Computer based design, synthesis and biological evaluation of novel indole derivatives as HCV NS3-4A serine protease inhibitors

Article abstract of DOI:10.1016/j.bmc.2008.07.084

A series of novel indoles were designed and their molecular modeling simulation study including fitting to a 3D pharmacophore model using CATALYST program and their docking into the NS3 active site was examined as HCV NS3 protease inhibitor. Several compo

Full text of DOI:10.1016/j.bmc.2008.07.084

Bioorganic & Medicinal Chemistry 16 (2008) 7877–7887
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Computer based design, synthesis and biological evaluation of novel indole
derivatives as HCV NS3-4A serine protease inhibitors
b
b
c
c
Nasser S. M. Ismail a, , Riham Salah El Dine , Masao Hattori , Kazunori Takahashi , Masataka Ihara
*
a Pharmaceutical Chemistry Department, Faculty of Pharmacy Ain Shams University, Elkhalifa ElMaamoon Street, 11566 Abbasseya, Cairo, Egypt
b Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan
c Hoshi University, 2-4-41, Ebara, Shinagawa, Tokyo 142-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel indoles were designed and their molecular modeling simulation study including fitting
to a 3D pharmacophore model using CATALYST program and their docking into the NS3 active site was
examined as HCV NS3 protease inhibitor. Several compounds showed significant high simulation docking
score and fit values. The designed compounds were synthesized and biologically evaluated in vitro using
an NS3 protease binding assay, where compounds 10a–k showed significant inhibitory activity (P67%
Received 3 July 2008
Accepted 26 July 2008
Available online 3 August 2008
Keywords:
Molecular modeling
HCV
Protease synthesis
Indole derivatives
inhibition at 100
lg/mL). Of these, compounds 10c and 10f demonstrated potent HCV NS3 protease
inhibitors with IC50 values of 15 and 13
l
M, respectively. Enantio-selective Michael addition of an indole
derivative in the presence of catalytic amount of AlCl3 and quinine at room temperature afforded the
adduct 7e in excellent yield with 73% ee. The product was converted into 10l, which showed lower activ-
ity than the mixture of the corresponding diastereoisomers.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Inhibition of this enzyme has proven effective in reducing viral
loads in humans, and considerable efforts by different research
Hepatitis C virus (HCV) was identified in 1989 (Choo et al.) as
the etiological agent for non-A, non-B hepatitis, which is a lethal
single positive-stranded RNA virus.1 An estimated 200 million
cases of HCV infection exist worldwide.2 Of those infected, over
85% will develop chronic hepatitis, and 20% of the chronic infec-
tions progress to liver cirrhosis and hepatocellular carcinoma.3
Presently, there is no vaccine for HCV and there is no broadly
effective therapy for all genotypes of HCV.4 The current approved
groups have been directed toward development of HCV NS3 prote-
ase inhibitors.11 There have been several studies of the three-
dimensional structure of HCV protease, including the holo-enzyme
and inhibitor complexes. There are now several released crystal
structure of the HCV protease in the PDB. The binding modes of
inhibitors have been elucidated in multiple structure of inhibitor/
protease complexes.12 Harper and co-workers13 proposed a struc-
ture–activity relationship (SAR) and disclosed enzyme bound crys-
tal structure for indoline based peptidomimetic replacements for
the N-terminal amino acid of 1 (Fig. 1).
They found that the heterocyclic scaffolds, which replace the N-
terminal amino acid and capping group in peptides inhibitors,
could (i) retain the double hydrogen bonding interaction with
Ala157 observed in the enzyme bound crystal structure of peptide
based inhibitors14; (ii) orient a p2-p1amino acid sequence as an ac-
tive site ‘anchor’; (iii) direct pendant functionality to engage the
P3/S2 side chain interaction; and (iv) function as a bridge to auxil-
iary binding regions, such as those accessed by the N-terminal cap-
ping group in the peptide series. Our current investigation is based
on optimization of lead compound by molecular modeling studies
(pharmacophores model and docking), using the enzyme bound
crystal structure of indoline based peptidomimetic inhibitor,
which involve the synthesis of new indole derivatives by the
replacement of the indoline ring of the lead compound 2 with in-
dole. (i) The nitrogen of indole ring system makes H-bond donor
with Ala157 and also can accommodate the requisite lipophilic
interaction with S4,S613; (ii) additionally, from the molecular mod-
therapy with interferon-
a (IFN-a) is only partially effective and
treatment is accompanied by undesirable side effects.5 Further-
more, many of those who begin therapy with the current standard
(IFN-a) with ribavirin do not achieve viral clearance and the sus-
tained virological response (SVR) rates were limited (below 50%),
thereby resulting in limited patient compliance.6 Thus, it is highly
desirable to develop effective chemotherapeutic agents for treat-
ment of HCV-infected patients. The viral RNA genome encodes a
polyprotein that includes two proteases; the NS2-3 protease medi-
ates a single cleavage at the NS2/NS3 junction, whereas the NS3-4A
protease cleaves at four downstream sites in the polyprotein. NS3-
4A is characterized as a serine protease with a chymotrypsin-like
fold.7 The catalytic activity of NS3 is augmented by formation of
complex with the viral NS4A protein, and heterodimeric NS3-
NS4A is believed to be the physiologically relevant form of the en-
zyme,8,9 and plays a pivotal role in replication of the HCV virus.10
* Corresponding author. Tel.: +02 0107910346; fax: +02 024051107.
E-mail address: saadnasser2003@yahoo.com (N.S.M. Ismail).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.07.084

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N. S. M. Ismail et al. / Bioorg. Med. Chem. 16 (2008) 7877–7887
O
OH
CHF2
O
O
H
N
COOH
N
H
O
N
H
O
O
1
2
S
COOH
CHF2
COOH
O
H
N
N
N
H
H
O
O
3
Figure 1. NS3/4A protease inhibitors and the crystal structure of compound 3 with the NS3/4A complex.
eling studies it was found that aryl substitution on side chain in-
creases the hydrophobic interaction with Cys 159 more than ali-
phatic substitution; (iii) amidic carbonyl group side chain makes
H-bond with Gly 137 and Ser 139; and (iv) amino acid residue
interacts with lys 136 S2.
protease complex13 was obtained from protein data bank website
(pdb). This regularized protein complex structure was used in
determination of the active site that is mentioned in the literature.
Docking process was carried out for the test set of compounds
(10a–k) using the compound energy as scoring function.16 Retro-
spectively, we were pleased to note that the docking results were
consistent with the hypothesis fit values discussed below (Table
1). The designed compounds which showed high fit values and
docking scores were synthesized following the sequence outlined
in Schemes 1, 2, predicting that they would have a potent HCV
NS3 serine protease inhibitors.
In this project, molecular modeling simulation studies were
performed in order to predict the biological activity of the pro-
posed compounds. Firstly, the hypothesis generation was per-
formed by the manual technique using CATALYST software.15
This method is applicable when the 3D structure of the bioactive
conformation is known. The main idea of this approach is to iden-
tify the ideal hypothesis, which represents the geometry of the ac-
tive sites as a collection of functional groups in space. The
generated HCV NS3 protease inhibitors hypothesis was subjected
to simulation compare/fit studies, using the best fit algorithm, with
the conformational model of a test set of the proposed compounds
(10a–k). Secondly, Docking Study Using Molsoft ICM software was
also performed, where the crystal structure of inhibitor (3)/NS3
2. Results and discussion
2.1. Synthesis
For the synthesis of the target compounds 10a–k, the follow-
ing straightforward pathway was pursued: This involved conden-
Table 1
Best fit and docking conformer for each compound in the test set (10a–k) mapped with generated hypothesis and active site of HCV protease
R3
R1
O
H
COOH
N
H
H
R2
O
N
H
10a-k
Entry
R1
R2
R3
Compound
Fit value
Docking value (kcal/mol)
1
2
3
4
5
6
7
8
9
CH3O
CH3O
CH3O
CF3
CF3
CF3
CH3O
CH3O
CF3
CH3O
CF3
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
Br
Br
Br
CH3O
CH3O
p-OH–C6H4
3-Indolyl
Phenyl
p-OH–C6H4
3-Indolyl
Phenyl
p-OH–C6H4
3-Indolyl
p-OH–C6H4
4-Imidazolyl
4-Imidazolyl
10a
10b
10c
10d
10e
10f
10g
10h
10i
4.65
4.61
4.71
4.64
4.59
4.69
4.41
4.53
4.64
4.57
4.67
ꢀ86.16
ꢀ79.15
ꢀ89.96
ꢀ90.48
ꢀ88.71
ꢀ91.67
ꢀ79.91
ꢀ76.11
ꢀ84.13
ꢀ86.97
ꢀ88.43
10
11
10j
10k

N. S. M. Ismail et al. / Bioorg. Med. Chem. 16 (2008) 7877–7887
7879
R1
R1
O
O
OH
i
+
H3C
CHO
OH
OH
4a-b
O
O
5a-b
H
R1
R2
O
R1
R2
O
ii
+
O
N
OH
H
O
5a-b
N
H
6a-b
7a-d
R3
R1
R2
R3
COOR4
O
R1
R2
O
H
H
COOR4
iii
N
OH
H
H
H2N
+
O
H
O
8a-d
N
H
N
H
9a-k
7a-d
R3
iv
R1
R2
O
H
COOH
N
H
H
O
R1 = CF3, CH3O
R2 = CH3O, Br
N
H
10a-k
R3 = Ph, p -OH-C6H4, 3-indolyl, 4-imidazolyl
R4 = CH3, C2H5
Scheme 1. Reagents: (i) pipridine, acetic acid, benzene; (ii) dry ethanol, I2 ; (iii) EDAC, 1-hydroxybenzotriazol hydrate, triethylamine, DMF; (iv) THF, ethanol, LiOH, H2O.
