1723,
1652, 1506, 1436, 1248, 1182, 1036, 835, PMR (DMSO-d6): d
8.03–8.05 (m, 1H), 7.67–7.71 (m, 2H), 7.54–7.56 (m, 1H), 7.45–
7.49 (m, 2H), 7.23–7.26 (m, 1H), 6.90–7.03 (m, 2H), 5.34 (s, 2H),
4.75–4.79 (q, 1H), 3.48–3.51 (m, 2H), 3.37–3.42 (q, 2H), 3.26–
3.23 (m, 2H), 1.93–2.03 (m, 2H), 1.52–1.54 (t, 3H),1.32–1.36 (t,
3H). Anal. Calcd for C29H27N3O4: C, 69.27, H, 6.28, N, 9.69. Found:
C, 69.04, H, 6.73, N, 9.47.
3.1.10.16. Ethyl 2-[3-(4-benzyloxyphenyl)-2-oxo-1-imidazolidi-
nyl]propionate (78A). Yield: 53.3%, Rf = 0.82 (50% EtOAc in n-hex-
ane), mp 102–104 °C, IR (KBr, cmꢀ1): 2985, 1732, 1685, 1519, 1438,
1280, 1242, 1008, 831, 738, PMR (CDCl3): d 7.45–7.48 (m, 4H),
7.41–7.42 (m, 2H), 7.33–7.35 (m, 1H), 6.95–6.99 (m, 2H), 5.06 (s,
2H), 4.71–4.77 (q, 1H, J = 7.50 Hz), 4.18–4.24 (m, 2H), 3.82–3.88
(m, 2H), 3.66–3.70 (m, 1H), 3.51–3.56 (m, 1H), 1.47–1.49 (d, 3H,
J = 7.60 Hz), 1.28–1.31 (t, 3H).
3.1.11.5. 2-{3-[4-(2-Phenyl-4-quinolinylmethoxy)phenyl]-2-oxo-
1-imidazolidinyl}propionic acid (82A). Yield: 71.3%, Rf = 0.22
(EtOAc), mp 120–122 °C, IR (KBr, cmꢀ1): 3442, 2980, 1751, 1652,
1512, 1419, 1237, 1181, 1076, 836, 756, PMR (CDCl3): d 8.36–8.38
(m, 2H), 8.15–8.17 (m, 2H), 8.05 (s, 1H), 7.97–7.99 (m, 1H), 7.76–
7.80 (m, 2H), 7.46–7.55 (m, 4H), 7.02–7.06 (m, 2H), 5.57 (s, 2H),
4.66–4.71 (q, 1H), 3.81–3.86 (m, 2H), 3.60–3.66 (m, 1H), 3.50–3.55
(m, 1H), 1.49–1.51 (d, 3H), MS (m/z): 490.1 (M+Na)+, 468.1 (M+H)+,
422.1 (MꢀCOOH)+.
3.1.10.17. Ethyl
2-[3-(4-benzyloxyphenyl)-2(1H)-oxotetrahy-
dro-1-pyrimidinyl]propionate (78B). Yield: 52.3%, Rf = 0.66 (50%
EtOAc in n-hexane).
3.1.10.18. Ethyl
2-{3-[4-(4-nitrobenzyloxy)phenyl]-2-oxo-1-
imidazolidinyl}pro- pionate (79A). Yield: 80.7%, Rf = 0.47 (50%
EtOAc in n-hexane), mp 126–128 °C, IR (KBr, cmꢀ1): 2923, 1732,
1693, 1514, 1487, 1352, 1272, 1197, 1047, 835, 738.
3.1.11. General procedure for the synthesis of acids (80–89)
Ester derivatives (70–79) (0.7 mmol) were dissolved in metha-
nol (5 mL). Sodium hydroxide (1.4 mmol) or lithium hydroxide
(3.5 mmol) was dissolved in distilled water (5 mL) and the solution
was added to the above reaction mixture drop-wise with stirring at
rt for 2 h. Methanol was recovered from the reaction mixture and
ice-water (20 mL) was added to it. The reaction mixture was acid-
ified with concd HCl (5 mL). The solid so appeared was filtered and
dried. The crude product so obtained was crystallized from meth-
anol to afford the desired compound.
3.1.11.6. 2-{3-[4-(2-Phenyl-4-quinolinylmethoxy)phenyl]-2(1H)-
oxotetrahydro-1-pyrimidinyl}propionic acid (82B). Yield: 86.0%,
Rf = 0.22 (10% MeOH in CHCl3), mp 124–127 °C, IR (KBr, cmꢀ1):
3412, 2937, 1734, 1639, 1602, 1508, 1444, 1298, 1182, 1028, 771,
PMR (DMSO-d6): d 8.17–8.23 (m, 2H), 8.10 (s, 1H), 8.04–8.06 (m,
1H), 7.80–7.86 (m, 2H), 7.61–7.65 (m, 1H), 7.46–7.56 (m, 3H),
7.22–7.24 (d, 2H, J = 8.88 Hz), 7.04–7.06 (d, 2H, J = 8.92 Hz), 5.60
(s, 2H), 5.02–5.08 (q, 1H, J = 7.29 Hz), 3.64–3.67 (m, 2H), 3.42–3.46
(m, 2H), 2.06–2.12 (m, 2H), 1.42–1.44 (d, 3H, J = 7.40 Hz). Anal. Calcd
for C29H27N3O4: C, 72.33, H, 5.65, N, 8.73. Found: C, 72.46, H, 5.87, N,
9.02.
3.1.11.1. 2-{3-[4-(2-Isobutyl-4-quinolinylmethoxy)phenyl]-2-
oxo-1-imidazolidinyl}propionic acid (80A). Yield: 69.9%,
Rf = 0.55 (70% EtOAc in n-hexane), mp 192–195 °C, IR (KBr,
cmꢀ1): 3483, 2981, 1748, 1652, 1512, 1487, 1248, 1075, 827,
750, PMR (DMSO-d6): d 8.02–8.04 (m, 1H), 7.78–7.82 (m, 1H),
7.62–7.66 (m, 1H), 7.57 (s, 1H), 7.43–7.52 (m, 3H), 7.01–7.04
(m, 2H), 5.56 (s, 2H), 4.64–4.70 (q, 1H, J = 7.50 Hz), 3.82–3.90
(m, 2H), 3.68–3.72 (m, 1H), 3.52–3.56 (m, 1H), 2.90–2.99 (m,
2H), 2.24–2.28 (m, 1H), 1.47–1.49 (d, 3H, J = 7.52 Hz), 0.98–
1.00 (d, 6H), MS (m/z): 470.0 (M+Na)+, 447.9 (M+H)+.
3.1.11.7. 2-{2-Oxo-3-[4-(2-pyridinylmethoxy)phenyl]-1-imidazo-
lidinyl}propionic acid (83A). Yield: 73.3%, Rf = 0.35 (70% EtOAc in n-
hexane), mp 179–180 °C, IR (KBr, cmꢀ1): 3444, 2980, 1752, 1652,
1506, 1436, 1250, 1134, 1027, 813, 744, PMR (DMSO-d6): d 8.57–
8.58 (m, 1H), 7.71–7.75 (m, 1H), 7.51–7.52 (m, 1H), 7.42–7.46 (m,
2H), 7.23–7.26 (m, 1H), 6.93–6.96 (m, 2H), 5.17 (s, 2H), 4.60–4.65
(q, 1H, J = 7.39 Hz), 3.77–3.85 (m, 2H), 3.65–3.68 (m, 1H), 3.50–
3.54 (m, 1H), 1.45–1.47 (d, 3H, J = 7.48 Hz). Anal. Calcd for
C18H19N3O4: C, 63.33, H, 5.61, N, 12.31. Found: C, 63.84, H, 5.98, N,
12.01.
3.1.11.2. 2-{3-[4-(2-Isobutyl-4-quinolinylmethoxy)phenyl]-2(1H)-
oxotetrahydro-1-pyrimidinyl}propionic acid (80B). Yield: 54.2%,
Rf = 0.22 (EtOAc), mp 129–131 °C, IR (KBr, cmꢀ1): 3445, 2980, 1734,
1652, 1436, 1242, 1178, 1026, 830, PMR (CDCl3): d 8.11–8.13 (m,
1H), 7.91–7.93 (m, 1H), 7.68–7.72 (m, 1H), 7.55–7.52 (m, 1H), 7.41
(s, 1H), 7.20–7.22 (d, 2H, J = 8.84 Hz), 7.01–7.03 (d, 2H, J = 8.84 Hz),
5.50 (s, 2H), 4.71–4.74 (q, 1H, J = 7.24 Hz), 3.64–3.67 (m, 2H), 3.41–
3.44 (m, 2H), 2.84–2.86 (d, 2H), 2.14–2.22 (m, 3H), 1.51–1.53 (d,
3H, J = 7.28 Hz), 0.95–0.97 (d, 6H). Anal. Calcd for C22H31N3O4: C,
70.26, H, 6.77, N, 9.10. Found: C, 69.92, H, 6.93, N, 9.23.
3.1.11.8. 2-{3-[4-(2-Pyridinylmethoxy)phenyl]-2(1H)-oxotetra-
hydro-1-pyrimidinyl}propionic acid (83B). Yield: 84.5%, Rf = 0.27
(80% EtOAc in n-hexane), mp 183–185 °C, IR (KBr, cmꢀ1): 3446,
2984, 1730, 1652, 1502, 1436, 1249, 1178, 1021, 826, 758, PMR
(DMSO-d6): d 8.57–8.58 (m, 1H), 7.69–7.72 (m, 1H), 7.50–7.52
(m, 1H), 7.24–7.27 (m, 1H), 7.16–7.18 (d, 2H, J = 8.88 Hz), 6.91–
6.94 (d, 2H, J = 8.96 Hz), 5.17 (s, 2H), 5.03–5.08 (q, 1H,
J = 7.41 Hz), 3.62–3.65 (m, 2H), 3.40–3.45 (m, 2H), 2.00–2.08 (m,
2H), 1.42–1.43 (d, 3H, J = 7.40 Hz), MS (m/z): 394.0 (M+K)+, 378.0
(M+Na)+, 355.8 (M+H) +, 309.7 (MꢀCOOH)+.
3.1.11.3. 2-{3-[4-(2-Ethyl-4-quinolinylmethoxy)phenyl]-2-oxo-
1-imidazolidinyl}propionic acid (81A). Yield: 89.5%, Rf = 0.50
(70% EtOAc in n-hexane), mp 214–215 °C, IR (KBr, cmꢀ1): 3446,
1730, 1637, 1514, 1485, 1442, 1242, 831, 746, PMR (DMSO-d6): d
8.25–8.27 (m, 1H), 7.99–8.03 (m, 2H), 7.84–7.88 (m, 1H), 7.67 (s,
3.1.11.9. 2-{3-[4-(4-Methoxybenzyloxy)phenyl]-2-oxo-1-imi-
dazolidinyl}propionic acid (84A). Yield: 77.2%, Rf = 0.14 (50%
EtOAc in n-hexane), mp 159–160 °C, IR (KBr, cmꢀ1): 2900, 1749,
1658, 1490, 1444, 1282, 1244, 1180, 1008, 873, 752, PMR (DMSO-

S. DasGupta et al. / Bioorg. Med. Chem. 17 (2009) 3604–3617
3615
d6):d 7.42–7.45 (m, 2H), 7.32–7.35 (m, 2H), 6.88–6.94 (m, 4H), 4.95(s,
2H), 4.60–4.63 (q, 1H, J = 7.52 Hz), 3.80–3.86 (m, 5H), 3.65–3.69 (m,
1H), 3.51–3.55 (m, 1H), 1.45–1.47 (d, 3H, J = 7.48 Hz). Anal. Calcd for
C20H22N2O5: C, 64.85, H, 5.99, N, 7.56. Found: C, 65.10, H, 6.29, N, 7.12.