sation of appropriate aldehydes 4a–b and levulenic acid using
catalytic amounts of piperidine and acetic acid in benzene under
reflux, with azeotropic removal of water using a Dean-Stark trap
to give hexenoic acid derivatives 5a–b.17 Under these conditions,
2.2. Molecular modeling
2.2.1. Generation of HCV NS3 protease inhibitors hypothesis
In this research, the bioactive conformer 3 was extracted from
the crystal structure of 3 with the NS3/NS4 complex published
by Harper et al. from 1w3c ‘PDB’ file using Cerus2 software. CATA-
LYST software was used for manual generation of hypothesis. The
validated hypothesis encompassed five features, namely hydro-
gen-bond acceptor (A), hydrogen-bond donor (D), two hydropho-
bic (H1 and H2), and negative ionizable (N) (Fig. 2). Recently,
Wei et al.21 reported a Hypogen-derived hypothesis generated
from a set of HCV NS3 protease inhibitors. Such a reported CATA-
LYST/HypoGen hypothesis consisted of five pharmacophore fea-
tures, namely hydrophobic, hydrophobic aromatic, hydrogen-
bond donor, hydrogen-bond acceptor, and negative ionizable.
However, the dimensions between the features in these Hypogen
hypotheses were not published. Herein, we report a new five-fea-
ture hypothesis (Fig. 2) that could be generated from the bioactive
conformer 3 in order to qualitatively prioritize the biological activ-
ity of the test set of HCV NS3 protease inhibitors. Such a hypothesis
has the same types of features such as the reported Hypogen
hypothesis. Additionally, we recorded the constraint angles and
distances between the different features of our hypothesis (see
Supporting Information). Crucially, we exploited our pharmaco-
phore model to design a small number of novel and potent HCV
NS3 protease inhibitors, and these were evaluated in vitro. The
structures of the test set of the target indoles were built using
the CATALYST software, and their conformational models were
generated in the energy range of 20 kcal/mol above the estimated
global energy minimum. The fitting of the tested compound was
performed using Best fit during the compare/fit process.15 Different
mappings for all the conformers of each compound of the test set
the enamine formed at the
a-methyl group of levulenic acid
adds to the aldehyde carbon followed by dehydration to afford
the arylidine keto acid derivatives 5a–b. 1H NMR shows the for-
mation of E-isomers where J = 16.15 Hz. The arylidene deriva-
tives 5a–b undergo Michael addition with indole derivatives
6a–b in the presence of catalytic amount of molecular I128 at
room temperature to afford the corresponding adducts 7a–d.
The attack on the indole nucleus occurred exclusively at the 3-
position. N-alkylation products have not been observed. Conden-
sation reactions of acidic derivatives 7a–d with amino acid es-
ters 8a–d using EDAC gave the corresponding ester derivatives
9a–k as a diastereoisomeric mixture, which was considered as
a prodrug.19 The obtained esters 9a–k were mildly hydrolyzed
to the target carboxylic acids 10a–k using lithium hydroxide at
room temperature.20
The above mentioned method for addition of indole to
a,b-
unsaturated ketones using molecular I2 affords 7a–d in racemic
mixture.18 The asymmetric version of this reaction can provide
a very useful approach to synthesis of single diastereoisomer
of the target compounds. Herein, we achieve effective asymmet-
ric synthesis for compound 7e (Scheme 2) through the reaction
of indole 6a with
a,b-unsaturated ketone 5a using quinine and
AlCl3 as a Lewis acid in chloroform to afford 7e with ½a D21
ꢁ
+16.51 (c 0.76%, methanol). The optical purity = 73% ee. was
determined by HPLC using chiral column Daicel chiralpak AD
(0.46 cm ꢂ 25 cm) eluting with hexane/i-PrOH = 95:5. The opti-
cally active intermediate 7e was then transformed into 10l,
½
a 2D2
ꢁ
ꢀ11.83 (c 0.79%, methanol).

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N. S. M. Ismail et al. / Bioorg. Med. Chem. 16 (2008) 7877–7887
H3CO
O
H
H3CO
O
H3CO
OH
i
O
+
OH
N
H
H3CO
O
NH
7e
6a
5a
ii
H3CO
O
H
OC2H5
O
H3CO
NH
7f
OCH3
H3CO
H
N
COOCH3
7e
COOH
H
H
H2N
8c
O
1-(iii)
2-(iv)
O
H
HN
10l
Scheme 2. Reagents: (i) quinine, AlCl3, CHCl3; (ii) dry ethanol, H2SO4; (iii) EDAC, 1-hydroxybenzotriazol hydrate, triethylamine, DMF, (iv) THF, ethanol, LiOH, H2O.
inhibitor 3 with the NS3/4A protease complex was used in deter-
mination of the active site, after regularization of protein and glo-
bal optimization of side chains,22 from the attached residues to the
ligand that are mentioned in the literature (Fig. 4a). In the flexible-
ligand-rigid enzyme docking, the enzyme was represented by six
potential energy maps, namely electrostatic, hydrogen bond,
hydrophobic, and three van der Waals. Interactive docking using
Mol table ligand was carried out for all the conformers of each
compound of the test set (10a–k) to the selected active site of
HCV protease. Each docked compound was assigned a score
according to its fit in the ligand binding pocket (LBP) (Table 1).
These molecular modeling simulation studies revealed that com-
pounds 10a, 10c, 10d, and 10f could be considered as promising
candidates, due to their high fit values as well as their high docking
scores. Accordingly, we synthesized these compounds and exam-
ined their biological activity.
Figure 2. Hypothesis of HCV NS3 protease inhibitors.
2.3. HCV protease assay
A HCV protease binding assay was carried out by competitive
displacement of the binding of peptide substrate (Ac-Asp-Glu-As-
to the hypothesis were visualized (Fig. 3) and the fit values of the
best-fitting conformers were found (Table 1).
p(EDANS)-Glu-Glu-Abu-w), the fluorescence intensities were mea-
sured, and the inhibition percentages were calculated (see
Supporting Information).19 The experiments were performed on
the candidate compounds as shown in Table 2. Over 67% inhibitory
2.2.2. Docking Study Using Molsoft ICM software
This technique considered as direct molecular modeling, where
the 3D structure of the enzyme was known and crystal structure of
Figure 3. Mapping of (a) compound 3, (b) compound 10c, and (c) compound 10f with the generated HCV NS3 protease inhibitors hypothesis.

N. S. M. Ismail et al. / Bioorg. Med. Chem. 16 (2008) 7877–7887
7881
Figure 4. Docking of (a) compound 3, (b) 10f, (c) compound 10a, (d) compound 10b, and (e) 10c, and (f) compound 10d to different representations for Y-shaped active site of
HCV NS3/4A protease enzyme.
Table 2
tively (Table 3). This promising result encourages us to enantio-
selective synthesis for (10l) to improve its inhibitory effect on ser-
Inhibitory effects of compounds 10a–k against hepatitis C virus (HCV) serine protease
ine protease. But compound 10l showed a lower activity than the
mixture of the corresponding diastereoisomers, this result could
be explained by the aid of molecular docking, where it was found
that the docking score of the (R,S) isomer of compound 10l was
ꢀ81.5 k cal/mol, while the other isomer (S,S) of compound 10l
was 91.4 k cal/mol (Fig. 5). This suggests that enantio-selective
synthesis of (7e) resulted in the (R) isomer, and consequently we
prepared the (R,S) isomer of compound 10l.
Compound
HCV-PR inhibition
(%) at100 g/Ml
HCV-PR inhibition
(%) at 50 g/mL
HCV-PR inhibition
(%) at 10 g/mL
l
l
l
10a
10b
10c
10d
10e
10f
10g
10h
10i
78.8
1
69.9 2.7
54.4 5.8
84.4 0.5
57.1 2.5
51.2 1.5
67.2 0.8
29.6
6
67.4 0.9
85.7 0.2
84.3 0.9
76.9 0.7
84.9 0.1
68.7 6.6
72.6 0.1
82.9 2.3
—
43.7 3.5
35.2 4.3
—
48.5 2.8
—
—
41.5
8
54.8 0.4
54.05 1.1
The low docking value of (R,S) isomer of compound 10l could be
attributed to the lack of formation of hydrogen bond between the
(NH) group of the indole ring system and ser 139 in the binding
19.1
22.4
23.5
4
3
5
10j
10k
75.7
77.6
3
1
59.2
62.5
8
7
Table 3
The IC50 values of the target compounds 10a–k
effects on the HCV-PR activity were demonstrated by all tested
compounds at 100 g/mL. Of these, four compounds exhibited sig-
l
Compound
IC50
(l
g/mL)
Compound
IC50 (lg/mL)
nificant inhibitory activity (P83% inhibition), namely compounds
10c, 10e, 10f, and 10i (Table 2). For compounds 10b, 10e, and
10h, 25 lg/mL concentration was carried out and their inhibition
% were 22.4 2.1, 37.5 0.7, and 43.3 1, respectively. The study
showed that compounds 10c and 10f were the most potent; and
their 50% inhibitory concentrations (IC50) are 15 and 13, respec-
10a
10b
10c
10d
10e
10f
27.2
44.8
15
39
47.9
13
10g
10h
10i
10j
10k
10l
63.3
44.1
39.2
31
30.5
36.5

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N. S. M. Ismail et al. / Bioorg. Med. Chem. 16 (2008) 7877–7887
Figure 5. Docking of (a and b) (S,S) isomer of compound 10l (c and d) (R,S) isomer of compound 10l to active site of HCV NS3/4A protease enzyme. Hydrogen-bond donor
(red), hydrogen-bond acceptor (blue), and hydrophobic (green).
site, in this conformation, while the (S,S) isomer could do (as
4.2. General procedure for the synthesis of (5E)-6-(substituted)-
shown in the Fig. 5).