7.41 (m, 2H), 7.31–7.33 (m, 1H), 7.03–7.06 (m, 2H), 5.04 (s, 2H),
4.62–4.68 (q, 1H, J = 7.48 Hz), 3.90–3.98 (m, 2H), 3.62–3.66 (m,
1H), 3.54–3.58 (m, 1H), 1.51–1.53 (d, 3H, J = 7.48 Hz). Anal. Calcd
for C19H20N2O4: C, 67.05, H, 5.92, N, 8.23. Found: C, 66.86, H, 6.13,
N, 8.12.
3.1.11.10. 2-{3-[4-(4-Methoxybenzyloxy)phenyl]-2(1H)-oxotet-
rahydro-1-pyrimidi- nyl}propionic acid (84B). Yield: 81.4%,
Rf = 0.61 (70% EtOAc in n-hexane), mp 184–186 °C, IR (KBr,
cmꢀ1): 3446, 2954, 1737, 1685, 1517, 1450, 1251, 1174, 1029,
833, 744, PMR (DMSO-d6): d 7.33–7.35 (d, 2H), 7.14–7.16 (d, 2H),
6.88–6.91 (m, 4H), 4.96–5.01 (m, 3H), 3.80 (s, 3H), 3.60–3.65 (m,
2H), 3.40–3.43 (m, 2H), 2.09–2.17 (m, 2H), 1.40–1.42 (d, 3H), MS
(m/z): 407.0 (M+Na)+, 384.8 (M+H)+.
3.1.11.17. 2-[3-(4-Benzyloxyphenyl)-2(1H)-oxotetrahydro-1-
pyrimidinyl]propionic acid (88B). Yield: 56.5%, Rf = 0.64(70%EtOAc
in n-hexane), mp 207–209 °C, IR (KBr, cmꢀ1): 2981, 1743, 1643, 1566,
1446, 1298, 1174, 1026, 831, 754, PMR(DMSO-d6): d7.38–7.43 (m, 4H),
7.30–7.33 (m, 1H), 7.15–7.18 (d, 2H, J = 8.96 Hz), 6.90–6.92 (d, 2H,
J = 8.92 Hz), 5.03–5.05 (m, 3H), 3.62–3.65 (m, 2H), 3.37–3.42 (m, 2H),
2.09–2.15 (m, 2H), 1.41–1.43 (d, 3H). Anal. Calcd for C20H22N2O4: C,
67.70, H, 6.25, N, 7.90. Found: C, 67.55, H, 6.46, N, 7.59.
3.1.11.11. 2-{3-[4-(1-Naphthylmethoxy)phenyl]-2-oxo-1-imidazo-
lidinyl}propionic acid (85A). Yield: 54.9%, Rf = 0.41 (70% EtOAc in n-
hexane), mp 187–190 °C, IR (KBr, cmꢀ1): 2926, 1728, 1635, 1510,
1446, 1276, 1170, 835, 756, PMR (CDCl3): d 8.05–8.07 (m, 1H), 7.84–
7.91 (m, 2H), 7.59–7.60 (m, 1H), 7.54–7.57 (m, 2H), 7.45–7.53 (m,
3H), 7.00–7.03 (m, 2H), 5.47 (s, 2H), 4.62–4.66 (q, 1H, J = 7.52 Hz),
3.78–3.88 (m, 2H), 3.65–3.71 (m, 1H), 3.50–3.56 (m, 1H), 1.47–1.48
(d, 3H, J = 7.48 Hz), MS (m/z): 412.8 (M+Na)+, 390.9 (M+H)+.
3.1.11.18. 2-{3-[4-(4-Nitrobenzyloxy)phenyl]-2-oxo-1-imidazo-
lidinyl}propionic acid (89A). Yield: 54.0%, Rf = 0.67 (EtOAc), mp
167–169 °C, IR (KBr, cmꢀ1): 2923, 1724, 1695, 1515, 1483, 1433,
1352, 1251, 1110, 839, 734, PMR (CDCl3): d 8.22–8.24 (d, 2H),
7.61–7.66 (d, 2H), 7.46–7.48 (d, 2H), 6.92–6.94 (d, 2H), 5.16 (s,
2H), 4.64–4.69 (q, 1H, J = 7.49 Hz), 3.80–3.88 (m, 2H), 3.73–3.78
(m, 1H), 3.49–3.55 (m, 1H), 1.46–1.48 (d, 3H, J = 7.52 Hz). Anal.
Calcd for C19H19N3O6: C, 59.22, H, 4.97, N, 10.90. Found: C, 58.94,
H, 5.24, N, 10.64.
3.1.11.12. 2-{3-[4-(1-Naphthylmethoxy)phenyl]-2(1H)-oxotet-
rahydro-1-pyrimidinyl}propionic acid (85B). Yield: 54.9%,
Rf = 0.73 (EtOAc), mp 207–209 °C, IR (KBr, cmꢀ1): 2985, 1737,
1643, 1502, 1444, 1296, 1180, 1024, 835, 777, PMR (DMSO-d6): d
8.02–8.05 (m, 1H), 7.85–7.91 (m, 2H), 7.55–7.61 (m, 2H), 7.45–
7.52 (m, 2H), 7.20–7.22 (d, 2H, J = 8.92 Hz), 6.99–7.01 (d, 2H,
J = 8.88 Hz), 5.47 (s, 2H), 5.04–5.08 (q, 1H, J = 7.44 Hz), 3.62–3.65
(m, 2H), 3.40–3.45 (m, 2H), 2.11–2.18 (m, 2H), 1.43–1.44 (d, 3H,
J = 7.40 Hz), MS (m/z): 343.0 (M+K)+, 427.0 (M+Na)+, 404.9 (M+H) +.
3.1.12. General procedure for the synthesis of hydroxamic acids
(90–99)
Hydroxylamine hydrochloride (75 mmol) was suspended in dry
methanol (10 mL). Potassium hydroxide (77 mmol) was dissolved
in methanol (10 mL) and added to the above suspension. The reac-
tion mixture was stirred at rt (around 35 °C) for 30 min. Ester
derivatives [(70–79) (0.7 mmol)] were added to the above reaction
mixture and it was stirred at rt for 3 h. Ice-water (15 mL) was
added to the reaction mixture. The reaction mixture was cooled be-
low 0 °C and concd HCl was added drop-wise until the pH was
around 6 and it was further stirred for 30 min. The aqueous layer
was extracted with chloroform (3 ꢂ 20 mL); the combined organic
layer was dried over anhydrous sodium sulfate and the solvent re-
moved to afford an oily product. The oil thus obtained was tritu-
rated with ether to obtain the desired product.
3.1.11.13. 2-{3-[4-(4-Biphenylmethoxy)phenyl]-2-oxo-1-imida-
zolidinyl}propionic acid (86A). Yield: 80.1%, Rf = 0.24 (EtOAc), mp
249–251 °C, IR (KBr, cmꢀ1): 3446, 2982, 1734, 1652, 1512, 1456,
1241, 1014, 826, 746, PMR (DMSO-d6): d 7.56–7.61 (m, 4H),
7.42–7.50 (m, 6H), 7.32–7.36 (m, 1H), 6.93–6.96 (m, 2H), 5.07 (s,
2H), 4.56–4.60 (q, 1H, J = 7.44 Hz), 3.76–3.83 (m, 2H), 3.65–3.67
(m, 1H), 3.49–3.50 (m, 1H), 1.43–1.45 (d, 3H, J = 7.44 Hz), Anal.
Calcd for C25H24N2O4: C, 72.10, H, 5.81, N, 6.73. Found: C, 71.92,
H, 6.12, N, 6.56.
3.1.12.1. N-Hydroxy-2-{3-[4-(2-isobutyl-4-quinolinylmethoxy)-
phenyl]-2-oxo-1-imidazolidinyl}propionamide
(90A). Yield:
3.1.11.14. 2-{3-[4-(4-Biphenylmethoxy)phenyl]-2(1H)-oxotetra
hydro-1-pyrimidinyl}propionic acid (86B). Yield: 69.8%, Rf = 0.26
(EtOAc), mp 204–205 °C, IR (KBr, cmꢀ1): 2981, 1743, 1641, 1446,
1242, 1180, 1026, 765, PMR (DMSO-d6): d 7.58–7.61 (m, 4H),
7.49–7.51 (m, 2H), 7.42–7.46 (m, 2H), 7.33–7.38 (m, 1H), 7.18–
7.20 (m, 2H), 6.96–6.94 (m, 2H), 5.06–5.10 (m, 3H), 3.63–3.66
(m, 2H), 3.38–3.44 (m, 2H), 2.10–2.19 (m, 2H), 1.44–1.46 (d, 3H),
Anal. Calcd for C26H26N2O4: C, 72.54, H, 6.09, N, 6.51. Found: C,
72.26, H, 6.27, N, 6.74.
62.2%, Rf = 0.24 (EtOAc), mp 190–192 °C, IR (KBr, cmꢀ1): 3440,
2985, 1684, 1623, 1506, 1456, 1241, 1076, 827, PMR (CDCl3): d
8.17–8.19 (m, 1H), 7.92–7.94 (m, 1H), 7.70–7.73 (m, 1H), 7.52–
7.55 (m, 1H), 7.39–7.45 (m, 3H), 6.98–7.02 (m, 2H), 5.49 (s, 2H),
4.71–4.68 (q, 1H, J = 7.28 Hz), 3.88–3.92 (m, 1H), 3.80–3.84 (m,
1H, 3.67–3.70 (m, 1H), 3.52–3.57 (m, 1H), 2.86–2.87 (d, 2H,
J = 6.48 Hz), 2.16–2.21 (m, 1H), 1.50–1.52 (d, 3H, J = 7.32 Hz),
0.95–0.96 (d, 6H). Anal. Calcd for C26H30N4O4: C, 67.51, H, 6.54,
N, 12.11. Found: C, 67.16, H, 6.97, N, 12.28.