4-oxohex-5-enoic acids (5a,5b)
Both the respective aldehyde (30 mmol) and levulinic acid
(30 mmol) were dissolved in benzene (100 mL) containing acetic
acid (3 mL) and piperidine (1 mL). The solution was heated under
reflux using Dean-Stark water trap under argon until the theoreti-
cal amount of water had been collected (ꢃ6 h) and TLC analysis (7%
methanol/CHCl3) indicated disappearance of the starting material.
The solvent was evaporated in vacuo and after cooling the solid
product was washed twice with 10 mL of diethyl ether and then
twice with 15 mL of 2 M HCl, dried and recrystallized from the
appropriate solvent (given below).
OCH3
H
H3CO
N(S)
COOH
(R)
H
O
O
H
10l
HN
3. Conclusion
4.3. (E)-6-[4-Methoxyphenyl]-4-oxohex-5-enoic acid (5a)
The strategy used in this study has demonstrated that molecu-
lar modeling of inhibitor bound to NS3/4A protease structures
proved to be a valuable tool in the design of a new series of potent
NS3 protease inhibitor. Compounds 10a, 10c, 10d, and 10f showed
high fit values and high docking scores. The synthesized com-
pounds 10a–k were biologically evaluated in vitro using HCV pro-
tease binding assay, and the result was consistent with molecular
modeling study. Compounds 10c and 10f were the most potent;
this suggests enantio-selective synthesis of 10l, but compound
10l showed a lower activity than the mixture of the corresponding
diastereoisomer.
Pal yellow crystals (recrystallized from benzene); Yield: 81%;
mp: 131 °C (reported 132 °C); IR
m
(neat, cmꢀ1): 2934, 2838,
1736, 1709, 1646, 1599, 1571, 1422, 1306, 1254; 1H NMR (CDCl3)
d ppm 2.74 (t, J = 7.2, 2H), 3.01 (t, J = 7.2, 2H), 3.85 (s, 3H) 6.63–
6.67 (d, J = 16.13, 1H), 6.93 (d, J = 8.3, 2H), 7.55–7.59 (d, J = 16.13,
1H); 13C NMR (500 MHz, CDCl3) d ppm 27.86, 35.31, 55.31,
124.88, 125.93, 125.96, 127.67, 128.45, 131.66, 131.93, 132.19,
132.44, 137.77, 141.12, 178.64, 197.44; MS (EI+): m/z: 234.2 [Mꢄ]+.
4.4. (E)-6-[4-(Trifluoromethyl)phenyl]-4-oxohex-5-enoic acid
4. Experimental section
(5b)
4.1. Chemical Experiments
Yellow crystals (recrystallized from toluene); Yield: 78%; mp:
147–184 °C; IR
m
(neat, cmꢀ1): 3443–2700 (br), 3045, 2927, 1712,
All reagents and solvents were purchased from Aldrich, Wako
and Tokyo Chemical Industry (TCI) and used as received. TLC was
performed on silica gel 60 Partisil K6F plates (Whatman) Melting
points are uncorrected and were measured on a Yanaco apparatus.
The IR spectra were recorded on a JASCO FT/IR-4100 spectrometer
using KBr disk.LC-MS (ESI+) spectra were recorded with a Shima-
dzu LCMS-2010EV spectroscopy or on National Laboratory Center
University of Hoshi, Tokyo. 1H NMR spectral data were obtained
from a Bruker 400 or vaian-500 spectrometer; TMS was used as
an internal standard and solvent peak was used as an internal stan-
dard for 13CNMR. The elemental analysis was performed with Ya-
nano CHN corder MT-5 element analyzer.
1661, 1615, 1577, 1415, 1323, 1206, 1166; 1H NMR (400 MHz,
CDCl3) d ppm 2.76 (t, J = 6.52 Hz, 2H), 3.03 (t, J = 6.52 Hz, 2H),
6.84 (d, J = 16.22 H, 1H), 7.72 (s, 4H) ; 13C NMR (500 MHz, CDCl3)
d ppm 27.87, 35.32, 122.71, 124.89, 125.93, 125.96, 127.67,
128.45, 131.66, 13193, 132.2, 132.45, 137.78, 141.12, 178.64,
197.44; MS (EI+): m/z: 273.2 [Mꢄ H]+.
4.5. General procedure for the synthesis of 6-[5-substituted-1H-
indol-3-yl]-6-(4-substituted phenyl)-4-oxohexanoic acid (7a–d)
A mixture of respective substituted indole 6a–b(3 mmol), 5a,b
(3 mmol), I2 (0.3 mmol) in dry ethanol (6 mL) was stirred in an

N. S. M. Ismail et al. / Bioorg. Med. Chem. 16 (2008) 7877–7887
7883
open vessel at room temperature (ꢃ6 h) and TLC analysis (7%
4.10. 6-[5-Methoxy-1H-indol-3-yl]-6-[4-methoxyphenyl]-4-
oxohexanoic acid (7e)
methanol/CHCl3) indicated disappearance of the indole derivative.
After standing 2 h the reaction mixture was evaporated in
vacuo,dissolved in ethyl acetate and wash by 2 M HCl, sodium
bisulfide and water. The organic layer was dried over sodium sul-
fate anhydrous and evaporated under vacuum. The crude mixture
recrystallized from the appropriate solvent (given below).
To cooled solution of quinine (0.4 mmol) in choroform, AlCl3
(0.3 mmol) was added portionwise. The ice bath was removed after
10 min and warmed to room temperature over 1 h. Compound 5a
(1 mmol) was added to resulting mixture, followed by addition of
compound 6a (1 mmol). The reaction mixture was stirred at room
temperature for overnight, then poured carfully into a solution of
1 N HCl. The organic layer was separated, and the aqueous layer
was extracted with chlorofom (3ꢂ25 mL). The combined organic
layer was dried over sodium sulfate anhydrous and evaporated un-
der vacuum to provide compound 7e.
4.6. 6-(5-Methoxy-1H-indol-3-yl)-6-(4-methoxyphenyl)-4-oxohexa-
noic acid (7a)
Light yellow crystals (recrystallized from aceton/n-hexane);
Yield: 89%; mp: 104–105 °C; IR
m
(neat, cmꢀ1): 3397, 2994, 2832,
1707, 1609, 1510, 1484, 1299, 1248, 1030; 1H NMR (400 MHz,
DMSO-d6) d ppm 2.30–2.33 (t, J = 7.15 Hz, 2H), 2.67–2.74 (m,
2H), 3.07–3.25 (m, 2H), 3.66 (s, 3H), 3.67 (s, 3H), 4.56–4.60 (t,
J = 7.57 H, 1H), 6.67 (dd, J = 8.73, 2.43 H 1H), 6.78–6.80 (m, 3H),
6.93 (d, J = 2.12 H, 1H), 7.2 (d, J = 8.65 H, 3H), 7.95 (s, 1H); 13C
NMR (500 MHz, CDCl3) d ppm 27.59, 37.42, 37.48, 49.46, 55.18,
55.81, 101.55, 111.81, 112.08, 113.86, 118.58, 122.06, 126.91,
128.32, 128.60, 131.80, 135.90, 153.73, 158.03, 177.89, 207.76;
MS (EI+): m/z: 382.1 [Mꢄ H]+.
71% yield as brigh yellow solid. mp: 124–125 °C; 1H NMR (400
MHz, DMSO-d6)d ppm 2.30–2.33 (t, J = 7.15 H, 2H), 2.67–2.74 (m,
2H), 3.07–3.25 (m, 2H), 3.66 (s, 3H), 3.67 (s, 3H), 4.56–4.60 (t,
J = 7.57 H, 1H), 6.67(dd, J = 8.73, 2.43 H 1H), 6.78–6.80 (m, 3H),
6.93 (d, J = 2.12 H, 1H), 7.2 (d, J = 8.65 H, 3H), 7.95 (s, 1H); MS
(EI+): m/z: 382.1 [Mꢄ H]+; ½a 2D1
ꢁ
+16.51 (c 0.76%, methanol). and opti-
cal purity (ee%)= 73%.
4.11. Ethyl 6-[5-methoxy-1H-indol-3-yl]-6-(4-methoxyphenyl)-
4-oxohexanoate (7f)
4.7. 6-(5-Methoxy-1H-indol-3-yl)-4-oxo-6-[4- (trifluoromethyl)-
phenyl]hexanoic acid(7b)
To a solution of 7a (15.5 mmol) in absolut ethanol (150 mL) was
added concentrated H2SO4(2 mL), and the mixture was refluxed
for 6 h. The reaction mixture was cooled to room temperature
and concentrated. The residue was taken in cold water, solid so-
dium bicarbonate was added until the solution become basic,
and the layer was extracted with diethyl ether (2ꢂ100 mL). the
combiend ether layer was dried over sodium sulfate anhydrous
and evaporated under vacuum. The crude product was purified
by silica gel column chromatography, eluting by chloroform:meth-
anol = 10: 0.5 (v/v) afford compound 7f yellow oil.