3.1.11.15. 2-{3-[4-(4-Methoxythiobenzyloxy)phenyl]-2-oxo-1-
imidazolidinyl}propionic acid (87A). Yield: 44.4%, Rf = 0.61
3.1.12.2. N-Hydroxy-2-{3-[4-(2-isobutyl-4-quinolinylmethoxy)-
phenyl]-2(1H)-oxotetrahydro-1-pyrimidinyl}propionamide)
(90B). Yield: 57.5%, Rf = 0.22 (EtOAc), mp 116–118 °C, PMR (DMSO-
d6): d 8.11–8.13 (m, 1H), 7.89–7.91 (m, 1H), 7.68–7.72 (m, 1H),
7.49–7.53 (m, 1H), 7.40 (s, 1H), 7.18–7.20 (d, 2H), 6.97–6.99 (d,
2H), 5.45 (s, 2H), 4.69–4.73 (q, 1H), 3.60–3.63 (m, 2H), 3.36–3.40
(m, 2H), 2.83–2.85 (d, 2H), 2.09–2.231 (m, 3H), 1.46–1.47 (d, 3H),
0.94–0.96 (d, 6H). Anal. Calcd for C27H32N4O4: C, 68.05, H, 6.77,
N, 11.76. Found: C, 67.85, H, 7.01, N, 11.42.
(EtOAc), mp 156–158 °C, PMR (CDCl3):
d 7.42–7.44 (d, 2H,
J = 8.28 Hz), 7.26–7.28 (d, 2H, J = 8.36 Hz), 7.12–7.14 (d, 2H,
J = 8.36 Hz), 6.78–6.80 (d, 2H, J = 8.32 Hz), 4.68–4.72 (q, 1H,
J = 6.84 Hz), 3.99 (s, 2H), 3.80–3.84 (m, 2H), 3.77 (s, 3H), 3.62–
3.66 (m, 1H), 3.51–3.55 (m, 1H), 1.50–1.52 (d, 3H, J = 6.72 Hz),
MS (m/z): 409.3 (M+Na)+, 387.1 (M+H)+, 341.1 (MꢀCOOH)+.
3.1.11.16. 2-[3-(4-Benzyloxyphenyl)-2-oxo-1-imidazolidinyl]pr-
opionic acid (88A). Yield: 97.8%, Rf = 0.24 (70% EtOAc in n-hexane),
mp 214–217 °C, IR (KBr, cmꢀ1): 2916, 1751, 1666, 1492, 1450, 1282,
1255, 1184, 1053, 819, 734, PMR (CDCl3): d 7.43–7.58 (m, 4H), 7.36–
3.1.12.3. 2-{3-[4-(2-Ethyl-4-quinolinylmethoxy)phenyl]-2-oxo-1-
imidazolidinyl}-N-hydroxypropionamide
(91A). Yield: 65.6%,
Rf = 0.25 (EtOAc), mp 130 °C, IR (KBr, cmꢀ1): 3444, 2972, 1684,

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S. DasGupta et al. / Bioorg. Med. Chem. 17 (2009) 3604–3617
1506, 1387, 1254, 1018, 825, PMR (DMSO-d6): d 8.04–8.06 (m, 1H),
7.94–7.96 (m, 1H), 7.68–7.72 (m, 1H), 7.48–7.54 (m, 4H), 7.00–
7.21 (m, 2H), 5.47 (s, 2H), 4.53–4.57 (q, 1H), 3.81–3.77 (m, 2H),
3.65–3.68 (m, 2H), 2.96–3.01 (q, 2H), 1.36–1.40 (m, 6H). Anal. Calcd
for C24H26N4O4: C, 66.34, H, 6.03, N, 12.89. Found: C, 65.98, H, 6.28,
N, 12.69.
(m, 2H), 3.47–3.40 (m, 2H), 2.10–2.16 (m, 2H), 1.42–1.44 (d, 3H,
J = 7.36 Hz), MS (m/z): 407.0 (Mꢀ14+Na)+, 398.9 (MꢀH)+.
3.1.12.10. N-Hydroxy-2-{3-[4-(1-naphthylmethoxy)phenyl]-2-
oxo-1-imidazolidinyl}propionamide (95A). Yield: 58.9%, Rf = 0.73
(EtOAc), mp 172–173 °C, IR (KBr, cmꢀ1): 3446, 1684, 1506, 1277,
1232, 996, PMR (DMSO-d6): d 8.03–8.05 (m, 1H), 7.83–7.89 (m,
2H), 7.43–7.58 (m, 6H), 6.98–7.01 (m, 2H), 5.44 (s, 2H), 4.57–
4.61 (q, 1H), 3.80–3.83 (m, 2H), 3.64–3.68 (m, 2H), 1.44–1.45 (d,
3H), MS (m/z): 428.6 (M+Na)+, 404.8 (MꢀH)+, 391.0 (Mꢀ14)+,
344.8 (MꢀCONHOH)+.
3.1.12.4. N-Hydroxy-2-{3-[4-(2-ethyl-4-quinolinylmethoxy)-
phenyl]-2(1H)-oxotetra-hydro-1-pyrimidinyl}propionamide
(91B). Yield: 56.1%, Rf = 0.17 (EtOAc), mp 179–180 °C, PMR (DMSO-
d6): d 10.47 (br s, 1H), 8.78 (br s, 1H), 8.24–8.26 (m, 1H), 8.03–8.07
(m, 2H), 7.88–7.91 (m, 1H), 7.42 (s, 1H), 7.26–7.28 (d, 2H), 7.06–
7.08 (d, 2H), 5.75 (s, 2H), 5.06–5.11 (q, 1H, J = 7.40 Hz), 3.66–3.69
(m, 2H), 3.49–3.55 (m, 2H), 3.37–3.40 (m, 2H), 2.11–2.21 (m,
2H), 1.55–1.58 (t, 3H), 1.43–1.45 (d, 3H, J = 7.40 Hz), MS (m/z):
449.4 (M+H)+, 434.1 (Mꢀ14)+, 388.1 (MꢀCONHOH)+.