Light yellow crystals (recrystallized from isopropanol); Yield:
88%; mp: 118–119 °C; IR
m
(neat, cmꢀ1): 3403, 2994, 2933, 2830,
1712, 1619, 1484, 1416, 1325, 1217, 1165; 1H NMR (400 MHz,
DMSO-d6) d ppm 2.34 (t, J = 6.52 H, 2H), 2.57–2.79 (m, 2H), 3.1-
3.25 (m, 2H), 3.66 (s, 3H), 4.75 (t, J = 7.45 H, 1H), 6.68 (dd,
J = 8.75, 2.38 H 1H), 6.83 (d, J = 2.27 H, 1H), 7.19 (d, J = 8.74 H,
1H), 7.26 (d, J = 2.29 H, 1H), 7.57 (s, 4H), 10.76 (s, 1H), 12.1(s,
1H); 13C NMR (500 MHz, CDCl3) d ppm 27.57, 37.42, 37.48, 49.46,
55.18, 101.55, 111.81, 112.08, 113.86, 118.58, 122.06, 126.91,
128.32, 128.60, 131.80, 135.90, 153.73, 158.03, 177.89, 207.76;
MS (EI+): m/z: 420.1 [Mꢄ H]+.
Yield 78%, 1H NMR (400 MHz, CDCl3)d ppm 1.23 (t, J = 7.15 H,
3H), 2.51 (m, 2H), 2.67 (m, 2H), 3.11–3.28 (m, 2H), 3.74 (s, 3H),
3.75 (s, 3H), 4.75 (t, J = 7.57 H, 1H), 6.79 (m, 4H), 6.81 (d,
J = 2.12 H, 1H), 7.21 (d, J = 8.65 H, 3H), 7.87 (s, 1H) ; MS (EI+): m/
z: 410.1 [Mꢄ H]+.
4.8. 6-(5-Bromo-1H-indol-3-yl)-6-(4-methoxyphenyl)-4-oxohexa-
noic acid (7c)
4.12. General procedure for the synthesis of alkyl 2-[6-(5-substi-
tuted-1H-indol-3-yl)-6-(4-substitutedphenyl)-4-oxo- hexanamido]
propanoate (9a–k)
Yellow crystals (recrystallized from isopropanol); Yield: 81%;
mp: 142–143 °C; IR
m
(neat, cmꢀ1): 3371, 3005, 2955, 2840,
1706, 1609, 1510, 1248, 1219; 1H NMR (400 MHz, DMSO-d6) d
ppm 2.32 (t, J = 6.68 H, 2H), 2.51–2.89 (m, 2H), 3.1-3.25 (m, 2H),
3.68 (s, 3H), 4.62 (t, J = 7.51 H, 1H), 6.79 (d, J = 8.58 H 2H), 7.12
(d, J = 8.58 H, 1H), 7.22 (d, J = 8.58 H, 2H), 7.31 (d, J = 7.41 H, 1H),
7.48 (s, 1H), 11.06 (s, 1H), 12.04 (br, 1H); 13C NMR (400 MHz,
CDCl3) d ppm 27.50, 37.46, 49.46, 55.20, 55.81, 101.50, 111.81,
112.06, 113.85, 118.58, 122.05, 126.91, 128.60, 131.77, 135.90,
153.71, 158.02, 176.90, 207.85; MS (EI+): m/z: 431.1 [Mꢄ H]+.
A mixture of respective carboxylic acid derivative (7a–d)
(31 mmol), amino acid ester derivative (8a–d) (34.9 mmol) and
1-hydroxybenzotriazole hydrate (38.5 mmol) were dissolved in
dimethylformamide (60 mL). The resulting solution was then
placed in a water bath at 0 °C and treated with triethylamine
(14 mL), followed by stirring for 10 min. To the resulting mix-
ture 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydro-
chloride (38.5 mmol) was added. After removing the water
bath, the mixture was stirred for 18 h at room temperature.
The reaction was diluted in water (200 mL), extracted with
ethyl acetate, dried over sodium sulfate anhydrous, concen-
trated under reduced pressure and purified by silica gel column
chromatography, eluting by chloroform:methanol = 10:1 (v/v) to
obtain the product.
4.9. 6-(5-Bromo-1H-indol-3-yl)-4-oxo-6-[4-
(trifluoromethyl)phenyl]hexanoic acid (7d)
Dark yellow crystals (recrystallized from isopropanol); Yield: 78
mp: 147–148 °C;%; IR
m
(neat, cmꢀ1): 3403, 2926, 1709, 1618,
1459, 1324, 1218, 1164, 1122, 1067, 771; 1H NMR (400 MHz,
DMSO-d6)d ppm 2.32 (t, J = 7.12 H, 2H), 2.58-2.68 (m, 2H), 3.07-
3.13 (m, 2H), 4.59–4.63 (t, J = 7.44 H, 1H), 6.79 (d, J = 8.69 H 2H),
7.12 (dd, J = 8.57, 1.76 H 1H), 7.22 (d, J = 8.69 H, 2H), 7.27 (d,
J = 8.74 H, 1H), 7.32 (d, J = 2.12 H, 1H), 7.48 (s, 1H), 11.06 (s, 1H),
12.14 (s, 1H); 13C NMR (500 MHz, CDCl3)d ppm 27.59, 37.42,
37.49, 48.55, 101.53, 111.81, 112.08, 113.86, 118.58, 122.06,
126.91, 128.32, 128.60, 131.80, 135.90, 153.73, 158.03, 177.89,
207.45; MS (EI+): m/z: 467 [Mꢄ]+, 469 [Mꢄ+2]+.
4.13. (2S) Ethyl 3-(4-hydroxyphenyl)-2-[6-(5-methoxy-1H-indol-
3-yl)-6-(4-methoxyphenyl)-4- oxo hexanamido] propanoate (9a)
Yield 81%, mp 83–84 °C; IR
m
(neat, cmꢀ1): 3353, 2994, 2833,
1733, 1717, 1657, 1612, 1511, 1484, 1442, 1246, 1214, 1175,
1030; 1H NMR (400 MHz, DMSO-d6) d ppm 1.08 (t, J = 7.09, H,
3H), 2.23 (t, J = 7.1 H, 2H), 2.60 (m, 2H), 2.7–2.84 (m, 2H ) 3.05–

7884
N. S. M. Ismail et al. / Bioorg. Med. Chem. 16 (2008) 7877–7887
3.11 (m, 2H), 3.66 (s, 3H), 3.67 (s, 3H), 3.99 (q, J = 7.03, H, 2H), 4.28
(dd, J = 13.6, 8.28 H, 1H), 4.57 (t, J = 7.57, H, 1H), 6.63–6.65 (m, 4H),
6.78 (d, J = 7.98 H, 2H), 6.97 (d, J = 7.92 H, 2H), 7.16 (d, J = 2.26 H,
1H), 7.1 (s, 1H), 7.22 (d, J = 8.58 H, 2H), 8.24 (d, J = 7.63 H, 1H),
9.22 (s, 1H), 10.65 (s, 1H); 13C NMR (500 MHz, DMSO-d6)d ppm
13.9, 28.66, 30.74, 36.41, 37.48, 48.54, 54.01, 54.88, 55.28, 60.26,
100.88, 110.69,111.85, 113.43, 114.95, 117.82, 122.26, 126.57,
127.09, 128.46, 129.97, 131.54, 136.96, 152.70, 155.95, 157.28,
162.26, 171.26,171.68, 207.79; MS (EI+): m/z: 572.2 [Mꢄ]+.
4.17. (2S) Methyl 3-(1H-indol-3-yl)-2-[6-(5-methoxy-1H-indol-
3yl)-4-oxo-6-(4- (trifluoromethyl) phenyl)hexanamido]
propanoate (9e)
Yield 81%, mp 89–90 °C; IR m
(neat, cmꢀ1): 3403 (br), 3051, 3005,
2952, 1739, 1712, 1661, 1619, 1582, 1485, 1457, 1438, 1324, 1214,
1165, 1120; 1H NMR (400 MHz, DMSO-d6)ppm 2.26–2.29 (t, J = 7.
2 Hz, 2H), 2.63–2.73 (m, 2H), 2.96–3.00 (m, 2H), 3.11–3.23 (m, 2H),
3.53 (s, 3H), 3.66 (s, 3H), 4.46 (dd, J = 14.05, 7.15 H, 1H), 4.73 (t,
J = 7.46, H, 1H), 6.68 (dd, J = 8.74, 2.33 H, 1H), 6.82 (d, J = 2.07 H,
1H), 6.97 (t,J = 6.28 Hz, 1H), 7.11 (s, 1H), 7.19, (d, J = 8.73 H, 1H),
7.25 (t, J = 7.49 H, 1H), 7.33 (d, J = 8.04 H, 2H), 7.46 (d, J = 7.83 H,
2H), 7.56 (s, 4H) , 8.29 (d, J = 7.46 H, 1H), 10.75 (s, 1H), 10.85 (s,
1H); 13C NMR (500 MHz, DMSO-d6) d ppm , 28.85, 36.07, 36.19,
37.55, 48.55, 54.14, 54.89, 101.59, 109.75, 111.26, 111.82, 112.09,
113.86, 118.49, 118.81, 119.59, 121.96, 122.03, 122.10, 122.14,
123.06, 126.99, 127.57, 129.61, 131.76, 136.06, 153.77, 158.01,
171.51, 172.31, 207.71; MS (EI+): m/z: 619.2 [Mꢄ]+.
4.14. (2S) Methyl 3-(1H-indol-3-yl)-2-[6-(5-methoxy-1H-indol-
3-yl)-6-(4-methoxyphenyl)-4- oxo hexanamido] propanoate
(9b)
Yield 76%, mp 95–96 °C; IR
m
(neat, cmꢀ1): 3344 (br), 3055,
2952, 2834, 1738, 1716, 1610, 1510, 1484, 1457, 1439, 1247,
1213, 1175, 748; 1H NMR (400 MHz, DMSO-d6)d ppm 2.28 (t,
J = 7.2 H, 2H), 2.65–2.86 (m, 2H), 3.0–3.07 (m, 2H), 3.09–3.12
(m, 2H), 3.54 (s, 3H), 3.661 (s, 3H), 3.67 (s, 3H), 4.4 (dd,
J = 13.6, 8.3 H, 1H), 4.58 (t, J = 7.53, H, 1H), 6.67 (dd, J = 8.68,
2.16 H, 1H), 6.79 (d, J = 8.71 H, 2H), 6.94–7.0 (t, J = 1A1, H, 2H),
7.06 (t, J = 7.51, H, 2H), 7.15 (d, j = 8.73 H, 3H), 7.22 (d,
J = 8.40 H, 2H), 7.33 (d, J = 8.02 H, 1H), 7.47 (d, J = 7.78 H, 1H),
7.95 (s, 1H), 8.29 (d, J = 7.14 H, 1H), 10.65 (s, 1H), 10.85 (s,
4.18. (2S) Methyl 2-[6-(5-methoxy-1H-indol-3yl)-4-oxo-6-(4-
trifluoromethyl)phenyl)hexanamido] -3-phenylpropanoate (9f)
Yield 89%, mp 107–108 °C; IR
m
(neat, cmꢀ1): 3352 (br), 2938,
2831, 1733, 1716, 1657, 1618, 1581, 1516, 1483, 1324, 1213, 1165,
1121, 1067; 1H NMR (400 MHz, DMSO-d6)d ppm 2.25 (t, J = 7.2 H,
2H), 2.61–2.73 (m, 2H), 2.84–2.87 (m, 2H), 3.21–3.24 (m, 2H), 3.55
(s, 3H), 3.66 (s, 3H), 4.41 (dd, J = 14.38–7.03, H, 1H), 4.72 (t,
J = 7.41, H, 1H), 6.68 (dd, J = 8.73, 2.04 H, 1H), 6.83 (d, J = 2.39 H,
1H), 7.17–7.25 (m, 5H), 7.57 (s, 4H), 8.32 (d, J = 7.58 H, 1H), 10.75
(s, 1H); 13C NMR (500 MHz, DMSO-d6)d ppm 28.9, 30.2, 36.9,
36.99, 37.5, 47.73, 48.55, 54.14, 54.89, 100.6, 110.93, 112.25,
116.68, 122.86, 123.29, 124.91, 125.44, 126.16, 126.33, 126.44,
126.58, 127.99, 128.39, 129.12, 129.25, 129.83, 131.5 137.69,
150.03, 152.89, 170.90, 173.44, 207.81; MS (EI+): m/z: 580.2 [Mꢄ]+.
1H);13
C NMR (500 MHz, CDCl3)d ppm 27.46, 29.71, 36.46,
37.32, 37.99,49.51, 52.33, 52.82, 52.86, 55.20, 101.59, 109.75,
109.82, 111.26, 1182, 112.09 113.86, 118.49, 118.81, 119.59,
121.96, 122.03, 122.10, 122.14, 123.06, 126.99, 127.57, 128.61,
131.76, 136.06, 153.77, 158.01, 171.51, 172.31, 208.37; MS
(EI+): m/z: 582.3.
4.15. (2S) Methyl 2-[6-(5-methoxy-1H-indol-3yl)-6-(4-
methoxyphenyl)-4-oxohexanamido]-3- phenyl propanoate (9c)
Yield 84%, mp 90–91 °C; IR
m
(neat, cmꢀ1): 3298, 3030, 2952,
1743, 1709, 1660, 1510, 1484, 1455, 1247, 1215, 1175, 1031,
753; 1H NMR (400 MHz, DMSO-d6)d ppm 2.23 (t, J = 7.3 H, 2H),
2.75 (m, 2H), 2.97 (m, 2H), 3.11 (m, 2H), 3.56(s, 1H), 3.66 (s,
3H), 3.67 (s, 3H), 4.37 (dd, J = 13.6, 8.28 H, 1H), 4.56 (t,
J = 7.38, H, 1H), 6.65–6.67 (dd, J = 8.74, 2.28 H, 1H), 6.79 (d,
J = 8.53 H, 2H), 7.16–7.25 (m, 10H), 7.95 (s, 1H), 8.32 (d,
J = 8.12 H, 2H), 10.65 (s, 1H); 13C NMR (500 MHz, CDCl3)d ppm
29.62, 36.05, 37.45, 38.08, 49.53, 52.27, 53.11, 54.16, 55.19,
55.83, 101.57, 111.76, 112.17, 113.86, 118.87, 121.94, 126.98,
127.10, 127.9, 128.56, 128.64, 129.08, 129.28, 129.58, 131.77,
135.82, 136.01, 153.81, 158.04, 171.46, 171.97, 208.34; MS
(EI+): m/z: 542.2 [Mꢄ]+.
4.19. (2S) Ethyl 2-[6-(5-bromo-1H-indol-3yl) -6-(4-methoxy-
phenyl)-4-oxohexanamido]-3-(4-hydroxyphenyl)propanoate (9g)
Yield 73%, mp 104–105 °C; IR
m
(neat, cmꢀ1): 3323, 2984, 2845,
1733, 1712, 1657, 1612, 1551, 1484, 1266, 1214, 1175, 771; 1H
NMR (400 MHz, DMSO-d6)dppm 1.1 (t, J = 7.09, H, 3H), 2.23 (t,
J = 7.1 H, 2H), 2.6 (m, 2H), 2.7–2.84 (m, 2H ) 3.05–3.11 (m, 2H),
3.6 (s, 3H), 3.67 (s, 3H), 3.99–4.0 (q, J = 7.03, H, 2H), 4.28 (dd,
J = 13.6, 8.28 H, 1H), 4.59 (t, J = 7.57, H, 1H), 6.64 (d, J = 8.15 H,
2H), 6.79 (d, J = 8.51 Hz, 2H), 6.98 (d, J = 8.15 H, 2H), 7.21 (d,
J = 8.32 H, 2H), 7.27 (d, J = 8.57 H, 2H), 7.3 (d, J = 7.63 H, 1H), 7.33
(s, 1H), 8.08 (d, J = 8.01 H, 1H), 9.19 (s, 1H),10.65 (s, 1H); 13C
NMR (500 MHz, CDCl3) d ppm 18.52, 29.62, 37.45, 37.83, 49.53,
52.27, 53.21, 54.16, 54.19, 101.57, 111.76, 112.17, 113.86, 118.87,
121.94, 126.98, 127.10, 127.90, 128.56, 128.64, 129.08, 129.28,
129.58, 131.77, 135.82, 136.01, 153.81, 158.04, 171.46, 171.97,
208.34; MS (EI+): m/z: 620.1 [Mꢄ]+;622.1[Mꢄ+2]+.
4.16. (2S) Ethyl 3-(4-hydroxyphenyl)-2-[6-(5-methoxy-1H-
indol-3yl)-4-oxo- 6-(4- trifluoromethyl) phenyl)hexanamido]
propanoate (9d)
Yield 85%, mp 70–71 °C; IR
m
(neat, cmꢀ1): 3327 (br), 2930,
1732, 1707, 1660, 1616, 1515, 1485, 1324, 1214, 1165, 1120,
1067; 1H NMR (400 MHz, DMSO-d6)d ppm 1.07 (t, J = 7.15 H, 3H),
2.26 (t, J = 7.1 H, 2H), 2.59–2.63 (m, 2H), 2.78–2.84 (m, 2H), 3.24
(m, 2H), 3.66 (s, 3H), 3.98–4.0 (dd, J = 13.94, 6.85 H, 2H), 4.29
(dd, J = 14.50, 7.02 H, 1H), 4.73 (t, J = 7.46, H, 1H), 6.64 (d,
J = 7.77 H, 2H), 6.67 (dd, J = 8.92, 2.28 H, 1H), 6.83 (d, J = 2.19 H,
1H), 6.97 (d, J = 7.23 Hz, 2H), 7.19 (d, J = 8.75 H, 1H), 7.24 (s, 1H),
7.57 (d, J = 2.13 H, 2H),7.95 (s, 1H), 8.24 (d, J = 7.54 H, 1H), 9.21
(s, 1H), 10.75 (s, 1H); 13C NMR (500 MHz, DMSO-d6)ppm 13.9,
28.66, 30.74, 36.07, 36.19, 37.55, 48.55, 54.14, 45.89, 110.80,
113.33, 113.56, 114.83, 117.93, 120.87, 123.36, 127.90, 128.12,
128.34, 130.02, 136.74, 155.75, 157.38, 170.26, 173.68, 207.72;
MS (EI+): m/z: 610.2 [Mꢄ]+.