3.1.12.11. N-Hydroxy-2-{3-[4-(1-naphthylmethoxy)phenyl]-2-
(1H)-oxotetrahydro-1-pyrimidinyl}propionamide (95B). Yield:
52.5%, Rf = 0.72 (EtOAc), mp 202–203 °C, IR (KBr, cmꢀ1): 3440,
2991, 1652, 1508, 1436, 1296, 1221, 1169, 835, 750, PMR (CDCl3):
d 8.02–8.04 (m, 1H), 7.85–7.91 (m, 1H), 7.58–7.60 (m, 2H), 7.52–
7.55 (m, 2H), 7.50–7.46 (m, 1H), 7.20–7.22 (d, 2H, J = 8.84 Hz),
7.00–7.02 (d, 2H, J = 8.88 Hz), 5.47 (s, 2H), 5.07–5.13 (q, 1H,
J = 7.39 Hz), 3.65–3.72 (m, 2H), 3.36–3.45 (m, 2H), 2.17–2.21 (m,
1H), 2.07–2.12 (m, 1H), 1.44–1.45 (d, 3H, J = 7.44 Hz), MS (m/z):
442.9 (M+Na)+, 427.0 (Mꢀ14+Na)+, 418.9 (MꢀH)+, 404.9
(Mꢀ14)+, 358.8 (MꢀCONHOH)+.
3.1.12.5. N-Hydroxy-2-{3-[4-(2-phenyl-4-quinolinylmethoxy)
phenyl]-2(1H)-oxotetrahydro-1-pyrimidinyl}propionamide
(92B). Yield: 60.5%, Rf = 0.17 (10% MeOH in CHCl3), mp 132–134 °C,
IR (KBr, cmꢀ1): 3414, 3203, 2937, 1680, 1602, 1508, 1444, 1238,
1182, 1028, 771, PMR (DMSO-d6): d 8.17–8.19 (m, 2H), 8.08 (s,
1H), 8.03–8.05 (m, 2H), 7.75–7.79 (m, 1H), 7.58–7.62 (m, 1H),
7.52–7.55 (m, 2H), 7.45–7.49 (m, 1H), 7.22–7.25 (d, 2H,
J = 8.88 Hz), 7.04–7.07 (d, 2H, J = 8.96 Hz), 5.60 (s, 2H), 5.03–5.06
(q, 1H), 3.62–3.68 (m, 2H), 3.39–3.46 (m, 2H), 2.07–2.16 (m, 2H),
1.37–1.39 (d, 3H). Anal. Calcd for C29H28N4O4: C, 70.15, H, 5.63,
N, 11.28. Found: C, 69.93, H, 5.89, N, 11.03.
3.1.12.12. 2-{3-[4-(4-Biphenylmethoxy)phenyl]-2-oxo-1-imida-
zolidin}-N-hydoxypropionamide (96A). Yield: 55.0%, Rf = 0.25
(EtOAc), mp 242–243 °C, IR (KBr, cmꢀ1): 3493, 1684, 1506, 1484,
1277, 1242, 1014, 826, PMR (DMSO-d6): d 7.59–7.62 (m, 4H),
7.49–7.51 (m, 2H), 7.42–7.47 (m, 4H), 7.33–7.36 (m,1H), 6.95–
6.97 (d, 2H), 5.09 (s, 2H), 4.62–4.66 (q, 1H, J = 7.48 Hz), 3.79–3.86
(m, 2H), 3.66–3.68 (m, 1H), 3.52–3.56 (m, 1H), 1.46–1.48 (d, 3H,
J = 7.48 Hz). Anal. Calcd for C25H25N3O4: C, 69.59, H, 5.84, N, 9.74.
Found: C, 69.07, H, 6.03, N, 9.59.
3.1.12.6. N-Hydroxy-2-{2-oxo-3-[4-(2-pyridinylmethoxy)phenyl]-
1-imidazolidinyl}propionamide (93A). Yield: 67.4%, Rf = 0.12 (70%
EtOAc in n-hexane), mp 170–171 °C, IR (KBr, cmꢀ1): 3448, 1684,
1615, 1517, 1436, 1248, 1056, 827, 749, PMR (CDCl3): d 8.58–8.59
(m, 1H), 7.71–7.75 (m, 1H), 7.51–7.53 (m, 1H), 7.41–7.44 (m, 2H),
7.23–7.26 (m, 1H), 6.94–6.96 (m, 2H), 5.17 (s, 2H), 4.61–4.65 (q,
1H), 3.77–3.90 (m, 2H), 3.64–3.68 (m, 1H), 3.51–3.55 (m, 1H),
1.45–1.47 (d, 3H), MS (m/z): 374.1 (M+NH4)+, 341.9 (Mꢀ14)+, 296.4
(MꢀCONHOH)+.
3.1.12.13. 2-{3-[4-(4-Biphenylmethoxy)phenyl]-2(1H)-oxotet-
rahydro-1-pyrimidinyl}-N-hydroxypropionamide (96B). Yield:
69.7%, Rf = 0.16 (EtOAc), mp 233–235 °C, IR (KBr, cmꢀ1): 1643,
1581, 1242, 1172, 1029, 839, 732, PMR (DMSO-d6): d 10.09 (br s,
1H), 8.61 (br s, 1H), 7.63–7.58 (m, 4H), 7.49–7.51 (m, 2H), 7.42–
7.46 (m, 2H), 7.33–7.37 (m, 1H), 7.17–7.20 (d, 2H), 6.92–6.97 (d,
2H), 5.10 (s, 2H), 4.99–4.95 (q, 1H, J = 7.20 Hz), 3.60–3.63 (m,
2H), 3.39–3.45 (m, 2H), 2.06–2.16 (m, 2H), 1.38–1.37 (d, 3H,
J = 7.24 Hz), MS (m/z): 484.2 (M+K)+, 473.2 (M+Na)+, 431.1
(Mꢀ14)+, 413.1 (MꢀNHOH)+, 385.1 (MꢀCONHOH)+.