4.20. (2S) Methyl 2-[6-(5-bromo-1H-indol-3yl)-6-(4-methoxy-
phenyl)-4-oxohexanamido]-3-(1H- indol-3yl)propanoate (9h)
Yield 86%, mp 204–205 °C; IR
m
(neat, cmꢀ1):3265, 2980, 2959,
1740, 1714, 1660, 1610, 1511, 1460, 1367, 1249, 1218, 1177, 1000,
885; 1H NMR (400 MHz, DMSO-d6) d ppm 2.32 (m, 2H), 2.67 (m,
2H), 3.09 (m, 2H ) 3.25 (m, 2H), 3.66 (d, J = 3.44, 3H), 4.85 (m,
2H), 6.12 (t, J = 7.23 H, 1H) 6.74 (m, 1H), 6.8 (d, J = 7.63 H, 1H),
7.1 (d, J = 2.45 H, 1H), 7.17 (d, J = 7.7 4 Hz, 1H), 7.17–7.21(m, 2H),
7.28 (m, 2H), 7.38 (d, J = 8.58 H, 2H), 7.49 (d, J = 8.59 H, 2H), 8.01(
br, 1H), 8.10 ( br, 1H); 13C NMR (500 MHz, CDCl3)d ppm 27.46,
29.71, 37.38, 37.99, 49.51, 52.33, 52.82, 55.20, 101.59, 109.75,
109.83, 111.26, 111.82, 112.09, 113.86, 118.49, 118.81, 119.59,

N. S. M. Ismail et al. / Bioorg. Med. Chem. 16 (2008) 7877–7887
7885
121.96, 122.03, 122.10, 122.14, 123.06, 126.99, 127.57, 128.61,
131.76, 136.06, 153.77, 157.37, 170.87, 173.41, 207.71; MS (EI+):
m/z: 629.1 [Mꢄ]+.
red at room temperature for 3 h. The progress of the reaction
was monitored by TLC. After the solution was concentrated in va-
cuo to one-third of its original volume, ethylacetate (60 mL), 1N
HCl (10 mL) and water (20 mL) were added and the organic layer
was separated. The aqueous solution was extracted with ethylace-
tate (2ꢂ50 mL). Organic solutions were combined, dried with so-
dium sulfate anhydrous, filtered, and concentrated to afford the
desired final target compounds 10a–k.
4.21. (2S) Ethyl2- [6-(5-bromo-1H-indol-3yl)-4-oxo-6-(4-trifluo-
romethyl)phenyl)hexanamido]- 3-(4-hydroxy phenyl) propanoate
(9i)
Yield 85%, mp 141–142 °C; IR
m
(neat, cmꢀ1): 3284 (br), 2930,
1731, 1716, 1661, 1514, 1452, 1376, 1324, 1217, 1164, 1122,
1067; 1H NMR (400 MHz, DMSO-d6)d ppm 1.11 (t, J = 7.15Hz,
3H), 2.26 (t, J = 7.1 H, 2H), 2.65 (m, 2H), 2.83 (m, 2H), 3.24 (m,
2H), 3.98–4.01 (dd, J = 13.94, 6.85 H, 2H), 4.30 (dd, J = 14.50,
7.02 H, 1H), 4.74 (t, J = 7.46, H, 1H), 6.64 (d, J = 7.77 Hz, 2H), 6.67
(dd, J = 8.92, 2.28 H, 1H), 6.83 (d, J = 2.19 H, 1H), 6.97 (d,
J = 7.23 H, 2H), 7.19 (d, J = 8.75 Hz, 1H), 7.24 (s, 1H), 7.57 (d,
J = 2.13 H, 2H),7.95 (s, 1H), 8.24 (d, J = 7.54 H, 1H), 9.21 (s, 1H),
10.75 (s, 1H); 13C NMR (500 MHz, DMSO-d6) d ppm 13.91, 28.66,
30.74, 36..07, 36.19, 37.55, 48.55, 54.14, 54.89, 111.05, 113.44,
114.75, 116.77, 120.65, 122.52, 123.24, 123.57, 123.81, 125.03,
125.06, 125.40, 126.47, 126.72, 127.95, 128.36, 130.03, 134.97,
149.78, 155.74, 157.37, 170.26, 173.68, 207.71; MS (EI+): m/z:
685.1 [Mꢄ]+, 660.1[Mꢄ+2]+.
4.25. (2S)-3-(4-Hydroxyphenyl)-2-[6-(5-methoxy-1H-indol-3yl)-
6-(4- methoxyphenyl)-4-oxo hexanamido]propanoic acid (10a)
Yield 82%, mp 156–157 °C; ½a D22
ꢁ
ꢀ11.03 (c 0.82%, methanol). IR
m
(neat, cmꢀ1): 3525–3150 (br), 3005, 2932, 2832, 1709, 1658, 1612,
1511, 1441, 1246, 1215, 1175; 1H NMR (400 MHz, DMSO-d6) d ppm
2.22 (t, J = 7.1 H, 2H), 2.58 (m, 2H), 2.88 (m, 2H), 3.11–3.23 (m, 2H),
3.66 (s, 3H), 3.67 (s, 3H), 4.28 (dd, J = 13.6, 8.28 H, 1H), 4.57 (t,
J = 7.49, H, 1H), 6.64 (d, J = 7.58 H, 2H), 6.67 (d, J = 1.93 H, 1H),
6.6.78 (d, J = 8.68 H, 3H), 6.98 (d, J = 7.68 H, 2H), 7.16 (s, 1H), 7.18
(s, 1H), 7.22 (d, J = 8.61 H, 2H), 8.08 (d, J = 7.79 H, 1H), 9.20 (s, 1H),
10.65 (s, 1H), 12.57 (br, 1H); 13C NMR (400 MHz, aceton-d6) d ppm
37.33, 38.03, 38.55, 49.98, 54.58, 55.34, 55.77, 101.9, 112.1, 112.6,
114.3, 115.9, 123.12, 128.0, 128.6, 129.5, 131.2, 133.0, 137.9,
154.4, 157.0, 158.8, 172.3, 173.1, 208.1; MS (EI+): m/z: 544.2 [Mꢄ]+.
4.22. (2S) Methyl 3-(1H-imidazol-4-yl)-2-(6-(5-methoxy-1H-
indol-3yl)-6-(4-metoxyphenyl)-4- oxo hexanamido)propanoate
(9j)
4.26. (2S)-3-(1H-Indol-3-yl)l)-2-[6-(5-methoxy-1H-indol-3yl)-6-
(4- methoxyphenyl)-4-oxo hexanamido]propanoic acid (10b)
Yield 79%, mp 97–98 °C; IR
m
(neat, cmꢀ1): 3346 (br), 2998, 2947,
Yield 85%, mp 139–140 °C; ½a D26
ꢀ23.42 (c 0.37%, methanol); IR
ꢁ
2832, 1738, 1713, 1659, 1605, 1505, 1480, 1432, 1231, 1030, 754; 1H
NMR (400 MHz, DMSO-d6) d ppm 2.26 (t, J = 7. 2 H, 2H), 2.63 (m, 2H),
2.85 (m, 2H), 3.06–3.13 (m, 2H), 3.55 (s, 3H), 3.66 (s, 3H), 3.67 (s, 3H),
4.42 (dd, J = 14.05, 7.15 H, 1H), 4.59 (t, J = 7.52, H, 1H), 6.66 (dd,
J = 8.74, 2.04 H, 1H), 6.78 (m, 4H), 7.18 (d, J = 8.64 H, 2H), 7.22 (d,
J = 8.65 H, 2H), 7.51 (s, 1H) , 8.22 (d, J = 7.13 H, 1H), 10.65 (s, 1H),
11.2 (s, 1H); 13C NMR (500 MHz, DMSO-d6)d ppm 29.62, 36.05,
37.45, 38.08, 49.53, 52.27, 53.11, 54.16, 55.19, 55.83, 101.57,
111.76, 112.17, 113.86, 118.87, 121.94, 126.98, 127.10, 127.9,
128.56, 128.64, 129.08, 129.28, 129.58, 131.77, 135.82, 136.01,
153.81, 158.04, 171.46, 171.97, 208.34; MS (EI+): m/z: 533.3 [Mꢄ H]+.
m
(neat, cmꢀ1): 3572–3200 (br), 3055, 2998, 2836, 1707, 1659,
1622, 1583, 1510, 1484,1457, 1360, 1246; 1H NMR (400 MHz,
DMSO-d6)d ppm 2.24 (t, J = 7. 2 H, 2H), 2.65–2.95 (m, 2H), 3.0–
3.1 (m, 2H), 3.22 (m, 2H), 3.661 (s, 3H), 3.67 (s, 3H), 4.4 (dd,
J = 13.6, 8.3 H, 1H), 4.56 (t, J = 7.53, Hz, 1H), 6.66 (dd, J = 8.73 H,
1H), 6.78 (d, J = 8.64 H, 2H), 6.8 (d, J = 2.07 H, 1H), 6.9 (t,
J = 6.28 H, 1H), 7.05 (t, J = 7.49 H, 1H), 7.11 (s, 1H), 7.16 (s, 1H),
7.18 (s, 1H), 7.22 (d, J = 8.59 H, 2H), 7.32 (d, J = 8.02 H, 1H), 7.51
(d, J = 7.87 H, 1H), 8.1(d, J = 7.14 H, 1H), 10.65 (s, 1H), 10.82 (s,
1H), 12.59 (br, 1H); 13C NMR (400 MHz, CDCl3)d ppm 18.3, 26.8,
29.3, 37.1, 49.2, 55..1, 55.7, 59.3, 101.6, 111.4, 111.7, 111.9,
113.7, 123.4, 126.9, 128.5, 131.7, 135.9, 157.8, 173, 174.1, 209.2;
MS (EI+): m/z: 567.2 [Mꢄ]+.
4.23. (2S) Methyl 3-(1-H-imidazol-4-yl)-2- [6-(5-methoxy-1it H-
indol-3yl))-4-oxo-6-(4-(trifluoromethyl)phenyl)hexanamido]
propanoate (9k)
4.27. (2S)-2-[6-(5-Methoxy-1H-indol-3yl)-6-(4-methoxyphenyl)-
4- oxohexanamido]-3-phenyl propanoic acid (10c)
Yield 75%, mp 111–112 °C; R
m
(neat, cmꢀ1): 3263 (br), 3005,
2950, 2843, 1742, 1714, 1610, 1510, 1459, 1367, 1248, 1218,
1177, 771; 1H NMR (400 MHz, DMSO-d6)d ppm 2.26 (t, J = 6.57 H,
2H), 2.73 (m, 2H), 2.91 (m, 2H), 3.12 (m, 2H), 3.56 (s, 3H), 3.68
(s, 3H), 4.45 (dd, J = 13.74, 7.54 H, 1H), 4.60 (t, J = 7.33, H, 1H),
6.69 (d, J = 8.43, H, 2H), 7.1 (s, 1H), 7.13 (d, J = 8.11 H, 1H), 7.25
(d,J = 8.57 H, 2H),7.27(d,J = 8.61 Hz, 1H), 7.31 (s, 1H), 7.7.48 (s,
1H) 7.8 (s, 1H), 8.24 (d, J = 7.13 H, 1H), 10.65 (s, 1H), 11.07 (s,
1H); 13C NMR (500 MHz, DMSO-d6)d ppm 28.69, 28.89, 36.85,
37.36, 47.73, 51.68, 52.36, 55.30, 100.16, 110.19, 112.00, 116.67,
122.66, 123.27, 124.90, 124.93, 125.44, 126.32, 126.41, 126.56,
128.38, 131.47, 134.77, 150.02, 152.88, 171.24, 172.03, 207.44;
MS (EI+): m/z: 571.2 [Mꢄ H]+.
Yield 85%, mp 132–1133 °C; ½a D26
ꢀ28.78 (c 0.31%, methanol); IR
ꢁ
m
(neat, cmꢀ1): 3523–3100 (br), 3059, 2991, 2833, 1710, 1661,
1609, 1583, 1510, 1484, 1455, 1247, 1214, 1175; 1H NMR (400
MHz, DMSO-d6)d ppm 2.22 (t, J = 7.1 H, 2H), 2.55-2.59 (m, 2H),
2.84 (m, 2H), 3.22–3.25 (m, 2H), 3.66 (s, 3H), 3.67 (s, 3H), 4.37
(dd, J = 13.6, 8.28 H, 1H), 4.57 (t, J = 7.49, H, 1H), 6.67 (dd,
J = 8.72, 2.38 H, 1H), 6.79 (d, J = 8.7 H, 3H), 7.15–7.3 (m, 9H), 8.16
(d, J = 8.04 H, 2H), 10.66 (s, 1H), 12.54 (br, 1H): 13C NMR (400
MHz, aceton-d6)d ppm 37.9, 38.09, 38.4, 41.3 49.9, 54.2, 55.3,
55.7, 101.9, 112.1, 112.6, 114.2, 115.9, 123.08, 127.3, 128.0,
129.04, 129.5, 130.1, 133.0, 137.3, 154.3, 158.8, 158.8, 172.2,
172.99, 208.07; MS (EI+): m/z: 528.2 [Mꢄ H]+
4.24. General procedure for the synthesis of 2-[6-(5-substituted-
1H-indol-3-yl)-6-(4-substituted phenyl)-4-oxohexanamido]-
propanoic acid (10a-k)
4.28. (2S)-3-(4-Hydroxyphenyl)-2-[6-(5-methoxy-1H-indol-3yl))-
4- oxo-6-(4-trifluoromethyl) phenyl) hexanamido]propanoic acid
(10d)
To a solution of alkyl esters 9a–k (0.742 mmol) in THF (20 mL)
and ethanol (10 mL) at room temperature was added an aqueous
solution of lithium hydroxide (2.92 mmol). The reaction was stir-
Yield 89%, mp 130–131 °C; ½a D28
ꢁ
ꢀ14.88 (c 0.91%, methanol); IR
m
(neat, cmꢀ1): 3515–3200 (br), 3066, 2940, 2832, 1709, 1652, 1616,
1515, 1484, 1441, 1324, 1215, 1118; 1H NMR (400 MHz, DMSO-

7886
N. S. M. Ismail et al. / Bioorg. Med. Chem. 16 (2008) 7877–7887
d6)d ppm 2.23 (t, J = 7.1 H, 2H), 2.59–2.6 (m, 2H), 2.8 (m, 2H), 3.3 (m,
2H), 3.66 (s, 3H), 4.28 (dd, J = 13.48, 8.07 H, 1H), 4.73 (t, J = 1M, Hz,
1H), 6.64 (d, J = 7.38 H, 2H), 6.67 (dd, J = 8.92, 2.28 H, 1H), 6.83 (d,
J = 1.68 H, 1H), 6.98 (d, J = 7.12 H, 2H), 7.19 (d, J = 8.74 H, 1H), 7.24
(s, 1H), 7.57 (s, 4H), 8.1 (d, J = 7.89 H, 1H), 9.19 (s, 1H), 10.75 (s,
1H), 12.57 (br, 1H),13C NMR (400 MHz, aceton-d6)d ppm 28.8,
30,23, 37.32, 38.33, 49.2, 54.56, 55.75, 101.5, 112.3, 112.8, 115.9,
118.2, 123.4, 125.7, 125.8, 127.8, 128.6, 129.4, 131.2, 150.9, 154.5,
157.0, 172.2, 173.1, 207.6; MS (EI+): m/z: 583.2 [Mꢄ H]+.
1510, 1417, 1361, 1247, 1178, 1101, 745; 1H NMR (400 MHz,
DMSO-d£)ppm 2.21 (t, J = 6.51 Hz, 2H), 2.67 (m, 2H), 2.92–2.98
(m, 2H) 3.04–3.11 (m, 2H), 3.67 (s, 3H), 4.26 (dd, J = 18.52,
9.11 H, 1H), 4.59 (t, J = 7.56, H, 1H), 6.78 (d, J = 8.41 H, 2H), 6.92
(t, J = 6.00 H, 1H), 7.02 (t, J = 7.23 H, 1H), 7.06 (s, 1H), 7.12 (d,
J = 8.19 H, 1H), 7.20 (d, J = 8.42 H, 2H), 7.25 (s, 1H), 7.29 (d,
J = 11.1 H, 2H), 7.46–7.49 (m, 2H), 10.72 (s, 1H),11.07 (s, 1H),
12.53 (s, 1H); 13C NMR (500 MHz, DMSO-d6) d ppm 28.68, 35.74,
36.85, 37.35, 47.72, 51.68, 53.16, 55.29, 100.61109.40, 110.92,
111.38, 112.00, 116.67, 117.93, 118.35, 120.90, 122.66, 123.27,
124.90,125.44, 126.32, 126.56, 127.05128.95, 131.47, 136.03,
150.01, 152.88, 171.27, 172.37, 207.45; MS (EI+): m/z: 615.1
[Mꢄ]+, 617.1[Mꢄ+2]+.
4.29. (2S)-3-(1H-Indol-3-yl)-2-[6-(5-methoxy-1H-indol-3yl)-4-oxo-
6- (4-(trifluoromethyl)phenyl) hexanamido]propanoic acid (10e)
Yield 79%, mp 143–144 °C; ½a D26
ꢀ20.71 (c 0.43%, methanol); IR
ꢁ
m
(neat, cmꢀ1): 3403 (br), 3005, 2936, 2836, 1711, 1660, 1619,
4.33. (2S)-2-[6-(5-Bromo-1H-indol-3yl)-4-oxo-6-(4- trifluoro-
methyl)phenyl)hexanamido]-3-(4-hydroxyphenyl) propanoic
acid (10i)
1583, 1530, 1484,1457, 1324, 1214, 1121; 1H NMR (400 MHz,
DMSO-d6)d ppm 2.27 (t, J = 7. 2 H, 2H), 2.60–2.63 (m, 2H), 2.73–
2.97 (m, 2H), 3.10–3.15 (m, 2H), 3.66 (s, 3H), 4.4 (dd, J = 13.6,
8.3 H, 1H), 4.73 (t, J = 7.33, H, 1H), 6.67 (dd, J = 8.29 H, 1H), 6.82
(d, J = 2.07 H, 1H), 6.96 (t, J = 6.28 H, 1H), 7.04 (t, J = 7.49 H, 1H),
7.11 (s, 1H), 7.19(d, J = 8.73 H, 1H), 7.24 (s, 1H), 7.32 (d, J = 8.07
Hz, 1H), 7.51 (d, J = 7.66 H, 1H), 7.56 (s, 4H), 8.13 (d, J = 7.48 H,
1H), 10.7 (s, 1H), 10.82 (s, 1H), 12.59 (br, 1H); 13C NMR
(400MHz, aceton-d6)d ppm 28.1, 30.28 38.3, 38.4, 49.2, 53.9, 55.7,
101.6, 110.9, 112.1, 112.4, 112.8, 118.2, 119.3, 119.5, 122.1,
123.5, 124.4, 125.8, 127.9, 128.7, 129.5, 133.0, 137.5, 150.9,
154.6, 172.3, 173.4, 207.6; MS (EI+): m/z: 605.2 [Mꢄ]+.