3.1.12.7. N-Hydroxy-2-{3-[4-(2-pyridinylmethoxy)phenyl]-2(1H)-
oxotetrahydro-1-pyrimidinyl}propionamide (93B). Yield: 67.4%,
Rf = 0.12 (70% EtOAc in n-hexane), mp 175–178 °C, IR (KBr, cmꢀ1):
3446, 1652, 1250, 1177, 1052, 827, 744, PMR (DMSO-d6): d 8.56–
8.57 (m, 1H), 7.72–7.76 (m, 1H), 7.49–7.51 (m, 1H), 7.25–7.28 (m,
1H), 7.15–7.17 (d, 2H, J = 8.36 Hz), 6.92–6.94 (d, 2H, J = 8.36 Hz),
5.14 (s, 2H), 4.96–4.99 (q, 1H, J = 7.44 Hz), 3.61–3.70 (m, 2H), 3.37–
3.48 (m, 2H), 2.05–2.15 (m, 2H), 1.41–1.43 (d, 3H, J = 7.40 Hz), MS
(m/z): 393.0 (M+Na)+, 378.7 (Mꢀ14+Na)+, 369.7 (MꢀH)+, 355.8
(Mꢀ14)+, 310.1 (MꢀCONHOH)+.
3.1.12.14. N-Hydroxy-2-{3-[4-(4-methoxythiobenzyloxy)phenyl]-
2-oxo-1-imidazolidinyl}propionamide (97A). Yield: 63.7%, Rf = 0.40
(EtOAc), mp 112–114 °C, PMR (DMSO-d6): d 7.52–7.55 (d, 2H, J =
8.76 Hz), 7.33–7.35 (d, 2H, J = 8.80 Hz), 7.21–7.23 (d, 2H, J = 8.52 Hz),
6.85–6.87 (d, 2H, J = 8.56 Hz), 4.65–4.69 (q, 1H, J = 7.40 Hz), 4.06 (s,
2H), 3.94–3.96 (m, 1H), 3.83–3.86 (m, 4H), 3.75–3.78 (m, 1H), 3.61–
3.64 (m, 1H), 1.49–1.51 (d, 3H, J=7.36 Hz). Anal. Calcd for C20H23N3O4S:
C, 59.83, H, 5.77, N, 10.47. Found: C, 59.48, H, 6.01, N, 10.29.
3.1.12.8. N-Hydroxy-2-{3-[4-(4-methoxybenzyloxy)phenyl]-2-
oxo-1-imidazolidinyl}propionamide
(94A). Yield:
57.0%,
Rf = 0.68 (70% EtOAc in n-hexane), mp 147–148 °C, IR (KBr,
cmꢀ1): 3448, 2985, 1695, 1506, 1456, 1245, 1175, 1007, 826,
PMR (DMSO-d6): d 7.41–7.45 (m, 2H), 7.33–7.35 (m, 2H), 6.89–
6.94 (m, 4H), 4.96 (s, 2H), 4.63–4.66 (q, 1H, J = 7.48 Hz), 3.79–
3.82 (m, 5H), 3.65–3.69 (m, 1H), 3.48–3.52 (m, 1H), 1.46–1.48
(d, 3H, J = 7.56 Hz), MS (m/z): 403.1 (M+NH4)+, 371.1 (Mꢀ14)+,
325.1 (MꢀCONHOH)+.
3.1.12.15. 2-[3-(3-Benzyloxyphenyl)-2-oxo-1-imidazolidinyl]-
N-hydroxypropionamide (98A). Yield: 77.8%, Rf = 0.30 (EtOAc),
mp 208–211 °C, IR (KBr, cmꢀ1): 3197, 2995, 1664, 1517, 1485,
1260, 1039, 735, PMR (CDCl3): d 10.70 (br s, 1H), 8.90 (br s, 1H),
7.48–7.52 (m, 4H), 7.42–7.46 (m, 2H), 7.35–7.39 (m, 1H), 7.02–
7.04 (m, 2H), 4.35–4.40 (q, 1H, J = 7.08 Hz), 3.78–3.87 (m, 2H),
3.62–3.68 (m, 1H), 3.51–3.58 (m, 1H), 1.32–1.34 (d, 3H,
J = 7.16 Hz). Anal. Calcd for C19H21N3O4: C, 64.21, H, 5.96, N,
11.82. Found: C, 64.03, H, 6.13, N, 11.67.
3.1.12.9. N-Hydroxy-2-{3-[4-(4-methoxybenzyloxy)phenyl]-2(1H)-
oxotetrahydro-1-pyrimidinyl}propionamide (94B). Yield: 60.9%,
Rf = 0.68 (70% EtOAc in n-hexane), mp 169–170 °C, IR (KBr, cmꢀ1):
3446, 1652, 1616, 1456, 1263, 1177, 1028, 827, 749, PMR (DMSO-
d6): d 7.33–7.35 (d, 2H), 7.15–7.17 (d, 2H), 6.89–6.91 (m, 4H),
5.01–5.05 (q, 1H, J = 7.40 Hz), 4.96 (s, 2H), 3.81 (s, 3H), 3.62–3.65
3.1.12.16. N-Hydroxy-2-{3-[4-benzyloxyphenyl]-2(1H)-oxotet-
rahydro-1-pyrimidinyl}propionamide
(98B). Yield:
67.6%,

S. DasGupta et al. / Bioorg. Med. Chem. 17 (2009) 3604–3617
3617
Rf = 0.34 (70% EtOAc in n-hexane), mp 175–177 °C, IR (KBr, cmꢀ1):
3059, 1693, 1566, 1508, 1444, 1242, 1174, 1026, 831, 752, PMR
(DMSO-d6): d 7.31–7.42 (m, 5H), 7.15–7.18 (m, 2H), 6.90–6.92
(m, 2H), 5.03 (s, 2H), 4.38–4.42 (m, 1H), 3.59–3.62 (m, 2H), 3.39–
3.41 (m, 2H), 2.07–2.17 (m, 2H), 1.40–1.43 (m, 3H). Anal. Calcd
for C20H23N3O4: C, 65.03, H, 6.27, N, 11.37. Found: C, 65.54, H,
6.68, N, 11.12.
were allowed to come to rt and the fluorescence was recorded
on spectrofluorimetric ELISA reader.
4. Conclusion
In this work, novel 2-imidazolidinones and tetrahydropyrimi-
din-2-(1H)-ones were synthesized and evaluated for their TACE
inhibitory activity. Most of the synthesized compounds showed
moderate to high TACE inhibitory activity. This work has provided
some important leads in the form of compounds (80A, 81A, 93A,
90A, and 91A) as potential TACE inhibitors. Biological activity data
are in accordance with the modeling study. Docking study clearly
reveals the importance of the P10 group for the TACE inhibitory
activity of these classes of compounds.
3.1.12.17. N-Hydroxy-2-{3-[3-(4-nitrobenzyloxy)phenyl]-2-oxo-
1-imidazolidinyl}propionamide (99A). Yield: 62.5%, Rf = 0.42 (70%
EtOAc in n-hexane), mp 128–129 °C, IR (KBr, cmꢀ1): 3232, 2923,
1670, 1515, 1483, 1436, 1346, 1249, 1058, 827, PMR (CDCl3): d
10.60 (br s, 1H), 8.80 (br s, 1H), 8.23–8.25 (d, 2H), 7.68–7.70 (d,
2H), 7.44–7.46 (d, 2H), 6.97–7.00 (d, 2H), 5.23 (s, 2H), 4.26–4.30
(q, 1H, J = 7.16 Hz), 3.70–3.77 (m, 2H), 3.54–3.60 (m, 2H), 1.25-
1.27 (d, 3H, J = 7.20 Hz). Anal. Calcd for C19H20N4O6: C, 57.00, H,
5.03, N, 13.99. Found: C, 56.87, H, 5.98, N, 14.16.
Acknowledgment
Two of the authors, S.D.G. and P.R.M., are thankful to All India
Council for Technical Education (A.I.C.T.E), Government of India,
New Delhi, India, for the award of National Doctoral Fellowship.
3.2. Molecular modeling (docking studies)
All the molecular modeling studies reported herein were per-
formed on a Silicon Graphics Fuel Workstation running on the
IRIX 6.5 operating system using SYBYL 6.9 molecular modeling soft-
ware from Tripos, Inc., USA31 and GLIDE from Schrödinger Inc.,
USA.32,33 All compounds used for docking were built from the
fragments in the SYBYL database. Each structure was fully geome-
try optimized using the standard Tripos force field with a dis-
tance-dependent dielectric function until a root mean square
deviation (rms) of 0.01 kcal/mol Å was achieved. Conformational
search was carried out using MULTISEARCH option in SYBYL 6.9.
The lowest energy conformer thus obtained was further mini-
mized using the Tripos force field and was subsequently used
in docking. The crystal structure of human TACE (pdb code:
2FV5) obtained from the Protein Data Bank (USA) was refined
to remove water molecules. The bond orders and formal charges
were adjusted prior to docking. Docking was performed using
References and notes
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GLIDE
protocol.32,33
software according to their previously reported
3.3. Biological screening
The method followed for the assay was as given in the proto-
col supplied by the manufacturer.28 The compounds were
weighed accurately in a micro-balance and dissolved in DMSO.
They were further diluted to prepare the desired concentrations.
The desired number of strips containing wells from the Innozy-
meTM TACE activity kit was removed and the remaining strips
were resealed in the foil pouch for further use. The wells were
washed well with wash buffer provided along with the kit for
two times and then the residual liquid was wiped off with paper
towel. The pure enzyme (Control) provided along with the kit
was diluted (1:50) with sample buffer provided in the kit as
per the protocol. Cell lysate was also diluted (1:50) with sample
buffer. 100 lL of control and cell lysate was added to all the
wells and covered with a plate sealer which was provided along
with the kit. It was then incubated at 25 °C for 1 h. The wells
were again washed with wash buffer for five times to remove
any deposited material on the wells. The test inhibitors
28. www.merckbiosciences.com/product/CBA042, User Protocol CBA042 Rev.
29. Crowe, P. D.; Walter, B. N.; Mohler, K. M.; Evans, C. O.; BVlack, R. A.; Ware, C. F.
J. Exp. Med. 1995, 181, 1205.
30. Aldrich Research Chemical Catalog, 2000, 1299.
31. SYBYL Molecular modeling system, version 6.9, Tripos, Inc., St. Louis, USA, 2003.
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Repasky, M. P.; Knoll, E. H.; Shelly, M.; Perry, J. K.; Shaw, D. E.; Francis, P.;
Shenkin, P. S. J. Med. Chem. 2004, 47, 1739.
(100
2 h at 25 °C. 20
l
L) were added to the designated wells and incubated for
L of diluted substrate (diluted with assay buffer
l
provided along with the kit, 1:10,000) was then added to each
well and then the wells were incubated at 37 °C for 4 h. They
33. Clark, M.; Crammer, R. D.; van Opdenbosh, N. J. Comput. Chem. 1989, 10, 982.