Yield 83%, mp 233–234 °C; ½a D26
ꢀ12.39 (c 0.85%, methanol); IR
ꢁ
m
(neat, cmꢀ1): 3328, 3016, 1720, 1645, 1615, 1514, 1445, 1324,
1231, 1165, 1121, 1067; 1H NMR (400 MHz, DMSO-d6) d ppm
2.23–2.27 (m, 2H), 2.59–2.67 (m, 2H), 2.96–271 (m, 2H), 2.88–
2.92 (m, 2H), 4.37 (dd, J = 13.6, 8.28 H, 1H), 4.77 (t, J = 7.19, H,
1H), 6.61 (d, J = 7.44 H, 2H), 6.95 (d, J = 7.58 H, 2H), 7.13 (dd,
J = 8.41, 1.17 H, 1H), 7.28 (d, J = 8.58 H, 1H), 7.40 (s, 1H), 7.56–
7.60 (m, 5H), 9.19 (br, 1H), 11.19 (s, 1H), 12.54 (br, 1H); 13C NMR
(500 MHz, DMSO-d6) d ppm 28.96, 36.36, 36.50, 37.52, 47.77,
54.51, 55.98, 111.05, 113.44, 114.75, 116.77, 120.65, 122.52,
123.24, 123.57, 123.81, 125.03, 125.06, 125.40, 126.47, 126.72,
127.95, 128.36, 130.03, 134.97, 149.78, 155.64, 170.63, 207.36;
MS (EI+): m/z: 630.1 [Mꢄ]+; 632.1[Mꢄ+2]+.
4.30. (2S)-2-[6-(5-Methoxy-1H-indol-3yl)-4-oxo-6-(4-trifluo-
romethyl) phenyl)hexanamido]-3-phenyl propanoic acid (10f)
Yield 91%, mp 156-157 °C; ½a D28
ꢁ
ꢀ22.64 (c 0.65%, methanol); IR
m
(neat, cmꢀ1): 3314 (br), 3026, 2938, 1724, 1660, 1612, 1557, 1484,
1455, 1366, 1324,1215, 1123; 1H NMR (400 MHz, DMSO-d6)d ppm
2.32 (t, J = 7.2 H, 2H), 2.63 (m, 2H), 2.82 (m, 2H), 3.04 (m, 2H), 3.66
(s, 3H), 4.38 (dd, J = 13.48, 8.07 H, 1H), 4.74 (t, J = 1M, Hz, 1H), 6.68
(dd, J = 8.61, 2.58 H, 1H), 6.83 (d, J = 2.39 H, 1H), 7.1–7.24 (m, 7H),
7.57 (s, 4H), 8.3 (s, 1H), 10.75 (s, 1H), 12.57 (br, 1H); 13C NMR (500
MHz, DMSO-d6)d ppm 28.89, 30.23, 36.86, 37.5, 47.73, 53.83, 55.30,
100.60, 110.92, 112.02, 116.68, 122.68, 123.29, 124.91, 125.44,
126.16, 126.32, 126.42, 126.58, 127.99, 128.39, 129.11, 129.24,
12983, 131.49, 137.96, 150.03, 152.89, 170.90, 173.44, 207.83;
MS (EI+): m/z: 566.2 [Mꢄ]+.
4.34. (2S)-3-(1H-imidazol-4-yl)-2-[6-(5-methoxy-1H-indol-3yl))-
6- (4-metoxyphenyl)-4-oxo hexanamido]propanoic acid (10j)
Yield 79%, mp 136–137 °C; ½a D27
ꢁ
+12.97 (c 0.78%, methanol); IR m
(neat, cmꢀ1): 3393 (br), 2956, 2927, 2851, 1715, 1705, 1668, 1623,
1509, 1485, 1248, 1215, 1175, 1031, 832; 1H NMR (400 MHz,
DMSO-d6) d ppm 2.24 (t, J = 7. 2 H, 2H), 2.63 (m, 2H), 2.80(m,
2H), 3.21 (m, 2H), 3.66 (s, 3H), 3.67 (s, 3H), 4.42 (dd, J = 14.05,
7.15 H, 1H), 4.59 (t, J = 7.52, H, 1H), 6.65 (dd, J = 8.69, 1.99 H, 1H),
6.77 (m, 4H), 7.17 (d, J = 8.62 H, 2H), 7.23 (d, J = 8.63 H, 2H), 7.51
(s, 1H), 8.22 (d, J = 7.13 H, 1H), 10.66 (s, 1H), 12.2 (s, 1H); 13C
NMR (500 MHz, DMSO-d6)d ppm 20.99, 26.16, 28.69, 30.20,
36.86, 37.30, 47.72, 51.10, 55.31, 100.16, 110.19, 112.00, 116.67,
122.66, 123.27, 124.90, 124.93, 125.44, 126.32, 126.41, 126.56,
128.38, 131.47, 134.77, 150.02, 152.88, 171.24, 172.03, 207.44 ;
MS (EI+): m/z: 519.2 [Mꢄ H]+.
4.31. (2S)-2-[6-(5-Bromo-1H-indol-3yl)-6-(4-methoxyphenyl)-
4- oxohexanamido]-3-(4-hydroxy phenyl)propanoic acid (10g)
Yield 85%, mp 137–138 °C; ½a D28
ꢀ15.16 (c 0.72%, methanol); IRv
ꢁ
(neat, cmꢀ1):3307, 3070, 3016, 2932, 2832, 1719, 1708, 1650,
1612, 1511, 1455, 1365, 1246, 1176; 1H NMR (400 MHz, DMSO-
d6) d ppm 2.23 (t, J = 7.1 H, 2H), 2.6 (m, 2H), 2.7–2.84 (m, 2H )
3.05–3.11 (m, 2H), 3.67 (s,3H), 4.28 (dd, J = 13.42, 8.56 H, 1H),
4.60 (t, J = 7.54, H, 1H), 6.64 (d, J = 8.15 Hz, 2H), 6.79 (d,
J = 8.51 H, 2H),, 6.98 (d, J = 8.15 H, 2H), 7.21 (d, J = 8.32 H, 2H),
7.27 (d, J = 8.57 H, 2H), 7.3 (d, J = 7.63 H, 1H), 7.33 (s, 1H), 8.09
(d, J = 8.01 H, 1H), 9.19 (s, 1H),11.06 (s, 1H), 12.53 (s, 1H); 13C
NMR (500 MHz, DMSO-d6)d ppm 28.85, 36.07 36.19, 37.55,
48.55, 54.14, 54.89, 110.80, 113.33, 113.55, 114.83, 117.92,
120.86, 123.36, 127.90, 128.12, 128.43, 130.02, 135.02, 136.73,
155.74, 157.37, 170.87, 173.41, 207.71; MS (EI+): m/z: 592.1
4.35. (2S)-3-(1H-Imidazol-4-yl)-2-[6-(5-methoxy-1H-indol-3yl)
-4-oxo-6-(4- (trifluoromethyl) phenyl)hexanamido]propanoic
acid (10k)
Yield 82%, mp 147–147 °C; ½a D27
ꢁ
+15.10 (c 0.89%, methanol); IR m
(neat, cmꢀ1): 3258 (br), 3143, 3011, 2943, 2901, 2832, 1714 (br),
1670, 1648, 1619, 1541, 1485, 1440, 1416, 1325, 1215, 1165, 1117,
1067; 1H NMR (400 MHz, DMSO-d6)d ppm 2.28 (t, J = 6.75 H, 2H),
2.66 (m, 2H), 2.97 (m, 2H), 3.27 (m, 2H), 3.67 (s, 3H), 4.50 (dd,
J = 13.62, 6.75 H, 1H), 4.73 (t, J = 7.38, H, 1H), 6.68 (dd, J = 8.73,
2.15, H, 1H), 6.83 (s, 1H), 7.2 (d, J = 8.75 H, 1H), 7.26 (d, J = 2.01 H,
1H), 7.35 (s, 1H), 7.57 (m, 4H) 8.31 (d, J = 8.08 H, 1H), 8.98 (s, 1H),
10.78 (s, 1H), 14.2 (s, 1H); 13C NMR (500 MHz, DMSO-d6)d ppm
26.16, 28.69, 36.85, 37.29, 47.72, 51.10, 55.31, 100.66, 110.85,
112.00, 116.59, 116.76, 122.68, 123.25, 124.91, 125.41, 126.31,
126.38, 126.56, 128.07, 128.37, 129.30, 130.04, 131.48, 133.55,
149.98, 152.85, 171.31, 171.95, 207.43; MS (EI+): m/z: 557.1 [Mꢄ H]+.
4.32. (2S)-2-[6-(5-Bromo-1H-indol-3yl)-6-(4-methoxyphenyl)-
4- oxohexanamido]-3-(1H-indol-3yl) propanoic acid (10h)
Yield 86%, mp 204–205 °C; ½a D27
ꢀ18.82 (c 0.69%, methanol); IR
ꢁ
m
(neat, cmꢀ1):3404, 3063, 3001, 2931, 2836, 1705, 1643, 1583,

N. S. M. Ismail et al. / Bioorg. Med. Chem. 16 (2008) 7877–7887
7887
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We are grateful to Dr. Ito, Synstar Japan Co., Ltd for valuable
information and his real support for this work. We also thank Prof.
Dr. Kunitada Shimotohno, Center for Integrated Medical Research,
Keio University School of Medicine for scientific discussion. We of-
fer special thanks to Pharmaceutical chemistry department, Fac-
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